Comprehensive Chiroptical Spectroscopy, Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules (Volume 2)

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Comprehensive Chiroptical Spectroscopy, Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules (Volume 2)

COMPREHENSIVE CHIROPTICAL SPECTROSCOPY Volume 2 COMPREHENSIVE CHIROPTICAL SPECTROSCOPY Volume 2 Applications in Stere

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COMPREHENSIVE CHIROPTICAL SPECTROSCOPY Volume 2

COMPREHENSIVE CHIROPTICAL SPECTROSCOPY Volume 2

Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules

Edited by Nina Berova Prasad L. Polavarapu Koji Nakanishi Robert W. Woody

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750–8400, fax (978) 750–4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748–6011, fax (201) 748–6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762–2974, outside the United States at (317) 572–3993 or fax (317) 572–4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data: Advances in chiroptical methods/edited by Nina Berova . . . [et al.]. p. cm. Includes index. ISBN 978-0-470-64135-4 (hardback : set)—ISBN 978-1-118-01293-2 (v. 1)—ISBN 978-1-118-01292-5 (v. 2) 1. Chirality. 2. Spectrum analysis. 3. Circular dichroism. I. Berova, Nina. QP517.C57A384 2012 541.7–dc23 2011021418 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

IN MEMORY OF CARLO ROSINI (1948–2010)

Carlo Rosini obtained his degree in Chemistry (1973) at the University of Pisa, where he completed his thesis on the stereochemistry of Ni(II) complexes. He entered the Italian CNR by joining the group of Professor Piero Salvadori and the research on determination of absolute configuration by Circular Dichroism. Later on, Carlo Rosini spent two years (1977–1979) at the King’s College in London, under the supervision of Professor Stephen F. Mason. During this period he studied polarized-light-based spectroscopy and its application to structural determinations. He was appointed as associate professor (1992) at the University of Pisa and then as a full professor (1997) at the University of Basilicata, Potenza. The field of chirality was fundamental to the scientific activity of Carlo Rosini. His broad scientific interests included many aspects of organic stereochemistry, like asymmetric organic synthesis, chiral discrimination mechanisms, chiral stationary phases for enantioselective chromatography, and structural characterization of organic molecules by Circular Dichroism. The last research projects of Carlo Rosini were oriented toward chemical/computational approaches for the determination of absolute configuration by linking experimental and theoretical studies. We miss his enthusiasm and his charisma, but we will remember his life and his contributions to the science and the chemical community. Carlo Rosini was one of the first scientists who accepted to contribute a chapter to this volume. Although his premature and tragic death prevented his submission, his spirit never died and is now, not only in the chapter contributed by his co-workers and former students, but also in the minds of all of us who had the privilege to know him and collaborate with him.

CONTENTS

PREFACE CONTRIBUTORS

PART I A HISTORICAL OVERVIEW

1

THE FIRST DECADES AFTER THE DISCOVERY OF CD AND ORD BY AIME´ COTTON IN 1895 Peter Laur

PART II ORGANIC STEREOCHEMISTRY

2

SOME INHERENTLY CHIRAL CHROMOPHORES—EMPIRICAL RULES AND QUANTUM CHEMICAL CALCULATIONS

xi xiii

1 3

37 39

Marcin Kwit, Pawel Skowronek, Jacek Gawronski, Jadwiga Frelek, Magdalena Woznica, and Aleksandra Butkiewicz

3

ELECTRONIC CD OF BENZENE AND OTHER AROMATIC CHROMOPHORES FOR DETERMINATION OF ABSOLUTE CONFIGURATION

73

Tibor Kurt´an, S´andor Antus, and Gennaro Pescitelli

4

ELECTRONIC CD EXCITON CHIRALITY METHOD: PRINCIPLES AND APPLICATIONS

115

Nobuyuki Harada, Koji Nakanishi, and Nina Berova

5

CD SPECTRA OF CHIRAL EXTENDED π -ELECTRON COMPOUNDS: THEORETICAL DETERMINATION OF THE ABSOLUTE STEREOCHEMISTRY AND EXPERIMENTAL VERIFICATION

167

Nobuyuki Harada and Shunsuke Kuwahara

vii

viii

CONTENTS

6

7 8

ASSIGNMENT OF THE ABSOLUTE CONFIGURATIONS OF NATURAL PRODUCTS BY MEANS OF SOLID-STATE ELECTRONIC CIRCULAR DICHROISM AND QUANTUM MECHANICAL CALCULATIONS Gennaro Pescitelli, Tibor Kurt´an, and Karsten Krohn DYNAMIC STEREOCHEMISTRY AND CHIROPTICAL SPECTROSCOPY OF METALLO-ORGANIC COMPOUNDS James W. Canary and Zhaohua Dai CIRCULAR DICHROISM OF DYNAMIC SYSTEMS: SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

217

251

289

Angela Mammana, Gregory T. Carroll, and Ben L. Feringa

9 10

11

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS Cheng Yang and Yoshihisa Inoue

317

THE ONLINE STEREOCHEMICAL ANALYSIS OF CHIRAL COMPOUNDS BY HPLC-ECD COUPLING IN COMBINATION WITH QUANTUM-CHEMICAL CALCULATIONS Gerhard Bringmann, Daniel G¨otz, and Torsten Bruhn

355

DETERMINATION OF THE STRUCTURES OF CHIRAL NATURAL PRODUCTS USING VIBRATIONAL CIRCULAR DICHROISM

387

Prasad L. Polavarapu

12

DETERMINATION OF MOLECULAR ABSOLUTE CONFIGURATION: GUIDELINES FOR SELECTING A SUITABLE CHIROPTICAL APPROACH

421

Stefano Superchi, Carlo Rosini, Giuseppe Mazzeo, and Egidio Giorgio

PART III INORGANIC STEREOCHEMISTRY

13

APPLICATIONS OF ELECTRONIC CIRCULAR DICHROISM TO INORGANIC STEREOCHEMISTRY

449 451

Sumio Kaizaki

PART IV BIOMOLECULES

14

ELECTRONIC CIRCULAR DICHROISM OF PROTEINS Robert W. Woody

473 475

ix

CONTENTS

15

ELECTRONIC CIRCULAR DICHROISM OF PEPTIDES Claudio Toniolo, Fernando Formaggio, and Robert W. Woody

499

16

ELECTRONIC CIRCULAR DICHROISM OF PEPTIDOMIMETICS

545

Claudio Toniolo and Fernando Formaggio

17

CIRCULAR DICHROISM SPECTROSCOPY OF NUCLEIC ACIDS Jaroslav Kypr, Iva Kejnovsk´a, Kl´ara Bedn´arˇ ov´a, and Michaela Vorl´ıcˇ kov´a

18

ELECTRONIC CIRCULAR DICHROISM OF PEPTIDE NUCLEIC ACIDS AND THEIR ANALOGUES

575

587

Roberto Corradini, Tullia Tedeschi, Stefano Sforza, and Rosangela Marchelli

19 20 21 22

23 24

CIRCULAR DICHROISM OF PROTEIN–NUCLEIC ACID INTERACTIONS Donald M. Gray

615

DRUG AND NATURAL PRODUCT BINDING TO NUCLEIC ACIDS ANALYZED BY ELECTRONIC CIRCULAR DICHROISM George A. Ellestad

635

PROBING HSA AND AGP DRUG-BINDING SITES BY ELECTRONIC CIRCULAR DICHROISM Mikl´os Simonyi

665

CONFORMATIONAL STUDIES OF BIOPOLYMERS, PEPTIDES, PROTEINS, AND NUCLEIC ACIDS. A ROLE FOR VIBRATIONAL CIRCULAR DICHROISM Timothy A. Keiderling and Ahmed Lakhani

707

STRUCTURE AND BEHAVIOR OF BIOMOLECULES FROM RAMAN OPTICAL ACTIVITY Laurence D. Barron and Lutz Hecht

759

OPTICAL ROTATION, ELECTRONIC CIRCULAR DICHROISM, AND VIBRATIONAL CIRCULAR DICHROISM OF CARBOHYDRATES AND GLYCOCONJUGATES

795

Tohru Taniguchi and Kenji Monde

25

ELECTRONIC CIRCULAR DICHROISM IN DRUG DISCOVERY Carlo Bertucci and Marco Pistolozzi

INDEX

819

843

PREFACE

Chirality is a phenomenon that is manifested throughout the natural world, ranging from fundamental particles through the realm of molecules and biological organisms to spiral galaxies. Thus, chirality is of interest to physicists, chemists, biologists, and astronomers. Chiroptical spectroscopy utilizes the differential response of chiral objects to circularly polarized electromagnetic radiation. Applications of chiroptical spectroscopy are widespread in chemistry, biochemistry, biology, and physics. It is indispensable for stereochemical elucidation of organic and inorganic molecules. Nearly all biomolecules and natural products are chiral, as are the majority of drugs. This has led to crucial applications of chiroptical spectroscopy ranging from the study of protein folding to characterization of small molecules, pharmaceuticals, and nucleic acids. The first chiroptical phenomenon to be observed was optical rotation (OR) and its wavelength dependence, namely, optical rotatory dispersion (ORD), in the early nineteenth century. Circular dichroism associated with electronic transitions (ECD), currently the most widely used chiroptical method, was discovered in the mid-nineteenth century, and its relationship to ORD and absorption was elucidated at the end of the nineteenth century. Circularly polarized luminescence (CPL) from chiral crystals was observed in the 1940s. The introduction of commercial instrumentation for measuring ORD in the 1950s and ECD in the 1960s led to a rapid expansion of applications of these forms of chiroptical spectroscopy to various branches of science, and especially to organic and inorganic chemistry and to biochemistry. Until the 1970s, chiroptical spectroscopy was confined to the study of electronic transitions, but vibrational transitions became accessible with the development of vibrational circular dichroism (VCD) and Raman optical activity (ROA). Other major extensions of chiroptical spectroscopy include differential ionization of chiral molecules by circularly polarized light (photoelectron CD), measurement of optical activity in the X-ray region, magnetochiral dichroism, and nonlinear forms of chiroptical spectroscopy. The theory of chiroptical spectroscopy also goes back many years, but has recently made spectacular advances. Classical theories of optical activity were formulated in the early twentieth century, and the quantum mechanical theory of optical rotation was described in 1929. Approximate formulations of the quantum mechanical models were developed in the 1930s and more extensively with the growth of experimental ORD and ECD studies, starting in the late 1950s. The quantum mechanical methods for calculations of chiroptical spectroscopic properties reached a mature stage in the 1980s and 1990s. Ab initio calculations of VCD, ECD, ORD, and ROA have proven highly successful and are now widely used for small and medium-sized molecules. Many books have been published on ORD, ECD, and VCD/ROA. The present two volumes are the first comprehensive treatise covering the whole field of chiroptical spectroscopy. Volume 1 covers the instrumentation, methodologies, and theoretical xi

xii

P R E FA C E

simulations for different chiroptical spectroscopic methods. In addition to an extensive treatment of ECD, VCD, and ROA, this volume includes chapters on ORD, CPL, photoelectron CD, X-ray-detected CD, magnetochiral dichroism, and nonlinear chiroptical spectroscopy. Chapters on the related techniques of linear dichroism, chiroptical imaging of crystals and electro-optic absorption, which sometimes supplement chiroptical interpretations, are also included. The coverage of theoretical methods is also extensive, including simulation of ECD, ORD, VCD, and ROA spectra of molecules ranging from small molecules to macromolecules. Volume 2 describes applications of ECD, VCD, and ROA in the stereochemical analysis of organic and inorganic compounds and to biomolecules such as natural products, proteins, and nucleic acids. The roles of chiroptical methods in the study of drug mechanisms and drug discovery are described. Thus, this work is unique in presenting an extensive coverage of the instrumentation and techniques of chiroptical spectroscopy, theoretical methods and simulation of chiroptical spectra, and applications of chiroptical spectroscopy in inorganic and organic chemistry, biochemistry, and drug discovery. In each of these areas, leading experts have provided the background needed for beginners, such as undergraduates and graduate students, and a state-of-the-art treatment for active researchers in academia and industry. We are grateful to the contributors to these two volumes who kindly accepted our invitations to contribute and who have met the challenges of presenting accessible, up-to-date treatments of their assigned topics in a timely fashion. Nina Berova Prasad L. Polavarapu Koji Nakanishi Robert W. Woody

CONTRIBUTORS

S´andor Antus, University of Debrecen, Research Group for Carbohydrates of the Hungarian Academy of Sciences, Debrecen, Hungary Laurence D. Barron, Department of Chemistry, University of Glasgow, Glasgow, United Kingdom Kl´ara Bedn´arˇ ov´a, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic Nina Berova, Department Chemistry, Columbia University, New York, New York, USA Carlo Bertucci, Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy Gerhard Bringmann, Institute of Organic Chemistry, University of W¨urzburg, W¨urzburg, Germany Torsten Bruhn, Institute of Organic Chemistry, University of W¨urzburg, W¨urzburg, Germany Aleksandra Butkiewicz, Polish Academy of Sciences, Institute of Organic Chemistry Warsaw, Poland James W. Canary, Department of Chemistry, New York University, New York, New York, USA Gregory T. Carroll, Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA Roberto Corradini, Department of Organic and Industrial Chemistry, University of Parma, Parma, Italy Zhaohua Dai, Department of Chemistry and Physical Sciences, Pace University, New York, New York, USA George A. Ellestad, Department of Chemistry, Columbia University, New York, New York, USA Ben L. Feringa, Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands Fernando Formaggio, Department of Chemistry, University of Padova, Padova, Italy Jadwiga Frelek, Polish Academy of Sciences, Institute of Organic Chemistry, Warsaw, Poland Jacek Gawronski, Department of Chemistry, A. Mickiewicz University, Poznan, Poland Egidio Giorgio, Department of Chemistry, University of Basilicata, Potenza, Italy xiii

xiv

CONTRIBUTORS

Daniel G¨otz, Institute of Organic Chemistry, University of W¨urzburg, W¨urzburg, Germany Donald M. Gray, Department of Molecular and Cell Biology, The University of Texas at Dallas, Richardson, Texas, USA Nobuyuki Harada, Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan Lutz Hecht, Department of Chemistry, University of Glasgow, Glasgow, United Kingdom Yoshihisa Inoue, Department of Applied Chemistry, Osaka University, Suita, Japan Sumio Kaizaki, Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan Timothy A. Keiderling, Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA Iva Kejnovsk´a, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic Karsten Krohn, Department of Chemistry, University of Paderborn, Paderborn, Germany Tibor Kurt´an, Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary Shunsuke Kuwahara, Department of Chemistry, Toho University, Funabashi, Japan Marcin Kwit, Department of Chemistry, A. Mickiewicz University, Poznan, Poland Jaroslav Kypr, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic Ahmed Lakhani, Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA Peter Laur, Institute of Inorganic Chemistry, RWTH Aachen University, Aachen, Germany Angela Mammana, Department of Chemistry, University of Dayton, Dayton, Ohio, USA Rosangela Marchelli, Department of Organic and Industrial Chemistry, University of Parma, Parma, Italy Giuseppe Mazzeo, Department of Chemistry, University of Basilicata, Potenza, Italy Kenji Monde, Faculty of Advanced Life Science, Frontier Research Center for Postgenome Science and Technology, Hokkaido University, Sapporo, Japan Koji Nakanishi, Department of Chemistry, Columbia University, New York, New York, USA Gennaro Pescitelli, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy Marco Pistolozzi, Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy

CONTRIBUTORS

Prasad L. Polavarapu, Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA Carlo Rosini, (deceased) Department of Chemistry, University of Basilicata, Potenza, Italy Stefano Sforza, Department of Organic and Industrial Chemistry, University of Parma, Parma, Italy Mikl´os Simonyi, Chemical Research Center, Department of Molecular Pharmacology, Hungarian Academy of Sciences, Budapest, Hungary Pawel Skowronek, Department of Chemistry, A. Mickiewicz University, Poznan, Poland Stefano Superchi, Department of Chemistry, University of Basilicata, Potenza, Italy Tohru Taniguchi, Faculty of Advanced Life Science, Frontier Research Center for Postgenome Science and Technology, Hokkaido University, Sapporo, Japan Tullia Tedeschi, Department of Organic and Industrial Chemistry, University of Parma, Parma, Italy Claudio Toniolo, Department of Chemistry, University of Padova, Padova, Italy Michaela Vorl´ıcˇ kov´a, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic Robert W. Woody, Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, USA Magdalena Woznica, Polish Academy of Sciences, Institute of Organic Chemistry, Warsaw, Poland Cheng Yang, Department of Applied Chemistry, Osaka University, Suita, Japan

xv

a

c

o

Projection along b-axis

Figure 5.38. Absolute stereostructure of the C60 fullerene cis-3 bisadduct (R,R,f,s A)-[CD(+)280]-32 (top) and projection along b-axis (bottom). (Redrawn from reference 54, with permission.)

(a)

(b)

(c)

Figure 8.1. Dynamic chirality at the molecular and supramolecular level detected by CD spectroscopy. (a) A chiral molecule can direct achiral molecules to self-assemble into chiral supramolecular structures. (b) A chiral molecular switch or motor undergoes conformational changes that include inversion of molecular helicity. (c) Chiral molecules can self-assemble into chiral supramolecular structures, the chirality of which is determined by the enantiomer in excess.

S

Rotor Axle Stator O

Legs

O O

O

n

n S

S

Au Surface

2 CD (mdeg)



0 –2



200

240

280

320

λ (nm)

Figure 8.6. Assembly of thiol-terminated light-driven rotary molecular motors on a semitransparent gold film provides a monolayer of chiroptical material that can be analyzed with CD spectroscopy. The CD signals invert between positive and negative bands, corresponding to changes in the helicity of the molecules comprising the monolayer upon the application of photons and thermal energy. The initial spectrum (solid black) inverts (dotted black) after irradiation with UV light (λmax = 365 nm) at room temperature. After heating the surface (70◦ C, 2 h) the spectrum inverts again to restore the original (solid gray). A second dosage of photons inverts the signal (dotted gray). Heating brings the rotors back to the original orientation relative to the substrate [30].

UV O NH N2N

S

S

O

DET-4o

O NH

Vis

HN NH2

H2N

+

S

S

O HN NH2

DET-4c

DET-4o



+ –

dG

dC

Figure 8.18. A photoswitchable chiroptical DNA complex. At the top is shown the photoequilibrium between the open (DET-4o) and closed (DET- 4c) forms of a dithienylethene molecular switch that contains pendant ammonium groups to confer water solubility and allow the switches to bind electrostatically to the polyanionic backbone of DNA when the amine is protonated. Photochemical ring closure was accomplished through the use of a UV lamp (λmax = 365 nm) using a 340-nm cutoff filter. Photochemical ring opening was performed with visible light using ® a 520-nm cutoff filter. Molecular models (created using Hyperchem ) show that the distance between the terminal ammonium functionalities closely resembles the distance between the anionic phosphate groups of a guanosine (G)–cytosine (c) base pair [58].

Interface

Interface

Compression

M-Chiral

Compression

Achiral

P-Chiral

Figure 8.24. A supramolecular chiroptical switch composed of achiral amphiphiles. Space-filling structures of achiral amphiphile (TARC18), which forms a Langmuir–Schaefer film at the air–water interface, and chiral supramolecular structures formed upon interface compression. (Reprinted by permission of John Wiley & Sons, Inc. [66].)

OR

complexation N

I

N

N

N

N

N

N

N

NOH

N OH

N mutarotation of glucose

N

N

42a: R = (C2H4O)8CH3 42b: R = n-C4H9

complexation

N

N

n

42

N

N

N

N

N OH

N N N

OH

left-handed helical complex

right-handed helical complex

Figure 9.24. Chiral self-aggregation of achiral polymer induced by a saccharide. (Reprinted with permission from reference 80. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.)

3 MeOH / water 5:1 6:1 7:1 CD/(mdeg)

CD/(mdeg)

2

1

0

–1 300

8

8:1 9:1 10:1 310

320

330

340

350

360

6 β-glucose +7 +2.4 mdeg 4 (337 nm) 2

time 0h 1h 3h 8h 15 h 24, 48 h 15, 24, 48 h 8h

0

5h 3h α-glucose –2 –3 +2.4 mdeg 1h 0h (337 nm) –4 300 310 320 330 340 350 360

λ (nm)

λ (nm)

(a)

(b)

Figure 9.25. (a) Induced CD spectra of a mixture of 42a (1mM in monomer unit) and D-glucose (0.3M) in 5:1–10:1 MeOH/H2 O at 25◦ C. (b) Time-dependent CD spectra of a mixture of 42a (1mM in monomer unit) and α- or β-D-glucose (0.3M) in 5:1 MeOH/H2 O at 25◦ C. (Reprinted with permission from reference 80. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.)

(a)

(b)

Figure 12.6. Exciton chirality defined by the allowed B naphthalene and S = O transitions in 1

(a) E-conformer of (S)-8 and (b) Z-conformer of (S)-9.

0.05 0

Δε

−0.05 Nd

−0.15

ν −0.25 14.00

(103 cm−1) 16.00

18.00

20.00

0.3 MI

Δε

0 −0.3 −0.6 −0.9 20.00

Ln Ho -SAPR-8-C4(llll)-M[Ln(+)-(hfbc)4] with an encapsulated alkali metal ion

ν (103 cm−1) 21.00

22.00

23.00

24.00

25.00

0.04

Δε

0 −0.04 −0.08 −0.12

ν (103 cm−1)

Er

−0.16 12.00 14.00 16.00 18.00 20.00 22.00 24.00

Figure 13.6. CD spectra in the hypersensitive 4f –4f transitions of Cs[Ln((+)-hfbc)4] in CHCl3 (left) and the proposed structure in solution (right).

200

Δε

100 0 −100 −200 250

300 λ (nm)

350

Figure 13.9. Exciton CD spectra of M[La((+)-hfbc)4 ] in CHCl3 . M: Cs (red), Rb (green), K (blue), Na (black).

Internuclear (net effect) Intranuclear (Ln end) Intranuclear (Cr end)

Δε (M−1cm−1)

50

CrIII

LnIII 0

N

N

−50

N

N

N

N

L2 275

300

375 325 350 Wavelength/nm

400

425

O N

Figure 13.10. Right: Structure of the ligand L2(below) and -[LnIII CrIII (L2)3 ]6+ (above). Left: Schematic vertical lines summering the dominant coupling effects in the CD spectra of -LnIII CrIII (L2)3 ]6+ . The black line corresponds to the CD spectrum of -[GdCr(III)(L2)3 ]6+ in CH3 CN.

10 8 6 4 Ellipticity (mdeg)

2 0 –2 –4 B-DNA hZαADAR1 yabZαE3L IsZαE3L orfZαE3L spZαE3L vZαE3L

–6 –8 –10 –12 –14 –16 230

240

250

260

270

280

290

300

310

320

2800

3200

3600

Wavelength (nm) (a) 6

Ellipticity (mdeg) at 255 nm

4 2 0 hZαADAR1 yabZαE3L IsZαE3L orfZαE3L spZαE3L vZαE3L

–2 –4 –6 –8 –10 0

400

800

1200

1600

2000

2400

Time (sec) (b)

Figure 19.1. (a) CD spectra of poly[d(G–C)] in the B form and in the presence of Zα domains from human ADAR1 editing enzyme (hZα), yaba-like disease virus (yabZα), lumpy skin disease virus (lsZα), orf virus (orfZα), swinepox virus (spZα), and vaccinia virus (vZα), listed in decreasing order of their abilities to convert B-DNA to Z-DNA. CD spectra of the added proteins contributed the negative signals at wavelengths shorter than about 250 nm. (b) Kinetics of the B to Z conversion in the presence of the same domains. Proteins were added to poly[d(G–C)] at a protein to base-pair ratio of 0.4 (with the final protein concentration being 90 μM), in a buffer of 10 mM HEPES, pH 7.4, 10 mM NaCl, and 0.1 mM EDTA, except for yabZα where the buffer included 100 mM NaCl. Spectra were taken at 25◦ C using a 2-mm-pathlength cell. CD values are in mdeg ellipticity. (Reproduced from Quyen et al. [6] by permission of Oxford University Press, copyright 2007.)

θ (mdeg)

5

0

–5

Sp1ZF6 (ER)4 + [2GC (10)] Sp1ZF6 (KE)4 + [2GC (10)] Sp1ZF6 (G4S)4 + [2GC (10)] Free [2GC (10)]

–10 200

220

240

260

280

300

320

Wavelength (nm)

Figure 19.8. CD spectra of a DNA containing two GC-box sequences separated by a 10-bp spacer, 2GC(10), complexed with each of three peptides containing six zinc fingers but with different linkers between zinc fingers 3 and 4: Sp1ZF6(ER)4 with linker (Glu–Ala–Ala–Ala–Arg)4 , Sp1ZF6(KE)4 with linker (Lys–Ala–Ala–Glu–Ala)4 , and Sp1ZF6(G4 S)4 with linker (Gly–Gly–Gly–Gly–Ser)4 . Spectra were taken at 20◦ C using a 1-mm-pathlength cell. Samples contained 4.5 μM peptide–DNA complex in 10 mM Tris–HCl (pH 8.0), 50 mM NaCl, 0.005% Nonidet P-40, and 1 mM dithiothreitol. CD values are mdeg ellipticity. (Reprinted with permission from Yan et al. [42], ©2005, American Chemical Society)

B-DNA

A-DNA

Z-DNA

Binding modes minor groove binding

major groove minor groove

major groove

intercalation

minor groove

Figure 20.1. Representation of the three principal secondary structures of DNA. The right¨ handed A and B form are obtained from standard parameters within the Schrodinger–Maestro graphical interface. The thinner and more elongated Z form is obtained from X-ray parameters of a hexamer as imported from the protein data bank (PDB). In this representation, three units of the hexamer are stacked in order to display the overall left-handed zig-zag helicity. The structure on the far right depicts drug–DNA double-helix interactions with the drug colored black: minor groove binding (top) and intercalation between base pairs (bottom).

Figure 21.1. Binding sites are indicated by specific ligands in white, warfarin (Site I, right-hand side) and diazepam (Site II, left-hand side). (Reprinted with permission from reference 3, copyright 1996, Elsevier.)

Cleft Thyroxine 5 2°: lodipamide

IIIB FA 5 Thyroxine 2,3 2° : Oxyphenbutazone 2° : Propofol

IIIA: Drug Site 2 FA 3, 4 Thyroxine 4 Diflunisal Diazeapam Halothane Ibuprofen Indoxyl sulphate Propofol 2° : CMPF

IB FA 1 Hemin 2° : Azapropazone 2° : Indomethacin 2° : TIB

FA 2 IIA: Drug Site 1 FA 7 Thyroxine 1 Azapropazone CMPF DIS Indomethacin Iodipamide Oxyphenbutazone IIA-IIB Phenylbutazone FA 6 2° : Diflunisal TIB 2° : Halothane Warfarin 2° : Ibuprofen 2° Indoxyl sulphate 3° Diflunisal

Figure 21.2. Ligand-binding capacity of HSA defined by crystallographic studies. (Reprinted with permission from reference 9, copyright 2005, Elsevier.)

Figure 21.16. Mutual positions of quercetin (molecular modeling 48) and warfarin (X ray [8]) in the cavity of Site I subdomain IIA. (Reprinted with permission from reference 48, copyright 2003, Elsevier.)

IB

IA

IIIB

site II IIA site I

IIIA

IIB

Figure 21.21. X-ray crystallographic structure of HSA [8] with curcumin molecules localized by docking. Subdomains are indicated. (Reprinted with permission from reference 55, copyright 2003, Elsevier.)

1 5

7 2 4 3 6 C16:0

Figure 21.37. Structure of HSA complexed with seven palmitic acid molecules. (Reprinted with permission from reference 105, copyright 2000, Elsevier.)

(a)

(b)

Figure 21.38. Conformational changes in warfarin binding (Site I) as a result of fatty acid binding. (a) Helices h2 and h3 are shown by light shades for defatted and by dark shades for myristate bound HSA. (Reprinted with permission from reference 8, copyright 2001, American Society for Biochemistry and Molecular Biology.) (b) The volume of Site I in defatted HSA is depicted by a light brown semitransparent surface that becomes expanded upon myristate binding (blue semitransparent surface), the red arrows point to structural changes associated with fatty acid binding. (Reprinted with permission from reference 9, copyright 2005, Elsevier.)

Figure 21.40. Two crocetin molecules fitted to FA3 and FA4 sites; the negative exciton dictates the horizontal crocetin molecule to be behind the slanting one. (Reprinted with permission from reference 108, copyright 2001, Elsevier.)

(a)

(b)

Figure 21.41. Electrostatic potentials of genetic variants. (a) lysophospholipid ligand binding at the surface of variant F1-S. (b) variant a. (Reprinted with permission from reference 124, copyright 2006, ACS.)

Figure 21.55. Preferred conformer of diazepam docked into the crystal structure of AGP F1. Hydrogen bonds of the carbonyl oxygen to Glu64 and Gln66, as well as contacts of the ring nitrogens with Arg90 and Tyr127, are indicated. (Reprinted with permission from reference 125, copyright 2008, Elsevier.)

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Figure 25.9. CD spectra of HR1–C25, HR2–C25, and their 1:1 mixture: [peptide] 50 μM, PBS, pH7.4, TFE as the co-solvent (0%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%). Difference CD spectra as a function of TFE concentration (0%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%) is also depicted. The difference CD spectra are calculated subtracting the two individual peptide spectra from those of the mixture. (Reproduced with permission from reference 69.)

PART I A HISTORICAL OVERVIEW

1 THE FIRST DECADES AFTER THE DISCOVERY OF CD AND ORD BY AIME´ COTTON IN 1895 Peter Laur

1.1. SCOPE: SUBJECTS AND TIME FRAME TO BE REVIEWED The story of the Cotton effect begins with its discovery in 1895. Although the news was hailed by leading physicists and chemists, studies to extend, exploit, and apply Cotton’s findings developed at a slower pace than one might have anticipated. One of the reasons for this delay was simply the necessity of the researchers to construct their own optical apparatus. Gradual technical improvements eventually allowed one, in the 1920s, to take chiroptical measurements in the ultraviolet as well as the visible, thus making accessible in principle a great many Cotton effects in colorless (mostly organic) compounds. Despite the paramount importance of such developments, neither the technical details nor the physics involved will be discussed in the following. Rather, a chemist’s view will prevail, paying attention chiefly to experimental results and the application of chiroptics to chemical problems. Since much of the work during the first 20 or so years after Cotton’s discovery was done by physicists and physicochemists, it is not surprising that many investigations were interconnected with or even motivated by the concomitant progress of the theory of optical activity. But also the discussion of this part of (theoretical) physics will be curtailed in the following. The exclusion in this chapter appears justified, because various comprehensive reviews are readily available, as they are for the field of optical instrumentation. By about 1935, Cotton effect measurements were possible with most organic and inorganic chromophores. It is rather surprising that not much use was made of the chiroptical techniques, especially by organic chemists. On the other hand, physical chemists had demonstrated the feasibility of Cotton effect studies in various classes of chemical compounds, but seemed satisfied with this result. Likewise, the advancement of optical Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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instruments for chiroptical measurements slowed down. All this led to a certain climax of chiroptical studies in the early 1930s, to be followed by a near standstill. It is not unreasonable to symbolically connect this phenomenon with the death in 1936 of T. M. Lowry, one of the most active scholars in the field. Arguably, the death of T. M. Lowry ended the first, pioneering period of chiroptical studies. The present chapter will concentrate on reviewing these first “historical” decades. Some work on the experimental study of the Cotton effect continued after 1936 until World War II on a minor scale, on, for example, organic compounds (S. Mitchell) or platinum complexes (I. Lifschitz). But at exactly the same time, new developments took place in the theory of optical activity and its application to chemical problems: Werner Kuhn’s calculation of the absolute configuration of lactic acid in 1935 rang in a new era. The waning interest of the experimentalists contrasts with the increased activity of theoretical chemists like J. G. Kirkwood, E. U. Condon, H. Eyring, or W. Kauzmann, who in the late 1930s advanced different models of optical activity. Still, chemistry had to wait for the period of 1950–1960 for a revitalization of chiroptics. Some reasons for the animation are: (1) the development of X-ray scattering methods for the determination of the absolute configuration, thus anchoring the stereochemistry unambiguously, following J. M. Bijvoet’s seminal publication of 1951; (2) the advent of new, commercially available measuring devices of ORD and CD; and (3) growing interest in natural products chemistry and, generally, optically active systems. But to discuss these topics would need another chapter.

1.2. EARLY CHIROPTICAL STUDIES The discovery of optical activity is credited to the two distinguished French mathematicians, physicists, astronomers, and geodesists (and more) Dominique-Franc¸ois Jean Arago (1786–1853, of Catalan origin) and Jean-Baptiste Biot (1774–1862) [1]. Arago and Biot had been closely associated at least since 1806 in the pursuit of other scientific subjects, and they sometimes published together. Both investigated the optical activity of quartz, and apparently they also shared their equipment to some extent. If, on the one hand, Arago was the first to go into print, Biot, on the other hand, soon became more active in this field and extended the studies. He undoubtedly observed optical activity for the first time in organic compounds such as natural oils and terpenes, or solutions of camphor [2] and cane sugar [3]. Biot continued his research on optical activity throughout his life, later concentrating particularly on tartaric acid. He noticed the wavelength dependence of the optical rotation even at the very beginning of his studies, albeit in a rather qualitative way. Whereas eventually the rotatory dispersion of quartz could be elucidated satisfactorily (which led to Biot’s law, stating that the rotation is inversely proportional to the square of the wavelength), similar solution studies were seriously impeded by experimental deficiencies, particularly the lack of suitable monochromatic light sources. Genuine chiroptical studies were, therefore, rather infrequent until the end of the nineteenth century. One of the most important papers here is a report by the Norwegian physicist Adam Arndtsen, who discussed his studies of aqueous solutions of (+)-tartaric acid [4]. Using sunlight, he was able to visually determine the angle of rotation at some of the principal Fraunhofer lines, that is, C (656), D (589), E (527), b (517), F (486), and e (438 nm). He could confirm and extend Biot’s earlier finding that the rotation exhibits a maximum in the spectral region studied, with its wavelength shifting from the

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blue to the red on increasing concentration. This unexpected and intriguing result led the Swiss chemist Hans Landolt (an important pioneer of the investigation and application of optical activity, as well as one of the “fathers” of Physical Chemistry) in 1877 to introduce the expression “anomale Rotationsdispersion” (anomalous rotation dispersion) [5], which since has become established for the description of such rotatory dispersion curves that run through a maximum or minimum, or show a reversal of sign. It had thus become apparent that spectropolarimetry promised to develop into an interesting field in the future. In his last and comprehensive paper on optical activity, Biot [6] suggested, therefore (translation from the French by the present author): I should like to draw the attention of experimentalists to a class of phenomena which, hitherto, has been little studied but which, nevertheless, for both theoretical and practical purposes, ranks in importance with that of the optical rotatory power itself of which it is a constituent element. I refer to the specific mode of dispersion that each optically active substance or compound imparts to plane polarized light of different wavelengths [literally: refrangibility].

Despite this exhortation, reports on rotatory dispersion remained scarce until the end of the century. This is also evident from the very first book on optical activity, where all data known at that time are summarized, which was published in Germany in 1879 by Landolt [7]. Here, he also describes in detail the optical equipment used by himself and his predecessors. Therefore, it is not necessary to dwell at this point on the measuring devices and optical methods. Although most of the rotations listed (many of which had been determined or redetermined by Landolt himself) refer to the sodium D line only, his book also has short sections on normal and anomalous rotatory dispersion. It is important to realize that so far all reported optically active liquids or solutions were based on organic compounds without absorption bands in the visible. In fact, Landolt emphasized that there is not a single inorganic substance known which shows optical activity in solution (or in the gas phase), from which he tentatively—but incorrectly—concluded that optical activity might be restricted to carbon compounds, except for the solid phase. Surprisingly, he gave no reference to any optically active transition metal complex, although at least Fehling’s solution (a mixture of several Cu(II) tartrate complexes) had been around since 1848 [8]. One might speculate whether such coordination compounds (of a still unknown nature) were ignored as a result of theoretical considerations. It should also be mentioned that measurements in general were limited to practically colorless samples and to merely certain frequencies of the visual solar spectrum. The only other reasonably monochromatic light sources available were based on lithium, sodium, and thallium salts heated in a Bunsen burner (invented in 1866), giving access to the wavelengths 671 nm (Li), 589 nm (Na), and 535 nm (Tl), respectively. It is worthwhile to briefly turn to the “anomalous” refractive dispersion using unpolarized light—that is, the characteristic sigmoidal variation of the index of refraction in the absorption region, running through a maximum and minimum, instead of steadily increasing as the wavelength decreases, as in normal dispersion. This behavior had been discovered in iodine vapor in 1862 by the French physicist F.-P. Leroux [9], and around 1870 it attracted the attention of several investigators, who published independently on anomalous dispersion in the visible, using solutions of organic dyes like fuchsine [10]. There was some dispute as to priority among the Danish physicist Christian Christiansen, the Swiss chemist and physicist Jacques-Louis Soret, and the German physicist August Kundt. While it is clear that Christiansen was the first to publish, the most extensive studies were carried out by Kundt. The relevance of these findings to the present subject

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lies in the fact that here was proven the possibility of successfully studying the index of refraction even near absorption bands in the visible. Consequently, a similar anomalous dispersion could be expected to exist for the optical rotation, keeping in mind the relation between the velocity of light, the index of refraction, and the optical rotation. This anomalous dispersion feature of the rotation should have been accessible by existing techniques, if only suitable colored optically active samples had been available. It took more than two decades, however, before this problem was addressed.

1.3. THE DISCOVERY OF THE COTTON EFFECT In 1895, two short papers (“notes”) appeared in the fortnightly journal of the French Academy of Sciences, entitled “Unequal absorption of right and left circularly polarized light by certain optically active substances” [11] and “Anomalous rotatory dispersion of absorbing substances” [12]. The author was the 26-year-old physicist Aim´e Auguste ´ Cotton (Bourg-en-Bresse 1869–S`evres 1951), a PhD student at the prestigious Ecole Normale Sup´erieure in Paris. The first of these papers describes and names the property of “dichro¨ısme circulaire” (what we now call “CD”) associated with an absorption band of an optically active compound in solution, and the second one introduces the corresponding effect in the dispersion mode (now called “ORD”). The full paper of 85 pages, also incorporating studies on magnetic optical activity, was published in 1896 under the heading “Investigations of the absorption and the dispersion of light by optically active media” [13]. It summarizes A. Cotton’s Th`ese de Doctorat, which he prepared from ´ November 1893 to July 1896 at the Physics Laboratory of the Ecole Normale with Professors Marcel Brillouin and Jules Violle as advisors. Based on his important discoveries, Cotton was accorded the degree of Docteur e` s Sciences in 1896. In his thesis, Cotton for the first time reports data of (a) optical rotations close to both sides of an absorption band in the visible, using solutions of Cu(II) and Cr(III) coordination compounds with tartrate or malate ligands, and (b) the associated circular dichroism. It is quite obvious that Cotton was successful to a large degree owing to both the quality of his optical components and the skillful and precise construction of the measuring devices, especially for the determination of very small values of the ellipticity, but also to his power of observation, and—last but not least—to a fortunate choice of optically active samples. In this chapter, however, his technical equipment and the underlying physical principles shall not be discussed in detail, because Cotton himself gives a full description in his major paper, and there are also comprehensive reviews elsewhere as, for example, in the books by Mitchell and Lowry (see below). While Cotton’s expression “dispersion rotatoire anomale” (anomalous rotatory dispersion) is self-explanatory, a comment concerning his novel term “dichro¨ısme circulaire” (circular dichroism) may be appropriate. Cotton did not always measure directly or indirectly the difference in absorption of left- and right-circularly polarized light by his sample [i.e., (εL –εR )], but rather the ellipticity of the emerging elliptically polarized light. In this case, his measuring device included, apart from a Nicol prism to provide plane-polarized light, a “double circular polarizer” consisting of two quarter-waveplates placed side by side in the plane-polarized light beam in such a way that their principal axes are at 90◦ to one another and at 45◦ to the plane of the incident light. This arrangement allowed the observation of left- and right-circularly polarized light beams next to each other. On the introduction of a sample showing circular dichroism, the beams would be differently absorbed, which could be detected visually or photometrically. The field of vision was thus divided into two halves by these λ/4 plates. When

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he used white instead of monochromatic light for the examination of his optically active sample solutions, these two halves showed different colors. This reminded him of the dichroism observed with certain doubly refracting crystals, where the ordinary and the extraordinary ray are absorbed unequally, as found by Biot in tourmaline and later by the Austrian mineralogist Haidinger in many other cases [14]. Cotton therefore chose the term “circular dichroism.” In fact, Haidinger had already discovered this phenomenon in amethyst quartz in 1847 [15]. Nowadays, the expression “circular dichroism” probably just awakens vague memories of the original visual observations; this context has been largely forgotten nowadays, with the advent of automated electronic spectropolarimeters. Actually, Cotton himself had already performed some photometric measurements, but had found them inferior to his visual results.

1.4. THE FIRST CD AND ORD CURVES Cotton’s measurements obviously were not only restricted to the visible, but also quite limited as to the wavelengths available. Even under favorable conditions, at most eight spectral lines were at his disposal, namely, 657 (red, near C), 589 (yellow, sodium D line), 581 (orange, near D), 562 (greenish yellow), 522 (green, between E and b), 475 (blue, near F), 459 (blue-violet), and 437 nm (violet, near e) [the letters C, D, E, b, F, and e refer to the Fraunhofer lines so designated]. A comparison with Arndtsen’s paper of 1858 [4] shows that hardly any improvement of the spectral availability had taken place until the end of the nineteenth century. However, on the positive side it can be seen that these lines are spread rather evenly across the whole visual region. Nevertheless, the generation of continuous absorption and rotation curves, as often published, on the basis of observations at some of these individual wavelengths, leaves much to the whim of the draftsman, especially concerning the position and magnitude of any maxima and minima. Such “data” should not be overinterpreted. This situation would prevail in the decades to come. It is not unexpected that, at the onset of his investigations, Cotton chose Fehling’s solution (“liqueur de Fehling”) for his studies. It is, after all, in the direct line of Biot’s research to look at derivatives of active tartaric acid. Secondly, the only area of importance where the application of optical activity had become established was saccharimetry; and thirdly, Fehling’s solution was a proven and powerful reagent in carbohydrate chemistry [16]. It seems that Cotton systematically progressed from the complex and notoriously unstable Fehling’s solution to simpler alkali copper(II) tartrates, the preparation of which he describes in detail. By the way, it is amusing to note that in one case he reports the precipitation of copper tartrate from a copper sulfate solution by adding the aqueous solution of a crystal of Seignette salt (potassium sodium tartrate); this crystal had been prepared by Pasteur himself. Unfortunately, these copper complexes proved to be very unstable; they changed or simply decomposed with time or at elevated temperature and were also light-sensitive. Furthermore, the chemical composition of these aqueous solutions was unknown (and, to some extent, still is), and attempts at isolating any well-defined compound failed. A solution of crystalline copper malate, perhaps more stable, did not show any observable circular dichroism. Despite these drawbacks, Cotton did obtain many ORD and some CD data, but obviously the reproducibility of the experiments remains questionable, and the curves shown in print [13] should be interpreted with caution.

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The most convincing chiroptical effects, however, were observed with aqueous solutions of potassium chromium(III) tartrate, prepared in situ. They shall be discussed here in some detail. Figure 1.1 is Cotton’s Figure 18 on page 408 of reference 13, and it shows a complete “Cotton effect” in the ORD and the CD near 570 nm. Because of its seminal importance, this figure has been later reprinted by others a number of times. The actually measured data are given as follows: 657 nm, rotation ρ + 1◦ 26 , ellipse [sic] φ + 32 ; similarly: 589, +2◦ 30 , (−3◦ 40 ); 581, +1◦ 46 , −4◦ 54 ; 562, −1◦ 21 , −4◦ 16 ; 522, −2◦ 50 , −1◦ 25 ; and 475, 1◦ 52 [no sign given in the paper; from the curve it is evident that ρ must be negative], +28 . Data were thus collected at six wavelengths only, because the onset of a second strong absorption band made observations at shorter wavelengths impossible. The parentheses around the ellipticity value at the sodium D line are Cotton’s and indicate that this number results from photometric measurements. Despite its beautiful appearance, there are unfortunately some flaws in this figure and the data as printed. A comparison of the figure with the data listed above makes evident two discrepancies at 562 nm: In the figure, the angle φ is given as −4◦ 46 (not −4◦ 16 ), and the corresponding angle ρ is given as −0◦ 21 (not −1◦ 21 ). On reexamination, the true values were verified to be φ − 4◦ 46 and ρ − 1◦ 21 . The figure should be redrawn, therefore, using this value of ρ. Such a modification would necessarily modify the shape of the ORD curve, while not basically changing it. Cotton gives these corrections in

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Figure 1.1. CD and ORD of potassium chromium(III) 657

589 581562

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tartrate (solvent H2 O). (From A. Cotton, Ann. Chim. Physique 1896, [7] 8, 347; Figure 18, p. 408.)

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a letter to Professor Ladislas Natanson in Cracow, Poland, quoted on pages 33/34 of reference 17. He explains the first error as a misprint, and he states that the second one is a mistake by the “dessinateur” (draftsman). However, the really important disagreement between the ORD and CD, as we can see immediately from the curves—with hindsight—lies in the incompatibility of their signs. If we accept the rotation values as correct, as seems reasonable, the sign of the CD is in error. And so it is! Cotton himself redressed this flaw two years later [18] in a paper, the first sentence of which runs as follows (translated from the French): ‘It is easy to be mistaken as to the sense of a circular vibration.’ Admitting his mistake in the assignment of the direction of the rays circularly polarized by a Fresnel rhomb, he imputed it to his misinterpretation of some of Billet’s tenets in the latter’s “Trait´e ” [19]. Apparently, Billet had used the expression “principal section” of a mica crystal in an unorthodox way and had also treated this crystal as positive, contrary to the common practice. Therefore, all of Cotton’s CD curves, and the sign of all ellipticities published before 1898, ought to be inverted. But not everyone read or responded to this correction; others did so, but without indicating it. The confusion that might have been generated was fortunately curtailed by the fact that very few scientists, apart from Frenchmen, studied the circular dichroism in the following decades. But as late as in 1923, (Ms.) N. Wedeneewa in Moscow (for example) still used the earlier “wrong” sign of the CD, when she reported the ORD and CD of camphor quinone [20]. Similarly, T. M. Lowry just reprinted Cotton’s Figure 18 in his famous classic of 1935 [21] without any comment, whereas S. Mitchell in his treatise on the Cotton effect [22] of 1933 simply shows an inverted CD curve in ostensibly the same figure (see Figure 1.2), also without any further comment. Another point of criticism could be raised because of the all-too-vague identity of the samples investigated. Although Cotton carefully describes the preparation of his samples, as mentioned earlier, their inherent instability cannot preclude changes with time, perhaps also as the result of shifting equilibria between the several complexes present. Indeed, small changes even in the synthesis of the tartrate complexes can lead to the total inversion of the anomalous rotatory dispersion, as has been observed by Wedeneewa [20]. All this calls for caution with respect to the early ORD and CD publications. However, concerning the key compound discussed at length, potassium chromium(III) tartrate, all doubts were finally set to rest by W. Kuhn [23], who much later very carefully repeated Cotton’s work and found it fully correct (Figure 1.3).

1.5. THE REACTION OF THE LEARNED WORLD TO COTTON’S DISCOVERIES Cotton’s papers raised the immediate attention of Wilhelm Ostwald (Nobel Prize 1909), who, one year after the publication of the original notes in the Comptes Rendues [11, 12], wrote two abstracts thereof himself for his journal Zeitschrift f¨ur Physikalische Chemie [24]. This was followed by his six-page review of Cotton’s full paper [13] in the same year [25], with several CD and ORD curves reprinted, including Cotton’s original Figure 18, discussed above. It should be pointed out that the lack of correspondence of the sign of the ORD and the CD could not have been noticed by Ostwald at that time, since the necessary theoretical background had not yet been provided. With these reviews, Ostwald acquainted the chemical world with Cotton’s results, and his name carried much weight. It is certainly unusual that preliminary notes by a foreign physics student and extracts of his

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Figure 1.2. CD and ORD of potassium chromium(III) tartrate (solvent H2 O). (From S. Mitchell, The Cotton Effect, Bell, London, 1933; Figure 12, p. 23; reproduced with permission.)

thesis should induce an already famous physical chemist to such a presentation. Incidentally, already the “sponsoring” of Cotton’s notes by the renowned physicist Gabriel Lippmann from Luxembourg (Nobel Prize 1908)—such notes had to be presented by an academician—attests to the importance attributed to them. One might well say that chiroptics had a splendid start. The speed with which the news was reported and hailed is altogether breathtaking. For example, the physical chemist Landolt referred to Cotton’s studies already in the second edition of his book, published in 1898 [7]. Mention should also be made of the German physicist Paul Drude, who included a treatment of Cotton’s “(anomalous) rotary dispersion” in his famous Lehrbuch der Optik of 1900 [26]. So, by the beginning of the twentieth century, the international world of physics and physical chemistry was well aware of Cotton’s results. It took only a few additional years before a thorough theoretical treatment was provided by L. Natanson, Professor of Theoretical Physics at the Jagiellonian University Krak´ow (Cracow, Poland). The title of his important paper, “On the elliptic polarization of light transmitted through an absorbing naturally-active medium” [27], with a supplementary note [17], needs no further comment. Here, Natanson treated the interdependence of absorption, optical rotation, and circular dichroism. Probably in order to spread his results further, also an amalgamated and shortened French translation of both papers by the Count of Ballehache was published very shortly thereafter [28]. The relations presented here between the sign of the rotation and the circular dichroism have become known as the “R`egle de Natanson” or “Natanson’s Rule” [29]. This finally allowed the

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Figure 1.3. UV, CD, and ORD of potassium chromium(III) tartrate (solvent H2 O). (From W. Kuhn, ¨ A. Szabo, Z. Phys. Chem. 1931, B15, 59; Figure 1, p. 62; Oldenbourg Wissenschaftsverlag Munchen, reproduced with permission.)

prediction of the sign of the circular dichroism associated with a specific absorption band, based on just the anomalous rotation curve, which should not be too difficult to obtain. Natanson’s papers included the following sentences on the first page: “Effects of this kind have been observed and investigated by Monsieur A. Cotton” [27] and “Des ph´enom`enes de ce genre ont e´ t´e observ´e et analys´es par M. Cotton” [28]. Here we find the seed that has developed into the important technical terms “Cotton’s Phenomenon” and “Cotton Effect,” which have been used ever since, with the first one preferred in the early decades of the twentieth century. At this point it may be timely to more formally give a definition of the Cotton effect as we understand it today. It may be interesting to compare the definition given in 1933 by Stotherd Mitchell on page 24 of his book on the Cotton effect (incidentally the first monograph of this kind) [22] with the definition by Werner Kuhn from 1960 [30]. Mitchell wrote: “A maximum ellipticity and zero rotation are found in this region [of the absorption band]. The rotation reaches a maximum value on one side of the band and

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a minimum on the other. This variation of rotation and ellipticity in the neighbourhood of an absorption band has been called the Cotton effect.” [Mitchell’s italics] Kuhn stated: “[Cotton] found that optical rotatory power as a function of the wavelength often shows, in the region where the substances show ordinary absorption, a characteristic anomaly which is associated with a circular dichroism in the absorption region and which after the name of its discoverer is called a Cotton effect.” [Kuhn’s italics] It is satisfactory that both definitions, published some 30 years apart, fully agree with one another; furthermore, we still can subscribe to both of them, even 50 years later. Many similar definitions can be found over the last 80 years, all of them stressing the point that the ensemble of rotatory dispersion and circular dichroism in the absorption region collectively constitute the Cotton effect. Nevertheless, quite commonly the term Cotton effect has loosely been used to characterize merely the “anomalous” rotation features, since in the decades following Cotton’s discoveries the available data were mostly limited to the optical rotation. In fact, in many cases it has been considered sufficient to have reached the first maximum of the rotatory dispersion curve, still outside the absorption band, to apply the term Cotton effect. In recent decades, when ORD effectively disappeared in favor of CD, the term usually means the CD curve only.

1.6. MORE TARTRATES: THE PHYSICIST’S PLAYGROUND Cotton’s discovery of circular dichroism raised so much interest in Brace’s Physics Laboratory at the University of Nebraska that it was decided to construct an improved and more sensitive apparatus for measuring both elliptical polarization and rotation, in order to repeat and extend the French findings. The American physicist DeWitt Bristol Brace was himself active in the field of optical activity and had in 1904 described an elliptical polarizer and compensator that was incorporated not only in the optical system used in Nebraska, but also later in Europe. Brace died in 1905 and had, therefore, no part in the further development. The first results on, for example, complex chromium, copper, cobalt, and nickel tartrates and copper malate were presented by M. F. McDowell in 1905 [31]. The ellipticity had been measured in “all parts of the spectrum,” which means at some 10 different wavelengths of the visual solar spectrum. Unfortunately, the calculation of the ellipticity was found to be incorrect, and some compounds were irreproducible. This was carefully rectified at the same laboratory in 1912 by L. B. Olmstead, who studied tartrates, malates, and lactates of chromium, copper, cobalt, and manganese [32]. Also here, the so-called “monochromatic” light, with a spectral band width of perhaps 20 nm, was obtained from sunlight. Although the optical part of the investigation seems to be impeccable (except that Cotton’s first—incorrect—sign protocol of the circular dichroism was still used), the identity of the compounds studied is uncertain. Olmstead himself points out: “No chemical analyses of the compounds were made; the names assigned being merely for convenience, and not indicating that the chemical formulæ are known.” [Olmstead’s italics]. He observed that Cotton’s results for potassium chromium tartrate could be repeated quantitatively when the sample was prepared from potassium dichromate and potassium tartrate, but an oppositely signed Cotton effect developed when the potassium dichromate was replaced by chromium acetate. Undoubtedly, the samples consisted of a mixture of complexes, as was also indicated by color changes of the solutions, depending on variations of the concentration and with time. As a result, even these carefully collected data are of a qualitative nature only.

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The same qualifications pertain to a large number of papers of the early twentieth century on the rotatory dispersion of transition metal complexes with optically active ligands. In addition, the rotatory dispersion data were often collected at only four or five rather ill-defined spectral bands in the visible. Examples are found in the report by H. Grossmann and A. Loeb on copper tartrate and malate coordination compounds [33], as well as in the paper by H. Volk on copper, nickel, and cobalt complexes with lactate ligands [34]. Also these investigations were initiated, by the way, in order to verify and extend Cotton’s findings. Cotton himself did not continue his work on the optically active tartrates, but motivated his student Georges Bruhat to address the problem again [35]. Bruhat tried to synthesize and isolate individual, well-defined compounds, but succeeded with most tartrates and malates in part only, because of the easy decomposition of the respective solutions. He did isolate and investigate uranyl tartrate that seemed to be stable and showed a Cotton effect near 500 nm. His optical equipment limited the quality of his measurements rather severely, however. After a disruption of the research by the First World War, he resumed his studies again in 1919 with a much more advanced apparatus. This allowed him to reduce the spectral band width from 30 nm to 10 nm, which was essential to avoid “flattened-out” dispersion curves. In this way, he obtained splendid CD and ORD data for uranyl tartrate and ammoniacal cobalt tartrate [36], for example. But regrettably, not even the high quality of the physical data allows any better analysis of the compounds responsible. The interest in this topic was not yet put to rest in Cotton’s laboratory. In the earlier work, the copper complexes had been particularly unsatisfactory. Therefore, the study of alkaline copper tartrate solutions was taken up again in order to enhance the quality of the samples [37]. Somewhat later, complex chromium [38] and cobalt tartrates [39] were reinvestigated. Good CD data could be collected, but the chemical identity of the species in solution remained uncertain, despite Mathieu’s extensive experiments. Such tartrate studies were not wholly limited to Paris. Also W. Pfleiderer in Basel, Switzerland, had returned to measuring the optical rotation of aqueous alkaline solutions of copper tartrate, and he found his data to qualitatively agree with Cotton’s of 1895 [40]. The chiroptical instability that Nina Wedeneewa in Moscow, Russia, had encountered with alkaline chromium tartrates in the absorption region has been mentioned already [20]. Last but not least, attention is drawn to W. Kuhn’s reevaluation of the same problem, as outlined earlier [23]. The overview presented here is not exhaustive. Because of the similarity of the problems, the preceding discussion pertains also to, for example, optically active lactates, malates, and “sucrates” of transition metals. The respective chiroptical results are not basically different from those with tartrate ligands. It remains to report that even many years later the chemical identity of these complicated coordination compounds has not been fully understood, with several questions still unsettled even today [41]. While some of the variability observed is certainly caused by the gradual replacement of coordinated water by the organic ligands, condensation processes leading to multinuclear species also seem to be involved. It is intriguing that the chiroptical properties of tartrate complexes dominate the study of circular dichroism for three decades. In fact, during these years very few CD measurements have been carried out outside of this area (see later). One might speculate whether this conservatism would perhaps result from the fact that practically all researchers were physicists, who might have had limited awareness of colored optically

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active compounds in other fields of chemistry. After all, with, for example, organic xanthates, such compounds did exist, but their investigation was largely confined to only one chemical research group in Russia, as will be seen. The question might well be asked, What motivated these tenacious tartrate investigations? It is obvious that genuine chemical topics were not addressed, such as the stereochemical correlation and the application of optical activity to the study of reaction mechanisms, or as a tool in the elucidation of the chemical constitution. This contrasts with the aims in connection with the Werner complexes, to be discussed in the following section of this report. But as to tartrates, the investigators were primarily interested in the circular dichroism in its own right. They tried to effect improvements in the optical instrumentation in order to enhance the sensitivity and precision of their measuring devices. For testing the various theories of optical activity and to compare calculated and experimental data, the latter should be measured with a maximum of accuracy and reliability. It might well have been felt that the continuation with “well-known” samples like the complex tartrates would be advantageous, with a host of data already existing for comparison.

1.7. WERNER COMPLEXES: INORGANIC CHEMISTS LEARN TO MAKE USE OF THE COTTON EFFECT According to common practice, the tartrate systems discussed in the previous section can be considered to belong to the realm of inorganic chemistry. But they were chosen for chiroptical research without paying much attention to their chemical nature. Chemists have performed hardly any systematic studies of these compounds and have instead tended to neglect them. The situation was quite different with regard to the chemically and structurally welldefined octahedral transition metal complexes, following the Alsatian Alfred Werner’s (1866–1919) introduction in 1893 of his geometric model for centers with the coordination number six [42]. At that time, Werner worked in the laboratory of his doctoral advisor, Professor Arthur Rudolf Hantzsch, at the University of Zurich, Switzerland. He had obtained his doctoral degree only in 1890, but was quickly promoted to a chair of chemistry at this University in 1895. Although his revolutionary concept eventually secured him the Nobel Prize in 1913, it met much resistance among his chemical colleagues. The opposition diminished, however, after he had achieved the resolution of some of his complexes into enantiomers [43], since the occurrence of optical activity was hard to reconcile with other than the octahedral geometry. The optically active compounds, mostly Co(III) complexes, were of greatly varying chemical and optical stability, often racemizing at room temperature within a few hours. It was found that chelating ligands like oxalate ions (O, O  -donor ligands) or 1,2-diamines (N , N  -donor ligands) led to increased stability. In the beginning, the optical rotation at only one wavelength was considered sufficient to characterize a specific complex. But it was soon realized that the stereochemical correlation should not be based on such an individual value, since it varied too much in magnitude and even in sign from one complex to the next, notwithstanding a close chemical relationship. Furthermore, as the enantiomeric purity of the compounds was often uncertain, a particular, selected rotation value could be quite misleading. On the other hand, these complexes were well-suited to measurements of the Cotton effect due to their color, which often brought them within the range of visual observation. The sign of this Cotton effect, associated with electron transitions at the coordinating metal

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center, was found to be a reliable, characteristic feature. Consequently, measuring the rotatory dispersion including, hopefully, a more or less complete Cotton effect became a common goal. The first Werner complex for which both ORD and CD data through an absorption band were obtained, namely, potassium (trisoxalato)iridate(III) dihydrate, K3 [Ir(C2 O4 )3 ]·2 H2 O, was resolved by M. Del´epine [44], and its chiroptical properties were determined by G. Bruhat [45]. A Cotton effect near 450 nm was found. This is, incidentally, one of the rare instances where the circular dichroism of a Werner complex has been determined in the early part of the twentieth century. In practically all other cases, the term Cotton effect just refers to the rotatory dispersion near or at an absorption band in the visible. Werner himself had already reported similar dissymmetric, optically active complexes with bidentate ligands like [Co(en)3 ]3+ or [Cr(ox)3 ]3 – (en = 1,2-diaminoethane; ox = oxalate ion C2 O4 2− ), but without any further spectropolarimetric data [46]. It is amusing to see that in some other cases the Cotton effect—or, rather, the anomalous rotatory dispersion—rests on measurements at only three different wavelengths as for [Rh(ox)3 ]3− , for example [47]. Werner’s concept achieved its final breakthrough when he published the resolution of the “completely inorganic” complex [Co{Co(NH3 )4 (OH)2 }3 ]Br6 , an octahedral Co(III) complex with bidentate O, O  ligands. This complex, without any carbon atom, is sterically related to the simpler [Co(en)3 ]3+ system. It showed a Cotton effect near 600 nm [48]. This finding finally put to rest the long-lived but obsolete theory that the presence of carbon atoms was essential for the unfolding of optical activity. Werner showed no particular interest in the Cotton effect in its own right, however, but rather made use of it for the stereochemical correlation and the characterization of his compounds. A further example which may be mentioned is [Co(NO2 )2 (en)(pn)], with pn = 1,2-diaminopropane, with either rac-pn or l -pn, that had Cotton effects in the 530- to 540-nm range [49]. In general, Werner’s interest in spectropolarimetry remained limited, and usually he left further chiroptical studies to others. Even when he reported Cotton effects, it is not always clear how, where, and by whom the data were obtained. Meanwhile, a new “center of gravity” for the examination of Werner complexes was developing in Groningen in the Netherlands. Here, the stereochemist Franciscus Mauritius Jaeger (1877–1945), Professor of Inorganic and Physical Chemistry at the Rijksuniversiteit Groningen (RUG) from 1908 to 1945, had by 1915 embarked on a program of the comprehensive investigation of these systems [50]. A great many new, and some already known, Werner complexes were synthesized and studied. Jaeger’s interests lay largely in their crystallographic description, but he also included optical activity in his research program. Most of the spectropolarimetric data generated “plain” ORD curves only, because the anticipated Cotton effect was often beyond the wavelength limit of the optical devices or inaccessible because of too strong an absorption. In Jaeger’s extensive paper of 1919 [51], many such plain curves are reported, but only two cases of a bona fide Cotton effect, namely, in K3 [Cr(ox)3 ] (Cotton effect near 565 nm) and K3 [Co(ox)3 ]·H2 O (near 620 nm). The chromium compound had already been synthesized and resolved by Werner in 1912, but had not been investigated by spectropolarimetry, whereas the (trisoxalato)cobaltate(III) was new. It was very advantageous that Jaeger could induce Israel Lifschitz (1888–1953), Private Docent at the University of Zurich, to join his laboratory in 1921. Lifschitz, whose special area of research had been the absorption spectroscopy and photochemistry of organic compounds, now became Private Docent of Electrochemistry and Photochemistry

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and tenured staff member at RUG. He turned to the spectroscopic study of transition metal complexes, with particular attention to spectropolarimetry. Largely owing to his efforts, the laboratory developed into a center of chiroptical spectroscopy, of international repute. Lifschitz had taken his doctorate in 1911 with A. Hantzsch in Germany (Hantzsch had changed from Zurich to the University of Leipzig) and had moved to Switzerland in 1914. It is interesting to note that he there worked close to Werner, who also had been a student of Hantzsch. Perhaps the shift of Lifschitz from organic photochemistry to coordination stereochemistry has thereby been influenced, but presently nothing is known of a personal interaction with Werner. It is difficult to assay in detail Lifschitz’s contribution to the Groningen laboratory, except for his own publications, since Jaeger as laboratory head regularly included the research results of his local colleagues in his own publications, without giving any individual credit. This procedure was rather common in those days. Only sometimes is Lifschitz mentioned in a vague way as a “collaborateur” (coworker). In 1923 Lifschitz started a series of papers called “Investigations of Rotatory Dispersion” [translated from the original German]. In the first paper, he presented and discussed ORD data of complexes of Cr(III), Co(III), Ni(II), and UO2 2− ions with optically active camphor derivatives, including nitrocamphor. These compounds exhibited Cotton effects in the visible. The paper is also noteworthy, because here the technical term “Cotton effect” was introduced into the chemical literature; the earlier term had been “Cotton phenomenon” [52]. In the second paper of this series, Lifschitz reported the ORD Cotton effects of Co and Cu complexes with amino acid ligands (alanine, asparagine), and also of the complex [Cu-(l -pn)2 ]SO4 (effect at 510 nm) [53]. Slightly later, Jaeger extended the chiroptical studies to cobalt complexes with 1,2-diamino ligands, and he reported the Cotton effects in [Co(rac-trans-1,2-diaminocyclopentane)3 ]Cl3 · 4H2 O at 470 nm and in [Co(rac-trans-1,2-diaminocyclopentane)(en)2 ]Br3 · 2H2 O at 500 nm [54]. A few years later, some of these Werner complexes were reinvestigated by Werner Kuhn, making use of advanced instrumentation. Measurements had now become possible down to 280 nm. With potassium (trisoxalato)cobaltate(III), for example, the Cotton effect at ∼600 nm was measured both in rotatory dispersion and in circular dichroism [55]. But now the aim had shifted from using the spectropolarimetric data for chemical and stereochemical correlation, as had been the purpose in Zurich and Groningen, to probing the stereochemistry in depth, with the elucidation of the absolute configuration in mind, and to testing new theoretical models of the optical activity. But it would take a few additional decades before eventually another experimental reinvestigation of the circular dichroism of some of these complexes, in connection with an analysis based on an improved theory, led to the desired knowledge of both the structure in solution and the absolute configuration. To this end, once again the circular dichroism of the (trisethylenediamine)cobalt(III) cation [56] and of the (trisoxalato)cobaltate(III) anion [57] was studied. But to trace this development would far exceed the scope of the present overview.

1.8. THE COTTON EFFECT IN ORGANIC CHEMISTRY, A RUSSIAN DOMAIN It would not be correct to claim that organic chemists neglected optical activity in the early twentieth century, except to characterize compounds by their D-line rotation. As an example to the contrary can be cited a series of papers by the Swiss chemist Hans Rupe (1866–1951) on the influence of the constitution on the rotatory power of optically active

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compounds, starting in 1903 [58]. However, usually colorless solutions were examined in the visible, as also done by Rupe, and could provide data on “plain” rotatory dispersion only. These investigations are, therefore, outside of the scope of the present overview. However, it must be admitted that, in general, organic chemists seem to have been less interested in chiroptical effects than their inorganic or physicochemical colleagues. Thus the study of organic molecules, as much as there is, had to rest on the “good will” of people from the latter fold. Here, credit is to be given first to the distinguished English physical chemist, Thomas Martin Lowry (1874–1936). Lowry’s interest in optical activity dates back to 1898, when he noted the change of optical rotation on nitrocamphor with time and introduced the term “mutarotation” to characterize this phenomenon [59]. He greatly improved the mathematical treatment and the theoretical understanding of rotatory dispersion and circular dichroism, based in part on the experimental data collected in his own research group in London, and later in Cambridge. It is interesting to see that there was a certain lack of understanding of the theory of optical activity on the part of some organic chemists. Even Rupe himself, for example, maintained as late as in 1921 that there had not been established with certainty any connection between the Cotton effect and the absorption of light [60]. In the earlier period of his career, Lowry dealt mostly with features outside of absorption bands; that is, he did not penetrate by experiment into the Cotton effect region itself. The state of the research on optical activity by the year 1914 has been summarized in the report “Optical Rotatory Power. A general Discussion” [61], and later in Lowry’s classic book [21], and it need not be described further in this paper. Lowry’s work in the early 1930s on the Cotton effect of organic molecules will be discussed later in this section. The most active pioneer in the study of the rotatory dispersion of organic molecules, and the only one who obtained data for the Cotton effect before World War I, is undoubtedly the Russian Leo [Lev] Alexandrovitsch Tschugaev (1873–1922) [62]. Tschugaev was a prolific research worker, who from the beginning of his career engaged in the chemistry of compounds like terpenes and camphor and, secondly, that of transition metal complexes. It was probably the study of optically active natural products that aroused his interest in optical activity generally. Eventually, he turned to a third research topic, after he had become Professor of Inorganic Chemistry at the Imperial University of St. Petersburg, and began in 1909 a series of papers on (anomalous) rotatory dispersion [63]. Tschugaev was fully aware of Cotton’s ground-breaking discoveries, and he was also aware of the problems inherently connected with the samples chosen for this early work. Therefore, he proudly, and correctly, pointed out in his initial papers that he now for the first time employed well-defined compounds for the study of the rotatory dispersion (he himself had no instrument that would allow him to measure the circular dichroism, in addition). But also he was still limited to visual observations at certain spectral lines. He used samples from two different families of sulfur-containing colored derivatives of optically active terpene alcohols like borneol, menthol, or fenchol, namely, xanthates RO–C(S)–SR and related compounds, along with “dithiourethanes” RO–C(S)–NPh–C(S)Ph (with Ph = C6 H5 ) and similar compounds. In all cases he found an anomalous dispersion of the rotation, but for different reasons. The xanthates give colorless or yellowish solutions, because there are no absorption bands in the visible. The anomalous rotatory dispersion detected is, therefore, of the type already observed for tartaric acid by Biot, and it is not caused by a Cotton effect in this spectral region. The red dithiourethanes, however, do show an absorption band at ∼520 nm, and the rotatory dispersion features indeed result from a Cotton effect associated with this absorption.

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It must be admitted that Tschugaev was only able to detect the first maximum of the ORD curve, because of the onset of high absorption near 450 nm precluding measurements of the short-wavelength part of the dispersion curve. Therefore, it might be considered stretching a point rather far to speak of his truly having detected Cotton effects, since this depends on quite some interpolation and interpretation. But his contention was much strengthened by G. Bruhat, to whom he had sent samples of both the d - and the l -bornyl dithiourethane mentioned above. Bruhat was able to measure the circular dichroism, both in toluene solution and in the melt [35, 64]. The CD maximum at 520–530 nm coincided with the absorption maximum at 520 nm. Bruhat could confirm, but not extend, Tschugaev’s ORD data, by the way. This then not only proved that Tschugaev’s interpretation of his rotatory dispersion curves had been correct, but also provided the first example of circular dichroism observed in a well-defined (organic) compound. With Tschugaev’s papers at hand, it is interesting to follow the progress of his search for a fitting technical term to describe what he initially calls an anomalous rotatory dispersion “in the sense of Cotton,” until he finally in 1912 arrived at the “Cotton phenomenon.” This then became the internationally accepted term to be used for two decades, until it lost ground against Lifschitz’s “Cotton effect.” T. M. Lowry revisited Tschugaev’s compounds in 1932, confirming the earlier data and extending the wavelength range of the observations, thanks to improvements in the optical instrumentation and the introduction of photography. He also performed calculations on a more advanced basis in order to analyze and simulate the data [65]. Now it had become possible to take photographic readings at many points of the wavelength scale down to 325 nm. Lowry not only supplemented and slightly extended Tschugaev’s earlier ORD results, but now he could additionally make available circular dichroism data for the xanthates. These compounds, with a weak absorption at 360 nm (which Tschugaev had missed) and a strong one at 280 nm, exhibit a CD maximum at ∼355 nm. The steep rise of the absorption toward shorter wavelengths still precluded the precise observation of the second ORD maximum at about 330 nm. It is notable that Lowry found his photographic CD measurements of the dithiourethanes in the year 1932 less exact than Bruhat’s visual measurements of 1911. Colored organic compounds were not unknown apart from the sulfur-containing derivatives discussed above, but were not easily available in optically active form. For chiroptical studies they should advantageously stem from the pool of optically active natural compounds or their derivatives, because the organic chemists of those days seem to have tended to avoid resolutions, contrary to their colleagues in the field of Werner complexes. Therefore, it is not surprising that the yellow camphor quinone attracted the attention of physical chemists and physicists alike. The Russian physicist Nina Wedeneewa detected in this compound a Cotton effect near 490 nm by ellipticity and rotatory dispersion measurements; although the work had been done in 1919, its publication was delayed until 1923 because of the political turmoil in Russia [20]. Her main interest was the analysis of the data in terms of the Drude theory of optical dispersion. Slightly later, in 1925, Israel Lifschitz also had tried to measure the optical rotation of camphor quinone near the absorption region, but could reach the first maximum only [53]. Lowry later repeated, confirmed, and extended Nina Wedeneewa’s findings, thereby tacitly correcting the sign of her circular dichroism data, as he studied camphor quinone both in solution and in the vapor phase [66]. Also this second case, in which the circular dichroism of an organic molecule has been measured successfully, in addition to Tschugaev’s/Bruhat’s dithiourethane,

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stems from Russia. Unfortunately, the First World War, the Russian Revolution, and Tschugaev’s premature death interrupted and eventually ended a period of intensive research on chiroptics in that country. Intriguing colored organic compounds are the “nitrosites” (1,2-nitroso-nitrites) and “pseudo-nitrosites” (1,2-nitroso-nitro compounds), which can be made by the addition of (formally) N2 O3 to olefins. These compounds exhibit green or blue colors in solution, provided that the nitroso group is monomeric. E. Deussen, working with the blue optically active caryophyllene nitrosite, had noticed an anomalous rotatory dispersion, minimalistically based on readings at just two wavelengths [67]. The suggestion by Tschugaev, that this might be caused by a Cotton effect in the visible [68], led Stotherd Mitchell in Glasgow in 1928 to check the chiroptical properties of this compound [69], but with readings taken at eight wavelengths between 691 and 436 nm. Indeed, a Cotton effect was found in the CD at ∼680 nm. It might be remarked that the absorption curves were measured separately with right- and left-circularly polarized light, whereas in practically all earlier cases data on ellipticities had been collected. In summary, the circular dichroism of only three (colored) organic compounds had become known by 1928. Although in some cases the claim has been put forward to have seen in such compounds a Cotton effect by rotatory dispersion, this should be taken with a grain of salt, because this cannot normally be substantiated by presenting the whole sigmoidal dispersion curve. Usually one wing of the curve is missing (commonly on the high-energy side of the absorption band), for reasons discussed above. It may come as a surprise, therefore, that as early as 1910, Eug`ene Darmois, one of Cotton’s students, published the ORD Cotton effect of even a colorless organic compound, namely, camphor, at ∼300 nm [70]. It is true that he had not been able to obtain rotation data at the absorption maximum itself, but only on either side of it (with a gap between 313 and 265 nm), but the dispersion curve can be easily completed by interpolation. This finding is all the more remarkable, because it demonstrated for the first time the possibility of taking rotation values down to ∼250 nm in the ultraviolet. Regrettably, the response of the chemical community was slow, probably because of the technical difficulties involved in the construction of a suitable spectropolarimeter. It took some 20 years before Darmois’s work could be taken up again; then, W. Kuhn published ORD, CD, and UV data of camphor, taken right through the absorption band [71], and T. M. Lowry likewise reported data of the related camphor-β-sulfonic acid [72]. It seems rather daring that Darmois [70] also tried to measure the chiroptical properties of olefins like α- and β-pinene or limonene, but—not unexpectedly—without much success. This chromophore still resisted the efforts of R. Servant in 1932, but at least this time some indication of a first ORD maximum seemed to be suggested at around 280 nm in the case of the pinenes [73]. From the foregoing it appears that rather suddenly, by around 1930, many more types of compounds were studied by chiroptical techniques. This resulted from the progress in instrumentation, to be related briefly in the next section. Now, a great many additional chromophores in colorless organic compounds, like nitro, azido, nitrito, and particularly carbonyl groups, opened the way for studies of the circular dichroism and the rotatory dispersion. Nevertheless, just a few typical samples were used to be investigated for physical–chemical purposes. It would take many more years before organic chemists made use of the now accessible optical techniques for stereochemical correlations and the determination of the absolute configuration. But this then is far outside the scope of this overview. These newer developments since the early 1930s will not be treated here, because many summaries are already available. The major source of information

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for the organic chemist on these later chiroptical investigations is Carl Djerassi’s book [74], which has become a “classic” in the field to which the reader should turn.

1.9. ADVANCES IN INSTRUMENTATION AND THEORY; THE WAY INTO THE ULTRAVIOLET Very briefly, the technical advances shall be sketched here that, around 1930, led to the (short-lived) upsurge in chiroptical activity mentioned in the foregoing section. Details shall be omitted, because comprehensive reviews are readily available. In addition to Lowry’s encyclopedic monograph of 1935 [21] and Mitchell’s book of 1933 [22], one should pay particular attention to Bruhat’s 1930 treatise on polarimetry, since most of the “newer” development of spectropolarimeters and ellipsometers resulted from the efforts at his laboratory in Paris [75]. Another active center was at the Technische Hochschule (Institute of Technology) Karlsruhe, Germany, where the Swiss physical chemist Werner Kuhn not only worked on theoretical and experimental chiroptics, but also developed his own apparatus [76]. Relevant optical instruments have also been reviewed by R. Descamps in Brussels, Belgium, who had himself constructed and perfected a spectropolarimeter for the UV region [77]. Of course, Lowry’s important contributions from his Laboratory of Physical Chemistry in the University of Cambridge, UK, are by no means to be forgotten. Progress in instrumentation for chiroptical studies meant, besides the obvious improvement of sensitivity and reliability, by and large the extension of the wavelength range into the ultraviolet. It was evident that the absorption bands of the vast majority of chemical compounds are located in the UV. It may come as a surprise that polarimetric measurements in the ultraviolet have been known for a considerable time and can be traced back to the nineteenth century. Various instruments for this purpose are described by Lowry [21], but the operation of the apparatus was laborious, the accuracy of the results questionable, and the accessible wavelength range rather limited. It does not seem, moreover, that these techniques have been applied to the detection of Cotton effects before the exceptional pioneering work of E. Darmois in 1911 [70]. One of the earlier attempts at measuring optical rotations in the UV was by Lowry himself, who in 1908 combined a half-shadow polarimeter with a UV spectrograph [78]. Darmois could collect data to the wavelength limit of 250 nm. But in order to make this wavelength range more generally accessible, and even extend it toward higher energy, three different problems had to be solved: first, with regard to the light sources; second, with the transparency of optical components to the UV light; and third, in connection with the efficiency of detectors. 1. The solar spectrum provided light in the laboratory only down to the limit of 300 nm, because of atmospheric absorption. Mercury vapor lamps allowed readings to be taken for another 50 nm, down to 250 nm. Beyond that wavelength, various other light sources have been used, in all cases providing an array of separate spectral lines—for example, the iron arc to 233 nm, or the cadmium spark to 210 nm. 2. The transparency limits of glass preclude its use in UV instruments for lenses, prisms, or similar optical devices, except for the near-UV range. Materials like Iceland spar (cutoff at 250 nm), fluorspar, or quartz had to be introduced to improve the transmittance of UV radiation. Even the Canada balsam used in

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conventional Nicol prisms had to be replaced by, for example, glycerol, in order to allow their utilization below 340 nm. 3. As to the detectors, the fluorescent screens of the early days were soon replaced by photographic implements, but the evaluation of the developed plates posed new problems in its own right. The improvements in all these areas led to the independent construction of two similar recording spectropolarimeters in the year 1926, giving access to UV measurements up to the high energy limit of 250 nm [79]. An important objective in the construction of these instruments was the desire to hold to a minimum the number of optical parts that had to be transparent to UV light. In Cotton’s photographic spectropolarimeter, the optical density of the photographs had to be evaluated by means of a photometer or, better, by a microphotometer. Although the recording was automatic, it was not continuous, but consisted of discrete exposures. Bruhat, on his part, used a photoelectric device. The data analysis could still be cumbersome, but the measurement of rotations in the UV had nevertheless become relatively easy. Bruhat’s polarimeter was perfected still further [80], to the extent that the photoelectric measurements became superior in precision to those obtained by the photographic method applied by Servant [73]. All the instruments mentioned so far are polarimeters. Similar advances had taken place in the construction of ellipsometers. Again, Bruhat was in the forefront with the development of a polarimeter–ellipsometer [81]. This widely used visual instrument consisted of an ordinary polarimeter, fitted with a mica λ/4 plate. Werner Kuhn developed an even more advanced photographic device for use in the ultraviolet [82]. It contained optical parts of quartz and fluorite only, and it allowed measurements to be taken all the way to 190 nm. This apparatus was the preferred instrument for many years to come and was marketed by the well-known makers of optical instruments in Berlin, Schmidt & Haensch. A similar ellipsometer was described by Mathieu in Paris [83]; it was designed particularly for the wavelength range of 450–280 nm. In conclusion, in the beginning of the 1930s, the development of instrumentation to measure the optical rotatory dispersion and the circular dichroism (in terms of ellipticities) had progressed to a state of perfection that was hard to improve upon in the decades to come. But, although it had been convincingly shown now that the Cotton effects of a wealth of optically active (organic) compounds were accessible, the chemical community at large was slow to make use of the chiroptical techniques. This resulted probably in part from the fact that the importance of stereochemistry had not yet been realized widely, especially among organic chemists. Also, the necessary apparatus still had to be built individually, and the measurement of ORD and CD was still far from being routine. Only with the advent of commercial recording instruments for ORD [84] and CD [85] many years later was the field of chiroptical investigations opened to the general chemist. Very few sentences must suffice on the contemporary development of the theory of optical activity, because this topic lies far away from the present overview. Paul Drude’s theory of optical activity in isotropic media, as expanded in his famous book of 1900 [26], has been the standard with which most physical(–chemical) research had to contend for the first three decades of the twentieth century. Many experimental investigations, including Lowry’s, have been motivated by the search for an improved version of the “Drude equation” of optical activity. An important step forward in this line was taken by L. Natanson, who in the year 1909 succeeded in deriving an equation that could approximate the optical dispersion within the absorption band, a problem that Drude’s original equation could not handle [17, 27, 28]. An advanced theory of optical activity

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was published by Max Born (1882–1970, Nobel Prize 1954) in 1915 [86] and at about the same time by C. W. Oseen [87] and F. Gray [88]. Although the importance of these papers, especially Born’s, was immediately recognized, practically no direct influence on the study of chiroptical properties was engendered. Likewise, the important paper by the Belgian physicist L´eon Rosenfeld (1904–1974) on the quantum-mechanical theory of optical activity did not affect the chemical community at the time [89]. It took Werner Kuhn’s (1899–1963) simplification of Born’s theory into his coupled-oscillator model to attract the chemists’ attention [76, 90]. Now the application of theoretical methods to actual problems of stereochemistry seemed to become realistic. Even the determination of the absolute configuration of molecules might come into reach. Indeed, Kuhn’s conclusion that (−)-butan-2-ol had the (R) configuration was the culminating point of his theoretical work [91]. A comprehensive overview of these developments in theory is found in Mathieu’s monograph on the molecular theories of natural optical activity [92].

1.10. SOME WORDS ON NOMENCLATURE: COTTON EFFECT, OPTICAL ROTATORY DISPERSION, CD, ORD The expression “Cotton effect” (originally in German) was introduced by Israel Lifschitz in 1922. The earlier technical term, first used by Tschugaev in 1912 (also originally in German), is “Cotton’s phenomenon.” This latter expression developed gradually by the contraction of phrases like “anomale Rotationsdispersion im Sinne A. Cottons” (anomalous rotation dispersion in the sense of A. Cotton) [93] or “la mani`ere de voir de M. Cotton” (literally: Mr. Cotton’s way of viewing) and “ph´enom`ene de la dispersion anormale” (phenomenon of anomalous dispersion) [94]. Tschugaev never used the word “Cotton effect” in whatever language. It is slightly confusing, therefore, to find this term in his Russian collected works [95], but on closer inspection this turns out to appear in a posthumous translation of his German papers into Russian. He himself always wrote ” (i.e., Cotton’s phenomenon). in Russian “ As can be seen from Table 1.1, both expressions were used side by side for a period of 10 years, but eventually “Cotton effect” was victorious. The situation is slightly simpler with “rotatory dispersion.” From the beginning in 1877, this term had become established, with minor variations as shown in Table 1.2. The only point meriting some attention is the question, Why has rotatory dispersion nowadays become “optical rotatory dispersion”? The “optical” was originally added in order to differentiate between the two effects of magnetic and optical rotatory dispersion, both of which were the subject of a series of papers by Lowry, with the first one appearing in 1913. Usually, however, it was considered unnecessary to point to this difference, because magnetic rotatory dispersion rarely plays a role in chemistry. The modern habit of always referring to “optical rotatory dispersion”, which also led to the common abbreviation “ORD,” seems to originate with Carl Djerassi, who used it since 1955 in a great many papers and who publicized it further by his textbook on ORD. The counterpart expression with respect to circular dichroism should be “optical circular dichroism,” in order to likewise differentiate between optical and magnetic circular dichroism. Indeed, the French “fathers” of modern CD instruments and their application in chemistry have used the term “dichro¨ısme circulaire optique” [96], but for reasons unknown, in this case the chemical community has continued to ignore the “optical.” For the first half of the twentieth century, abbreviations were not much used in (physical) chemistry. With fashions changing, this became a craze, however, in the second half, especially in the United States and the Soviet Union. Typical is the general use

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TAB L E 1.1. The Change from Cotton’s Phenomenon to the Cotton Effect The Cotton Phenomenon 1912 1913 1914

1915 1922 1922 [1925]

1926

1930, 1933

L. Tschugaeff: Cottonsches Ph¨anomena L. Tchougaeff: ph´enom`ene Cottonb L. Tschugaeff: Cotton’s phenomenonc M. Del´epine: les ph´enom`enes d´ecouverts par M. Cottond H. Rupe: Cottonsches Ph¨anomene H. Grossmann: Cotton-Ph¨anomenf F. M. Jaeger: ph´enom`ene de Cottonh

The Cotton Effect

1922

J. Lifschitz: Cottoneffektg

1922 [1925] 1923

F. M. Jaeger: l’effet de M. Cottonh F. M. Jaeger: l’effet Cottoni

1928 1929 1930

S. Mitchell: Cotton Effectk W. Kuhn: COTTON-Effektl G. Bruhat: l’effet Cottonn

1935

T. M. Lowry: Cotton Effecto

W. Pfleiderer: Cottonsches Ph¨anomenj

T. M. Lowry: Cotton phenomenonm

Cotton effect (Engl.); Cottoneffekt (German, Danish); effet Cotton (French); Effeto Cotton (Italian); Efekt Cottona (Polish); (Russian) a L. Tschugaeff, J. Prakt. Chem. 1912, [2] 86 , 545–550; L. Tschugaeff, G. Glinin, Ber. Dtsch. Chem. Ges. 1912, 45 , 2759–2764. b L. Tchougaeff, A. Kirpitcheff, Bull. Soc. Chim. Fr. 1913, [4] 13 , 796–803. c L. Tschugaeff, Trans. Faraday Soc. 1914, 10 , 70–79. d M. Del´ epine, C. R. H. Acad. Sci . 1914, 159 , 239–241. e H. Rupe, Liebigs Ann. Chem. 1915, 409 , 327–357. f H. Grossmann, M. Wreschner, Die anomale Rotationsdispersion, Sammlung chem. u. chem.-techn. Vortr¨ age, W. Herz, ed., Enke, Stuttgart, 1922, 26 , 259–314. g J. Lifschitz, Rec. Trav. Chim. Pays-Bas 1922, 41 , 627–636. h F. M. Jaeger, Rapp. Disc. Inst. Int. Chimie Solvay (Conseil Chim. 1922, Bruxelles), Gauthier-Villars, Paris, 1925, 199–202. i F. M. Jaeger, Bull. Soc. Chim. Fr. 1923, [4] 33 , 853–889. j W. Pfleiderer, Z. Phys. 1926, 39 , 663–685. k S. Mitchell, J. Chem. Soc. London 1928, 3258–3260. l W. Kuhn, Z. Phys. Chem. 1929, B4 , 14–36. m T. M. Lowry, Trans. Faraday Soc. 1930, 26 , 266–271; T. M. Lowry, H. Hudson, Philos. Trans. 1933, A232, 117–154. n G. Bruhat, Trait´e de Polarim´etrie, Editions de la Revue d’Optique, Paris, 1930. o T. M. Lowry, Optical Rotatory Power, Longmans, Green and Co., London, 1935; reprint: Dover Publications, New York, 1964.

of “RD” in C. Djerassi’s book published in 1960, incidentally one of the first major applications of this abbreviation. It is amusing to note that here “RD” still refers to “rotatory dispersion,” of course, while the same author had already adopted “optical rotatory dispersion” for some years. It was consistent with adding “optical” to “rotatory dispersion,” to also add the letter “O” to the abbreviation “RD”: The birth of “ORD” took place in Djerassi’s environment in the early 1960s.

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TAB L E 1.2. From Rotatory Dispersion to Optical Rotatory Dispersion Rotatory Dispersion, Dispersion Rotatoire, Rotationsdispersion

1913 1914 1915 1917 1935

H. Landolta: (anomale) Rotationsdispersion [German] A. Cottonb: dispersion rotatoire (anomale) [French] H. Grossmannc: (anormale) Rotationsdispersion [German] L. Tschugaeffd: anomale Rotationsdispersion im Sinne A. Cottons [German] L. Tschugaeffe: dispersion rotatoire ano(r)male [French] T. M. Lowryf : rotatory dispersion [English] T. S. Pattersong: (normal/abnormal) rotation-dispersion [English] T. M. Lowryh: an exact definition of normal and anomalous rotatory dispersion F. M. Jaegeri : rotatie-dispersie [Dutch] T. M. Lowryj : (normal and anomalous) rotatory dispersion [English]

1913 1926 1955 1959 1960

T. M. Lowryk: magnetic and optical rotatory dispersion [English] W. Pfleidererl : optische/magnetische Rotationsdispersion [German] C. Djerassim: Optical Rotatory Dispersion Studies [1st paper] [English] F. Woldbyen: optical rotatory dispersion [English] C. Djerassi: Optical Rotatory Dispersion, McGraw-Hill, New York [English]

1877 1895 1908 1911

Optical Rotatory Dispersion

a

H. Landolt, Liebigs Ann. Chem. 1877, 189 , 241–337 (p. 274). Cotton, C. R. H. Acad. Sci . 1895, 120 , 989–991. c H. Grossmann, H. Loeb, Z. Ver. Deutsch. Zuckerind., Allg. Teil 1908, 58 , 994–1009. d L. Tschugaeff, Z. Phys. Chem. 1911, 76 , 469–483. e L. Tschugaeff, A. Ogorodnikoff, Ann. Chim. Phys. 1911, [8] 22 , 137–144. f T. M. Lowry, J. Chem. Soc. London 1913, 103 , 1062–1067. g T. S. Patterson, Trans. Faraday Soc. 1914, 10 , 111–117. h T. M. Lowry, J. Chem. Soc. London 1915, 107 , 1195–1202. i F. M. Jaeger, Chem. Weekbl . 1917, 14 , 706–732. j T. M. Lowry, Optical Rotatory Power, Longmans, Green and Co., London, 1935. k T. M. Lowry, T. W. Dickson, J. Chem. Soc. London 1913, 103 , 1067–1075. l W. Pfleiderer, Z. Phys. 1926, 39 , 663–685. m C. Djerassi, E. W. Foltz, A. E. Lippman, J. Am. Chem. Soc. 1955, 77 , 4354–4359. n F. Woldbye, Acta Chem. Scand . 1959, 13 , 2137–2139. b A.

The abbreviation “CD” for circular dichroism was introduced at about the same time. Whereas “OCD” has never become popular, “MCD” for magnetic circular dichroism is a logical and accepted abridgment. In the same vein, a reasonable abbreviation for magnetic rotatory dispersion should be “MRD”. The misnomer “MORD” (which in German means “murder,” by the way) should fall into disuse. Details concerning these various abbreviations are collected in Table 1.3. It remains to remind the reader that the terms “rotatory dispersion” and “circular dichroism” as well as their abbreviations might change, if languages other than English are used. Some examples are collated in Table 1.4.

1.11. BIOGRAPHICAL NOTICES: G. BRUHAT, A. COTTON, W. KUHN, I. LIFSCHITZ, T. M. LOWRY, L. NATANSON, AND L. TSCHUGAEV It is a moot question how far a treatise on the history of natural sciences ought to be supplemented by a personalized account. It is the present author’s contention that such an approach is helpful to provide a balanced background for the scientific results

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TAB L E 1.3. From RD to ORD (but not from CD to OCD) 1960

C. Djerassi,a Optical Rotatory Dispersion: “abbreviated RD (curves)”

1960

W. Klyne, Adv. Org. Chem. 1 , 239–348: “abbreviated R.D. curves”

1965

P. Crabb´e,b Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry: “circular dichroism, abbreviated CD; rotatory dispersion curves, abbreviated RD”

1965

L. Velluz, M. Legrand, M. Grosjean,c Optical Circular Dichroism: “CD-curves”

1963

D. Lightner,d PhD Thesis: ORD

1966

K. Mislow,e Introduction to Stereochemistry: ORD, CD [preface September 1964, © 1965, published 1966]

1967

G. Snatzke,f ed., Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry [Summer School, Bonn, 24 September–1 Oct., 1965]: ORD, CD; “MORD”, MCD

1972

P. Crabb´eg, ORD and CD in Chemistry and Biochemistry

a

McGraw-Hill, New York. Holden-Day, San Francisco. c Verlag Chemie, Weinheim/Academic Press, New York. d Stanford, CA. e W. A. Benjamin, New York. f Heyden & Son, London. g Academic Press, New York. b

TAB L E 1.4. ‘CD’’ and ‘‘ORD’’ [and ‘‘CE’’] in English, French, German, and Russian CD RD ORD

DC DR DRO

КД

circular dichroism, Circulardichroismus rotatory dispersion, Rotationsdispersion optical rotatory dispersion, optische Rotationsdispersion Круговой дихроизм

dichro¨ısme circulaire dispersion rotatoire dispersion rotatoire optique

ДОВ

Дисперсия оптического вращения

[CE

Cotton effect, Cotton-Effekt]

[EC

effet Cotton]

discussed in the foregoing sections. After all, the common expression “it was found that” is deceptive insofar as it tends to obscure the fact that these results were not “found” by anonymous agencies, but earned by individual scientists, working at a specific time and under specific circumstances that pertain to both their professional and their private lives. Among the many actors in the first decades after the discovery of the Cotton effect, who could be considered for some biographical notices, here seven scientists are selected, as listed in the section title in alphabetical order. These names may reflect some personal predilection, but it is not too difficult to defend these choices impartially: Cotton is, of course, of outstanding importance. Natanson opened the route to an understanding of the interconnection of CD, ORD, and absorption generally. Tschugaev pioneered the investigation of chiroptical properties of organic molecules, while Lifschitz did the same with coordination compounds and has, moreover, coined the technical term “Cotton effect.” Bruhat was of particular importance for the development of instruments for chiroptical studies, together with Lowry and Kuhn, while the two latter scientists (both of them chemists, by the way) were instrumental also for the progress in the application

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of the theory of optical activity to chemical problems. All of these persons earned universal recognition, and even fame, also in other fields of chemistry or physics. All of them would merit attention, even if their part in the progress of chiroptics were to be neglected. Actually, for some among them, their activity in this field was rather incidental, if seen against their lifetime achievements. In the following, summary biographies of these scholars will be related in sequence according to their date of birth, with Cotton’s biography at the end, however. The theoretical physicist Ladisla(u)s [Władysław] Natanson (1864–1937) was born in Warszawa (Warsaw), Poland, the son of a medical doctor. Warsaw was under Russian rule at the time, and Natanson was a Russian subject. After graduation from a classical school in 1882, he enrolled as a student at the Faculty of Sciences of the University of St. Petersburg, where he became a “Candidate” (Licentiate) in 1886. After a few months at the Cavendish Laboratory at Cambridge, U.K., he returned to Imperial Russia in order to fulfil the requirements necessary for Russian subjects who wanted to embark on an academic career. Therefore, in 1887 he moved to Dorpat, Livonia (now Tartu, Estonia), to work for his doctorate with the physicist Professor A. von Oettingen, which he obtained in 1888. Incidentally, the official language at the University of Dorpat was German. After some postdoctoral studies with L. Boltzmann at the University of Graz, Austria, he returned to Warsaw to write an “Introduction to Theoretical Physics” [97]. This book was met with much acclaim, which helped him to be granted a position at the Jagiellonian University Krak´ow (Cracow), Poland (then under Austrian rule). There he moved up through the academic ranks: 1894 Titular Professor, 1899 Extraordinary Professor, and finally 1902 Professor of Theoretical Physics. Later he was also appointed Dean of the Faculty, and in 1922/23 he became Rector of the University. Elected to the Academy of Sciences in 1893, he became President of the Section of Mathematical and Natural Sciences in 1926, until he resigned from both the Academy and the University in 1935 for health reasons. His professional achievements are expanded upon in the obituary notice by L´eon Klecki, which includes a bibliography [98]. The chemist Lev Aleksandrovi(ts)ch Tschugaev (Chugaev) (1873–1922) was born in Moscow, Russia. After completing his studies at the University of Moscow in 1894, he became Assistant at the Bacteriological Institute of the University, where he started his research on the optical activity of organic compounds. From the beginning, Tschugaev strove to be competent in organic as well as inorganic chemistry. His master’s thesis in 1903 dealt with studies in the terpene and camphor series, while in his doctoral thesis (habilitation) of 1906 he presented results from coordination chemistry. Throughout his life, he successfully followed this dichotomy in his research, with some excursions into physical chemistry. In 1906 he was appointed Professor at the Technical University in Moscow, and in 1908 he was called to the Chair of Inorganic Chemistry at the Imperial University of St. Petersburg (later: University of Petrograd). He held this position at the time of his death. During World War I and the Russian Revolution he was mainly active in the field of technical and applied chemistry. He was one of the founders of the Institute of Applied Chemistry in Petrograd and became its director. In the aftermath of the revolution, he died of typhoid fever at Wologda, Russia, at the age of not yet 50. Obituary notices have appeared in England [62] and in Germany [99], acknowledging his abundant contributions to chemistry. Attention should also be paid to his “Selected Works” [95]. The physical chemist Thomas Martin Lowry (1874–1936) was born at Low Moor, Bradford, Yorks., U.K., the son of a Wesleyan Chaplain. He studied at the Central Technical College, South Kensington, London. From 1896 to 1913 he was assistant to Professor

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H. E. Armstrong and from 1904–1913 he was Lecturer in Chemistry at the Westminster Training College. In 1913 he became Head of the Chemical Department in Guy’s Hospital Medical School and Professor of the University of London. In 1920, finally, he was appointed to the newly created Chair of Physical Chemistry at Cambridge University. He continued at Cambridge for the rest of his life. In his extensive obituary notice, W. J. Pope wrote [100]: “[The book] on “Optical Rotatory Power” was issued in 1935 and will long remain a standard work on the subject. The immense amount of accurate experimental work which Lowry has left on record secures him a permanent place in the history of the science to which he was devoted.” But, although chiroptical methods are central to this overview, Lowry’s important contributions to other areas should not be forgotten. Mention may be made of his studies of the polymorphism of inorganic salts, his “Studies of Valency” and of the nitrogen oxide/water system, the nature of the sulfur halides, and the stereochemistry of tellurium compounds. In all cases he tried to apply modern physical concepts to chemical problems. Lowry was a member of the Faraday Society from its beginnings in 1903 and acted as its president in 1928–1930. He became a Fellow of the Royal Society in 1914. The physicist Georges Bruhat (1887–1945) was born in Besanc¸on, France, the ´ son of a civil servant. He was admitted with honors into the renowned Ecole Normale Sup´erieure (ENS) in Paris in 1906. After having obtained his B.Sc. (“licence e` s sciences physiques”) at the University of Paris, he acquired the qualification to teach at secondary schools (as “Professeur agr´eg´e ”) and taught at a high school in Paris for one year. Perhaps this interval in his scientific career awakened his interest in teaching and in writing textbooks for this purpose. He then got a position as laboratory assistant (“pr´eparateur”) at the ENS, which enabled him to work under the guidance of A. Cotton on his doctoral dissertation: “La dispersion anormale du pouvoir rotatoire mol´eculaire” (the anomalous dispersion of the molecular rotatory power). After an interruption by his military service during the First World War, he could continue his academic career in 1919 in Lille, France, where he was Professor of General Physics from 1921 to 1927. His successor was Marcel Pauthenier, by the way, who had been his partner in the construction of UV spectropolarimeters [79]. Bruhat returned to the University of Paris in 1929 as Lecturer and Professor Extraordinary. In 1938 he was promoted to the Chair of Theoretical and Celestial Physics. During this time he published four compendious textbooks on general physics: Electricity (1924), Thermodynamics (1926), Optics (1930), and Mechanics (1934). These books have become standard texts in French universities, with many editions; Optics, for example, has been reedited as recently as 2004. Bruhat also continued his association with the ENS, serving as “Sub-Director” from 1935, and as acting director during World War II. In the beginning of August 1944, he was arrested by the political police (“Gestapo”) of the German occupation powers and held prisoner in lieu of a student accused of activities in the French Resistance Movement. He was taken to Germany into a concentration camp and died there on January 1, 1945, of pneumonia and exhaustion. The chemist Israel Lifschitz (1888–1951) was born in Shklov, Russia (now Belarus) (see Figure 1.4). His family was German and lived in Leipzig, Germany. His mother had moved to Shklov just for her confinement, motivated by family regards. He studied chemistry at the University of Leipzig and worked there for his doctoral degree under the guidance of A. Hantzsch. His dissertation of 1911 dealt with the spectroscopic properties of various organic nitrogen compounds. Faithful to the ideas already developed in this dissertation, his main interest became the correlation of chemical constitution and bonding with electronic absorption. Although by training he was an organic chemist, his research

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Figure 1.4. Israel Lifschitz. (Photograph provided by Ms. E. H. Lifschitz, Haifa, and reproduced with her permission.)

led him far into physical chemistry and, later, also inorganic chemistry. Leaving Leipzig in 1911, he moved to the University of Zurich, Switzerland, for his habilitation. To this end, he submitted a second dissertation on the changes of light absorption by organic acids on salt formation. As a result, the title of “Private Docent of Chemistry” was conferred on him in 1914, allowing him to do independent research, but not connected with any paid position. The life of a Private Docent was difficult, unless one was privately affluent. The economic troubles after World War I also forced Lifschitz to interrupt his work at the university in 1920, in order to look for a source of income outside of Academia, to support his growing family. Lifschitz extended his investigations to include the optical rotatory dispersion of transition metal coordination compounds (see, e.g., paper V of a series on the function of chromophores [101]); after 1920 this became his central area of research. From these papers it can be deduced that he had established a cooperative arrangement with the Dutch inorganic stereochemist F. M. Jaeger at the Rijksuniversiteit Groningen (RUG) in the Netherlands, by 1919 at the latest. Jaeger invited Lifschitz to join his laboratory and offered him a tenured staff position as “Conservator”. This induced Lifschitz to move to Groningen, although he had become a Swiss citizen and probably had intended to stay in that country. As a result, in the summer of 1921, Lifschitz became Private Docent

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of Electrochemistry and Photochemistry, as well as Conservator at the Laboratory of Inorganic and Physical Chemistry at RUG. He helped to develop the department into a center of chiroptical spectroscopy. RUG became the birthplace of the “Cotton effect,” since Lifschitz coined this technical term there. The relevance of his research was readily acknowledged by stereochemists and physical chemists at other institutions. Already in 1935, J.-P. Mathieu in Paris had pointed out that Lifschitz was the first to systematically investigate the relations between the experimental data on the Cotton effect and the chemical bonds in optically active compounds [83]. Lifschitz held his position at RUG until he was dismissed in November 1940 for political reasons. Under the German occupation of the Netherlands in World War II, the situation of Jewish people deteriorated continually. Since Lifschitz was unable to continue his research at RUG, he turned again to his private studies of the mystical movements in Judaism, of which he was a dedicated and competent scholar. He was a deeply religious person, who had also published on related subjects. Now he became absorbed again in his studies of Chassidism, and he gave even private lessons on the Zohar. All this ended, when he, his wife, and their five children were detained in February 1943. He was eventually deported to the Theresienstadt Concentration Camp in Bohemia in September 1944, separated from his three sons, two of whom did not survive the ordeal. Liberated at the end of the war, he, his wife, and the three children left returned to Groningen, where he was reinstalled at RUG. He died in the Netherlands in 1953 and was buried in Haifa, Israel. The dire story of the family’s fate has been reported by his elder daughter Esther Hadassa Lifschitz [102]. It had proved to be fatal that the Dutch authorities had insisted, shortly before the war, that the family accept Dutch citizenship while relinquishing their Swiss citizenship. An attempt to regain Swiss nationality during World War II failed. It is likely that they could have otherwise left for Switzerland. The present paper may perhaps draw some attention to Lifschitz, who has been undeservedly forgotten. The physical chemist Werner Kuhn (1899–1963) was born at Maur am Greifensee, Switzerland, the son of a pastor. He studied chemistry at the ETH Z¨urich and obtained his doctorate at the University of Zurich in 1923, with a dissertation on a photochemical topic. After working with Niels Bohr in Copenhagen, Denmark, for two years, he returned to Zurich for his habilitation in physical chemistry in 1927. He moved to Germany thereafter. For three years he worked at the University of Heidelberg, where he started his research on optical activity; in 1930–1936 he worked at the Technische Hochschule Karlsruhe, and in 1936 he occupied the Chair of Physical Chemistry at the University of Kiel. In the year 1939 he returned to his home country, when he was called to the Chair of Physical Chemistry at the University of Basel. Later he was also elected rector of the University. He remained there until the end of his life. A report on “Leben und Werk von Werner Kuhn” (life and work of W. K.), including a bibliography, appeared in 1984 in connection with a “Werner Kuhn Symposium” of the Swiss Chemical Society [103]. The physicist Aim´e Auguste Cotton (1869–1951) was born in the French provincial town of Bourg-en-Bresse, where his father taught mathematics (see Figure 1.5). He was ´ a student of physics at the Ecole Normale Sup´erieure (ENS) in Paris from 1890 to 1893. He completed his doctoral studies, in the course of which he discovered the “Cotton effect” at the Laboratory of Physics with M. Brillouin and J. Violle and earned the title “Docteur e` s-sciences physiques” in 1896. It is noteworthy that he included in his thesis his first attempts at measuring magnetic optical activity, since his future scientific career was to be centered on the physics of magnetism and magneto-optics. It would be in these fields, rather than in research on natural optical activity, that he would rise to eminence.

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Figure 1.5. Aime´ Auguste Cotton. (From L. de Broglie, Notice sur la vie et l’œvre de Aime´ ´ Cotton, Academie des sciences—Institut de France, Paris, 1953; reproduced with permission.)

After a few years at the Faculty of Sciences of the University of Toulouse as Assistant/Associate Professor (Maˆıtre de Conf´erences, Professeur adjoint), he returned to the ENS in Paris, entrusted with the substitution of the Academician J. Violle, his teacher, for the period of 1900–1904. From 1904 to 1922 he served as Lecturer (Charg´e de cours) at the Faculty of Sciences of the University of Paris, delegated to the ENS. He was promoted to Professeur-adjoint in 1910 and became Professor of Theoretical and Celestial Physics at the Sorbonne in 1920. Finally, he was called to the Chair of General Physics there in 1922, succeeding G. Lippmann (Nobel Prize 1908). In 1923 he was elected a member of the illustrious Academy of Sciences as successor to J. Violle. He even became President of the Academy in 1938. Cotton retired from the Sorbonne in 1941, but continued until his death as Director of the Laboratory for Magneto-Optical Studies that he had founded in 1927. In France, A. Cotton is considered to be one of the eminent physicists of the twentieth century. He himself described his scientific aims and accomplishments in a 1923 pamphlet on the occasion of his election to the Academy [104]. As he pointed out, he had worked extensively on the Zeeman effect, but even more on the magneto-optical properties of colloids and molecular solutions. Many of the latter investigations were performed in

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cooperation with the biologist Henri Mouton (1869–1935) of the Institute Pasteur (later Professor of Physical Chemistry at the University of Paris). Together they discovered in 1907 the important “Cotton-Mouton-Effect” (magnetic field induced linear birefringence) [105]. Cotton’s fame in physics rests, arguably, more on this discovery than on the “Cotton effect” in natural optical activity. Detailed information on his life and work is easily available thanks to various obituaries [106] and to a notice published on the occasion of the centenary of his birth [107]. Cotton received many honors and was awarded many prizes. He was nominated for the Physics Nobel Prize in the years 1915, 1916, 1920, 1922, 1925, 1927, 1928, 1929, 1930, 1931, 1932, 1933, 1934, 1944, and 1949, but without success [108]. His memory is kept alive in France with the “Laboratoire Aim´e Cotton,” as his former Laboratory for Magneto-Optical Studies has been renamed. It is now the Atomic and Molecular Physics Laboratory of CNRS, associated with the University Paris XI and situated on its campus in Orsay. Also the “Prix Aim´e Cotton” should be mentioned, which was established by the French Physical Society in 1953 in memory of A. Cotton and is awarded annually. In what esteem he is held by the French physicists is also apparent by the fact that he is one of the twelve “most eminent” physicists chosen by the Academy on the occasion of the World Year of Physics 2005 (WYP2005/UNESCO). Among chemists of countries other than France, and especially among the younger fold, the name “Cotton” rarely brings to their minds memories of a specific person, unfortunately, unless they mistake it for the name of the distinguished American inorganic chemist A. Albert Cotton (1930–2007) of textbook fame. However, whether they know anything about the person or not, for the chemists working in chiroptics or stereochemistry, T. M. Lowry’s words of 1935 still hold true [21]: Cotton’s discovery in absorbing optically-active media of the twin phenomena of circular dichroism and of anomalous rotatory dispersion, which are indissolubly associated with his name, is [. . .] amongst the “classics.”

ACKNOWLEDGMENTS It is a pleasure to acknowledge the kind cooperation of Ms. E. H. Lifschitz in Haifa, Israel, who has provided important information on her father, Israel Lifschitz, and has permitted the publication of his photograph. It is a privilege to acknowledge also the untiring help of Dr. Henry Joshua of New York City, who has overcome many difficulties in his endeavors to establish contacts with Ms. Lifschitz, whose whereabouts had been unknown. The author is also grateful to Professor Jerome Gurst of Pensacola, Florida, for language counseling and for his helpful critique of the manuscript.

REFERENCES 1. D. F. Arago, M´em. Cl. Sci. Math´em. Phys. Inst. France 1811, 12 , I, 1–16, 113–134 (published 1812); [J. B.] Biot, Phys. Inst. France 1812, 13 , I, 1–372 (May 1813). 2. J. B. Biot, Bull. Sci. Soc. Philomath. 1815, [3] 2 , 190–192. 3. J. B. Biot, M´em. Acad. Roy. Sci. Inst. France 1817, [2] 2 , 41–136 (September 1818). 4. A. Arndtsen, Ann. Chim. Phys. 1858, [3] 54 , 403–421; Pogg. Ann. 1858, [2] 105 , 312–317.

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5. H. Landolt, Liebigs Ann. Chem. 1877, 189 , 241–337 (p. 274). 6. J. B. Biot, Ann. Chim. Phys. 1860, [3] 59 , 206–326; appendix 326–345 (page 266/7, Section III, 8). In this appendix, by the way, Biot refutes claims that the Baltic-German physicist Thomas Johann Seebeck (1710–1831) might have been the first to observe optical activity in solutions. 7. H. Landolt, Das optische Drehungsverm¨ogen organischer Substanzen und die praktischen Anwendungen desselben, Vieweg und Sohn, Braunschweig, 1879; English translation: Handbook of the Polariscope, D. C. Robb, V. H. Veley, translators, Cambridge, 1882 (reprint: BiblioLife, Charleston, SC, 2009). 2nd ed. Vieweg und Sohn, Braunschweig, 1898; English translation: The Optical Rotating Power of Organic Substances, J. H. Long, translator, Chemical Publishing Co., Easton, PA, 1902. 8. H. Fehling, Arch. Physiol. Heilkunde 1848, 7 , 64–73; Ann. Chem. Pharm. 1849, 72 , 106–113. 9. F. (-)P. Leroux, C. R. H. Acad. Sci . 1862, 55 , 126–128; Pogg. Ann. 1862, [2] 117 , 659–660. 10. C. Christiansen, Pogg. Ann. 1870, [2] 141 , 479–480; Pogg. Ann. 1871, [2] 143 , 250–259. A. Kundt, Pogg. Ann. 1870, [2] 142 , 163–171; Pogg. Ann. 1871, [2] 143 , 149–152; Pogg. Ann. 1871, [2] 143 , 259–269. J.-L. Soret, Arch. Sci. Phys. Natur. 1871, [2] 40 , 280–283. 11. A. Cotton, Absorption in´egale des rayons circulaires droit et gauche dans certain corps actifs, C. R. H. Acad. Sci . 1895, 120 , 989–991. 12. A. Cotton, Dispersion rotatoire anomale des corps absorbants, C. R. H. Acad. Sci . 1895, 120 , 1044–1046. 13. A. Cotton, Recherches sur l’absorption et la dispersion de la lumi`ere par les milieux dou´es du pouvoir rotatoire, Th`ese de Doctorat, Paris, 1896; Ann. Chim. Phys. 1896, [7] 8 , 347–432; summary: J. Phys. Th´eor. Appl . 1896, [3] 5 , 237–244. 14. [J. B.] Biot, Bull. Sci. Soc. Philomath. 1815, [3] 2 , 26–27; W. Haidinger, Pogg. Ann. 1845, [2] 65 , 1–30. 15. W. Haidinger, Pogg. Ann. 1847, [2] 70 , 531–544. 16. It would be interesting to know if Fehling’s solution was indeed Cotton’s very first sample. Apparently his papers, including his laboratory notebooks 1895–1920, are at the Niels Bohr Library, American Center for Physics, College Park, MD. 17. L. Natanson, Bull. Int. Acad. Sci. Cracovie, Cl. Sci. Math. Nat., Jan. 1909, 25–37. 18. A. Cotton, J. Phys. Th´eor. Appl . 1898, [3] 7 , 81–85. 19. F. Billet, Trait´e d’optique physique, Mallet-Bachelier, Paris, 1858/59 (2 vols.). 20. N. Wedeneewa, Ann. Phys. 1923, [4] 72 , 122–140. 21. T. M. Lowry, Optical Rotatory Power, Longmans, Green and Co., London, 1935; reprint: Dover Publications, New York, 1964. 22. S. Mitchell, The Cotton Effect and Related Phenomena, G. Bell & Sons, London, 1933. 23. W. Kuhn, A. Szabo, Z. Phys. Chem. 1931, B15 , 59–73. 24. W. O. [i.e., W. Ostwald], Z. Phys. Chem. 1896, 19 , 383, no. 87 and 88. 25. W. O. [i.e., W. Ostwald], Z. Phys. Chem. 1896, 21 , 158–163. 26. P. Drude, Lehrbuch der Optik , Hirzel, Leipzig, 1900; English translation: The Theory of Optics, C. R. Mann, R. A. Millikan [Nobel Prize 1923], translators, Longmans, Green & Co., London, 1902; reprint: Dover Publications, New York, 1959. 27. L. Natanson, Bull. Int. Acad. Sci. Cracovie, Cl. Sci. Math. Nat., O eliptycznej polaryzacyi s´wiatła, przepuszczonego przez ciało naturalnie , Oct. 1908, 764–783. 28. L. Natanson, J. Phys. Th´eor. Appl . 1909, 8 , 321–347. 29. A. Cotton, C. R. H. Acad. Sci . 1911, 153 , 245–247.

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30. W. Kuhn, Proc. [2 nd] Conf. Rotatory Dispersion, Santa Fe, CA, 20–22 Jan., 1960; Tetrah. 1961, 13 , 1–12. 31. M. F. McDowell, Phys. Rev . 1905, 20 , 163–171. 32. L. B. Olmstead, Phys. Rev . 1912, 35 , 31–46. 33. H. Grossmann, A. Loeb, Z. Ver. Deutsch. Zuckerind., Allg. Teil 1908, 58 , 994–1009. 34. H. Volk, Ber. Dtsch. Chem. Ges. 1912, 45 , 3744–3748. 35. G. Bruhat, Th`ese de Doctorat, Paris, June 1914; Ann. Physique 1915, [9] 3 , 232–282, 417–489. 36. G. Bruhat, Ann. Physique 1920, [9] 13 , 25–48. 37. R. de Mallemann, P. Gabiano, C. R. H. Acad. Sci . 1927, 185 , 350–352. 38. J.-P. Mathieu, C. R. H. Acad. Sci . 1931, 193 , 1079–1081; Ann. Physique 1935, [11] 3 , 371–460. 39. J.-P. Mathieu, C. R. H. Acad. Sci . 1932, 194 , 1727–1729. 40. W. Pfleiderer, Z. Phys. 1926, 39 , 663–685. 41. R. D. Gillard, Progr. Inorg. Chem. 1966, 7 , 215–276. Oddly, this author maintains that “Aim´e Cotton (1872–1944) discovered the [Cotton] effect while Professor of Physics at the Sorbonne in Paris.” Both the dates (recte: 1869–1951) and the professorship are erroneous (Cotton became a Professor at the Sorbonne in 1910, but had discovered the effect in 1895). 42. A. Werner, Z. Anorg. Allg. Chem. 1893, 3 , 267–330; see also: Vierteljahresschrift der Z¨urch. Naturf. Ges. 1891, 36 , 129–169. 43. A. Werner, Ber. Dtsch. Chem. Ges. 1911, 44 , 1887–1898. 44. M. Del´epine, C. R. H. Acad. Sci . 1914, 159 , 239–241; Bull. Soc. Chim. Fr. 1917, [4] 21 , 157–172. 45. G. Bruhat, Bull. Soc. Chim. Fr. 1915, [4] 17 , 223–227. 46. A. Werner, Ber. Dtsch. Chem. Ges. 1912, 45 , 121–130; 3061–3070. 47. A. Werner, J. Poupardin, Ber. Dtsch. Chem. Ges. 1914, 47 , 1954–1960. 48. A. Werner, Ber. Dtsch. Chem. Ges. 1914, 47 , 3087–3094. 49. A. Werner, Helv. Chim. Acta 1918, 1 , 5–32. 50. Important reviews of stereochemistry and optical activity at Groningen: F. M. Jaeger, Proc. Akad. Wet. Amsterdam 1915, 17 , 1217–1236; Lectures on the Principle of Symmetry, Elsevier, Amsterdam, 1917 (2nd enlarged edition 1920); Bull. Soc. Chim. Fr. 1923, [4] 33 , 853–889; Spatial Arrangements of Atomic Systems and Optical Activity, McGraw-Hill, New York, 1930. 51. F. M. Jaeger, Rec. Trav. Chim. Pays-Bas 1919, 38 , 171–314. 52. J. Lifschitz, Z. Phys. Chem. 1923, 105 , 27–54. It may be pointed out that the author abbreviated his first name, Israel, in print usually by the letter “J”; this was not uncommon in those days. 53. J. Lifschitz, Z. Phys. Chem. 1925, 114 , 485–499. 54. F. M. Jaeger, H. B. Blumendal, Z. Anorg. Allg. Chem. 1928, 175 , 161–230. 55. W. Kuhn, K. Bein, Z. Anorg. Allg. Chem. 1933/34, 216 , 321–348 (ORD); Z. Phys. Chem. 1934, B24 , 335–369 (CD). 56. R. E. Ballard, A. J. McCaffery, S. F. Mason, Proc. Chem. Soc. London 1962, 331–332. 57. A. J. McCaffery, S. F. Mason, Proc. Chem. Soc. London 1962, 388–389. 58. H. Rupe, Zeltner, W. Lotz, M. Silberberg, Liebigs Ann. Chem. 1903, 327 , 157–200 (first paper of the series); H. Rupe, L. Silberstrom, Liebigs Ann. Chem. 1918, 414 , 99–111 (ninth paper). 59. T. M. Lowry, J. Chem. Soc. London 1899, 75 , 211–244.

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60. H. Rupe, A. Krethlow, K. Langbein, Liebigs Ann. Chem. 1921, 423 , 324–342 (thirteenth paper of the series [58]). 61. T. M. Lowry, ed., Trans. Faraday Soc. 1914, 10 , 44–138. 62. So transliterated by T. M. Lowry in the obituary note (J. Chem. Soc. London 1923, 123 , himself, who often published in Germany, usually spells his name 956–958). . A. there Tschugaeff, and sometimes Tch´ugaeff or Tschugajew, in France also Tchougaeff. Chemical Abstracts always list him as L[ev] A[leksandrovich] Chugaev. In the references to this overview, the original spelling as given in the papers has been chosen. 63. L. Tschugaeff, Ber. Dtsch. Chem. Ges. 1909, 42 , 2244–2247 (paper I of the series); L. Tschugaeff, A. Ogorodnikoff, Z. Phys. Chem. 1910, 74 , 503–512 (II); L. Tschugaeff, Z. Phys. Chem. 1911, 76 , 469–483 (III); L. Tschugaeff, A. Ogorodnikoff, Z. Phys. Chem. 1912, 79 , 471–480 (IV); L. Tschugaeff, A. Ogorodnikoff, Z. Phys. Chem. 1913, 85 , 481–510 (V); L. Tschugaeff, W. Pastanogoff, Z. Phys. Chem. 1913, 85 , 553–572 (VI). See also: L. Tschugaeff, A. Ogorodnikoff, Ann. Chim. Phys. 1911, [8] 22 , 137–144; L. Tschugaeff, J. Prakt. Chem. 1912, [2] 86 , 545–550; L. Tchougaeff, Bull. Soc. Chim. Fr. 1912, [4] 11 , 718–722; L. Tschugaeff, G. Glinin, Ber. Dtsch. Chem. Ges. 1912, 45 , 2759–2764; L. Tchugaeff, A. Kirpitcheff, Bull. Soc. Chim. Fr. 1913, [4] 13 , 796–803; L. Tschugaeff, , A. A. , , B. [L. Trans. Faraday Soc. 1914, 10 , 70–79; . A. 1915, A. Tschugaev, A. A. Glebko, G. V. Pigulevskii], J. Russ. Phys. Chem. Soc. 47 , 774–775. 64. G. Bruhat, C. R. H. Acad. Sci . 1911, 153 , 248–250. 65. T. M. Lowry, H. Hudson, Philos. Trans. 1933, A232 , 117–154. 66. T. M. Lowry, H. K. Gore, Proc. Roy. Soc. 1932, A135 , 13–22. 67. E. Deussen, J. Prakt. Chem. 1912, [2] 85 , 484–488. 68. L. Tschugaeff, J. Prakt. Chem. 1912, [2] 86 , 545–550. 69. S. Mitchell, J. Chem. Soc. London 1928, 3258–3260. 70. E. Darmois, Ann. Chim. Phys. 1911, [8] 22 , 247–281, 485–590; Th`ese de Doctorat, Paris, 1910. 71. W. Kuhn, H. K. Gore, Z. Phys. Chem. 1931, B12 , 389–397. 72. T. M. Lowry, H. S. French, J. Chem. Soc. London 1932, 2654–2658. 73. R. Servant, C. R. H. Acad. Sci . 1932, 194 , 368–369. 74. C. Djerassi, Optical Rotatory Dispersion. Applications to Organic Chemistry, McGraw-Hill, New York, 1960. ´ 75. G. Bruhat, Trait´e de Polarim´etrie [with a preface by A. Cotton], Editions de la Revue d’Optique th´eorique et instrumentale, Paris, 1930. 76. Review: W. Kuhn, Theorie und Grundgesetze der optischen Aktivit¨at [theory and fundamental principles of optical activity], in Stereochemie, K. Freudenberg, ed., Deuticke, Leipzig, 1933, pp. 317–434. 77. R. Descamps, Trans. Faraday Soc. 1930, 26 , 357–371. 78. T. M. Lowry, Proc. Roy. Soc. 1908, A81 , 472–474; Philos. Trans. 1912, A212 , 261–297; T. M. Lowry, W. H. C. Coode-Adams, Philos. Trans. 1927, A226 , 391–466. 79. A. Cotton, R. Descamps, C. R. H. Acad. Sci . 1926, 182 , 22–26; R. Descamps, Rev. Opt. Th´eor. Instr. 1926, 5 , 481–501; G. Bruhat, M. Pauthenier, C. R. H. Acad. Sci . 1926, 182 , 888–890 (with comments by A. Cotton, C. R. H. Acad. Sci . 1926, 182 , 890–891); G. Bruhat, M. Pauthenier, Rev. Opt. Th´eor. Instr. 1927, 6 , 163–184. 80. G. Bruhat, P. Chatelain, C. R. H. Acad. Sci . 1932, 195 , 462–465; J. Physique 1932, [7] 3 , 501–511; G. Bruhat, A. Guinier, C. R. H. Acad. Sci . 1933, 196 , 762–764; Rev. Opt. Th´eor. Instr. 1933, 12 , 396–416. 81. G. Bruhat, Bull. Soc. Chim. Fr. 1930, [4] 47 , 251–261.

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82. W. Kuhn, Ber. Dtsch. Chem. Ges. 1929, 62 , 1727–1731; W. Kuhn, E. Braun, Z. Phys. Chem. 1930, B8 , 445–454. 83. J.-P. Mathieu, Ann. Physique 1935, [11] 3 , 371–460. 84. H. Rudolph, J. Opt. Soc. Am. 1955, 45 , 50–59; Rudolph Photoelectric Spectropolarimeter®, O. C. Rudolph & Sons, Caldwell, NJ. 85. M. Grosjean, M. Legrand, C. R. H. Acad. Sci . 1960, 251 , 2150–2152 (Centre de Recherche Roussel-Uclaf); Dichrograph®, Societ´e Jouan, Paris. 86. M. Born, Phys. Z . 1915, 16 , 251–258; Ann. Phys. 1918, [4] 55 , 177–240. 87. C. W. Oseen, Ann. Phys. 1915, [4] 48 , 1–56. 88. F. Gray, Phys. Rev . 1916, [2] 7 , 472–488. 89. L. Rosenfeld, Z. Phys. 1928/29, 52 , 161–174; Rosenfeld was at that time a postdoctoral associate with M. Born in G¨ottingen, Germany. 90. W. Kuhn, Z. Phys. Chem. 1929, B4 , 14–36. 91. W. Kuhn, Z. Phys. Chem. 1935/36, B31 , 23–57. 92. J.-P. Mathieu, Les Th´eories Mol´eculaires du Pouvoir Rotatoire Naturel , Gauthier-Villars, Paris, 1946. 93. L. Tschugaeff, Z. Phys. Chem. 1911, 76 , 469–483. 94. L. Tschugaeff, A. Ogorodnikoff, Ann. Chim. Phys. 1911, [8] 22 , 137–144. , , Publishing House of the Academy of Sciences of the SSSR, 95. . A. Moscow, 1955. 96. L. Velluz, M. Legrand, M. Grosjean, C. R. H. Acad. Sci . 1963, 256 , 1878–1881. do fizyki teoretycznej , Redakcye “Prac Matematyczno-Fizycznych”, War97. L. Natanson, saw, 1890. 98. L. Klecki, Prace Matematyczno-Fizyczne 1939, 46 , 1–18 (in French). 99. J. Salkind, Ber. Dtsch. Chem. Ges. 1922, 55 , 141A–142A. 100. W. J. Pope: Thomas Martin Lowry, Obituary Notices of Fellows of the Royal Society 1938, 2 , 287–293. 101. J. Lifschitz, E. Rosenbohm, Z. Wiss. Photogr., Photophys. Photochem. 1920, 19 , 198–214. 102. E. H. Lifschitz, Er was weinig begrip voor de joden [there was not much sympathy with the Jews], in Terug van weggeweest, J. van Gelder, ed., Stichting Geldersboek, Groningen, 1993, pp. 141–148 (Chapter 15); also: private communication to the author. 103. H. Kuhn, Chimia 1984, 38 , 191–211. 104. A. Cotton, Notice sur les Travaux Scientifiques, Presses Universitaires de France, Paris, 1923. 105. A. Cotton, H. Mouton, Ann. Chim. Phys. 1907, [8] 11 , 145–203, 289–339. 106. M. Javillier, C. R. H. Acad. Sci . 1951, 232 , 1521–1527; J. Cabannes [Cotton’s successor at the Sorbonne], Ann. Physique 1951, [12] 6 , 895–898; Louis [Prince] de Broglie [Nobel Prize 1929], Notice sur la vie et l’œvre de Aim´e Cotton, Institut de France, Acad´emie des Sciences, Paris, 1953 [30 pages]. 107. A. Kastler, C. R. H. Acad. Sci . 1969, 269 , 70–74. 108. E. Crawford, The Nobel Population 1901–1950: A Census of the Nominators and Nominees for the Prizes in Physics and Chemistry, Universal Academy Press, Tokyo, 2002. (Nomination 1915, page 62 (C. Fabry, nominator). Similarly: 1916, p.64 (M. Brillouin); 1920, p.80 (J. Bordet); 1922, p.84 (J. Bordet); 1925, p.94 (J. Bordet); 1927, p.102 (J. Bordet, C.E. Guillaume, C.E. Guye, A.Schidlof); 1928, p.106 (C.E. Guillaume); 1929 , p.110 (C.E. Guillaume); 1930, p.116 (C.E. Guillaume, H. Villat); 1931, p.120 (C.E. Guillaume, R. de Mallemann); 1932, p.124 (C.E. Guillaume, G. Reboul); 1933, p.128 (C.E. Guillaume); 1934, p.132 (H. Buisson, C.E. Guillaume, C.E. Guye, J. Perrin, V. Posejpal, P. S`eve); 1944, p.170 (H. Beghin); 1949, p.186 (M. Pauthenier)).

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PART II ORGANIC STEREOCHEMISTRY

2 SOME INHERENTLY CHIRAL CHROMOPHORES—EMPIRICAL RULES AND QUANTUM CHEMICAL CALCULATIONS Marcin Kwit, Pawel Skowronek, Jacek Gawronski, Jadwiga Frelek, Magdalena Woznica, and Aleksandra Butkiewicz

Molecules that do not contain center of chirality can still be chiral if their structure does not contain a plane of symmetry. Typical examples are hexahelicene and biphenyl (Figure 2.1) in which the chromophoric system (in these cases π electron system) is helical due to steric reasons preventing enantiomerization of the molecule at ambient temperature. Examples discussed in this chapter include (a) conjugated chromophoric systems of dienes, (b) enones, (c) helical chalcogenides, and (d) nonplanar amide chromophores. Many molecules of natural origin contain chromophores of either of this type (e.g. steroids, terpenes, amino acids, antibiotics, and metabolites); hence interpretation of their ECD may be useful for their absolute structure elucidation.

2.1. DIENES AND TRANS-ENONES Dienes and enones form a class of chromophores that can be helical due to nonplanarity of the π -bond system. Their chiroptical properties have been a subject of numerous studies over the past 50 years [1], aimed at clarifying the role of twist of the π -bond system and chirality of the molecule on the ECD spectra and optical rotation. There are other types of helical chromophoric systems; among these are dichalogenides (disulfides, diselenides, ditellurides), which are distinctly different due to their non-π -electron chromophore, and these will be discussed in detail in the following section (Figure 2.2). The conformations of these molecules may be conveniently described by considering their helicities. 1,3-Dienes can exist in two planar conformations defined as s-trans and s-cis and an infinite number of nonplanar, skewed forms, traditionally called cisoid or Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

39

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Figure 2.1. Hexahelicene and biphenyl—examples (M)-Hexahelicene

of inherently chiral (helical) chromophores.

(M)-Biphenyl

(a)

(b) C C

C

C

C

C

O

w=C=C−C=C

C

Ch Ch

C

C

C

C

w=O=C−C=C

R

C

w = C − Ch − Ch − C (Ch = S, Se, Te)

t=C−C=C−R

Figure 2.2. Simple helical chromophores and definitions of torsion angles ω (a) and definition of angle τ that describes distortion of the C=C bond from planarity (b).

transoid , depending on the conformation of the nearer planar form. The conformation can otherwise be described by torsion angle ω, which can be either positive (P ) or negative (M ) (see Scheme 2.1). The same is true for enones and dichalcogenides; however, in the last case both planar s-trans and s-cis conformations represent the transition states, not any stable structures. Additional classification of chromophore structures may be accomplished on the basis of molecular symmetry [1b]. Both butadiene and symmetrically disubstituted dichalcogenides in planar forms belong to either C2h or C2v symmetry point group, respectively, for s-trans and s-cis conformers. Rotation around the C–C or Ch–Ch bonds reduces the

(a) X

X S-cis (sp)

X Cisoid

Planar

P-helical

Cisoid

X Transoid

X S-trans (ap)

X Transoid

(b)

M-helical

P-helical

Planar

M-helical

X = CH2 (1,3-dienes) X = O (enones)

Scheme 2.1. (a) Possible planar and nonplanar conformations of 1,3-dienes and enones and (b) definition of M- and P-helicities in the cases of cisoid and transoid 1,3-dienes.

S O M E I N H E R E N T LY C H I R A L C H R O M O P H O R E S

symmetry to C2 in skewed, chiral conformations. Unlike butadiene and dichalcogenides, the simplest enone (acrolein) exhibits only trivial C1 symmetry when skewed and Cs symmetry for both planar forms. The electronic transitions of 1,3-dienes and enones are reflections of their structures. The degree of electron delocalization determines intensity and energy of the low-energy π –π * electronic transition in the diene chromophore. For the most populated s-trans conformation of butadiene, the most intense band is found at 210 nm with εmax > 20,000 [2], whereas for s-cis planar conformation, both the intensity and energy of the π –π * electronic transition is significantly lower. In the case of cyclopentadiene the long-wavelength absorption band appears at 240 nm (εmax = 3500) [2]. The extinction coefficients and energies of the low-energy π –π * electronic transitions for skewed dienes are higher for transoid compared to cisoid structures and reach a minimum (λmax = 190 nm) for perpendicular diene confomation (ω = ±90◦ ) [2, 3]. In the case of 1,3-cyclohexadiene the observed UV maximum appears at 256 nm (εmax = 9000) [4]. The lowest-energy π –π* electronic transition has been used as a diagnostic band for solving stereochemical problems with the use electronic circular dichroism (ECD) spectroscopy. Contrary to dienes, α, β-unsaturated ketones typically exhibit two absorption bands: one very weak near 330 nm (R-band) and the second at around 230 nm (K-band). The lowest-energy band originates from a forbidden transition from nonbonding 2py orbital into antybonding π * orbital; thus this electronic transition is defined as n –π * [5, 6]. In the case of 2-cyclohexenone the lowest-energy n –π * transition is found at 320 nm (ε = 36) [7]. For chiral enones the dissymmetry factor (g) for the lowest-energy n –π * electronic transition is in the range 10−1 to 10−2 . The second UV absorption band in enone chromophore has the character of an intramolecular charge transfer transition from the vinyl to the carbonyl group and exhibits much higher intensity compared to the lowest-energy n –π* electronic transition. Oscillator strengths for transoid enones are usually higher than for cisoid . The dissymmetry factor for π –π * electronic transition is in the range 10−3 to 10−4 . In the case of 2-cyclohexenone, this band appears at 225 nm (εmax = 13800) [7]. Although only two bands are observed in the UV spectra of enones, ECD spectra of α, β-unsaturated ketones exhibit three (sometimes four) Cotton effects between 360 and 185 nm. The weak UV absorption at about 300 nm is responsible for the long-wavelength Cotton effect of moderate intensity. This band is followed by a π –π * transition Cotton effect corresponding to the UV band placed between 220 and 250 nm. Another Cotton effect that does not have the corresponding UV maximum appears at around 200 nm and usually exhibits a high rotatory strength, sometimes even higher than that for the π –π * electronic transition. The origin of this Cotton effect is not clear. Earlier calculations by Liljefors and Allinger suggested that this is another π –π * transition of low intensity in nearly planar enones [8]. Snatzke suggested that this is the second forbidden n –π * electronic transition [1i, 9]. The direction of polarization of this transition has been determined by linear dichroism measurements [10]. The fourth electronic transition is observed between 195 and 185 nm in ECD spectra of some enones having an axial substituent in α  or β  positions. This transition was considered as n –σ * excitation [1d–1f]. During the last few decades, various empirical rules have been proposed to correlate the signs of the Cotton effects of 1,3-dienes and α, β-unsaturated ketones with their stereochemistry (Table 2.1). Whereas some of the correlation rules are of historical value, two basic stereochemical concepts underlying the development of such correlations are briefly considered below.

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TAB L E 2.1. Empirical Rules Correlating Cotton Effect for a Given Electronic Transition with the Chirality of Compounds Containing 1,3-Diene and Enone Chromophores Electronic Transition

Rule

π –π * (dienes) π –π * (dienes) π –π * (dienes) π –π * (dienes) π –π * (planar s-trans dienes) π –π * (enones) n –π * (enones) n –π * and π –π * (enones) n –π * (planar s-trans enones) n –π * and π –π * (enones) 210-nm transition (cyclic enones)

References

Diene Helicity Rule (Moscowitz et al., 1961) Allylic Axial Chirality Rule (Burgstahler and Barkhurst, 1970; Burgstahler et al., 1976) Quadrant Rule (Moriarty et al., 1979) Sector Rule (Weigang, 1979) Planar Diene Rule (Duraisamy and Walborsky, 1983)

11 12, 13

Enone Helicity Rule (Djerasi et al., 1962, Whalley, 1962) Enone Helicity Rule (Snatzke, 1965) Orbital Enone Helicity Rule (Kirk, 1986)

17, 18 19 1e

Sector Rule (Snatzke, 1979; Snatzke, 1965)

1h, 19a

Allylic Axial Chirality Rule (enones) (Burgstahler and Barkhurst, 1970) Carbon–Carbon Bond Chain in Cyclic Enones Rule (Gawronski, 1982)

14 15 16

12 1d

For correlating the chiroptical phenomena with the diene or enone structure, two fundamental effects had to be taken into account: (a) the contribution from the helicity of the chromophore and (b) the effect of extrachromophoric perturbation. Whereas the first of these effects correlates conformation of the chromophore with its spectroscopic properties, the second is related to the configuration at the stereogenic center(s). Both effects may act in the same or in opposite direction, so determining the dominant contribution is an important yet not always easy task. In the case of rigid 1,7,7-trimethyl2,3-dimethylene-bicyclo[2.2.1]heptane (1), chirality originates from the presence of the methyl group connected to C1 carbon atom [20]. As long as the chromophore is planar, the effect of extrachromophoric perturbation dominates. On the other hand, in the case of highly flexible (3S,8S,E,E )-dimethyl-deca-4,6-diene (2), both effects contribute to the π –π * transition Cotton effect [21], whereas in the case of the rigid structure of ergosterol (3) a negative twist of diene moiety is considered as the origin of the long-wavelength Cotton effect [22]. C9H17

H HO 1

2

De = −0.6 (250 nm)

De = +3.0 (230 nm)

3 w = −11° De = −18.0 (269 nm)

According to the Diene Helicity Rule (DHR) [11a], the sign of the long-wavelength Cotton effect reflects directly the sense of helicity of the chromophore; that is, for positive twist of the 1,3-diene system a positive long-wavelength π –π * transition Cotton effect is expected (Figure 2.3a).

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S O M E I N H E R E N T LY C H I R A L C H R O M O P H O R E S

(a)

(b)

Figure 2.3. Empirical correlating P +C.e. w > 0°

M −C.e. w < 0°

+C.e. for right-handed angle Caxial −Callyl −C = C

−C.e. for left-handed angle Caxial − Callyl −C = C

rules for 1,3-dienes: (a) Diene Helicity Rule and (b) Allylic Axial Chirality Rule.

The validity of DHR has been challenged by calculations at different levels of sophistication [3, 23–31]. Most of them were performed for simple models like 1,3butadiene and generally confirmed the validity of DHR, but it should be noted that some of the calculations gave opposite results [28, 31]. To overcome the inadequacy of the Diene Helicity Rule for certain types of diene structures, the concept of allylic axial substituent contributions to optical activity of conjugated dienes was proposed by Burgstahler and co-workers (Allylic Axial Chirality Rule, hereafter referred to as AACR) [12, 13]. According to this concept, the sign of the long-wavelength Cotton effect of conjugated dienes is primarily due to the contribution of allylic axial substituents, such as alkyl groups. The sign of the contribution is determined by the helicity (+ or −) of the Caxial –Callyl –C=C bond system (Figure 2.3b). Thus, antipodal CD curves of 15-methylene-5α-cholest-8(14)-en-3β-ol acetate (4) and 3-isopropylidene-A-norcholest-5-ene (5) were explained as due to contribution from the allylic axial substituents; these dienes exhibit Cotton effects of opposite signs to those required by the DHR. + AcO

H + + – H H H w = +20° 4 De = +4 (250 nm)

H – H



w = +20°

– H

5 De = −5 (250 nm)

A corollary to this rule is a low contribution of the diene chromophore to the rotational strength of the π –π * transition. Certain substituents attached to one of the diene carbon atoms (e.g., the CN group) can cause sign reversal of the long-wavelength Cotton effect, in the absence of any obvious structural change [32], and this is another example of inconsistency with the Diene Helicity Rule. An experimental and theoretical study of α-phellandrene (6) and other 5-alkyl-1,3cyclohexadienes (7, 8) by Lightner et al. [30] for the first time provided a dissection of the contributions of various structural elements to the cyclohexadiene 260 nm Cotton effect. In the case of (5R)-5-methyl-1,3-diene (7), variable-temperature ECD spectra were invariant, due to a low energy difference between equatorial and axial conformers, estimated as 0.05 kcal mol−1 (Figure 2.4a,b), and exhibited a positive long-wavelength Cotton effect ( ε = +5 at 260 nm). A dramatic change of ECD spectra with temperature was observed when a tert-butyl group was attached to the 1,3-cyclohexadiene skeleton. At slightly elevated temperature, the sign of the long-wavelength Cotton effect was positive ( ε = +2.5 at +31◦ C) and stepwise decreased upon lowering the temperature. At −180◦ C the value of the long-wavelength Cotton effect was ε = −3.0, which corresponds to energy difference Gax-eq = 0.4 kcal mol−1 .

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

The rotatory strengths estimated from ECD spectra for 8 are positive for axial P helical conformer (R = +55.6 × 10−40 cgs units) and negative for equatorial M -helical conformer (R = −15.0 × 10−40 cgs units). The sign of the contribution due to the s-cisdiene moiety alone is calculated opposite to that predicted by the Diene Helicity Rule for 5-alkyl-1,3-cyclohexadienes, and the sign and magnitude of the Cotton effect are apparently dominated by the contributions of the axial allylic bonds (groups) (Figure 2.4c). Recently, a more advanced ab initio calculation by Hansen and Bak [33] in the random phase approximation (RPA) using Aug-cc-pVTZ atomic basis set provided important confirmation of the earlier findings on the role of allylic substituents. The effects of the allylic methyl groups were found to follow a quadrant rule being almost additive, and the contributions from axial substituents were calculated significantly larger than those from the equatorial groups. Analysis of chiroptical properties of compounds having enone chromophore is usually much more laborious. The first difficulty is due to small energy differences between conformers, and the second is the origin of the electronic transitions. While the n –π * electronic transition has origin similar to that of saturated ketones, higher energy transitions in enones are not pure and involve various types of orbitals. Estimated inversion barrier for 2-cyclohexenone is lower than the inversion barrier experimentally determined for cyclohexene [34]; and full inversion cycle involves a number of structures, each characterized by out-of-plane position of at least one saturated carbon atom. The diversity of possible conformation does not vanish even if a 2-cyclohexenone ring is a part of polycyclic systems, as in steroids and terpenoids. For example, for testosterone (9) molecule in the crystal lattice the dihedral angle ω that characterizes chromophore helicity takes different values, both positive and negative,

(a)

(c)

(b)

Figure 2.4.

Conformational drawings of (R)-α-phellandrene (6) (a) and (5R)-5-alkyl-1,3-

cyclohexadienes 7 and 8 (b) showing the axial or equatorial position of the alkyl group in relation to diene helicity and estimated group contributions to the rotatory strength (R (×10−40 cgs units) for the lowest-energy π −π ∗ electronic transition of (P)-1,3-cyclohexadiene (c).

45

S O M E I N H E R E N T LY C H I R A L C H R O M O P H O R E S

depending on the space group and on the presence or not of other molecules forming hydrogen bonds or complexes [35–38].

Almost 50 years ago, Djerassi et al. [17], Whalley [18], and Snatzke [19] proposed rules for the first two Cotton effects: positive enone helicity was correlated with a negative n –π * and a positive π –π * Cotton effect. This rule was thereafter applied by Kirk to s-cis and s-trans enones unperturbed by polar substituents, and (P ) π orbital helicity at C1 and C2 carbon atoms was correlated with a positive n –π * and a negative π –π * Cotton effect (Figure 2.5a,b) [1e]. These rules worked well for cyclohexenones, but for cyclopentenones inverse rules were proposed [1d, 1f, 19b]. Snatzke proposed a modification of the octant rule that correlates the sign of the n –π * Cotton effects with the stereostructure of planar enones [1h,1i,19c]. The n –π * Cotton effects of steroidal enones in oriented (anisotropic) systems were later studied by Kuball et al. [39]. Their studies demonstrated that sector or helicity rules can be applied, provided that vibronic progressions originating from various conformers are taken into account. On the other hand, Burgstahler and Barkhurst [12] has shown for the first time the importance of allylic axial substituents that led to a breakdown of the enone helicity rule for the π –π * transition of some s-cis steroid enones. The electronic transition observed between 220 and 200 nm in ECD spectra of some enones [9, 40] is characterized by a low oscillator strength, making it difficult to detect in (a)

(b)

O

O

s-cis (P)

O

s-trans (P)

s-cis (P)

−C.e. (n−p*), +C.e. (p−p*) (c)

O

O

s-trans (M )

+C.e. (n−p*), −C.e. (p−p*) (d)

O

R b′ O

O

+C.e. (~220 nm)

−C.e. (~220 nm)

a′ R

b′

b

a′

a O

Figure 2.5. (a) The first Enone Helicity Rule. (b) Kirk’s Enone Orbital Helicity Rule. (c) correlation rule for the third Cotton effect. (d) Correlation rule for the sign of the fourth Cotton effect in 2-cyclohexenones.

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the UV spectra, and a high rotatory strength, resulting in some cases in overlap with the Cotton effect originating from the π –π * electronic transition. Attempts to correlate the sign of the third Cotton effect with structural parameters were met with many difficulties. Burgstahler correlated the sign of the third Cotton effect with the chirality of α  carbon atom [12]. In the case of 4 -3-ketosteroids, a positive value of the third Cotton effect is in agreement with the chirality due to an axial 2β-substituent. This relationship can only be treated as tentative due to numerous exceptions. Gawronski suggested that the sign of the third Cotton effect is connected with the presence of saturated carbon–carbon bond chain, especially in polycyclic enones. It shows a clear relation to the absolute configuration at the allylic position (Figure 2.5c) [1d, 1f]. The fourth electronic transition, thought to involve n and σ ∗ orbitals, has been found in enones having α  or β  substituents in an axial position. The sign of this Cotton effect is dominated by the orientation of substituent, with assumption of a sofa(5) conformation of 2-cyclohexenone skeleton (Figure 2.5d).[1d–1f]. In the light of the above-mentioned facts, proper determination of the nature of electronic transition(s) involved is mandatory for rational stereochemical analysis of compounds containing the enone chromophore. This is of special interest in the case of molecules containing polar groups, which may influence strongly both the sign and the magnitude of the Cotton effects [41]. On the basis of DFT calculation at the B2LYP/6-311 + +(2d,2p) level and with the use of NBO method [42], it was possible to determine the origin of the first three electronic transition for a group of model compounds. For s-trans-acrolein, 2-cyclohexenone, (4S )-4-hydroxy-2-cyclohexenone (10), and (5R)-5-hydroxy-2-cyclohexenone (11), characterized by planar conformation of the chromophore (ω = 180◦ , τ = 0◦ ) and sofa(5) conformation of the cyclohexenone skeleton, the origin of the first two electronic transitions did not raise doubts (Figure 2.6). The long-wavelength electronic transition with a small oscillator strength involves HOMO(−1)–LUMO orbitals (nC=O –πC=C * type), whereas the second electronic transition with the highest oscillator strength is of CT character, involving HOMO and LUMO orbitals (πC=C –πC=O * type). The third electronic transitions, responsible for the third strong Cotton effect observed in the ECD spectra of enones, is characterized by a small oscillator strength. For acrolein the third electronic transition involves both πC=O –πC=O * and nC=O –σ * transitions, while in the case of 2-cyclohexenone it is a mixture of electronic transitions of the πC=C –πC=C * type (HOMO–LUMO(+1), the main contribution) and πC=C –σ * [HOMO–LUMO(+2)]. This supports the earlier suggestion [1d] that the configuration of saturated C–C bond chain in cyclic enones may be, in the absence of polar substituents, the controlling factor of the sign of the short-wavelength Cotton effect. The presence of a hydroxy group in enones 10 and 11 causes a change of the character of the third electronic transition, compared to 2-cyclohexenone. This electronic transition appearing at ∼190 nm involves the lone pairs of the hydroxy group [HOMO(−2)] and LUMO orbitals and thus may be referred to as nOH –πC=O * type. This may suggest that the third, short-wavelength Cotton effect in 2-cyclohexenones having polar substituents at C4 and/or C5 position depends on the helicity of the (H)O–C · · · C=O bond system [41]. In the analysis of the origin of optical activity of cyclic 1,3-dienes and enones the effect of nonplanarity of the C=C bond(s) is usually neglected. Recently, Diedrich and Grimme [43] performed an advanced quantum chemical calculation of the rotatory strength for the electronic transitions of twisted (−10 deg) ethylene. The calculated rotatory strength for the π –π * transition was of the order 75–198 × 10−40 cgs units, depending on the method used. Since nonplanar ethylene generated a high rotatory

47

S O M E I N H E R E N T LY C H I R A L C H R O M O P H O R E S

(a)

(b)

O 10

IIIb

OH 11

IIId

IIIc

LUMO(+1)

LUMO

(d)

O

O

O

LUMO(+2)

OH

(c)

I II IIIa

I II

I II IIIe

I II IIIe

HOMO

HOMO(−1)

HOMO(−2)

Figure 2.6. Molecular orbitals obtained with the use of the NBO method for representative planar enones: (a) Acrolein and (b) I nC=O –πC=O ∗, II πC=C –πC=O *, IIIa πC=O –πC=O *, IIIb nC=O –σC(O) – H *, IIIc πC=C –πC=C ∗, IIId πC=C –σC – C ∗ /σC – H *, IIIe nOH –πC=O *.

strength, neglecting such an effect in the case of π –π * electronic transitions of nonplanar enone and diene seems unjustified. Nonplanar conformations of simple 1,3-butadiene and acrolein may be chiral due to nonplanarity of the C=C bonds, defined as the sign and value of torsion angle τ (Figure 2.2). Thus, nonplanar molecular conformations may be due to nonzero values of either angle ω or angle(s) τ , or both. If both torsion angles ω and τ are considered, chromophore conformation may be defined as homohelical (if the signs of angles ω and τ are the same) or as heterohelical , if the signs of angles ω and τ are opposite [44]. In the case of s-trans acrolein and 2-cyclohexenone, deformation of the C=C bond from planarity results in the appearance of nonzero rotatory strength. Enone Helicity Rule is obeyed as long as the twist of the C=C bond and enone helicity are of opposite sense (heterohelical [41]). We will now discuss the effect of substitution of 1,3-cyclohexadiene and 2-cyclohexenone, which sometimes leads to contrasting effects. (S , S )-trans-1,2-Dihydroxy-3,5-cyclohexadiene (12) in the crystal phase forms an M -helical conformer (ω = −11.5◦ ), with the hydroxy groups occupying equatorial positions. Variable-temperature ECD spectra measured in methanol reveal that the rotatory strengths for both P- and M-helical conformers are positive, in accordance with the helicity of O–Callyl –C=C system, and the rotatory strength for diaxial P -conformer is one order of magnitude higher than that for the diequatorial one (Scheme 2.2) [45]. Significant solvent effect can be observed in the ECD spectra of 12. ECD spectrum in methanol solution at room temperature shows a Cotton effect ( ε = +11.2 at 258 nm),

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

w = −11.5° (X-ray)

OH

H

OH O

OH

H

12

O

methanol

H

cyclohexane

H

H

Δep−p* +6 (cyclohexane) +11 (methanol)

H M (more abundant) R p−p* > O

OH P R p−p* >> O

Scheme 2.2. Conformational equilibrium of dihydroxydiene 12.

due to increased population of P -helical conformer, whereas in nonpolar solvent the presence of intramolecular OH· · ·O bond favors the diequatorial M-conformer, with concomitant decrease of the long-wavelength Cotton effect ( ε = +6 at 259 nm). According to recent calculation performed for 12 at the DFT/B3LYP/6-311++G(d,p) level, diaxial P conformer is of 0.7 kcal mol−1 higher energy relative to the diequatorial one. Rotatory strength of the π –π * electronic transition, calculated at the mPW1PW91/6311++G(2d,p) level for P -helical 12 is almost four times higher than that for the lowest-energy diequatorial M conformer [46], consistent with the experimental ECD data. More complex systems are represented by arene metabolites 13–17 [41, 46–48]. These compounds, being valuable chiral building blocks and ligands in organic synthesis [49], are characterized by the presence of a vicinal cis-diol system and a 1,3-diene or enone chromophore. All of them can exist in solution in an equilibrium of diastereoisomeric diene (enone) conformers of P or M helicity with one of the OH group in an axial and the other in an equatorial position.

The main problem with stereochemical analyses of compounds of this type is reliable determination of conformer population. In general, the number of available conformers is not limited to M and P diastereoisomeric structures. Intramolecular hydrogen bond patterns of the hydroxy groups further increase the number of distinct stereoisomeric structures (Scheme 2.3). Thus, either C1(or C4)–OH or C2(or C5)–OH can be a hydrogen bond donor, and the orientation of the O–H bond against the vicinal C–H bond

49

S O M E I N H E R E N T LY C H I R A L C H R O M O P H O R E S

4

R

3

H

R

H O R2

O

3

R4

1

R

R1 2

H

R

4

R

2 1

R

R

4

H

3 R O

H

2

R H

H

R

1

R

4

3 R O

R2

R1

O

H

O

H

H P3

H P1

H M3

H

H a OH

3

R

O H

O

H H M1

R w

R

H

enones, R3

b OH

==O

4

R

R

3

H

O H R2

O

1

R H

H M2

4

R

3

H

R

O

2

R

R H

O H H M4

1

4

R

H 3 O R

R2 H

H H P2

O

1

R

R

4

3 R O

H

H

R2 O

1

R

HH P4

Scheme 2.3. Diastereomeric Pand M conformers of arene metabolites 13–17 and the definition of torsion angles α, β, and ω.

can be either syn or anti . This makes the number of available conformers up to eight (M 1–M 4, P 1–P 4), and the number can still be higher if one includes the rotamers due to the presence of nonspherical substituents in the ring. Contrary to 1,3-cyclohexadiene derivatives, in the case of cis-ketodiols 15–17 the conformational equilibrium is strongly affected by solvent polarity. Calculations performed at MP2/Aug-cc-pVTZ//B3LYP/6-311++G(2d,2p) level and with the use of a PCM model led to a conclusion that in polar surroundings a conformer of type P 4 dominates, in contrast to 1,3-cyclohexadiene derivatives, where conformer P 4 does not participate in conformational equilibrium even to a small extent [46–48]. It should be noted that X-ray diffraction analysis may provide quite different results, since in the crystal lattice the most important structure-determining factor is the possibility of formation of intermolecular hydrogen bonds. Thus, in the case of fluorinated ent-14e the molecular structure found in the crystal corresponds to conformer M 4. In contrast to M 1, M 2, and P 1 are calculated at the B3LYP/6-311++G(d,p) level as the lowest-energy

Figure 2.7. Potential energy surface calculated at the B3LYP/6-311++G(d,p) level for P- and M-helical conformers of fluorinated derivative 14e (a) and X-ray diffraction determined structure of ent-14e (b).

50

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(a)

(b)

13b 13d

2 OH OH

Dioxygenase TDO-O2

OH

Dioxygenase TDO-O2

OH

0 Δe −2 13c

−4 minor

major

−6

13e 220

13a 13b 13c 13d 13e

13a 240

260

280

300

320 nm

Figure 2.8. (a) Empirical rule correlating the stereochemical course of arene cis-dihydroxylation with the relative size of substituents. (b) ECD spectra of cis-diols 13a-13e measured in cyclohexane solution.

conformers (Figure 2.7) for isolated molecule 14e [47]. The calculated preferred conformations of dihydrodiols substituted at the positions C3 or C6 by trifluoromethyl group are strongly affected by the presence of sequence of hydrogen bonds Oeq H · · · Oax H · · · FCF2 , which may shift the conformer equilibrium into such a conformer. The CD spectra measured in nonpolar solvent for a number of 3-substituted cisdihydrodiols 13a–13e differ markedly in the sign of the diagnostic long-wavelength spectral region (Figure 2.8b). This suggests that either the absolute configuration assigned according to Figure 2.8a is wrong, or the absolute configuration at C1 carbon atom is the same for the whole series and the cis-dihydrodiols 13a–13e differ in chiroptical properties [46]. Extensive computational study on the structure and chiroptical properties of arene metabolites led to a conclusion that the presence of substituents X and/or Y, as well as the hydroxy groups, is the decisive factor in shifting the P ↔ M conformer equilibrium in one or another direction, and this determines the sign and magnitude of the longwavelength diene Cotton effect. The substituent effect on the ECD spectra of cis-diols 13–14 may be ordered as follows: CN > Br > CH3 > CF3 > F = H. This study indicates that no simple empirical model, including the DHR and the AACR, can fully account for the experimental CD data of all cis-dihydrodiols. In relation to the Diene Helicity Rule, rotatory strength contribution from helical cyclohexadiene chromophore is in any case weak and, in certain cases (Br, CN substituents at C3), does not correlate with the sign of diene torsion angle. The failure of the AACR results from mutually canceling contributions due to allylic hydroxy groups, both axial and equatorial, in conformers of P and M helicity. Deceptively simple cis-ketodiols 15–17 are in fact complex systems, due to their conformational equilibria. Circular dichroism spectra measured in acetonitrile solutions and calculated at the PCM/B2LYP/Aug-cc-pVTZ level are quite similar, regardless the enone structure and in the case of cis-ketodiols 15 exhibit a positive/negative/positive sequence of Cotton effects. However, in the case of 16 and 17 the sign of the longwavelength nC=O –πC=O * Cotton effect appears affected by the substituent in C6 position, but the patterns of the second πC=C –πC=O * and the third nOH –πC=O * Cotton effects are similar to that measured and calculated for 15. Surprisingly, detailed inspection of the ECD spectra calculated for individual conformers of 15a shows the same pattern, but not the magnitudes, of Cotton effects [41]. Rotatory strengths calculated for M -helical conformers remain in agreement with DHR and also with the alternative AACR, which

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assigns a dominant contribution to the axial hydroxy group at the allylic position. On the other hand, ECD spectra calculated for the P conformers, which dominate in the conformational equilibrium, are not in agreement with the empirical rules and show much higher magnitudes than those calculated for their M -helical counterparts. In the case of P -helical conformers a dominant contribution is assigned, rather unexpectedly, to the equatorial hydroxy group [41]. With the use of modern computational approach, Kwit et al. estimated the effect of structural factors on the rotatory strengths of electronic transitions by replacing systematically the hydrogen atoms at C3–C6 in (P )-2-cyclohexenone with either a polar hydroxy group or a nonpolar methyl group. As expected, the dominant role of substituent at C4 over substituents in either C5 or C6 positions is clearly visible, regardless their electronic nature and orientation. For the πC=C –πC=O * transition of monosubstituted (P )2-cyclohexenones the substituent contributions, including signs, are as follows: 4eq-OH (−), 4ax-OH (+), 4ax-Me (+) > 4eq-Me (−), 5ax-OH (−), 6eq-OH (+) > 5ax-Me (+), 6ax-Me (−) > 5eq-OH (+), 5eq-Me (−), 6eq-Me (+), 6ax-OH (+). Another striking result revealed for the first time is that the sign of the principal πC=C –πC=O * transition Cotton effect is less dependent on the enone nonplanarity (angle ω) and more dependent on nonplanarity of the C=C bond [41, 46b]. The models of ECD contributions for arene metabolites of mono-substituted 1,3cyclohexadiene and cis-ketodiol type are proposed shown in Figure 2.9. These models redefine the importance of structural factors previously considered as responsible for chiroptical properties of dienes and enones. Nonplanarity of the C=C bonds, usually neglected, is of equal or even higher importance compared to the distortion of the whole conjugated chromophore from planarity.

2.2. DICHALCOGENIDES: MOLECULES WITH INHERENTLY CHIRAL CHROMOPHORES Dichalcogenides are unique examples of molecules with an inherently chiral chromophore. The dichalcogenide Ch–Ch moiety (Ch = S, Se, or Te) exists in the form of two helical enantiomeric P /M conformations. Both enantiomeric conformers give opposite Cotton effects that cancel in the experiments. When the dichalcogen moiety is placed in a chiral surrounding, the conformers are no longer of equal energy and this (a)

(b)

Figure 2.9. Estimated bond contributions to the rotatory strength R (×10−40 cgs units) of the lowest-energy π − π * electronic transition of arene metabolites of (a) the type (P)-1,3cyclohexadiene derivative (a) and (b) the type (P)-2-cyclohexenone derivative.

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Scheme 2.4. Full interconversion scheme for dichalcogenide R–Ch–Ch–R conformers.

gives rise to the Cotton effects in the CD spectra. The conformer equilibrium involves transition states (TS) of either s-cis or s-trans structure in which the Ch–Ch moiety is planar (Scheme 2.4). C–S–S–C torsion angle (ω) for dimethyl disulfide in the gas phase was reported in the review as 90.44◦ (±0.45◦ ) [50]. Values 85◦ , 82◦ , and 87◦ were found for dimethyl diselenide based on the microwave [51] and vibrational spectra [52] as well as on the electron diffraction data [53]. The data from low temperature X-ray diffraction of dimethyl dichalcogenides are shown in Table 2.2. For benzene solution the values of torsion angle ω calculated from the dipole moment measurements (68.5 ± 2.0◦ for Me2 S2 , 65.4 ± 4.0◦ for Me2 Se2 , 35.9 ± 10.0◦ for Me2 Te2 ) [55] are much smaller than those found in the gas phase. This difference was explained by interactions between the solvent and the solute molecules. Data found for the diphenyl dichalcogenides in the crystal state and for benzene solution are more coherent— that is, 96.2◦ vs. 81.3◦ for Ph2 S2 , 97.1◦ vs. 62.6◦ for Ph2 Se2 , 88.5◦ vs. 84.0◦ for Ph2 Te2 [55]. Skewed structure of dichalcogenides is explained by the gauche effect, which was introduced for disulfides [50] but which can be extended to diselenides and ditellurides. In the dichalcogenide molecule the nonbonding electron pairs that reside on the p orbitals perpendicular to the Ch–Ch bond are partially overlapping. The destabilization due to the lone-pair–lone-pair repulsion in orthogonal position is reduced in nonplanar cisoid and transoid conformations of the dichalcogenide molecule. Hyperconjugation by which the p lone pairs of the chalcogen atoms are overlapping with the σ * molecular orbitals of the R–Ch bonds located in the same plane provides additional stabilizing effect [56]. Rotation barrier for the interconversion between enantiomeric conformers of dichalcogenides is low enough to allow free rotation of the Ch–Ch bond in acyclic molecules at room temperature (Scheme 2.4). Due to the repulsion between substituents on the chalcogen atoms, s-trans transition state is of lower energy. For S–S bond the rotation barrier is estimated in the range 6.8–13.2 kcal mol−1 [57–61]. Calculations (including MP2 method) give the value ca. 5 kcal mol−1 through the s-trans transition TAB L E 2.2. X-ray Data for Dimethyl Dichalcogenides Me2 Ch2

˚ Ch–Ch [A]

˚ C–Ch (A)

ω (degrees)

Me2 S2 Me2 Se2 Me2 Te2

2.03 2.31 2.71

1.80 1.94 2.15

86 85 90

Source: Data taken from reference 54.

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state and 9 kcal mol−1 through the s-cis transition state. [50, 62, 63]. Calculated rotation barrier for H2 Se2 is lower (4.47 and 6.21 kcal mol−1 , respectively). Substitution with the phenyl group does not change significantly the magnitude of the rotation barrier which was calculated for diphenyl disulfide, diselenide, and ditelluride as 8.6, 8.2, and 5.3 kcal mol−1 through a s-cis transition state and 5.4, 5.2, and 3.7 kcal mol−1 through a s-trans transition state [64]. It is seen that the rotation barrier is lowered with the increase of the length of the Ch–Ch bond (see Table 2.2). A model for interpretation of the CD spectra of disulfide chromophore was proposed by Bergson [65, 66] and later verified by Linderberg and Michl [67] and by Woody [68]. Woody has shown the dependence of the rotation strength on the torsion angle of disulfide chromophore. In this model the sign of the long-wavelength Cotton effect obeys a quadrant rule (Figure 2.10). Bergson’s model due to its simplicity has been very successful. Recent study of the disulfide transitions using advanced computational methods led to similar conclusions [69–71]. As molecular structures of dichalcogenides are similar, this rule can be easily extended to diselenides and ditellurides [70–73]. It has to be noted that the longwavelength Cotton effect is of differing nature at different values of the torsion angle. The two lowest-energy electronic transitions are described as nA –σ * and nB –σ *. In the range 0◦ –90◦ , nA is a HOMO whereas nB is HOMO(−1). The highest energy difference between nA and nB orbitals is calculated for values of the dichalcogenide torsion angle. This difference diminishes at around 90◦ where nA and nB orbitals are almost degenerate. For the torsion angle greater than 90◦ , nB becomes HOMO and this leads to a change of the rotational strength. Similar switch of orbital positions takes place at −90◦ (Figure 2.11) [71, 72]. The first attempt to experimental study of chiroptical properties of dichalcogenide chromophore was made by Djerassi et al. [74], who recorded the ORD spectra for cystine and selenocystine. They observed negative Cotton effects at 250 and 290 nm, respectively. Ringdahl et al. [75] have found a long-wavelength Cotton effect at around 320 nm in the ECD spectra of selenocystine Other examples of CD spectra are provided by 2,2-dithioand 2,2-diseleno derivatives of propionic acid [76, 77]. It was expected that the CD spectroscopy based on the disulfide chromophore will find application in the analysis of protein structure. However disulfide CD bands in proteins are difficult to identify since the average number of disulfide bonds in proteins is low and the CD band originating from

0° −C.e.

+C.e.

180°

90°

+C.e.

Δe 0

−C.e. −90° −180

−90

0

90

180

Torsion angle R-S-S-R

Figure 2.10. Relation between the torsion angle in R–S–S–R disulfides and observed sign of the long-wavelength Cotton effect.

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l [nm] 480

Rotational strength (R)

20

460 10

440 420

0

400

−10

360 340

−20

Figure 2.11. Rotatory strength (R ×10−40 cgs units,

320

solid line) and wavelength (dashed line) of the long-wavelength transition for dimethyldiselenide. (Data from reference 72.)

380

0

30

60

90

120

150

Dihedral angle C-Se-Se-C

180

the disulfide chromophore is often overlapped by the CD bands originating from aromatic residues, as well as from the amide chromophore. Laur [78] presented the CD spectra of rigid cyclic (9S , 10S )-trans-2,3-dithiadecalin (18a) and (9S ,10S )-trans-2,3-diselenadecalin (18b) and open-chain disulfide (19a), diselenide (19b), and ditelluride (19c) substituted by (S )-2-methylbutyl groups (Figure 2.12). For rigid trans-decaline derivatives (18a, 18b) in a chair–chair conformation, C–Ch–Ch–C bond forms a left-handed (M ) helix. The long-wavelength Cotton effects for 18a and 18b are negative, in direct correlation with the twist direction of the helix. Due to distortion of the dichalcogenide chromophore from the optimum 90◦ value to ∼60◦ , the position of the UV absorption bands and consequently of the Cotton effects is red-shifted by around 40 nm. The torsion angle of the open-chain derivatives 19 is not confined to just one value, so it is expected that these compounds exist as a mixture of freely interconverting diastereoisomers with the torsion angle C–Ch–Ch–C around 90◦ or −90◦ . A small energy difference between distereoismers due to steric repulsion between the alkyl chains leads to a small difference in their population and to the rise of small, but nonzero, Cotton effects. Indeed, the observed Cotton effects are about 30–50 times lower than those observed for trans-decalin 18.

0.4

4

0.2

2

H Ch Ch H 18 a, Ch = S b, Ch = Se

Ch Ch

19 a, Ch = S b, Ch = Se c, Ch = Te

0 Δe

Δe 0.0 −0.2

18b 19b

−0.4 250

300

350

400

450

−2 −4

500 l[nm]

Figure 2.12. ECD spectra of the diselenadecalin (18b) (right-hand scale) and diselenide (19b) (left-hand scale) in acetonitrile. (Redrawn using the data from reference 78.)

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Further examples are the CD spectra of sugar-substituted diselenides and ditellurides [79]. The authors characterize the observed bands but do not consider the effect of chiral substituents on the dichalcogenide conformation. Recently, the CD spectra of diglycosyldisulfides and diselenides were reported, and a good agreement between the experimental and the calculated CD spectra of di(teraacetylated glycosyl)diselenide using the TDDFT method was obtained [71]. The CD spectra of several symmetrical diselenides with chiral alkyl substituents allowed us to determine the effect of chirality of the alkyl groups on the chirality of the diselenide moiety with the aid of TDDFT calculation. Thus, the S configuration of the carbon atom adjacent to the Se atom correlates with positive long-wavelength Cotton effect. This effect was explained by a model based on steric repulsion between bulky substituents [72]. The CD spectra measured for the dichalcogenides substituted with the same chiral alkyl groups show a shift of the position of the long-wavelength n –σ * Cotton effects toward a longer wavelength and a significant reduction of the Cotton effect intensity on going from S to Te. This trend is observed in the CD spectra of di[(S )2-methylbutyl] derivatives of dichalcogenides [78] and also for dineomenthyl derivatives 20 (Figure 2.13). The decrease of the Cotton effect intensity in this series is a result of elongation of the chalcogen–chalcogen and chalcogen–carbon bonds, as shown in Table 2.2, which causes significant reduction of steric repulsion between the substituents and hence lowering of free energy difference between the diastereomeric conformers of dichalcogenides of M and P helicity. Contemporary procedure for the analysis of ECD spectra of chiral dichalcogenides requires computation of conformer distribution and then the average CD spectra [71, 72, 80]. However, from a practical point of view the information about helicity of the dichalcogenide moiety can be obtained directly from the sign of the Cotton effect due to the long-wavelength nA –σ * transition. Higher-energy nB –σ * transition usually overlaps with other transitions and may be not distinguishable in the observed CD spectra. Orbitals nA and σ * involved in the long-wavelength transition are localized on the dichalcogenide moiety and are not affected by alkyl substituents. A further simplification of the analysis of rotational strength of complex chiral dichalcogenides can be based on the data obtained for dimethyl dichalcogenide. Calculation of the whole system seems justified only for structures with the C–Ch–Ch–C torsion angle very close to 90◦ (or −90◦ ) where nA and nB are almost degenerate and their exact energy may depend on the substituents in the molecule.

1.6 Ch Ch

1.2 Δe

20 a, Ch = S b, Ch = Se c, Ch = Te

20a 20b 20c

0.8 0.4 0.0 250

300

350

400

450

500

550 l[nm]

Figure 2.13. ECD spectra of the dineomenthyl disulfide 20a, diselenide 20b, and ditelluride 20c in cyclohexane solution.

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2.3. THE AMIDE CHROMOPHORE IN BI- AND POLICYCLIC β-LACTAM RING SYSTEMS The amide chromophore has been recognized as a basic unit in a variety of bioactive compounds. Among them the β-lactam family of antibiotics represents some of the most clinically relevant antibiotics known [81–84]. This is attributable to their broad spectrum of antibacterial activity and a relatively low level of toxicity [83, 85]. To connect the biological activity with a defined stereochemistry of β-lactams, many research groups were engaged in the analysis of their chiroptical properties [86–99]. In the case of monocyclic β-lactams the planarity of the amide chromophore was demonstrated [90, 96, 99, 100]. The assumption of planarity of this chromophore has allowed to explain many features of protein structure. The (3R, 4S )-3-phenoxy-4-vinylazetidin-2-one presented below is an example of monocyclic β-lactam with a planar β-lactam moiety (Figure 2.14). The O=C2–N1–C4 torsion angle equal to 177.28◦ , derived from its X-ray structure, clearly demonstrates the planarity of amide chromophoric system. According to Moscowitz [101–103], such a planar amide chromophore has to be categorized as inherently achiral but chirally perturbed by its neighborhood. Therefore, one has to take into consideration the chiral perturbation (mainly through space), and this is usually achieved by the help of different sector rules. However, based on both the X-ray and computational studies, it has been demonstrated that in small cyclic peptides and medium-sized lactams the amide chromophore can be slightly nonplanar [94, 97, 104–108]. The skewness of the amide unit causes its inherent chirality, and thus such a nonplanar chromophore now belongs to the Moscowitz inherently chiral class of chromophores [101–103]. These chromophores are characterized by very strong CD effects mainly governed by their chirality. It means that the contributions from all the other atoms and groups may be neglected, so that the rules correlating the stereostructure with CD data can be classified as “chirality rules” or “helicity rules.” As a result of the extensive studies of lactam chromophores, several sector and helicity rules for the correlation between the structure and Cotton effect (CE) signs of n –π* transition have been established. Among them the β-lactam octant rule [90, 97, 109], Weigang’s sector rule [100], a modification of Weigang’s lactam rule [99], and Ogura’s [91] and Wolf’s [96] helicity rules can be mentioned. These empirical rules correlate the sign of the CE designated as the n –π * transition of the β-lactam chromophore with the absolute configuration of monocyclic azetidinones. The 4π electrons and two free electron pairs of the amide chromophore are located on the carbonyl oxygen atom. The molecular orbital (MO) occupied by the highest energy electron pair is largely (80–90%) located on the carbonyl oxygen and is a 2p orbital. Its axis is located in the plane of the amide group and is perpendicular to the direction of the

Figure 2.14. Crystal structure of (3R, 4S)-3-phenoxy-4-vinylazetidin-2-one. Thermal ellipsoids are shown at 50% probability level.

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C=O bond. The second pair of free electrons, with a much lower energy, occupies orbitals extensively overlapping with d orbitals. This orbital is of both 2s and 2p character, and its axis is directed along the C=O bond (Figure 2.15). Four electronic transitions can theoretically occur within the amide chromophore, namely π0 –π * (around 190 nm), π+ –π * (around 140 nm), n –π * (around 220 nm), and n  –π *. The last transition is predicted theoretically but has not been observed experimentally. Amide transition π0 –π * is electrically allowed (εmax ∼ 104 M−1 cm−1 ), and the direction of the electric transition moment μ approximately defines a line connecting the N and O atoms (Figure 2.15). The n –π* transition is electrically forbidden (εmax ∼ 102 M−1 cm−1 ); however, it has a large magnetic transition moment m directed along the line passing through the C=O bond (Figure 2.15). In penicillins and cephalosporins the β-lactam unit is nonplanar and its nitrogen atom is pyramidal. The relationship between an (R) AC at the ring junction carbon atom and the positive sign of the lowest energy CE attributed to the amide n –π * transition which occurs in penicillins and cephalosporins at around 230 nm and 260 nm, respectively, was well-documented [86, 89, 93, 104, 110–112]. There is a nontrivial question whether the same regularity is valid for the oxa- and carbaanalogues of penicillins and cephalosporins. To clarify this, a study was undertaken to establish a correlation of the absolute stereostructure of a variety of β-lactam derivatives with the sign of the amide n –π * transition in their CD spectra. In addition, to rationalize the experimental results and to find out the scope and limitations of observed regularities, the calculation of chiroptical properties of β-lactam antibiotic analogues at B3LYP/TZVP level of theory were performed.

2.3.1. General Structures of Penicillins and Cephalosporins The chiroptical properties of oxacephams have been studied on variety of bi-, tri-, and tetracyclic oxacephams [113, 114]. Some of them, namely oxacephams 21–29, are presented in Chart 2.1 while the CD spectra of representative members of this group are shown in Figure 2.16. As can be seen in Figure 2.16, the investigated compounds exhibit, generally, two CD bands at around 220 and 190 nm. The 220-nm CD band can be assigned to the n –π * electronic transition of β-lactam unit, whereas the band at around 190 nm corresponds (a)

(b) π* O C μπ→π*

mn→π*

π*

π0

n→π* π0→π* n π0 n′

N

C N

n

C N

n′

π+ π+

Figure 2.15. (a) Molecular orbitals and electronic transitions within the amide chromophore. (b) Directions of the magnetic m and electric μ transition moments defining the electronic transitions within the amide system.

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Chart 2.1.

(a)

(b)

Figure 2.16. (a) CD spectra of selected oxacephams 21 (——), 26 (· · ·), and 27 (– – –) recorded in acetonitrile. (b) Crystal structures of compounds 26 and 28 with the crystallographic numbering scheme. Thermal ellipsoids are shown at 50% probability level.

to the π –π * excitation of the same unit. With respect to the sign of band at 220 nm, the oxacephams fall into two different groups. In the first group, consisting of compounds with (6R) absolute configuration, the sign of this CD band is positive, whereas in the second group, represented by compounds with (6S ) absolute configuration, this band is negative [113]. Based on that data, additionally corroborated by the specifics of their synthetic pathway and the X-ray analysis obtained for compounds 26 and 28 [113], it can be unambiguously established that the (6R) AC corresponds to a positive CE at around 220 nm whereas (6S ) AC corresponds to a negative sign of the same CE.[113, 114] The data indicate the nonplanarity of the amide chromophore and the pyramidal configuration of the amide nitrogen in the studied oxacephams. Thus, the β-lactam chromophore is inherently chiral, and the sense of its chirality is expressed as a right or left helicity that correlates well with the AC at C6 carbon atom. The helicity appears to be independent of the kind and the position of other substituents present in the oxacepham moiety [113, 115, 116].

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The nonplanarity of the chromophore excluded application of the known sector rules for the prediction of the n –π * CE sign, since these rules were developed for the planar amide chromophore only [90, 97, 100]. In such case, the helicity rule should, in principle, be able to correlate the chiroptical properties and structure. However, for the studied oxacephams a breakdown of Ogura’s [91] and Wolf’s [96] helicity rules was found [113]. The spiral rule [107, 108] based mostly on the CD results obtained for the nonplanar α-lactams and monocyclic β-lactams that correlates the positive/negative torsional angle O=C–N–C with a negative/positive n –π * CE, respectively, in general, was valid for oxacephams studied. However, it was found that the absolute configuration of the bridgehead carbon atom determines the sign of the O=C–N–C torsional angle. Therefore, to connect directly the AC of this carbon atom with the sign of the CE due to n –π * transition observed around 220 nm in oxacephams, a simple helicity rule has been proposed [113]. According to this rule, a positive sign of the 220 nm CE corresponds to an (R) AC at the bridgehead carbon atom, whereas a negative sign of the same CE is related to a (6S ) AC. The rule was experimentally demonstrated to be correct for a variety of oxacephams [114–119]. The DFT conformational analysis of oxacepham 21 at B3LYP/TZVP level of theory indicates the skewness of the β-lactam unit by negative O9–C8–N1–C2 and O9–C8–N1–C6 torsion angles of −24.1◦ and −175.7◦ , respectively. The six-membered ring in the computed lowest energy conformer of oxacepham 21 is in a chair conformation with β-lactam ring in energetically favorable equatorial position. Furthermore, it has been found that the positive long-wavelength CE around 220 nm (Figure 2.16) is in an excellent agreement with the TD-DFT simulated positive CD band of 21 (Figure 2.17a) and also follows the helicity rule. The band at 220 nm has mainly the character of an amide n(O)–π * transition. In summary, the agreement between simulated and experimental CD spectra confirms not only the absolute configuration and conformation of 21 but also the validity of helicity rule for this oxacepham. The same helicity rule works very well also for cephams [118], as demonstrated in Figure 2.17b with cepham 30 as representative example of this group of compounds. As expected for the (R) AC at the ring junction, cepham 30 exhibits, similarly to oxacephams, a positive CE at around 220 nm. The six-membered ring of 30 is in a chair conformation, equally as in 21. Similarly to previously described cephams [118], the conformational flexibility in 30 is limited to the side-chain substituent at C7. The simulated CD spectrum (a)

(b)

Figure 2.17. (a) Simulated at B3LYP/TZVP theory level CD spectrum of 21 (– – –) compared with its experimental CD spectrum (——) and calculated structure of the lowest-energy conformer of 21. (b) Simulated at B3LYP/TZVP theory level CD spectrum of 30 (– – –) compared with its experimental CD spectrum (——) and calculated structure of the lowest energy conformer of 30. The vertical bars represent calculated at B3LYP/TZVP level rotatory strengths. Protons are omitted for clarity.

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of lowest energy conformer is in a good agreement with experiment (Figure 2.17b). The positive band at 212 nm is caused by transitions out of the amide n(N) into the amide n(O)π* orbital, as well as by transitions out of the sulfur lone pair into the same acceptor orbitals. The negative excitations at around 235 and 207 nm result mainly from the sulfur lone pair transitions, with some admixture of the amide n(O) as donor orbital. With a torsion angle O=C–N–C6 equal to −175◦ for 30, the helicity rule is satisfied. The applicability of the helicity rule was also tested for carbacephams [118]. Similarly to the earlier discussed cephams and oxacephams, two bands are present in their CD spectra in the 280- to 190-nm spectral range. The long-wavelength band assigned to the n –π * excitation occurs at around 220 nm while the second band, of the π –π * origin, appears at around 200 nm. As shown in Figure 2.18, carbacephams with (6R) configuration possess a positive CE at around 220 nm while carbacephams with an (S ) AC at C6 have a negative CE in the same spectral range. The signs are exactly what one would expect to see applying the helicity rule. Thus, the CD spectra of discussed compounds conform to the rule developed for oxacephams. The presence of isolated double bond in compounds 32 and 33 does not influence their CD spectra, which appear similar to their saturated counterpart 31 (Figure 2.18a). Completely different situation occurs in the case of compounds 34 and 35 where a conjugated double bond is present. The presence of such an α,β-unsaturated amid chromophore, defined also as cephem, causes a red shift (by about 30–40 nm) and the crucial CD band arises, depending on actual substitution, at 250 nm or 260 nm (Figure 2.18b). Except for other differences, compounds with substituents at C2 absorb at longer wavelength when compared to those unsubstituted at this carbon atom. This regularity is independent of the type of heteroatom present at position 5 in a six-membered ring fused with an azetidinone ring. Additional examples, including the 7-aminocephalosporanic acid, the active nucleus for the synthesis of cephalosporins and intermediates, and its derivatives, can be found in the recently published review [119]. The model carbacepham 31 demonstrates the impact of conformational factors on the CD spectra. As predicted by DFT calculations, the six-membered ring of the lowestenergy conformer of this carbacepham exists in a chair conformation [118, 119]. Note also that the only chromophore of 31 that absorbs above 180 nm is the amide group of the azetidin-2-one ring. It is thus very unexpected that despite this apparent structural simplicity, the computed CD spectrum of the lowest-energy conformer of 31 displays little, if any, resemblance with the experimental CD spectrum, shown in Figure 2.19. The computed amide n(O)–π * CD band is considerably blue-shifted, while the amide n(N)–π ∗ band is not only notably shifted to a higher-energy region but even has the wrong sign.

Figure 2.18. (a) CD spectra of carbacephams 31 (——), 32 (– – –), and 33 (· · ·) recorded in acetonitrile. (b) CD spectra of carbacephems 34 (——), 35 (·– · – · –·) and oxacephem 36 (– – –) recorded in acetonitrile.

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Figure 2.19. Simulated CD spectrum of carbacepham 31 at 0 K (– – –) and

5

OH H H

20

N

10

O

31

0

0 −5

−10

−10

−20 190

Rvel⋅10−40 cgs

Δε (M−1cm−1)

10

350 K (· · ·) compared to experiment (——). The 0 K curve corresponds to the optimized PBE0/SV(P) conformer of 31 shown on the right. (From J. Frelek, P. Kowalska, M. Masnyk, A. ´ Kazimierski, A. Korda, M. Woznica, M. Chmielewski, F. Furche, Circular dichroism and conformational dynamics of cephams and their carba and oxa analogues, Chem. Eur. J. 2007, 13, 6732–6744. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.)

230 210 250 Wavelength (nm)

In order to investigate the impact of thermal effects on the CD spectrum, molecular dynamics (MD) simulations of 31 at 350 K were carried out and demonstrated that the saturated six-membered ring system shows a considerable flexibility. The results of the MD simulations revealed that the CD spectrum is highly dependent on the conformation of both the four- and the six-membered rings, with sign inversions occurring for both bands at various points of the MD simulation [118]. The simulated CD spectrum at 350 K compares much better with the experiment than the 0 K spectrum (Figure 2.19). Both bands are broadened and red-shifted compared to the 0 K spectrum and have the correct sign. This result is not surprising because the experimental CD spectra were measured at room temperature and thus represent a thermal average over the CD spectra of many different conformations. This effect more clearly reflects the spectrum at 350 K, taking into consideration all possible conformations. On the basis of the aforementioned discussion, it can be stated that regardless of the presence of carbon, oxygen, or sulfur atom at 5 position of the six-membered ring, all cepham analogues absorb in the same absorption range. The sign of the decisive CE at around 220 nm depends on the AC at C6 only. Thus, oxacephams, cephams, and carbacephams with (6R) AC display a positive CD band in this spectral region, whereas

(a)

(b)

Figure 2.20. (a) CD spectra of penicillin V (38) (– – –) and penam 39 (——) recorded in water and acetonitrile, respectively. (b) Simulated at B3LYP/TZVP theory level CD spectrum of lowestenergy conformer of 39 (– – –) compared with its experimental CD spectrum (——) and calculated structure of lowest energy conformer. The vertical bars represent calculated at B3LYP/TZVP level rotatory strengths. Protons are omitted for clarity.

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their counterparts with (6S ) AC exhibit a negative sign of the n –π * CE in the same spectral range. Therefore, it can be concluded that all those groups of compounds are subject to the helicity rule. In the case of conformationally flexible compounds, however, the additional theoretical support for the experimental data is recommended. The penams also conform perfectly to the helicity rule. As can be seen in Figure 2.20, the penam representatives 38 (penicillin V) and 39 possess a positive CE in the longwavelength part of the spectrum in accordance with the (R) stereochemistry at the ring junction. The shift of the CD maxima into the lower-energy spectral region by ≈10 nm is related to the penam-constrained backbone. The bicyclic system of penams is relatively rigid, and its conformational lability is largely restricted to the side-chain substituent at C6 carbon atom. Its relatively unrestricted mobility is evident, considering the results of conformational search for penam 39 for which seven conformers in the energy range of 2.8 kcal mol−1 are found. In respect to the five-membered ring conformation space, however, only two conformers exist. In the first one, populated at the conformational equilibrium over 88%, the five-membered ring is in an envelope conformation with C2 carbon atom below the average plane passing through the ring (Figure 2.20). In the second conformer, the five-membered ring adopts again an envelope conformation but with the sulfur atom above the ring plane. Beyond these two, the other individual conformers show differences only in the conformation of substituent at C6 carbon atom which demonstrates its relatively substantial flexibility. The computed O=C–C7–N1–C2 and O=C–C7–N1–C5 torsion angles for all conformers of penam 39 are calculated to be negative, thus providing corroborating evidence for the nonplanarity of amide chromophore. In simulated at B3LYP/TZVP theory level ECD spectra the sign of the lowest-energy excitations is positive for all conformers, as predicted by the helicity rule for (5R) AC. The positive CE at around 240 nm is in accordance with both the helicity rule and the calculations. Based on this we can conclude that for penams the requirements of the helicity rule are met, and therefore the rule can be successfully applied to this group of compounds. Oxaanalogues of penicillins, commonly referred to as clavams, exhibit the same shape of the CD spectra as oxacephams and penams (Figure 2.21). The positive sign of the decisive CD band arising at around 240 nm in clavam 40 corresponds to its (R)configuration at C5, and the negative one corresponds to the (S )-configuration of the ring junction in its local enantiomer 41. This finding validates the proposed rule for clavams too. As can be seen in Figure 2.21a, the shape of CD spectra of clavams corresponds very well with the shape of spectra of natural penicillins. (a)

(b)

Figure 2.21. (a) CD spectra of clavams 40 (——) and 41 (· · ·) recorded in acetonitrile compared with the CD spectrum of penicillin V (38) (– – –). (b) Simulated at B3LYP/TZVP theory level CD spectrum of lowest energy conformer of 42 (– – –) compared with experimental CD spectrum (——) and calculated structures of its two lowest-energy conformers. Protons are omitted for clarity.

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A more complex situation is encountered when considering the spectra of clavams with an additional, interfering chromophore in the molecule such as phenyl, which substantially perturbs the electronic structure of the system and therefore significantly influences the CD spectra. However, the recent study on this subject demonstrated that even in the case like that, the requirements of helicity rule have been met and the rule can be successfully applied to correlate the structure and the respective chiroptical properties for unsubstituted and substituted clavams as well [120]. In the ECD spectra of the representative members of carbapenams 43–45, the 240nm ECD band is negative for compounds 43 and 45 with (5S ) AC and positive for 44 with (5R) AC, as predicted by helicity rule (Figure 2.22). Even the presence of interfering chromophores in compound 45 (i.e., phenoxy group and double bond) does not alter the relationship between the sign of 240-nm CD band and absolute configuration of the C5 carbon atom [121]. Similarly to clavams and penams, the bicyclic system of carbapenams is relatively rigid and its conformational lability is largely restricted to substituents at the C6 carbon atom and in the five-membered ring. Although for carbapenam 43 nine conformers were found in the energy range of 2.4 kcal mol−1 , in respect to the five-membered ring conformation space, however, there were only two distinct conformers present. In the first one, populated in the conformational equilibrium over 75%, the five-membered ring is in an envelope conformation with C4 carbon atom below the average plane passing through the ring. In the second conformer the five-membered ring adopts a halfchair conformation with C2 and C3 carbon atoms located above and below the ring plane, respectively (Figure 2.22). Beyond these two, the other individual conformers show differences in the substituent at C6 carbon atom which demonstrates its relatively substantial flexibility. The average ECD spectrum shows very close agreement between experiment and theory, thus providing evidence that these conformers are present in solution under given conditions (Figure 2.22). The negative CE at around 240 nm is in accordance with both the helicity rule and the calculations [121]. In order to show that the nonempirical correlation between chiroptical properties and stereochemistry is not restricted specifically only to very simple cases, more complex

Figure 2.22. CD spectra of carbapenams 43 (——), 44 (·–·–·–), and 45 (– – –) recorded in acetonitrile and simulated at B3LYP/TZVP theory level CD averaged spectrum of 43 (· · ·) as well as lowest-energy envelope (E) and half-chair (H-C) conformers of 43. Protons are omitted for clarity.

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compounds such as carbapenam 46 which incorporates a conjugated diene chromophore at C4 in addition to the amide chromophore have been studied. Although the sign of observed at 240-nm CD band in 46 apparently is consistent with the helicity rule, CD contributions to this band of other electronic transitions can play a decisive role (Figure 2.23). In fact, the TDDFT calculations brought some more insight about the complex UV and CD relationship in carbapenam 46. The five-membered ring in this compound is nearly planar with a nitrogen atom slightly deviated from the plane formed by remaining four carbon atoms. The conformational differences in 46 are limited mostly to the conformation of the side chain. In all four conformers calculated for 46, the O8–C7–N1–C2 and O8–C7–N1–C5 torsion angles are negative, and thus helicity rule requirements are met. Consequently, the simulated CD spectrum for these geometries showed an expected positive band at ∼240 nm (Figure 2.23) [121]. The analysis show that the electronic transitions from the amide and diene chromophores are mixed and appear in approximately the same energy range. Thus, the longwavelength CD band is an admixture of the amide n –π * and diene π –π * excitations occurring at 240 nm and 252 nm, respectively (MO49 → MO∗ 52 and MO49 → MO∗ 51, respectively). Regardless of this complexity within the band at 240 nm, the positive sign of its component related to the amide n –π* excitation and its decisiveness in terms of the helicity rule are in accord with the rule. In addition, the agreement between the experimental and Boltzmann-averaged ECD spectra is very accurate and confirms both absolute configuration and conformation of carbapenam 46 [121]. It should be added that very recently the helicity rule was reformulated. The reason for this was the fact that presence of substituents in the vicinity of the ring junction may cause the change of AC descriptors of the bridgehead carbon atom from R to S , and vice versa. According to the CIP priority rules, such a change causes an allyl group at C4 in 46 whereas propionic acid methyl ester substituent attached to the same carbon atom in 45 does not. Therefore, to avoid misunderstandings, after reformulation the rule connects the sign of the n –π * amide transition with the d or l configuration, as defined by Wo´znica et al. [121].

(a)

(b)

Figure 2.23. (a) Simulated ECD and UV spectra of lowest energy conformer of carbapenam 46 (——) and experimental ECD spectrum of 46 (– – –). (b) Dominant contributions of MOs of particular excitations of carbapenam 46 lowest-energy conformer.

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As was mentioned before, the molecular dynamics (MD) simulations carried out for some carba- and oxacephams revealed a considerable flexibility of the saturated sixmembered ring and high dependency of the ECD spectra on the conformation of both the four- and the six-membered rings [113, 118]. In some cases this dependency resulted in a breakdown of the helicity rule caused by a change of the conformation of the pyranose ring from a chair to a boat. Therefore, the question arose about scope and limitations of the helicity rule. To answer this question, chiroptical properties of several model compounds with β-lactam ring fused to a seven-member ring were studied. These ringexpanded cephalosporin analogues 47–50 (Figures 2.24 and 2.25) were chosen due to their increased conformational flexibility in comparison with investigated earlier bicyclic β-lactams with six- and four-membered rings condensed together. In addition, a decrease of the skeletal strain energy expected for compounds in question may result in overall flattening of the system. Therefore, a subsequent breakdown of the helicity rule cannot be excluded. Up to four absorption bands are present in the ECD spectra of investigated compounds 47–49 in the spectral range of 185–300 nm (Figure 2.24). The band occurring around 220 nm attributed to the amide n(O)–π ∗ transition is of a particular interest because this band is the subject of the helicity rule. According to the helicity rule for compounds 47–49 belonging to the (7R)configurational series, a positive CD is expected, whereas for β-lactam ent 48 with (7S )-configuration a negative one is expected. In fact, in both cases opposite bands at around 215 nm were observed in disagreement with the helicity rule (Figure 2.24). The question arises whether compounds 47–49 constitute an exception or the rule itself is imperfect. A finding the reasons for this inconsistency appears undoubtedly very important considering the future applicability of the helicity rule. Among the factors that may play a role are the higher conformational flexibility of compounds 47–49 and/or a significant change in the geometry of β-lactam chromophore by adopting a planar conformation that does not obey the rule [113]. In order to throw light into the origin for observed deviations from the rule, TDDFT calculations were carried out for β-lactams 47 and 48 (Figure 2.24). In these cases, depending on the compound, the main ECD band is a composite of excitations out of the amide n –π * transition and transitions out of the sulfur or oxygen lone pairs into the same acceptor orbitals. In addition, the transitions out of the double-bond orbitals mix strongly with the amide n –π * transition. Some of the structures of conformers of (a)

(b)

Figure 2.24. (a) ECD spectra of β-lactams: 47 (· · ·), ent 48 (– – –); and 49 (——) recorded in acetonitrile. (b) Simulated at B3LYP/TZVP theory level average CD spectrum of 47 and 48 compared with experimental spectra (ε is the molar decadic absorption coefficient. Protons are omitted for clarity.

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(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 2.25. (a–g) Computed structures of conformers of β-lactam 50 and their simulated ECD spectra. (h) The Boltzmann-averaged spectrum compared to experiment (ε is the molar decadic absorption coefficient). Protons are omitted for clarity.

S O M E I N H E R E N T LY C H I R A L C H R O M O P H O R E S

β-lactams 47 and 48, calculated within the range of 3 kcal mol−1 , demonstrate presence of a small deviation from planarity of the amide chromophore manifested by a slight pyramidality of the amide nitrogen. Nevertheless, the negative sign of the decisive ECD band in both experimental and Boltzmann-averaged ECD spectra clearly demonstrates the breakdown of the helicity rule for these compounds. For saturated carbaanalogue 50, seven conformers within the energy range of 2.4 kcal mol−1 were found. To simplify and speed up the calculations, the large substituent at C8 carbon atom (OSit BuMe2 ) was substituted by a smaller OSiMe3 group. Both groups have very similar electronic properties, and the change should not significantly influence the electronic spectra. As can be seen in Figure 2.25, two of seven conformers obtained for 50, namely 3 and 4, have slightly skewed amide chromophore, whereas in the remaining five conformers the chromophoric system is planar. The population ratio of conformers with a planar and with a nonplanar chromophore in β-lactam 50 is approximately 4:1. Therefore, because the average ECD spectrum is, by definition, the sum of weighted contributions of all conformers, the negative sign of the decisive band should predominate, which is indeed the case (Figure 2.25h). However, a small positive ECD band at around 240 nm, originating from the twisted conformers 3 and 4, is present in both experimental and simulated spectra. The band at around 220 nm has primarily the character of an amide n –π * transition. The average ECD spectrum shows a very close agreement between experiment and theory, thus providing strong evidence that these conformers are present in solution under given conditions. The seven-membered ring in conformers of 50 is in a chair or a twist–chair conformation, and the azetin-2-one ring is in equatorial position at C7 (Figure 2.25). Beyond that, the individual conformers show conformational differences mostly within the substituent at C8 carbon atom. Independent evidence comes from the X-ray diffraction data for a thioanalogue of β-lactam 50, namely thiolactam 50a, the only one forming crystals suitable for such an analysis. The solid-state structural data clearly demonstrates the planarity of the amide chromophore and the chair form of seven-membered ring. Additionally, the dihedral angle C9–C7–C2–N1 equal to −2.0◦ points to the sp 2 hybridization of the amide nitrogen atom.

50

50a

In conclusion, the combined experimental and theoretical studies have shown that the ring-expanded β-lactam analogues do not follow the helicity rule since they do not belong to β-lactam type with nonplanar amide chromophore, for which the rule is valid. Therefore, these β-lactam analogues belong to the second class of Moskowitz’s chromophores [102, 103]—that is, to locally achiral but chirally perturbed. Thus, depending on the type of chiral perturbation originating from either chiral conformation of the ring incorporating achiral chromophore or from bonds closely connected to the chromophore, the chirality of the second or third sphere, respectively, should govern the CD of these compounds, as proposed by Snatzke [122]. According to this view, chirality or sector rules can correlate the stereochemistry around the chromophore with the sign of respective CD bands.

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ACKNOWLEDGMENTS The preparation of this chapter and the work of our research group (JF, AB, MW) described herein has been supported by the Ministry of Science and Higher Education, grants N N204 123507 and N N204 092935.

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3 ELECTRONIC CD OF BENZENE AND OTHER AROMATIC CHROMOPHORES FOR DETERMINATION OF ABSOLUTE CONFIGURATION ´ Sandor ´ Tibor Kurtan, Antus, and Gennaro Pescitelli

3.1. BENZENE DERIVATIVES WITH CONTIGUOUS CHIRALITY CENTER; SECTOR AND CHIRALITY RULES The benzene chromophore is a common structural feature in numerous optically active synthetic and natural products, and hence Cotton effects (CEs) of the characteristic π –π ∗ electric transitions are regularly utilized for the determination of their absolute configurations. Above 175 nm, benzene shows three π –π ∗ electronic absorption bands, centered at 184, 204, and 254 nm and designated as 1 Ba,b (E1u ), 1 La (B1u ), and 1 Lb (B2u ), respectively [1–3]. Depending on the substitution pattern of the aromatic ring, the position and intensities of these absorption bands can be somewhat altered, but the spectrum is essentially unchanged. It is the longest wavelength CE belonging to the 1 Lb (B2u ) band, which is most often used to determine the absolute configuration of benzene derivatives. The 1 Lb transition is both electronically and magnetically forbidden in benzene, and its electronic absorption intensity derives from vibronic borrowing from the allowed 1 Ba,b transition. The 1 Lb band shows well-defined vibrational fine structure, and its CEs are associated with allowed transitions from the lowest-energy vibrational mode in the ground state to totally symmetric vibrational modes in the lowest-energy electronically excited state, and the lowest-energy CE corresponds to the 0–0 vibrational transition 1 Lb CE. Sometimes two distinct vibrational progressions appear with similar spacing and a small separation. The two progressions may have CEs with opposite signs, and in this situation the CD in the 1 Lb region appears as a succession of a sequence of minima and maxima or of maxima of alternating sign [4–6]. Upon substitution of the benzene ring, an additional intensity is attributed to the induced electric transition moment due to the substituent that destroys the symmetry of benzene [7]. In optically active benzene Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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TAB L E 3.1. 1 Lb Band CEs of (R)-Phenylmethylcarbinols in Methanola H

R C

OH CH3

Compound (R)-1 (R)-2 (R)-3 (R)-4 (R)-5 (R)-6 (R)-7 a Spectroscopic

CD [λ, nm (ε × 102 )

R H p-Cl p-CF3 m-Cl m-CF3 o-Cl o-CF3

268 276 268 274 271 273 270

Reference

(−17) (+2.5) (−12) (−28) (−15) (+6.7) (−13)

9 9 9 10 10 10 11

moments [8]: qCl = +6, q(CF3 ) = −9 [(cm mol)/L]−1/2 .

derivatives, the rotational strength of the 1 Lb CEs is influenced by the 1 Ba,b transitions through vibronic coupling as well as by the induced transition moments of the aromatic substituents. In previous papers [10, 12–16] and a review [17] on the ECD study of phenyl- and benzylcarbinols, phenyl- and benzylcarbinamines, and 1-substituted indans and tetralins, Smith applied an empirical sector rule to describe the vibronic contribution to the 1 Lb CE in monosubstituted benzene derivatives with a contiguous chirality center. This sector rule divides the space around the benzene chromophore into 12 sectors, but it is simplified to a quadrant rule for monosubstituted benzenes, since only sectors surrounding the chirality centers have to be considered (Figure 3.1). In the quadrant rule, the plane of the benzene ring defines a nodal plane, while the other one, perpendicular to the former, is allocated by the attachment bond of the benzylic carbon as shown in Figure 3.1. In substituted benzene derivatives with hydrogen atom at the contiguous chirality center, the benzylic hydrogen eclipses or nearly eclipses the plane of the benzene ring as supported by X-ray [18, 19], 1 H NMR [20, 21], and molecular modeling [22]. Since the observed chiroptical properties are dependent on both the conformation and absolute configuration, the knowledge of the proper conformation regarding the rotation about the benzylic

(a)

(b)

(c)

H C* R1

H

H C*

R2

R1

* R2

R1

R2

Figure 3.1. (a) Sector rule for third sphere contribution to the 1 Lb CE in monosubstituted benzene derivatives with contiguous chirality center. The plane of the benzene ring is also a nodal plane; signs are for the upper sectors. (b) Quadrant sector rule of monosubstituted benzene derivatives with benzylic chirality center. The plane of the benzene ring is also a nodal plane; signs are for the upper sectors. (c) Quadrant sector rule with signs of all the four sectors viewed from the direction of the benzylic carbon. Thick line represents the benzene ring, defining a nodal plane. Benzylic hydrogen eclipces or nearly eclipses the plane of the benzene ring.

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attachment bond is crucial for the correct application of the sector rule. If the benzylic hydrogen is not totally eclipsed with the benzene ring as observed by Pescitelli et al. [23] (vide infra) in the ECD analysis of PhCH(Me)t-Bu supported by TDDFT-ECD calculation, and by Butz and co-workers for α-phenylethyl alcohol (1) from gas-phase data [24], the application of the benzene sector rule becomes ambiguous (Table 3.1). If the benzylic hydrogen lies in the plane of the benzene ring (nodal plane), it does not have significant contribution, while the R1 and R2 groups are in front and rear sectors with negative and positive contributions, respectively. Based on experimental ECD data, a sequence of magnitudes of the contribution to the 1 Lb CE of various groups (related to group polarizabilities) has been determined [13]. For example, in (R)-α-phenylethyl alcohol [(R)-1, R1 = Me, R2 = OH, Figure 3.1], the methyl group, located in the negative lower front sector, has larger rotatory contribution than the hydroxyl group, which implies a negative 1 Lb band CE as found experimentally for (R)-1. Similarly, the sector rule can predict the sign of 1 Lb band CE and thus determine the absolute configuration from the experimental 1 Lb band CE for monosubstituted benzene derivatives with benzylic chirality centers if the sequence of rotatory contributions are known for the benzylic substituents R1 and R2 (Figure 3.1). It must, however, be stressed that the relative order of magnitude, for example, the methyl vs. the hydroxyl group contribution in 1 has been disputed [24]. While it is only the vibronic contribution (orientation and sequence of R1 and R2 ) that determines the 1 Lb band CE of monosubstituted benzene derivatives, with additional achiral ring substituents there is an additional induced rotatory contribution to the 1 Lb CE, which may have the same or opposite sign as that of the vibronic contribution. The magnitude of the induced electronic transition moment is related to the spectroscopic moment of the ring substituent, introduced by Platt [25] and Petruska [8]. Depending on the spectroscopic moment and ring position(s) of the substituent(s), the induced rotatory contribution can reinforce, decrease, or even override the vibronic contribution, whose effects are summarized by a chirality rule [17]. When (R)-α-phenylethyl alcohol [(R)1)] is substituted with a chlorine atom, having a negative spectroscopic moment, the induced rotatory contribution overrides the negative vibronic contribution and results in positive 1 Lb CEs for o- and p-substitution [(R)-6 and (R)-2, respectively], while for msubstitution the negative 1 Lb CE is preserved [(R)-4]. In contrast, when the trifluoromethyl group, having a positive spectroscopic moment, is the aromatic substituent, o-, m- and p-substituted derivatives [(R)-3, (R)-5, (R)-7] give equally negative 1 Lb CEs; i .e. the induced rotatory contribution of the trifluoromethyl substituent does not overshadow the negative vibronic contribution of the chirality center. It seems that phenylalkylcarbinols and phenylalkylcarbinamines ortho- or para-substituted by an atom or group with positive spectroscopic moment (Cl, Br, CH3 , OH, OMe) show 1 Lb CEs of opposite sign to that of the unsubstituted parent compound. In contrast, derivatives having a substituent with negative spectroscopic moment (CF3 , CN) in the meta position have the same sign of 1 Lb CEs as that of the unsubstituted parent. As a summary, the unambiguous configurational assignment of benzene derivatives with a benzylic chirality center by semiempirical rules has to meet the following conditions: 1. Benzylic hydrogen is eclipsed with the plane of the benzene ring or else the exact conformation must be known. 2. Reliable priority order for the rotatory contributions of the benzylic R1 and R2 substituents (vibronic contribution to the 1 Lb CE).

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3. Clear-cut allocation of the R1 and R2 substituents to sectors. 4. When vibronic and induced contributions have opposite signs, one has to know which is the dominant contribution. Even in the absence of auxochromic substituents on the phenyl ring, the consistency of the sector rule for benzene 1 Lb transition has been recently called into question by different reports having in common the use of high-level quantum-mechanics calculations for predicting ECD spectra. It must be stressed that ECD calculations offer a valuable chance for validating sector rules, the benefit of which the original authors of the rules didn’t have. In fact, provided that a reliable calculation method is chosen, the calculations allow one to observe the chiroptical response of a molecule in a certain specific geometry (that used as an input). Moreover, such a geometry may be manipulated accessing hypothetical conformations which cannot be physically observed. Pescitelli et al. have reported the ECD spectra of a homologous series of simple chiral aliphatic compounds (R)-PhCH(Me)R [(R)-8-11] with R = Et, nPr, i Pr and tBu, respectively [23]. Compound (R)-11 showed a negative 1 Lb CE in agreement with Smith’s rule; however, the lowest-energy conformation for this derivative had the C–H bond not coplanar with the ring as prescribed by the rule, thus the agreement was fortuitous. The lowest-energy conformations of the remaining compounds do have the prescribed conformation. Low-temperature ECD spectra (at 183 K), which should be dominated in all cases by the respective lowest energy conformer, consist of a series of more intense maxima with positive sign alternated by a series of weaker maxima with negative sign (Figure 3.2). The first series is allied with the allowed vibrational progression with spacing 920–1000 cm−1 , and its sign is at odds with that predicted by the 1 Lb CE sector rule. Time-dependent density functional theory (TDDFT) calculations reproduced instead the dominant sign of 1 Lb CE’s, although a more correct treatment would necessarily include vibronic effects [26, 27]. A further exception to the 1 Lb CE sector rule has been reported by Butz et al. [24] concerning (R)-α-phenylethyl alcohol [(R)-1]. According to these authors, the apparent consistency between the negative 1 Lb CE observed for (R)-1 and the sector rule is due to an incorrectly assumed conformation. The correct lowest-energy structure, found by geometry optimizations and gas-phase experiments, has the methyl bond roughly perpendicular to the plane of the phenyl, and the C–H bond is well oustide from the plane. To reconcile such a structure with the observed ECD spectrum, the sector signs for the rule must be reversed. Later, the authors substantiated their conclusions by TDDFT calculations also using a solvent model [28]. In this study, the relevant dihedral angles for 1 (Ph-Cα and Cα-O) were varied systematically and their impact on the sign of calculated 1 Lb CE was ascertained. Moreover, a rigorous theoretical approach was followed by Autschbach and co-workers in their critical evaluation of the same sector rule. The authors generated true nodal surfaces delimiting the sectors by placing a negative charge on a grid set on the top of a benzene ring at a fixed distance and varying its position systematically [29]. Since the benzene ring becomes dissymetrically perturbed by the charge, its transitions acquire non-negligible rotational strengths. In this case too, the signs obtained for the 1 Lb sector rule were opposite to the original ones. The above findings demonstrate that at least for simple benzenes with chiral substituents (i.e., endowed with third-sphere chirality in Snatzke’s terminology) [30, 31], the sector rule for 1 Lb CE is far from being generally valid and should be used with caution. Since in previous papers [13–15, 17], Smith reviewed the application of sector and helicity rules to benzene derivatives with contiguous chirality center in detail, the present chapter focuses mainly on benzene natural products with condensed carbocyclic and especially heterocyclic rings such as in tetralin, dihydrobenzo[b]furan, chroman, isochroman

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1

1 (a)

×20

×20

(b) 0

0 ×2

293 k 183 k

–1

–1

×2

293 k 183 k

Δε

Δε

–2

–2

nPr

Et

–3

–3 (R)-(1-methylpropyl)-benzene [(R)-8]

(R)-(1-methylbutyl)-benzene [(R)-9]

–4

–4 190 200 210 220 250 260 270 280 λ (nm)

190 200 210 220 250 260 270 280 λ (nm)

1 (c)

0 (d)

×20

0

–1 Δε

–2

×2

293 k 183 k

×20 293 k 173 k

–4 Δε

–2 iPr

–6 tBu

–8

–3

–4

(R)-(1,2,-dimethylpropyl)-benzene [(R)-10] ×.5 190 200 210 220 250 260 270 280 λ (nm)

–10 ×.5 –12

(R)-(1,2,2-trimethylpropyl)benzene [(R)-11]

190 200 210 220 250 260 270 280 λ (nm)

Figure 3.2. Experimental ECD spectra of (R)-PhCH(Me)R derivatives (R)-8-11 at room temperature (solid lines) and at 173–183 K (dashed lines) in hexane or heptane. (Reprinted from reference 23, with permission from Elsevier).

and benzodioxane derivatives. In these derivatives the phenyl chromophore is embedded in a chiral ring, thus they exhibit second-sphere chirality [30, 31]. Some of Smith’s results have been outlined above to underscore the parallelism between the theories describing the two families of benzene derivatives. The major goal of the recent chapter is to provide guidelines for nonspecialists in the determination of absolute configuration of cyclic natural products with fused benzene ring by means of benzene semiempirical helicity rules.

3.2. TETRALIN AND TETRAHYDROISOQUINOLINE DERIVATIVES 3.2.1. Tetralins and Tetrahydroisoquinolines without Aromatic Ring Substituents; P/M Helicity → Positive/Negative 1 Lb CE In terms of chromophoric system, chiral tetralin and 1,2,3,4-tetrahydroisoquinoline derivatives belong to the benzene chromophores with chiral second sphere [30, 31]. In

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(a)

6 X

P helicity

positive

5a

4 3

X

X2 8a 1 8 ωC5a,C4,C3,X < 0 X: CH2 tetralin X: NH tetrahydroisoquinoline negative M helicity sign of the 1Lb-band CE 7

ωC5a,C4,C3,X > 0

5

(b)

X

Figure 3.3. (a) Snatzke’s helicity rule or correlation between the sign of the second sphere contribution of tetralin (tetrahydroisoquinoline) and the 1 Lb band CE [30, 32]. The arrow indicates the direction of the overall spectroscopic moment. P- and M-helicity refer to the absolute conformation of the nonaromatic ring. (b) Sector rules for the third (fourth) sphere contributions to the 1 Lb band CE in tetraline (tetrahydroisquinoline). The plane of the benzene ring is a nodal plane, and signs refer to upper sectors.

these cases, the achiral benzene chromophore (first sphere) is chirally perturbed by the fused chiral ring (second sphere) and the substituents of the heterocyclic ring (third sphere), which gives rise to the observed Cotton effects. In tetralin derivatives having no substituents on the fused aromatic ring, the 1 Lb CE is determined mainly by the absolute conformation [30] of the fused nonaromatic chiral ring adopting usually a half-chair conformation–that is, the P - or M -helicity defined by the ωC5a,C4,C3,X torsional angle, which in turn is directed by the absolute configuration of the fused ring (Figure 3.3). Snatzke and Ho [32] developed a so-called helicity rule for the benzene chromophore of chiral tetralin and tetrahydroisoquinoline derivatives (Figure 3.3) according to which if the benzene ring is not further substituted, P -helicity of the nonaromatic ring leads to a positive CE within the 1 Lb band and, vice versa, M -helicity is manifested in a negative one. Moreover, a sector rule [33–36] was introduced to evaluate the contribution of the third sphere, namely, the presence of substituents attached to the nonaromatic ring. This sector rule is similar to the sector rule of benzene derivatives with benzylic chirality center (Figure 3.1a) except for that an additional plane is added, perpendicular to the benzene ring and coinciding the C2 axis, resulting in 16 sectors (Figure 3.3b). There is a simple relationship between the helicity rule and sector rule of tetralin; the two non-coplanar carbon atoms of tetralin lie in positive sectors with P -helicity affording the same prediction by the two rules. Since it is the chiral sphere nearest to the chromophores that generally determines the sign of the 1 Lb CE, the helicity of the nonaromatic ring has to be considered as the dominant contribution. If the relationship between the helicity of the nonaromatic ring and the sign of 1 Lb band CE is known, the chirality (absolute conformation) of the heterocyclic ring can be deduced from the measured ECD spectrum. Since the relative configuration of the substituents at the chiral centers as well as their equatorial or axial orientation can be obtained from NMR experiments (3 JH,H , 3 JC,H , NOE effects) or X-ray analysis, their absolute configurations can be also assigned. For instance, in the (2S , 3S )-12 tetraline derivative (Table 3.2), the trans-diequatorial arrangement of the C2 and C3 methyl groups and half-chair conformation of the carbocyclic ring can be determined from NMR experiments (e.g., large value of 3 J2H,3H ); and then according to the helicity rule, the measured positive 1 Lb CE suggests that the nonaromatic ring adopts P -helicity [36]. The combination of these two data allows the determination of the absolute configuration as (2S , 3S )-12. Similarly, the positive 1 Lb CEs of (2R)-13, (1R)-14, and (4aS , 9aS )15 derive from P -helicity of the dominant conformer with half-chair conformation. In

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

order to reduce van der Waals repulsion between the 1-Me and peri 8-H in (1R)-14, the 1-Me group preferably adopts a quasi-axial orientation with a distorted half-chair conformation [36]. The measured positive 1 Lb CE implies P -helicity, which is only feasible with (1R)-14 absolute configuration. With a half-chair conformation of the fused ring B, the benzylic 9-Me group of (4aS , 9S , 9aR)-16 would be in an equatorial orientation, however, C9 moves into the plane of the benzene ring to shift the 9-Me to a quasi-axial position and thus reduces the repulsion with peri 8-H and 1-H, resulting in a twist boat conformation. Since the nonaromatic ring adopts a conformation considerably different from the half-chair one, and other equilibrating conformers may also contribute, the helicity rule fails to determine the right absolute configuration in this case. In contrast, the epimeric (4aS , 9R, 9aR)17 corroborates well the helicity rule, since the fused cyclohexene ring has half-chair conformation with an axial 9-Me as the major conformer. The tetrahydroisoquinoline derivatives 18–21 behave similarly, and M -helicity results in a negative 1 Lb CE and vice versa.

3.2.2. Tetralins with Achiral Ring Substituents Snatzke et al. [31, 39] also showed that achiral substituents of the benzene ring with large spectroscopic moment {e.g., qOMe = +21 [(cm mol)/L]−1/2 } [8] in specific positions inverted the helicity rule. This inversion was attributed to the change of the direction of the sum spectroscopic moment [8, 25, 40, 41] vector which gives the electric transition moment vector (μ)–namely, the translation of the electron charge during the transition. This effect was called the induced rotatory contribution and was described by the chirality rule (vide supra) for benzene derivatives with contiguous chirality center. In Snatzke’s terminology, the achiral ring substituents can induce the inversion of the original helicity rule, which is the consequence of rotating the electric transition moment by approximately 30◦ . Figure 3.4a shows a polarization diagram of the tetralin chromophore, in which the addition of the spectroscopic moments oriented the electric transition moment along the direction of the C2 axis of the chromophore, which gives a positive 1 Lb -band CE for P -helicity of the nonaromatic ring (helicity rule of unsubstituted tetraline). The same helicity rule is valid for 6,7-dimethoxytetralins (Figure 3.4b), since in the presence of the two methoxy substituents at position 6 and 7, the direction of the electric transition moment does not change. In contrast, when tetralin has only one methoxy or hydroxy group at C6, the sum of the spectroscopic moments rotates the electric transition moment by approximately 30◦ , which leads to a sign inversion as shown in Figure 3.4c. Similarly, the inverse helicity rule holds for 5,7-dimethoxytetralins. A systematic study [31, 39] was carried out on substituted tetralin derivatives to reveal the effect of different substitution patterns on the sign of the 1 Lb band. This study clearly demonstrated that 5,8- and 6,7-disubstituted and 5,6,7-trisubstituted tetralins follow the same helicity rule as the unsubstituted tetralin, while 6-monosubstituted and 5,6- and 5,7-disubstituted tetralins obey the inverse one (Figure 3.5). The tetralin chromophore is found in pharmacologically active chiral synthetic derivatives such as melatoninergic ligands 22 [42] and 23 [43], the 5-HT1A receptor antagonist 24 [44], and 2-aminotetralin-2-carboxylic acids 25a,b [45, 46], the absolute configuration of which could have been determined by tetralin helicity rules (Chart 3.1). In 1-aryltetralin lignan natural products such as burseranin (26) [47], the 1-aryl group has exciton coupled interaction with the fused benzene ring [48], which determines the ECD spectrum (Chart 3.1). The absolute configurations of 1-aryltetralines are elucidated

79

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TAB L E 3.2. Helicity and 1 Lb band CE of Tetralin and Tetrahydroisoquinoline Derivatives 8 7

R1 8a 1

6

5

5a

4

R1 3

4a

R2 2

6

1 10 R 4

5

7 8

3 R3

R2

R2

9a

9

R3

2

NH

1

H

R3

12 : R1 = H, R2, R3 = Me

15 : R1 = Me, R2 , R3 = H

18 : R1, R2 = H, R3 = Me

13 : R1, R3 = H, R2 = Me

16 : R1, R3 = H, R2 = Me

19 : R1, R3 = H, R2 = Me

1

2

3

1

14 : R = Me, R , R = H

2

3

17 : R , R = H, R = Me

20 : R1 = H, R2, R3 = Me 21 : R1, R3 = Me, R2 = H

Compound

Helicity of the Low-Energy Conformer H

(2S , 3S )-12

Me

1

Lb band CE [λ, nm (ε)a or [θ]b

Reference

272 (+0.191)a

36

264.5 (+0.248) Me H

(2R)-13

(1R)-14

H Me

H Me Me

(4aS , 9aS )-15 H2C

H

(4aS, 9S, 9aR)-16

H 2C

H

272 (+0.161)a 265 (+0.176)

36

272.5 (+0.226)a 264.5 (+0.233)

36

272.5 (+0.303)a 265 (+0.330)

36

272.5 (-0.058), 270 (+0.012)a 265 (−0.33), 257.5 (−0.027)

36

273 (+0.568)a 266 (+0.558)

36

266 (−290)b 273 (−800)b

37 38

270 (+292)b

37

CH2

CH2 H Me

H

(4aS, 9R, 9aR)-17

Me

H2C

H

H

H N

(1S )-18

H Me

H

(3S )-19 Me

N H

81

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

TAB L E 3.2. (Continued ) 1

Helicity of the Low-Energy Conformer

Compound

Lb band CE [λ, nm (ε)a or [θ]b

37

265 (+613)b

37

265

H

Reference

(+718)b

H

Me

(1R, 3S )-20 N H Me

H

H

(1R, 3R)-21

N H a CE b CE

Me

Me

reported as ε. reported as θ .

(a)



5

+

+

– –

(b)

4

6

3

7

2

+

+

+

MeO

8 1 P-helicity positive1LbCE

– –

+ P-helicity positive1LbCE

(d)

(c) MeO +



MeO



+

MeO +

MeO –



+



MeO –

– P-helicity negative1LbCE

+

+ OMe

OMe P-helicity negative1LbCE

Figure 3.4. Polarization diagram of the 1 Lb band, direction of the overall spectroscopic moment, and helicity rule of (a) tetralin (b) 6,7-dimethoxytetralin (c) 6-methoxytetralin, and (d) 5,7dimethoxytetralin.

from the sign of the relatively intense CE in the 270- to 290-nm region, governed by the exciton coupling of the two 1 Lb transitions, and thus the helicity rule cannot be applied for this type of tetralin derivatives [49, 50].

3.3. BENZENE CHROMOPHORES WITH FUSED HETEROCYCLIC RING In the following, the applicability of benzene helicity rules is to be discussed in O-heterocyclic natural products, in which the fused benzene ring is part of a 2,3dihydrobenzo[b]furan, isochroman, chroman, or 1,4-benzodioxane moiety (Chart 3.2). The correlation between the n –π ∗ CE and the absolute geometry will be also

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R1 R2

6

R3 7

R1 4

5

3

P-helicity positive 1Lb CE

2 8

tetralin: R1,R2,R3,R4= H 5,8-dimethoxytetralin: R1,R4= OMe, R2,R3= H 6,7-dimethoxytetralin: R1,R4= H, R2,R3= OMe 5,6,7-trimethoxytetralin:R1= H, R2,R3,R4= OMe

4 3

P-helicity negative1Lb CE

2

R3 7

1

R4

5

R2 6

8

1

6-methoxytetralin: R1,R3= H, R2= OMe 5,6-dimethoxytetralin: R1,R2= OMe, R3= H 5,7-dimethoxytetralin: R1,R3= OMe R2= H

Figure 3.5. Effect of achiral ring substituents of large spectroscopic moment (e.g., OMe) on the tetralin (tetrahydroisoquinoline) helicity rule.

O NHCOEt MeO

OH

NHC

n-Pr N

MeO

22

23

n-Pr

Me 24

O O O

NH2

O

COOH R

O O burseranin (26)

25a: R = H 25b: R = OH

Chart 3.1. Structures of tetralin derivatives 22–26.

R1

6

7 7a 1 O

5 4

4a 3

2 R2

2,3-dihydrobenzo[b]furan

R1

6

5 5a 4

7 8

8a 1 X

3 O2

R1

R2

X: H2 isochroman X: =O dihydroisocoumarin

R1

7 6

7 6

8 8a 1 O 2 R2 3 5 5a 4 X

X: H2 chroman X: =O chroman-4-one

8 8a 1 O 2 R2 3 5 5a O 4

1,4-benzodioxane

Chart 3.2. Chromophores with fused benzene ring.

addressed in some of the related carbonyl derivatives such as dihydroisocoumarins and chromanones. ECD spectroscopy has been often utilized for the elucidation of absolute configuration of these flavonoids by simply comparing the ECD spectra of similar derivatives without a deeper understanding of the factors that determine their chiroptical properties. We aimed to establish helicity rules for unsubstituted chromophores by the synthesis and

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

ECD study of derivatives with known absolute configurations to see whether the original or inverse tetralin helicity rule is valid for these chromophores. Since the benzene rings are substituted in most of the natural products containing these chromophores, the effect of aromatic ring substituents on the helicity rule has to be studied as well, which will help natural product chemists to choose appropriate ECD reference compound for the unambiguous determination of absolute configuration of novel natural products. The determination of absolute configuration of natural benzene-fused heterocycles has to follow the protocol outlined below: 1. Determination of the relative configuration and axial /equatorial orientation of the ring substituents by NMR methods (3 J H,H , 3 JC,H , NOE effect), X-ray single crystal diffraction, computational conformational analysis or their combinations. These studies also provide information on the conformation of the fused nonaromatic ring whether it has a half-chair, envelope, or boat conformation. 2. Determination of the absolute conformation (helicity) of the fused heterocyclic ring on the basis of benzene ECD helicity rules from the measured 1 Lb band CE. The helicity rule of the unsubstituted chromophore and the effect of ring substituents with large spectroscopic moment have to be known. The helicity of the heterocyclic ring is governed by the absolute configuration of the chirality centers and the preferred equatorial/axial orientation of the substituents. Large substituents prefer equatorial orientation due to 1,3-diaxial interaction, although benzylic substituents sometimes tend to favor axial position in order to reduce van der Waals repulsion with the peri aromatic hydrogen. 3. For a safe configurational assignment, a major conformer with known conformations and high population is required that dominates the ECD parameters. 4. By merging the information on the helicity, relative configuration, and axial/equatorial orientation of the substituents, the absolute configuration can be deduced.

3.3.1. Benzodioxane Chromophore; P/M-Helicity → Positive/Negative 1 Lb CE The benzodioxane chromophore occurs in chiral nonracemic natural flavanolignans [51–53] and neolignans [54–57] as well as in synthetic derivatives of pharmacological interest [58–62]. Antus et al. [51] prepared 1,4-benzodioxane steroid derivatives 27a–c of known absolute configuration and helicity, the ECD study of which showed that the same 1 Lb band helicity rule is valid for unsubstituted 1,4-benzodioxanes as for analogous tetralins; the P /M -helicity of the heteroring leads to a positive/negative 1 Lb band CE, respectively (Chart 3.3, Table 3.3). This result also afforded the configurational assignment of the natural flavanolignan (−)-silandrin and (−)-isosilandrin isolated from Silybum marianum [51, 53]. The unsubstituted 1,4-benzodioxane helicity rule was applied to deduce the absolute configurations of synthetic glycogen phosphorylase inhibitors 28a–b, having a 1,4-benzodioxane moiety connected to a N -(β-D-glucopyranosyl)amide unit (Chart 3.3) [60]. Their opposite 1 Lb band CE is governed by the helicity of the heteroring (Table 3.3), which in turn is dictated by the equatorial orientation of the C2 substituent and then the absolute configuration of the C2 chirality center. The chirality centers of the sugar unit are manifested only in the transitions of the amide chromophore, which are not in a mirror image fashion, but they do not interfere with the characteristic 1 Lb band CE. The ECD data of (2R, 3S )-29a,b, (S)-30a,b, and

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1 H O 2 3 O 4 H 2-H 27a β 27b α 27c β

OH

OH HO HO H 3-H β α α

R2 6

O

R1 7

O

1

OH

O

R2 7

O

R1

2 1

O 2-C 28a (R) 28b (S) OH

6

OH

R1 R2 (S)-30a CH2OAc H (S)-30b H CH2OAc

O

OH

5

O

NHCOMe

4

R2 H (2R,3S)-29a (CH2)2NHCOMe H (CH2)2NHCOMe (2R,3S)-29b

OMe

2 3

O

R1

O

1

O

1 2 3

OH R 7

2

H N

O

8

EtO

6

O 1

OH

OMe R (2S, 3S)-31a (CH2)3OH (2S, 3S)-31b CH=CHCH2OH

2

OH

O (S)-32

Chart 3.3. Structures of benzodioxane derivatives.

TAB L E 3.3. Helicity and ECD Data of Benzodioxane Derivatives cpd. 27ac 27bc 27cc (R)-28a (S )-28b (2R, 3S )-29a (2R, 3S )-29b (S )-30a (S )-30b (2S , 3S )-31a (2S , 3S )-31b (S )-32

Helicity

CE {λ, nm (ε)a or [θ]b}

Reference

M M P M P P P M M M M M

285 (−1.49)a 285 (−1.09)a 284 (+1.59)a 279 (−0.09)a,d 278 (0.04)a,d 280 (+389)b 280 (+400)b 284 (−0.18)a 285 (−0.21)a 299 (−1010)b 282 (+2549)b 315sh (−0.41), 289 (−0.58)a

51 51 51 60 60 56 56 61 61 54 54 e

reported as ε. reported as θ . c With cholestane skeleton. d Absolute configurations are erroneously shown in reference 60. e Unpublished ECD data of reference 61. a CE b CE

(2S , 3S )-31a, containing ring substituents with small spectroscopic moment in different positions, also corroborates the unsubstituted 1,4-benzodioxane helicity rule. One may expect that similarly to the isochroman chromophore (vide infra), ring substituents (devoid of any chirality center) do not invert the helicity rule, because the two benzodioxane oxygens fix the electric transition moment along the long axis of the chromophore. However, this expectation is contradicted by the example of the neolignan (2S , 3S )-31b chemically correlated to (2S , 3S )-31a, which has a C7 3-hydroxy1-propen-1-yl substituent and for which the positive 1 Lb CE derives from M helicity of its heteroring. Although (S )-32, bearing a conjugated C6 α,β-unsaturated ester moiety,

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

OMe OMe 1

O

7

1

8

O

O

OMe

2 3

2 3

Me

4

(2S,3S)-33 M-helicity negative 1Lb CE

6

5

OMe

O

Me

4

(2R,3R)-34a trans-eusiderin P-helicity negative 1Lb CE

Chart 3.4. Structures of synthetic (2S, 3S)-33 and natural trans-eusiderin [(2R, 3R)-34]. a Absolute configuration is shown as proposed in reference 63.

apparently follows the unsubstituted helicity rule, the application of this rule is prone to error in the presence of such conjugated chromophore. Compound (2S,3S )-33, a synthetic benzodioxane of known absolute configuration, was prepared from optically active 1-phenyl-1,2-epoxypropanes and showed negative 1 Lb CE pointing at M -helicity of its heteroring in agreement with the helicity rule (Chart 3.4) [63]. Its ECD data in the 220 to 250-nm 1 La region were opposite to that of the neolignan trans-eusiderin [(2R,3R)-34], on the basis of which the (2R,3R) absolute configuration was assigned to trans-eusiderin [63]. However, both (2S,3S )-33 and trans-eusiderin showed negative 1 Lb CEs, which suggests that they are homochiral if the ring substituents do not interfere. Since the C5 methoxy and C7 allyl substituents are not expected to invert the helicity rule, the absolute configuration of trans-eusiderin most likely has to be revised to (2S,3S ). The 1 La region is more sensitive to substituent effects and overlapping from other chromophores, which may explain the opposite CEs of (2S,3S )-33 and trans-eusiderin (34) in this region. These examples confirm that the benzodioxane helicity rule can be applied safely for unsubstituted derivatives or compounds in which the fused aromatic ring has alkyl or other substituents of low spectroscopic moments. However, ECD calculations are required whenever conjugated groups such as alkenyl or formyl are attached to the fused aromatic ring.

3.3.2. Isochroman Chromophore; P/M-Helicity → Positive/Negative 1 Lb CE Although the isochroman skeleton is far less common in natural products than the 2,3dihydrobenzo[b]furan one, there are several natural 3-alkylisochromans of remarkable biological activities whose absolute configurations have not been determined yet. For instance, absolute configurations of tricyclic derivatives 35a–c [64] and the anticoccidial optically active 3-methylisochroman derivative 36 [65], isolated from Penicillium sp., were not reported, as well as those of the topoisomerase II inhibitor CJ-12,373 (cis-37) [66] and the isochroman toxin trans-38 [67], natural 1,3-disubstituted isochromans with a benzylic hydroxy group (Chart 3.5). Moreover, there are several synthetic optically active isochroman derivatives reported with remarkable pharmacological activities such as selective 5-HT1D agonist [68–70], D1 agonist [71, 72], and D4 antagonist [73], which are promising for the treatment of migraine headache, Parkinson’s disease, and schizophrenia, respectively. It was shown that absolute configurations of these compounds play a decisive role in their pharmacological activities; the (S ) enantiomers of the 5-HT1D agonist 39a (PNU-109291) [68]

85

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H

R1

O

R2 3

R 35 a b c

R1 OH OH OH

CH3 R2 R3 H H OH H H OH

4

5

HO 6 7

3 Me 2

O 8

n-C7H15

HO O

HOOC

1

5

4

8

O

Me

OH OH trans-38 OH

R2

3

2 1 O

7

Me

OH OH cis-37

OMe 36 R1 6

MeO

HO N

O

N

NH2 HCl

39 R2 R1 a CONHMe OMe b H SO2NH2

(1R,3S)-40 (A68930)

Chart 3.5. Structures of natural (35a-c, 36-38) and synthetic (39a,b and 40) isochromans.

and the selective D4 antagonist sonepiprazole 39b (U-101387) [73] possessed a superior affinity for the binding site compared to the (R) enantiomers, while the (1R, 3S ) enantiomer of 40 (A68930) is almost exclusively responsible for the observed selective D1 agonist activity of the racemate [71]. In spite of the apparent importance of chirality in these derivatives, apart from the calculation of ECD parameters, there is no direct and general method for the configurational assignment of the isochroman skeleton available which can be used on μg quantity of a noncrystalline derivative. Thus, so far X-ray diffraction [72, 73] and correlations [68, 71] were applied to determine the absolute configurations of optically active isochromans. In order to establish a relationship between the helicity of the isochroman heteroring and the sign of the 1 Lb band CE and study the effect of ring substituents, rigid (41–43) and flexible (45a–g) isochroman derivatives with known absolute configuration and different ring substitution pattern were prepared and their ECD spectra were recorded (Figure 3.6, Scheme 3.1) [74]. Based on the synthetic steroid derivatives 41 and 42 (Figure 3.6a), the same helicity rule holding for tetralins and tetrahydroisoquinolines could be proposed for the isochroman chromophore having no aromatic substituents: P helicity of the heteroring leads to a positive Cotton effect (CE) in the 1 Lb band, and M -helicity is manifested in a negative

(b)

(a) 12 H H 11 O 12a H H 3 10a 6a 4 10 H H

H 12a

H 1 2

6a H

H 11 O

6a

O

11

12a H

P-helicity ωC–10a,C–11,O–12,C–12a>0

M-helicity ωC–10a,C–11,O–12,C–12a>0

positive1Lb CE

negative1LbCE

λmax [nm] Δε 6a–H 12a–H helicity α β M 274 (–0.05), 272 (+0.02), 270 (–0.08) α α P 272 (+0.33), 269 (+0.24) β β P 273 (–0.16), 268 (–0.08), 266 (–0.11) 1L CEs b

41 42 43

Figure 3.6. (a) Structures of steroid-fused isochroman derivatives 41–43 with the helicity of their heterorings and measured 1 Lb band CEs. (b) Helicity rule for the isochroman chromophore with no substituent on the aromatic ring represented on the example of 41 and 42.

87

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

one (Figure 3.6b) [74]. However, a negative 1 Lb band CE was measured for the 6aβ-H, 12aβ-H derivative 43 whose heteroring should adopt P -helicity, provided that ring A of the cholestane skeleton has chair conformation. This discrepancy was attributed to the contribution of a conformer with a boat conformation in ring A, but it made the former helicity rule ambiguous for the configurational assignment of natural isochromans. Thus 3-methylisochroman derivatives (+)-S -45a–g with different substitution pattern on the aromatic ring have been synthesized by ring closure of the (+)-(S )-1-arylpropane-2-ols 44a–f (Scheme 3.1), in turn prepared by kinetic resolution (44a–c) with Pseudomonas cepacia or chiral bioreduction (44d,e) [75]. Because the configuration of the chirality center is retained during the oxaPictet–Spengler ring closure of optically active alcohols (+)-(S )-44a–f, the absolute configurations of isochromans 45a–f can be determined readily, provided that the absolute configurations of the arylpropanols 44a–f are known. For this purpose, we envisaged the employment of the zinc porphyrin tweezer exciton chirality CD [76] and the Mosher’s NMR method [77], both developed for the configurational assignment of secondary alcohols [75]. The helicity and ECD data of the isochromans (S )-45a–g and (4aR,10bS )-46 are tabulated in Table 3.4. (S )-45a and (4aR,10bS )-46, bearing no substituents on their aromatic rings, have heterorings of P - and M -helicity (see Scheme 3.1 for definition and representation), respectively, wherein the C3 methyl group of (S )-45 is oriented equatorially (J3H,4H = 10.9 and 3.1 Hz) while the 4a–H and 10b–H of the trans-annulated (4aR,10bS )-46 have a trans-diaxial configuration [75]. Because the 1 Lb bands of (S )-45 of P -helicity and (4aR,10bS )-46 of M -helicity (Scheme 3.1, Table 3.4) show positive and negative CEs, respectively, it follows that the unsubstituted isochroman chromophore obeys indeed the helicity rule established for unsubstituted chiral tetralins and tetrahydroisoquinolines [32]: P /M -helicity of the heteroring results in positive/negative 1 Lb band CE , respectively. This corroborates well the similar spectroscopic moments of the hydroxymethyl (qCH2 OH = −5), aminomethyl (qCH2 NH2 = −5), and ethyl (qEt = +4.5) groups [8]. Since natural or synthetic isochroman derivatives of pharmacological interest often contain substituents with large spectroscopic moment (O-alkyl, hydroxy) on the fused

R4 R3

H

R4 Me

MeOCH2Cl

5

ZnCl2/Et2O 0°C

OR

R2

2

R2

R1 (+)-(S)-44a-f R2 R3 R1 H H a H OMe b OMe H H c OMe H H OMe OMe d -OCH2 OH e H OMe H f OMe H 45g H

44,45

H

4

R3

8

8a

H Me

Me

R5 H H H H H H H

O

1

2

ωC-8a,C-1,O-2,C-3 >0 P-helicity

4 H 5 3

1

4

O

R1 (+)-(S)-45a-g R4 H H H H H Br H

3

3

O 4a

6

10a 6a

2 10b 1 H 10

46

5

H 10b 7 8 9

O 6 4a

H

ωC-6a,C-6,O-5,C-4a 0 P-helicity

λmax [nm] Δε

266 (+0.03), 260 (+0.02), 255sh (+0.01) 287 (+0.59), 282 (+0.69), 275sh (+0.063)

Scheme 3.2. Preparation, preferred helicity, and ECD data of (−)-(1R,3S)-47a,b 1,3-disubstituted isochromans.

the heteroring has half-chair conformation [78]. The heteroring of (1R, 3S )-47a,b has P -helicity, and their positive 1 Lb CEs are practically the same as that of (S )-45a,d, which proved that the introduction of an axial benzylic alkoxy group does not change the isochroman helicity rule as long as the conformation or helicity of the heteroring remains the same. This result allows the configurational assignment of 1-alkoxy- or 1-hydroxyisochromans such as cis-37 and trans-38 from their ECD spectra. On the basis of the isochroman helicity rule, the absolute configuration of pseudoanguillosporin A (48a) and B (49), isolated from the endophytic fungus Pseudoanguillospora sp, could be deduced from their ECD spectra (Chart 3.6 and Figure 3.7) [79]. Since pseudoanguillosporin A (48a) shows a negative 1 Lb band CE [284 nm (ε = −0.4 nm)], its heteroring adopts M helicity (Figure 3.7, right), which implies a (3R) absolute configuration with equatorial C3 substituent. In contrast, the synthetic compound (3S )-45b [75] had a positive 1 Lb band CE and P -helicity. Both (3R)-48a and (3S )-45b showed a positive CE around 240 nm in the 1 La region, which is known to be more sensitive to the effect of achiral substituents of the aromatic ring. The absolute configuration of pseudoanguillosporin B (49) at C3 was deduced as (R), since its CD spectrum was nearly identical to that of 48a. Moreover, the absolute configuration of the C6 chirality center on the side chain of pseudoanguillosporin B, distant from the chromophore, was determined by the Mosher’s NMR method [79]. The interpretation of the ECD spectrum of compounds 48a and 49 (vide infra) is also supported by the calculation of the ECD spectrum of the model compound (R)-48b [79], which reproduced well the pattern of bands discussed above for (R)-48a (Figure 3.8). R4 3

R1

R O

HO

3

O OR R1 48a 48b

n-heptyl CH3

2O

6′

OH

1

2

R2 H H

1′

R3 R4 C-3 H CH3 R H CH3 R

OH (3R,6′R)-49

Chart 3.6. Structures of pseudoanguillosporins A (48a) and B (49), and the ECD model compound (R)-48b.

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

O2

0,8

4

(3S)-45b

Δε [cm2 mmol–1]

1 R 3 H ωC-8a,C-1,O,C-2 > 0 P-helicity

0,4 0,0 (3R,6'R)-49

H 3 R

–0,4 1

(3R)-48a

4

–0,8 –1,2

O 2 220

240

260

280

300

ωC-8a,C-1,O,C-2 < 0 M-helicity

λ [nm]

Figure 3.7. Left: Measured ECD spectra of (3R)-48a, (3R, 6 R)-49 and (3S)-45b in acetonitrile. Right: P and M-helicity of the isochromane ring; pseudoanguillosporin A (3R)-48a and B (3R, 6 R)-49 have M-helicity.

2

Δε [cm2 mmol–1]

1 0 Absolute minimum –1 Experimental for (3R)-48a in ACN Calculated with BP86/TZVP on (R)-48b

–2

(Boltzmann-weighted over 4 structures at 300 K)

–3 –4

220

240

260 λ [nm]

280

300

320

Second minimum (+0.10 kcal mol–1)

Figure 3.8. Experimental CD spectrum of pseudoanguillosporin A (48a) compared with the ECD calculated on model compound (R)-48b with TDBP86/TZVP as Boltzmann average over four DFT-optimized structures (B3LYP/6-31G(d)); the two most stable ones are shown on the right.

3.3.3. 2,3-Dihydrobenzo[b]furan Derivatives Unsubstituted 2,3-Dihydrobenzo[b]furan Derivatives; P/M-Helicity → Negative/Positive 1 Lb CE. While a tetralin derivative may be described as a benzene derivative with two alkyl substituents having the same magnitude of spectroscopic moments, this condition is not given for the 2,3-dihydrobenzo[b]furan chromophore, since the spectroscopic moment of the alkoxy moiety is larger than that of the alkyl part based on the spectroscopic moment of methoxy (qOMe = +21) and ethyl group (qEt = +4.5) as determined by Petruska [8]. Therefore, it is expected that the electric transition moment vector (μ) does not lie in

91

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

TAB L E 3.5. Helicity of the Heteroring and 1 Lb Band CEs for Rigid and Flexible 2,3-Dihydrobenzo[b]furan Derivatives Compound

Standard Projection

(−)-50

O C1

1L

b

CE {λ, nm (ε),a [θ]b }

Reference

M

297 (+0.89)a ,c

80, 81

P

289 (−3.30)a ,c

80, 81

P

280 (−2.51)a ,d

81, 82

M

292 (+2.95)a ,e

81–83

M M

288 (+0.72)a ,e 292 (−0.05)a ,c

81, 83 81, 83

P

281 (−0.37)a ,e

84

H

P P

a ,e

285 (−1.61) 300 (+0.46)a ,e

84 84

CH3

M

282 (+2658)b ,e

85, 86

C4 H H

H

(+)-51

Helicity

C1 H

O

C4

(+)-(2S , 3S )-52

H Ph O

CH3 H

(−)-(2R, 3S )-53 (−)-(2R, 3S )-54 (+)-(2R, 3S )-55 (+)-(2S , 3S )-56f f

(+)-(2S , 3S )-57 (+)-(2S , 3S )-58f

H O Ar

CH2

H

OH

H Ph O

CH3

(−)-(2R, 3S )-59f O Ph

H H

CE reported as ε. CE reported as θ . Solvent of ECD measurement is c n-hexane, d ethanol, e methanol, f revised absolute configuration. Note: The standard projections show the definition of the helicity for the heteroring in the major conformer; M-helicity corresponds to negative ωC7a,O,C 2,C 3 torsional angle.

a b

the direction of the pseudo C2 axis of this chromophore, which can lead to an inversion of the original tetralin helicity rule. In order to obtain a correlation between the stereochemistry of chromophores (helicity of the heteroring) and the sign of the 1 Lb band CE, a stereocontrolled synthesis, conformational and ECD study of rigid [(−)-50, (+)-51] [80] and flexible [52–55 (Chart 3.7)] [82, 83] 2,3-dihydrobenzo[b]furan derivatives with known absolute configuration was performed. The 1 Lb band CD data and the preferred helicity of the five-membered O-heterocyclic ring in (−)-50, (+)-51, 52 (−)-53, 54 and (+)-55 are tabulated in Table 3.5. A comprehensive NMR study on the conformation of the dihydrofuran ring and ring A of the cholestane skeleton revealed that the heterocyclic ring of the cholestane derivatives (−)-50 and (+)-51 adopt M -and P -helicity, respectively. The known helicity of the heterocyclic rings in (−)-50 and (+)-51 and their measured 1 Lb band CE allowed us to set a helicity rule for the unsubstituted 2,3-dihydro-benzo[b]furan chromophore [80]. P /M -helicity of the heterocyclic ring leads to a negative/positive CE within the 1 Lb band; that is, the inverse form of the tetralin helicity rule is applicable, which is attributed to the large spectroscopic moment of furan O-1.

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Substituted 2,3-Dihydro-benzo[b]furans; Effect of Substitution. On the basis of the above helicity rule, the originally reported (2R, 3R) absolute configuration of trans-norneolignans (+)-56 and (+)-57, isolated from Krameria cystisoides [84], had to be revised as (2S,3S ) (Chart 3.7, Table 3.5). Although both (+)-56 and (+)-57 have a 3hydroxyprop-1-yl aromatic substituent at C5, this was not expected to invert the helicity rule due to the small spectroscopic moment of alkyl groups. Since the ECD spectra of (+)-56 and (+)-57, published by Achenbach et al. [84], exhibit a negative CE at 281 and 285 nm, respectively, their heteroring should adopt P helicity. Taking into account that the C2 and C3 substituents are equatorial in both cases (3 J2H3H 8.9 and 9.3 Hz), their absolute configurations are (2S ,3S ). Because (+)-conocarpan [(+)-58] was chemically correlated with (+)-(2S , 3S )-56, its absolute configuration had to be revised to (+)-(2S , 3S ) as well [80, 81]. However, (+)-conocarpan [(+)-58] has a positive 1 Lb CE at 300 nm (Table 3.5), which suggested that a conjugated C5 1-propen-1-yl substituent inverts the helicity rule. With (+)-(2S , 3S ) configuration, the heteroring of (+)-conocarpan preferably adopts P -helicity to ensure the low-energy quasi -equatorial arrangement of the C2 and C3 substitutents; that is, the positive 1 Lb CE derives from P -helicity of the heterocyclic ring. This observation corroborates well the large spectroscopic moment of the 1-propen-1-yl group (q = +15). Recently, conocarpan (58) possessing a wide range of biological activites [87–89] have attracted the attention of synthetic chemists and enantioselective synthesis of (−)-(2R, 3R)-conocarpan [90, 91], and its enantiomer [(+)-(2S,3S )-58] [86] was reported, which unequivocally confirmed our configurational assignment by ECD. (−)-Epi -conocarpan [(−)-59], the C2 epimer of (+)-conocarpan [(+)-58] isolated from roots of Piper regnelli [85], was synthesized and converted to (+)-(2S, 3S )-conocarpan [(+)-58] [86], which confirmed its (−)-(2R,3S ) absolute configuration (Chart 3.7, Table 3.5). (−)-(2R,3S )-epi -conocarpan has a positive 1 Lb CE at 282 nm and a heteroring of P -helicity with an equatorial orientation of the C2 aryl group, which does not follow the expected helicity rule. The cis orientation of the C2 and C3 substituents forces the dihydrofuran ring into a nearly planar conformation and thus the third sphere contribution and especially that of the pseudo-axial C3 methyl group most likely overrides the second sphere contribution—that is, the helicity of the heteroring. Flexible unsubstituted 2,3-dihydrobenzo[b]furans (+)-52, (−)-53 and (−)-54 prepared in a stereocontrolled manner also confirmed the validity of the helicity rule

6 5

7 7′a

4

1

H 1 O

4′a

O

2A 34 5

H

H

6 5

H

H

(−)-50

H

(+)-51

O

(+)-(2S,3S)-52

7

A

R2

1

O2 3

B

R3

CH2OH (−)-(2R,3S)-53: R1,R2,R3= H (−)-(2R,3S)-54: R1 = H,R2 = OMe, R3 = OH (+)-(2R,3S)-55: R1 = OMe,R2 = OMe, R3 = OH

R1 OH

HO

R1

7 7a 1 O2 Ph 3 4a 4 CH3

O

CH3

CH3

(+)-(2S,3S)-56: R1 = H (+)-(2S,3S)-57: R1 = OMe

(+)-(2S,3S)-58 (+)-conocarpan

O OH

OH CH3 (–)-(2R,3S)-59 (–)-epi-conocarpan

Chart 3.7. Structures of 2,3-dihydrobenzo[b]furan derivatives for Table 3.5.

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

Ph O

93

CH3

H CH3 H

P-helicity 2,3-trans relative configuration pseudoequatorial Ph and Me groups

O H

H Ph

M-helicity 2,3-trans relative configuration pseudoaxial Ph and Me groups

Figure 3.9. Equlibrating conformers of (+)-(2S, 3S)-52 with the P-helicity conformer as the dominant one.

established for the unsubstituted chromophore based on the steroid derivatives (−)-50 and (+)-51. The P - or M -helicity of the heterocyclic ring is controlled by the equatorial arrangement of the phenyl group at C2 (Figure 3.9), whose contribution to the ECD is less significant compared to that of the 2,3-dihydrobenzo[b]furan chromophore, possibly because of increased mobility and distance relatively to the chirality elements. Thus, the substitution pattern of the C2 phenyl (ring B) does not influence significantly the 1 Lb band CE either; (−)-53 and (−)-54 have consistently positive 1 Lb band CE. On the contrary, the substitution of the aromatic ring A at C7 position by a methoxy group (qOMe = +21) [8] changes the sign of the 1 Lb band CE, since the homochiral (−)-54 and (+)-55 show opposite signs for the M -helicity of the heterocyclic ring. The weak negative 1 Lb band CE of (+)-55 proved that a substituent at C7 such as a methoxy group possessing a large spectroscopic moment (q) also reversed the helicity rule; that is, P /M -helicity of the heterocyclic ring leads to positive/negative 1 Lb band CD, respectively. Although chiroptical methods (ECD, ORD, and optical rotations) are extensively used in the configurational assignment of natural 2,3-dihydrobenzo[b]furan neolignans, the number of publications in which the absolute configuration of a neolignan was determined independently, by X-ray or chemical correlation, and its ECD was also measured, are very limited. Rare examples were presented by Yuen et al. [92], who characterized synthetic neolignans 60, 61, 64, and 65 by ECD and also determined their absolute configurations unambiguously by X-ray analysis and chemical correlations (Chart 3.8). The negative 1 Lb band CE of (−)-(2R, 3S )-60 confirmed our results regarding the effect of a methoxy group at C7 (Table 3.6), since its heterocyclic ring adopts M -helicity due to the equatorially oriented bulky aryl group at C2. The 7-methoxy group is quite a common substituent in numerous dihydrobenzo[b]furan neolignans, and thus its effect on the sign of the 1 Lb band CE could lead to many erroneous configurational assignment if not properly taken into account. The ECD data of the homochiral analogue (−)-(2R, 3S )-61 revealed that the introduction of an additional conjugated 3-hydroxy-1-propen-1-yl group at C5 does not induce a further change in the sign of the 1 Lb band CE in the presence of a 7-methoxy group. The ECD data of (−)-(2R, 3S )-60 and (−)-(2R, 3S )-61 also proved that the published absolute configurations of (−)-62 [93] and (+)-63 [84] are incorrect. In fact, ring B substituents do not influence the sign of the 1 Lb CE; therefore measured positive 1 Lb band CE for (−)-62 and (+)-63 should stem from P -helicity, which implies (−)-(2S , 3R) and (+)-(2S , 3S ) absolute configuration, respectively [81]. The neolignan licarin B, differing from (+)-63 in the substitution of ring B (3,4-methylenedioxy instead of 4-hydroxy), was used by Achenbach et al. [84] as an ECD reference, but its absolute configuration published by Aiba et al. [97] also has to be revised. In (−)-(2R, 3S )-64 and (−)-(2R, 3S )-65, a C5 α,β-unsatured carbonyl moiety is conjugated with the benzene ring and the resultant chromophore cannot be considered identical with the previous ones. If the intense negative CEs around 330 nm are

94

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

OMe

OMe

OMe

7

O OMe HO

HO (CH2)3

5

O

R1

3

OH

2

CH2OH

CH2OH R

(−)-(2R,3S)-60

1

CH3 2

(−)-(2R,3S)-61: R = OH, R = H (−)−(2S,3R)-62: R1,R2 = OMe (woorenogenin)

OMe

(+)-(2S,3S)-63

OMe

HO 6

O

O R

OMe

OMe

1

O2

CH2OH

OH MeOOC 5

OH HO CH3

OH

(CH2)3 5

(+)-(2S,3S)-66

(−)-(2R,3S)-64: R = CHO (−)-(2R,3S)-65: R = COOMe

O

(2S)-67 (S)-hexahydromarmesin R2

OMe R1O

O

O Ar

HO

OH (2S)-68 wutaiensol

MeO CH3 trans-(2R,3R)-69 R1 = H or allyl R2 = H or allyl

Chart 3.8. Structures of 2,3-dihydrobenzo[b]furan derivatives for Table 3.6. Ar in (2R, 3R)-69 is O-methyl-O, O-methylenepyrogallyl, piperonyl, or tri-O-methylpyrogallyl group.

TAB L E 3.6. Helicity of the Heteroring and 1 Lb Band CEs for 2,3-Dihydrobenzo[b]furan Derivatives Compound (−)-(2R, 3S )-60c (−)-(2R, 3S )-61c (−)-(2S , 3R)-62d (+)-(2S , 3S )-63d (−)-(2R, 3S )-64c (−)-(2R, 3S )-65c (+)-(2S , 3S )-66d (2S )-67c (2S )-68 (2R, 3R)-69d

Helicity M M P P M M P P P M

CE {λ, nm (ε)a or [θ]b} 296 (−1739)b 279 (−11372)b 265 (+1.0)a 295 (+1.36), 270 (+5.30)a 335 (−9862), 279 (+2240)b 376 (+806), 327 (−9884)b 263sh (+2600)b 292 (−2435)b 272 (+3223)b negative CE from ORD

Reference 92 92 93 84 92 92 85 94 95 96

reported as ε. reported as θ . c absolute configuration was determined independently from ECD data. d Revised absolute configuration. a CE b CE

taken into account, these compounds apparently follow the inverse form of the helicity rule but accompanying weaker opposite CEs indicate that the n –π ∗ transitions can make the assignment ambiguous. The neolignan (+)-(2S , 3S )-66 (Chart 3.8, Table 3.6) possesses a C5 methoxycarbonyl group, which has a large negative spectroscopic moment

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

(qCOOMe = −17) [8]. It was shown earlier that a substituent with large spectroscopic moment at C5 such as a 1-propen-1-yl group (q = +15) inverts the helicity rule of the unsubstituted chromophore. Thus a similar behavior may be expected from a C5 methoxycarbonyl substitutent; that is, P-helicity results in a positive 1 Lb CE as shown in Table 3.6. This assumption is supported by the fact that (+)-66 was isolated together with (+)-(2S , 3S )-conocarpan (58) from Piper regnellii [85], which suggests that they are most likely homochiral derivatives. The absolute configuration of (S )-hexahydromarmesin [(2S )-67] was deduced unequivocally by a chemical correlation to (S )-marmesin [94], and the negative 1 L band CE corresponds to P -helicity of its heteroring with pseudoequatorial C2 b substituent. This implies that a C6 hydroxy substituent (qOH = +20) does not invert the helicity rule of the unsubstituted chromophore. The related (2S )-68 neolignan, wutaiensol, has a C5 3 -hydroxy-1-propen-1-yl and a C5 OMe substituent, the presence of which inverts the unsubstituted helicity rule as shown earlier. Thus the published (S ) absolute configuration is in accordance with our findings, since it shows positive 1 Lb CE and its heteroring has P -helicity [95]. Gottlieb et al. [96] classified benzofuranoid neolignans into structurally homogeneous groups by constitution and ORD curves and proposed their configurational assignment. The structure (2R, 3R)-69 represents a group of neolignans with 5,6-dioxygenated benzo[b]furan chromophore. Because we have already shown that the presence of a C5 substituent with large spectroscopic moment inverts the unsubstituted helicity rule, the same is expected for the 5,6-dioxygenated chromophore. Accordingly, negative 1 Lb CEs of 69 derivatives originates from M -helicity and (2R, 3R)-69 absolute configuration. As a consequence, the absolute configurations assigned to these neolignans may have to be revised as denoted in Chart 3.5. There are numerous publications that used incorrect absolute geometries and ECD results of the presented structures for the configurational assignment of isolated dihydrobenzo[b]furan neolignans. Whenever the effect of an aromatic substitution pattern on the sign of the 1 Lb CE was not taken into account and an improper ECD reference compound was chosen for comparison, the determination of absolute configuration by ECD data led to incorrect absolute geometry [84, 85, 93, 96–104]. In contrast, there are recent publications that use the dihydrobenzo[b]furan helicity rule [80, 81] properly taking care of the substitution pattern [54, 105–107]. As an example, the C2 and C3 absolute configuration of difengpiol A (70), a neolignan with a nonprecedented C2 cyclohexenediol and a C7 methoxy substituent, was determined as (2S , 3R) on the basis of the positive 1 Lb CE and P -helicity of its heteroring (Chart 3.9). The 9,10-dihydrophenanthrofuran derivative (−)-pleionesin A (71) was isolated from the orchid Pleione yunnanensis together with three related derivatives [108] and the dihydrobenzo[b]furan helicity rule [80, 81] was applied to determine the absolute configuration. However, (−)-pleionesin A (71) contains an inherently chiral biphenyl chromophore with an axial chirality element along the biaryl axis instead of the benzene chromophore of dihydrobenzo[b]furans, and therefore the helicity rule cannot be utilized safely for the configurational assignment. Similarly, the helicity rule should not be applied whenever there is an additional benzylic chirality center in the dihydrobenzo[b]furan lignan [109, 110] as exemplified by (−)-radulignan (72) [110], in which the contribution of the benzylic chirality center may override that of the dihydrobenzo[b]furan moiety rendering the assignment ambiguous.

95

96

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Our observations in Tables 3.5 and 3.6 can be concluded in the following points and are summarized in Figure 3.10: 1. P /M -helicity of the heterocyclic ring results in negative/positive 1 Lb CE, respectively, if the aromatic ring has no other ring substituent (we refer to this statement as the unsubstituted helicity rule). 2. Substituents with low spectroscopic moment such as an alkyl or 3-hydroxypropan1-yl at C5 and possibly in other positions do not change the unsubstituted helicity rule. 3. A hydroxyl or alkoxy group at C6 does not invert the unsubstituted helicity rule even in the presence of a C4 alkyl group. 4. 2,3-dihydrobenzo[b]furans with C5 substituents having a large spectroscopic moment such as 1-propen-1-yl, CHO, COOMe, OH, OMe follows the inverse helicity rule. 5. A C7 methoxy group in the presence or absence of C5 1-alken-1-yl substituent also causes inversion. 6. Cis-dihydrobenzo[b]furans do not follow the expected helicity rule because the contribution of the pseudoaxial benzylic substituent, belonging to the third sphere, determines the sign of the 1 Lb CE.

3.3.4. Chroman Chromophore; P/M-Helicity → Negative/Positive 1 Lb CE In chroman derivatives, the magnitude of the spectroscopic moment belonging to the alkoxy part of the molecule (qOMe = +21) [8] is approximately five times larger than that of the alkyl moiety (qEt = 4.5) [8]. Therefore, similarly to the unsubstituted dihydrobenzo[b]furan chromophore, the sum vector is rotated by more than 30◦ and a sign inversion of the tetralin helicity rule is expected (Figure 3.11). On the basis of the spectroscopic moment belonging to the N -methyl group (qNHMe = 27) [8], one can predict that the same rule holds for tetrahydroquinoline chromophore as well. Structures, ECD data, helicity, and references of selected synthetic and natural chroman and tetrahydroquinoline derivatives are tabulated in Chart 3.10 and Table 3.7. The 1 Lb band CEs of rigid synthetic steroid model compounds (−)-73 and 74 and the flexible (−)-(S )-flavan [(S )-75, see conformation in Figure 3.12a], prepared with known absolute

OH OMe HO

7

6 5

1

O 2 1′ 3

4

4′

OH

3′ 2′ CH2OH OH

HO HO

O O O

(+)-(2S,3R,3′S,4′R)-70 difengpiol A 286 nm (+0.49) HO

OMe

OH

MeO

OMe

(−)-pleionesin A (71) 290 nm (+0.53)

Chart 3.9.

O O OH

OH

O

CH2OH OH (−)-radulignan (72) 290 nm (+5.0)

97

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

configuration, confirmed unambiguously the above assumptions. In fact, P/M-helicity of the chroman or tetrahydroquinoline chromophore having no aromatic ring substituents results in a negative/positive 1 Lb band CE, respectively (Chart 3.10, Table 3.7) [81, 111]. The helicity rule is also applicable to the cis-4-hydroxyflavan (−)-(2R,4R)-76, in which both the C2 phenyl and C4 hydroxy groups adopt equatorial orientation if the heteroring has half-chair conformation with M -helicity (Figure 12b) affording a positive 1 Lb band CE [81, 112]. Since the chroman chromophore frequently has aromatic ring substituents of large spectroscopic moment (such as hydroxy or methoxy groups) in natural products, the effect of ring substitution on the chroman helicity rule has to be addressed as well. Although the corresponding 5- and 7-hydroxy or -methoxy substituted rigid model compounds have not been synthesized, the effect of substitution on the chiroptical properties can be assessed from the published ECD data of natural chroman derivatives [113]. The comparison of the ECD data of (+)-catechin [(2R, 3S )-77], (−)-rubinetinidol [(2R, 3S )78], (+)-afzelechin [2R, 3S )-79], all of which have P -helicity and negative 1 Lb band CE (Figure 3.12c), with the ECD data of unsubstituted derivatives [(−)-73, (−)-75] of P -helicity proves that neither 5-hydroxy nor 5- and 7-dihydroxy substitutions of the ring A have an influence on the sign of the 1 Lb CE [81]. The same conclusion can be made

R

4

R O

R6 7 6

5

5

O1

2

3 4 R3

R1

R2

O

1

P-helicity positive 1Lb CE inverse helicity rule

P-helicity negative Lb CE unsubstituted helicity rule −R3,R4,R5,R6 = H

−R4 = 1-propen-1-yl, R3,R5,R6 = H

−R4=

−R6 = OMe, R3,R4,R5 = H or alkyl

3

alkyl or 3-hydroxypropan-1-yl 5

6

−R6 = OMe, R4 = 3-hydroxyprop-1-en-1-yl

R ,R ,R = H −R5

4

3

6

R3,R5 = H

= OH, R = alkyl, R ,R = H

−R4 = CHO or COOMe, R3, R5,R6 = H* −R4,R5 = OH or OMe, R3,R6 = H

Figure 3.10. Dependence of the 2,3-dihydrobenzo[b]furan helicity rule on the substitution pattern of the aromatic ring. *Benzaldehyde or benzoic acid methyl ester chromophore instead of the benzene.

X X chroman: X = O tetrahydroquinoline: X = NH

X μ = Σq

P-helicity negative 1Lb CE

Figure 3.11. Platt polarization diagram of the 1 Lb band for chroman (X = O) and tetrahydroquinoline (X = NH) chromophores having no substituents on the aromatic ring. P-helicity results in a negative 1 Lb band CE. Smaller arrows represent the spectroscopic moment vectors (q), while the longer one represents the electric transition moment vector (μ).

98

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

H1

1 H

2 3

R1

O

4

4

R1

R4

O

OAc

H

H

R2

(+)-(2R,3S)-80: R1,R2,R4 = H, R3 = OMe (−)-(2R,3S)-81: R1,R3 = OMe, R2,R4 = H (+)-(2R,3S)-82: R1,R2,R3,R4 = OMe

OAc

5

R2

4 H

B

R5

OH

R1 (2R,3S)-77: R1,R2,R3,R4 = OH, R5 = H (+)-catechin R4 (2R,3S)-78: R1,R3,R4,R5 = OH, R2 = H (−)-rubinetinidol (2R,3S)-79: R1,R2,R4 = OH, R3,R5 = H (+)-afzelechin

HO 6

R1 R

6

A

1 H O C3 2

(+)-(2S,3S)-83: R1,R2,R4 = H, R3 = OMe (+)-(2S,3S)-84: R1,R3 = OMe, R2,R4 = H (+)-(2S,3S)-85: R1,R2,R3,R4 = OMe

O

HO 7

R1 7

3

OH (−)-(2R,4R)-76

(−)-(S)-flavan (S)-75 R3

H

H

R2

2 3

H4 H (−)−73: X = O 74: X = NH

R4

O

2

X

R2

1 H

O

O

2

(R)-86: R1,R2 = H (S)-87: R1= H,R2 = OMe (S)-88: R1 = Me,R2 = OMe R1

O C 3

4′

8′

O

8

CH3

(−)−(R)-89

A

2

OH H

R2

(2R,4′R,8′R)-90 δ-tocopherol H6

O 2 1 Me R3 (−)-(S)-91: R1,R2,R3 = H (+)-(2R,6S)-93 (+)-(S)-92: R1,R2,R3 = OMe H

B

Chart 3.10. Structures of chroman derivatives 73–93.

on the basis of ECD data of synthetic trans-3-acetoxyflavans (2R, 3S )-80–82. Cis-3acetoxyflavans (2S , 3S )-83–85 would apparently also follow the helicity rule if their heterorings had half-chair conformation with M -helicity and equatorial C2 aryl group. However, the small coupling constants of 2-H and 3-H [for (2S , 3S )-83, 3 J2,3 = 1.5 Hz, 3 J3,4 = 4.5 and 3.0 Hz) [114] suggest that the heteroring preferably adopts a boat or twist boat conformation with axial or pseudo-axial C2 aryl group. The comparison of the ECD data of (−)-(S )-75 with those published for (R)-7-hydroxy-flavan 86 [115], having M helicity and a positive 1 Lb band CE, revealed that 7-hydroxy substitution does not invert the original rule either [81]. The positive 1 Lb CE of (R)-86 served as a reference to determine the correct absolute configuration of flavans (S )-87 and (S )-88 (Figure 3.12a), although the possible effect of an additional C5 methoxy group was not considered [115]. The ECD data of (−)-(R)-89 [116] and δ-tocopherol [(2R, 4 R, 8 R)-90] [117] corroborate the chroman helicity rule and the case of δ-tocopherol also demonstrates that the presence of a C6 hydroxy substituent does not put a limit to the empirical rule (Figure3.12d,e). Reported ECD data of synthetic [118] and natural [120] isoflavans such as those of (−)-(S )-91 and (+)-(S )-92 would suggest that isoflavans surprisingly follow an inverse helicity rule with respect to flavans; P /M -helicity of the heteroring gives positive/negative 1 Lb CE [121]. For instance, the heteroring of synthetic derivative (+)(S )-92 has a half-chair conformation of M -helicity with an equatorial C3 aryl group (Figure 3.12f), and it shows an intense negative CE at 288 nm accompanied by weak

99

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

TAB L E 3.7. Helicity and ECD Data of Chroman Derivatives Compound (−)-73c 74c (−)-(S )-75 (−)-(2R, 4R)-76 (+)-(2R, 3S )-77 (−)-(2R, 3S )-78 (+)-(2R, 3S )-79 (+)-(2R, 3S )-80 (−)-(2R, 3S )-81 (+)-(2R, 3S )-82 (+)-(2S , 3S )-83 (+)-(2S , 3S )-84 (+)-(2S , 3S )-85 (R)-86 (S )-87 (S )-88 (−)-(R)-89 (2R, 4 R, 8 R)-90 (−)-(S )-91 (+)-(S )-92 (+)-(2R, 6S )-93

Helicity

CE {λ, nm (ε)a or [θ]b}

References

M M P M P P P P P P

277 (+1.83)a 308 (+3.14)a 276 (−1.01)a 276 (+1.28)a 282 (−0.36)a 284 (−1.50)a 270 (−0.44)a 272 (−6800)b 284 (−10000)b 279 (−5100)b 274 (+6800)b 273 (+2600)b 271 (+1100)b Positive 1 Lb CE Negative 1 Lb CE Negative 1 Lb CE 278 (+0.09), 270 (+0.06)a 298 (−0.33)a 282sh (−0.60), 275 (−0.63)a,f 300 (−78), 288 (−4780), 274 (+17)b 283sh (−0.57), 276 (−0.67)

81, 111 81, 111 81, 111 81, 112 113 113 113 114 114 114 114 114 114 115 115 115 116 117

e e e

M P P M P M M M

d

118 119

CE reported as ε. CE reported as θ . c with cholestane skeleton. d unpublished ECD data. e not determined, conformation of heteroring is different from half-chair. f1 La CE: 228 (−1.39). a b

transitions at higher and shorter wavelength (Table 3.7). This finding is contradictory to the expectations, since the preferred conformation of the heteroring does not deviate from the half-chair, there is no axial benzylic substituent, and the contribution of the third sphere is not considered significant. In order to explain this discrepancy, TDDFT calculations were carried out on the synthetic isoflavan (−)-(S )-91, and, for comparison, on flavan (−)-(S )-75. In both cases, DFT-optimized geometries (at B3LYP/6-31G(d) level) were employed as input structures, which showed the heteroring in the expected halfchair conformation with helicity depicted in Figure 3.12a,3.12f. Surprisingly, none of the low-energy transitions of isoflavan (S )-91 are of pure 1 Lb character as found for flavan (S )-75. On the contrary, three transitions predicted by B3LYP/TZVP calculations between 247 and 257 nm result from a combination of exciton-coupled excitations centered on the two aromatic rings, plus charge-transfer transitions. Since exciton-coupled interactions are determined by the relative orientation of the electric transition moments, which is in turn are influenced by the substitution pattern of ring A and B, the ECD of isoflavans with different substitutions cannot be compared easily and ECD calculations should be considered for a safe configurational assignment. On the basis of the above considerations, the determination of absolute configuration for some recently reported isoflavan derivatives 94–98 using the inverse chroman helicity rule of isoflavans [121] is possibly prone to error (Chart 3.11) [122–125]. This is especially true in the presence of a conjugated double bond ring substituent as in desmodin A [(−)-94] [122] and glabridin (96)

100

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

H

(a) Ar O

H

OH

O Ph

(e)

OH

(g)

H

2

Ar

Me (2R,4′R,8′R)-90 P-helicity negative 1Lb CE

(R)-89 M-helicity positive 1Lb CE

H (2R, 3S)-3-hydroxyflavans 77-79 (2R, 3S)-3-acetoxyflavans 80-82 P-helicity negative 1Lb CE

(f) O R

O

Ar O OR

H H (2R,4R)-76 M-helicity positive 1Lb CE

(S)-flavans 75,87,88 P-helicity negative 1Lb CE (d)

H

(c)

(b)

6

O (S)-isoflavans 91,92 M-helicity negative 1Lb CE

Me O

(2R,6S)-93 M-helicity negative 1Lb CE

Figure 3.12a–g. Preferred low-energy conformations and helicity of chroman derivatives viewed from the direction of the fused aromatic ring.

O

O

O

O

Me

O

O

O

OMe

OH

Me OMe

OH

desmodin A [(−)-94]

OMe

OH

OH

desmodin B [(+)-95]

glabridin (96)

OMe

O

O

OH

HO OH isoflavan-4-ol (97)

(+)-98

Chart 3.11. Structures of isoflavans 94–97 and the homoisoflavan derivative (+)-98.

[123] or with an additional chiral dihydrobenzo[b]furan ring as in desmodin B [(+)-95] [122]. The bridged tricyclic tetrahydro-2,6-methano-2H -1-benzoxocine derivative (+)(2R, 6S )-93 also follows the inverse helicity rule; that is, its negative 1 Lb CE (Table 3.7) corresponds to a fixed half-chair conformation of M -helicity (Figure 3.12g) [119]. Due to the bridged structure, the C2–C3 and C6–C5 bonds are axially oriented and the contribution of the third sphere presumably overrides that of the second sphere (helicity of the heteroring), thus inverting the helicity rule. As a summary, the same helicity rule (P /M -helicity negative/positive 1 Lb CE) was found for the unsubstituted chroman chromophore as for the unsubstituted dihydrobenzo[b]furan, but, in contrast to the latter, methoxy or hydroxy ring substituents do not change the correlation. The chroman helicity rule can be safely utilized for the configurational assignment of flavans, cis-4-hydroxyflavans, trans-3-oxygenated flavans, and 2-alkylated chromans [81, 121], while the helicity of the heteroring is not decisive for the 1 Lb CE of isoflavan and bridged tetrahydro-2,6-methano-2H -1-benzoxocine derivatives.

101

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3.4. TETRALONE, DIHYDROISOCOUMARIN, AND CHROMAN-4-ONE CHROMOPHORES In this section, the carbonyl derivatives of tetralin, isochroman, and chroman—that is, tetralones, dihydroisocoumarins, and chroman-4-ones—are discussed, in which besides the π –π * transition, the carbonyl n –π * transition is frequently used for determination of absolute configuration.

3.4.1. Tetralone Derivatives Tetralone (3,4-dihydronaphthalen-1(2H )-one) derivatives, containing both a tetraline and acetophenone chromophore, are widespread in nature [126–134], and their n –π * transition of the conjugating carbonyl group above 300 nm may be used for the determination of absolute configuration instead of the 1 Lb band, since its sign is expected to be independent from the substitution pattern of the aromatic ring [112]. The fused carbocyclic ring of tetralones most likely adopts an envelope conformation with C3 out of the plane of the benzene ring [127], the conformation (helicity) of which is expected to determine the sign of the n –π * CE as found also for natural flavanones and isoflavanones [121]. ECD data and preferred conformation of the carbocyclic ring of natural tetralones (Chart 3.12) are tabulated in Table 3.8. For tetralones 99–103 and 105, 106 having diverse substitution pattern, the M -helicity of the fused carbocyclic ring with envelope conformation results in positive n –π* CEs, although (2S , 4R)-100 had a very weak negative low-energy CE. In contrast, tetralones 104 and 107–110 show contradictory correlations; P -helicity of the heteroring affords positive n –π * CEs. Although absolute configurations were determined independently from ECD study by either Mosher’s NMR method or X-ray analysis for 99, 100, 103, 104, 108 and 109, some of these derivatives also show an inconsistent relationship between the helicity of the nonaromatic ring and the sign of the n –π * CE. This finding suggests that in contrast to the case of flavanones and isoflavanones [121], there is no straightforward general correlation between the sign of the n –π * CE and conformation of the nonaromatic ring. A possible explanation can be that conformers other than the represented envelope one as well as the position and nature of the substituents may play a non-negligible role, which renders the configurational assignment difficult if based only on the helicity of the nonaromatic ring or a simple comparison of the ECD

O

O

OH O OH

CH2 OH

H3C

O

CH3

OH

R1 R2 R1 R2 callianthone A [(2S,4R)-101]: R1= OH, R2= H (2S,4S)-99: R1= H, R2 = OH (2S,4R)-100: R1 = OH, R2 = H callianthone B [(2S,4S)-102]: R1= H, R2= OH O

O H3C

O

O

O OH (2R,4S)-104

hemiculone [(3S,4S,1′R)-103]

OH O

OH O Me

H3C

Me OH (3S,4S)-105

Me OH

OH

pyrolone A [(3S,4S)-106]

Me R1 R2 OH pyrolone B cis-isoshinanolone 1 2 [(2R,4S)-107] (3R,4R)-108: R = OH, R = H trans-isoshinanolone (3R,4S)-109: R1= H, R2= OH

O

Ar

OH

Chart 3.12. Structures of tetralone derivatives for Table 3.3.

(3R)-110 Ar: 3,4-dihydroxyphenyl

102

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

TAB L E 3.8. Conformation of the Carbocylic Ring with Orientation of the Substituents and Their n –π * CEs Low-Energy Conformera Helicityb CE {λ, nm (ε),c [θ],d θ e}

Compound (2S , 4S )-99

f

(2S , 4R)-100f

301 (+272)d

126

OH

M

341 (−285)d 304 (+520)

126

OH

M

324 (+5.29)e

127

H

M

345 (+1.68)e

127

M

301 (+1.5)c

128

P

321 (+4160)d

131

M

333 (+1200), 323 (+1070)d

131

M

338 (+2.4), 316 (+0.8)e

130

P

323 (+2.4)

130

P

331 nm positive CEi

129

P

positive CEi

129

M

320 (−2.2)a

133

H

O H

OH

HO O H

HO O H

CH3

(2S , 4S )-102

M

HO

H

(2S , 4R)-101

Reference

HO O

OH

CH3

(3S , 4S , 1 R)-103f

H

OH O

O

H

(2R, 4S )-104f

H

H

O

OH

Me

(3S , 4S )-105g

H

Me

O

H

OH

(3S , 4S )-106 H

(2R, 4S )-107

H

O

OH

Me

(3R, 4R)-108h

OH O OH

H

H

(3R, 4S )-109h

H O OH

OH

H H

(3R)-110

Ar O

a

Envelope conformer is in equilibrium with the distorted chair but their helicities are identical. Defined by the sign of the ωC5a,C4,C3,C2 torsional angle. c CE reported as ε. d CE reported as θ . e CE reported as θ ε. f Absolute configuration was determined by Mosher’s method. g The reported absolute configuration is probably wrong and should be reassigned as (3R, 4R)-105. h Determination of absolute configuration is based on X-ray diffraction analysis of a related derivative. i From HPLC-CD. b

103

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

spectra. In this case, the configurational assignment is especially prone to errors and a thorough conformational analysis and ECD calculation cannot be spared. As an example to demonstrate what was stated, we analyzed the conformation and ECD spectra of compounds 100, 104, 105, and 109 with molecular modeling (MMFF conformational search and DFT optimization at B3LYP/6-31G (d) level) and TDDFT ECD calculations. For tetralones 100, 104, and 109, the substituents of the carbocyclic ring adopt a preferred equatorial position in the lowest-energy conformer (populations above 85% at 300 K) which constrains the ring in a more or less fixed envelope conformation with well-defined helicity (Table 3.9). The result of ECD calculations run with TDDFT method, B3LYP/TZVP level, on the three compounds are also shown in Table 3.9. Apparently, ECD calculations reproduce experimental data for 100, 104, and 109, apart from a wavelength shift, and confirm the assigned absolute configuration. However, at least in the case of tetralone (2S , 4R)-100 the assignment based on the n –π *

TAB L E 3.9. Summary of Geometry Optimizationsa and CD Calculationsb for Selected Tetralones Compound (2S , 4R)-100

Lowest-Energy Conformerc (Population)c

Structure OH O

1L

Helicity

n –π * CE λ (sign)

b CE λ (sign)

M

285 (+)

300 (−)

P

317 (+)

261 (−)

M

331 (−)f

273 (−)f

P

298 (+)a

295 (−)a

OH

HO

OH

O H

(86%)d

OH

(2R, 4S )-104

H

O

H

H

O

OH

Me (89%)d

OH

(3S , 4S )-105c

O

H

Me

O

H

OH (85%)e

OH

(3R, 4S )-109

OH

O

H O OH OH a With

OH

H (87%)d

B3LYP/6-31G(d) on MMFF-calculated low-energy minima. B3LYP/TZVP. c Optimizations with B3LYP/6-311+G(d,p) in methanol (IEF-PCM); TDDFT calculations with B3LYP/TZVP in methanol. d At 300 K, using internal energies. e Using free energies; includes two 4-OH rotamers. f Boltzmann-weighted average for four low-energy structures. The result for the absolute lowest-energy minimum was similar. b With

104

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

helicity rule must be considered fortuitous. In fact, the relative position of aromatic 1 Lb and carbonyl n –π * bands varies for the three compounds due to to the presence of OH groups hydrogen-bonded to the carbonyl. On passing from 104 (unbound C = O) to 109 (one C = O· · ·HO bond) and to 100 (two C = O· · ·HO bonds), the n –π * transition experiences the expected hypsochromic effect moving from 317 nm (104) to 298 nm (109) and to 285 nm (100). In this latter case the first calculated transition (corresponding to the negative CE observed at 341 nm) turns out to be the 1 Lb and not the n –π * one, while for tetralone 109 the two transitions are almost degenerate (and heavily mixed). Moreover, the calculated rotational strength for the n –π * transition for (2S , 4R)-100 is positive, in contrast with the M -helicity of the carbocylic ring. The conformational situation for tetralone (3S , 4S )-105 is less clear-cut because the 3-methyl and 4-hydroxy substituents are not allowed to occupy simultaneously an equatorial position. On the basis of relative conformational energies [135], the methyl group is expected to dictate the conformation of the ring, showing a stronger preference for the equatorial position than the hydroxyl group. This is confirmed by NMR experiments [131] and by our calculations. In this case, we run B3LYP geometry optimizations using a larger basis set (6-311+G(d , p)) and including a solvent model (IEF-PCM) for methanol, followed by frequency calculations to estimate true free energies. The two lowest-energy conformers show an equatorial 3-methyl group (they differ for the rotation of 4-OH) and amount to an overall population of 85%. They are followed by two other minima (overall 15% population) with axial 3-methyl and equatorial 4-OH group. ECD calculations were run with B3LYP/TZVP including again IEF-PCM for methanol and considering all four minima. Very interestingly, the average TDDFT-calculated ECD spectrum for (3S , 4S )-105 (which is dominated by the lowest-energy structure at long wavelengths) shows negative CEs for both n –π * and 1 Lb , in contrast with the experimental data (compare Tables 3.8 and 3.9). According to this outcome, the reported absolute configuration for (3S , 4S )-105 is wrong and should be reassigned as [(+)-ECD(333)]-(3R, 4R)-105. The above calculation results demonstrate that the observed n –π * CEs for tetralones depend heavily on the substitution pattern of both the aromatic and carbocyclic rings; therefore we discourage the use of the relative helicity rule for configurational assignments.

3.4.2. Dihydroisocoumarin Chromophore Optically active synthetic isochromans (S )-45a,d,c (Scheme 3.1) were converted to the corresponding dihydroisocoumarins (S )-111a–c by oxidation with Jones reagent [136] or dimethyldioxirane (DMDO) [137] as shown in Scheme 3.3 [75]. The (S )-dihydroisocoumarins 111a–c have very similar ECD patterns; positive π –π * and n –π * transitions at 278–307 nm and 252–268 nm, respectively, followed by a negative and positive band in the high-energy region (Table 3.10). Their ECD TAB L E 3.10. ECD Data for Dihydroisocoumarins (S )-111a–c Compound (S )-111a (S )-111b (S )-111c

CD λmax [nm] (ε) π → π ∗ : 289sh (+1.08), 278sh (+2.00); n → π ∗ : 252 (+4.19); 230 (−4.73), 204 (+13.83). π → π ∗ : 307sh (+1.10), 300 (+1.28), 294sh (+1.20); n → π ∗ : 268 (+7.62); 244 (−4.64), 226 (+10.48), 204 (−6.22). π → π ∗ : 304sh (+2.44), 296 (+2.48); n → π ∗ : 258 (+4.17); 239 (−1.29), 229sh (+0.67), 206 (+11.21).

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

data confirmed that regardless of the substitution pattern of the aromatic ring, the positive n –π * transition of 3-alkyldihydroisocoumarins derives from P -helicity of the heteroring and thus (S ) absolute configuration, in accordance with previous ECD studies on synthetic steroidal dihydroisocoumarin derivatives of 41–43 [74] (Figure 3.6a). The heteroring of (S )-dihydroisocoumarins 111a–c adopts a half-chair or envelope conformation with P -helicity, as defined by the positive ωC-5a,C-4,C-3,O torsional angle, to ensure the favorable equatorial orientation of the C3 methyl group (Scheme 3.3). The dihydroisocoumarin n –π * transition was consistently applied to the configurational assignment of synthetic derivatives [138] and natural products [139–144] in agreement with the above helicity rule. In order to check the applicability of the dihydroisocoumarin helicity rule for 3,4disubstituted dihydroisocoumarins, the 3,4-cis-dimethyl-dihydroisocoumarin derivative 113 was prepared by catalytic hydrogenation of (S )-(+)-ascochin (112), a natural product isolated from the endophytic fungus Ascochyta sp. (Scheme 3.4), and its chiroptical data were measured and reproduced by calculation [145]. The addition occurred with cis diastereoselectivity due to the inherent (4S ) chirality center (the formyl group was also reduced during the hydrogenation), resulting in (3S , 4S ) absolute configuration for 113. The ECD spectrum of 113 shows a negative CE at 307 nm and a positive one at 267 nm (Figure 3.13). Thus, according to the literature [74, 146], the lactone n –π * CD band should be assigned to the latter band. Interestingly, the synthetic (3S )-3-methyldihydroisocoumarin derivative 111b (Scheme 3.3) has also a positive CE at 268 nm [75], and except for this transition, its ECD curve was almost the mirror image of that of 113 (Figure 3.13). In order to confirm the position of the lactone n –π * ECD transition and hence the semiempirical rule of dihydroisocoumarins, a TDDFT calculation was carried out

(S)-45a Jones reagent (S)-45c (S)-45d or DMDO/ dry acetone

H

H 5a 4 Me 2 3 1 O

R3 R2

R1

1

4

O

O

R2 H OMe H

3

Me

R3 H OMe H

O

2

positive n-π* CE in the 252 – 268 - nm range

H

(S)-111a-c R1 111a H 111b H 111c OMe

3

Me

1

4

O

ωC-5a,C-4,C-3,O >0 P-helicity

Scheme 3.3.

O

11 6 5

HO 7

HO 11 10

10 4

9 3

1 O

HO 6 H2-Pd/C 7

8

OH O (S)-(+)-ascochin (112)

5 4 8

H 9

3

1 O

OH O (3S,4S)-tetrahydroascochin (113)

Me H4 Me

3

1

O

O

2

P-helicity ωC-8a, C-1, O, C-3 > 0

Scheme 3.4. Conversion of (S)-(+)-ascochin (112) to 113. P-helicity of 113 and DFT-calculated most stable conformation.

105

106

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

12 9 n→ π*

Δε and R [10–40 cgs]

6 3

(S)-111b

0

×10 113

–3 –6 –9 –12

200

220

240

260

280

300

320

340

λ (nm)

Figure 3.13. Measured ECD spectra of 113 (solid line) and (S)-111b (dotted line), and TDDFTcomputed rotational strengths R (vertical bars) for the absolute minimum of (3S, 4S)-113 found by DFT (Scheme 3.4).

on the absolute minimum-energy structure computed for 113 [145]. The conformational analysis of 113 resulted in a hydrogen-bonded (O-11 → HO-7) conformer as the most stable structure (1.7 kcal/mol lower DFT-energy than the second minimum), as shown in Scheme 3.4. The TDDFT CD calculation on this conformer demonstrated that the lactone n –π * CD transition of 113 appears with positive CE as the third computed transition from the red at 246 nm, namely as part of the 250 to 270-nm ECD band, overlapped with aromatic π –π * transitions (Figure 3.13). In particular, the most redshifted transition computed at 288 nm is of the 1 Lb -type, and it is apparently responsible for the weak ECD signal above 280 nm. Since 113 has (3S , 4S ) absolute configuration and P -helicity of the heteroring (Scheme 3.4), its computed positive n –π * transition is in accordance with the semiempirical rule. (S )-111b has again P -helicity, also resulting in positive n –π * CE at 268, although all the other corresponding transitions have opposite signs to those of 113, due to the different substitution pattern of the aromatic ring. Since the lactone n –π * transition is only one of the contributors to the 267-nm ECD band among several π –π * transitions, its application for a safe configurational assignment is endangered in the current case by overlapping transitions. Another example for the combined use of the dihydroisocoumarine helicity rule and TDDFT calculations is offered by natural products phomolactone A (114) and B (115), isolated from Phomopsis sp. (Chart 3.13) [147]. The n –π * CE of 114 at 262 nm is

R1 R2 6

5

5a

4

R4 3

7 3

R

8

O2

8a

OH

1

O

R1 R2 R3 114 115 116 117

OH Cl OH H OH Cl OH H

R4

H n-Pr H n-Pr H Me H Me

n-π* CE 262 (−5.84) 258 (−2.08)

Chart 3.13.

107

E L E C T R O N I C C D O F B E N Z E N E A N D O T H E R A R O M AT I C C H R O M O P H O R E S

8 6

Δε [cm2 mmol–1]

4 2 0 –2 Experimental CD of 113 Experimental CD of 114 Calculated CD of 116

–4 –6 200

220

240

260

280

300

320

340

360

λ (nm)

Figure 3.14. Measured (MeCN) ECD spectrum of 114 (solid line) compared with TDDFT-calculated ECD of (R)-116 (gray dotted line) and experimental ECD of 113 (dashed–dotted line).

negative and its high-energy ECD transitions are also opposite to those of (3S , 4S )tetrahydroascochin (113), which suggests that 114 has a heteroring with M helicity and hence (3R) absolute configuration (Figure 3.14). Dihydroisocoumarin 115 showed the same −/+/–/+ ECD pattern from the low-energy to the high-energy region as 114, which allowed its assignment as (3R) as well. TDDFT ECD calculations were employed to confirm the configurational assignment and support the ECD correlation discussed above. The calculations confirmed that neither the length of the alkyl chain nor its conformation affects the shape of ECD bands allied with the dihydroisocoumarin chromophore. Their sign is entirely determined by the ring A chirality, which is in turn dictated by the absolute configuration of C3. This finding corroborated the ECD correlation for n –π * CE of dihydroisocoumarin discussed above, and also simplified the treatment of compounds 114 and 115, instead of which we could consider the methyl analogues 116 and 117 (Chart 3.13). Figure 3.14 shows the TDDFT-calculated ECD spectrum (B3LYP/TZVP) as Boltzmann-weighted average over two DFT-optimized geometries for (R)-116, in a good agreement with the experimental spectrum of 114 below 300 nm, which confirms the absolute configuration established above as (R)-114.

3.4.3. Chroman-4-one Chromophore The chroman-4-one chromophore is found in natural flavanones, 3-hydroxyflavanones, 2-alkylchroman-4-ones, and isoflavanones exemplified by compounds 118–121 (Figure 3.15). Snatzke established a relationship between the chirality of cyclic aryl ketones and their high-wavelength n –π * CEs [148] which was extended to correlate the helicity of the heteroring and the sign of the n –π* CE in flavanones [149], 3-hydroxyflavanones [149], 2-alkylchromanones [150], and isoflavanones (Figure 3.15) [121, 151]. According to this rule, P -helicity of the heteroring adopting envelope conformation is manifested in a positive n –π * CE above 300 nm, such as in (S )-flavanone, (2R, 3R)-3-hydroxyflavanone, (R)-2-methylchroman-4-one and (R)-isoflavanone.

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1

O 4

H

H

1

O

2 3

4

R

O (S)-flavanone [(S)-118]: R = H (2R,3R)-3-hydroxyflavanone [(2R,3R)-119: R = OH

1

Me

O

2 3

4

2 3

O (R)-isoflavanone [(R)-121]

O (R)-2-methylchroman-4-one [(R)-120] H

H R

Ph O

Ph

Me O

O

O

O

O

H

H envelope conformation P-helicity positive n-π* CE

envelope conformation P-helicity positive n-π* CE

envelope conformation P-helicity positive n-π* CE

Figure 3.15. Correlation between the helicity of the heteroring in (S)-flavanone, (2R, 3R)-3hydroxyflavanone, (R)-2-methylchroman-4-one, and (R)-isoflavanone and the sign of the n–π * CE.

1

O

1

O

O

8a

2 4 5

OR

Me O

(R)-122: R = H (R)-123: R = Me

Br

C

3

3

4 2

O

H ωC8a,O1,C2,C3 > 0 P-helicity positive n→π* negative 1Lb (π→π*)

O

O

O 124

Chart 3.14. Structures of chromanones 122–124 and preferred conformation of the heteroring for (R)-122 and (R)-123.

A recent application of the chromanone n –π * helicity rule is demonstrated by the 2-methyl-chroman-4-one derivatives 122 and 123 isolated from the endophytic fungus Nodulisporium sp. with 6% enantiomeric excess (Chart 3.14) [152]. The separations of their enantiomers were carried out with HPLC using a chiral stationary phase; and then their LC/CD spectra were recorded on-line, which allowed their configurational assignment on the basis of their long-wavelength n –π * CEs (Figure 3.16). Since the first-eluted enantiomers of both 122 and 123 have positive n –π * and negative π –π * CEs around 340 and 310 nm, respectively, their heterorings adopt P -helicity, which implies (R) absolute configuration, provided that the methyl group is equatorial ly oriented [152]. In fact, the X-ray data of the p-bromobenzoate of 122 (compound 124) showed that the chromanone heteroring has an envelope conformation with torsion angles ωC8a,O1,C2,C3 44.9(7)◦ and ωC5,C4a,C4,O − 1.3(7)◦ . The equatorial position of the methyl group is further in agreement with the large coupling constant of J = 12.8 Hz observed for the transdiaxial protons 2-Hax and 3-Hax . It must be stressed that similarly to tetralone derivatives, intramolecular hydrogen bonding of the carbonyl group may cause considerable blue shift of the characteristic n –π * transition, and thus the unambiguous assignment of the n –π *

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9 6

(S)-122

n π* (R)-122

π π* 3 0 Δε

–3 (S)-123

–6 –9 –12

240

270

300

330

360

390

Wavelength (nm)

Figure 3.16. LC/CD spectra of (S)-122 (solid line), (R)-122 (dotted line), and (S)-123 (dashed line) in hexane/isopropanol 9:1.

and π –π * transitions may require ECD measurements in solvents of different polarity or excited-state calculations.

3.5. CONCLUSION The large amount of ECD data compiled on natural and synthetic derivatives containing a fused benzene chromophore makes it often possible to compare the measured ECD data of a new compound with those of analogues with known absolute configuration, allowing a fast determination of absolute configuration. The present chapter aimed to give guidelines for the scope and limitation of these correlations by discussing the safe applications and pitfalls of semiempirical helicity rules on benzene derivatives. As demonstrated by some examples, the application of high-level quantum-mechanics calculations may be extremely useful, especially in ambiguous cases, to explain the background and limitation of these semiempirical rules.

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4 ELECTRONIC CD EXCITON CHIRALITY METHOD: PRINCIPLES AND APPLICATIONS Nobuyuki Harada, Koji Nakanishi, and Nina Berova

4.1. INTRODUCTION AND HISTORICAL OVERVIEW The electronic CD exciton chirality method enables one to determine the absolute configuration (AC) of various chiral compounds in a nonempirical manner without reference to compounds with known AC [1–7]. Namely, if a compound contains two identical chromophores in a chiral position, where each chromophore undergoes an intense π –π ∗ transition, these two electrically allowed π –π ∗ transitions interact with each other to generate the so-called bisignate intense CD Cotton effects (CEs). The sign of the bisignate CEs reflects the absolute arrangements of the two chromophores in the molecule. By observing the exciton coupled CD, one can determine the AC of chiral compounds. The exciton CD is very intense and its generation mechanism is simple. Since the exciton chirality rule can be proven by derivation of quantum mechanical equations without numerical calculation as shown below, the CD exciton chirality method (ECM) is classified as a nonempirical rule. The nature and mechanism of the CD exciton coupling are explained in this chapter. The science of stereochemistry started when Louis Pasteur first succeeded in the so-called “optical resolution” of racemic tartaric acid in 1848 [8, 9], and the theory of “tetrahedral carbon atom” was then proposed independently by J. H. van’t Hoff and J. A. Le Bel in 1874 to explain the enantiomeric structures of optically active compounds (Figure 4.1) [9–12]. In 1895, A. Cotton discovered an anomalous dispersion effect in the optical rotation phenomena, which became known as the Cotton effect (CE) [13]. However, because it was not possible to determine the ACs of chiral compounds at that time, E. Fischer proposed a convention where the (D)-AC was arbitrarily assigned to (+)-glyceraldehyde as the standard of chiral organic compounds [14]. Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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Figure 4.1. Historical overview of the determination of AC.

Quantum mechanics appeared upon entering the twentieth century; and in 1928, L. Rosenfeld reported the equation expressing the rotational strength R, a parameter governing the sign and magnitude of optical rotation, which is equal to the imaginary part of the scalar product between electric transition moment and magnetic transition moment [15]. In the 1930s, physicists and physical chemists challenged to determine the AC of chiral compounds by the calculation of optical rotation, developing their own theories. For example, W. Kuhn proposed the coupled-oscillator concept based on the classical theory [16]. E. U. Condon, W. J. Kauzmann, and H. Eyring applied the quantum mechanical one-electron theory [17], while J. G. Kirkwood developed the polarizability theory [18]. However, none were sufficiently convincing to claim that ACs of chiral compounds could be determined. For example, the coupled-oscillator theory, later extended to the exciton CD theory, had been applied to compounds with regular substituents, but not to compounds with two or more chromophores. The optical rotations of target compounds were small and not suited for determining ACs. The concept of “exciton coupling” was later developed by A. S. Davydov in 1948 for studying the UV spectra of molecular crystals [19]. The history of AC determination of chiral compounds could have been quite different, if physicists and physical chemists had realized in the 1930s that the coupled-oscillator theory would be more suited for the compounds with two identical chromophores and collaborated with organic chemists to synthesize such compounds. That is, it would have been possible to determine the AC of chiral organic compounds prior to Bijvoet’s discovery in X-ray crystallography. Unfortunately, at that time, the concept of the chiral interaction between two identical chromophores had not yet been adopted. It was later that the UV exciton theory was developed by A. S. Davydov. In 1951, the AC of a chiral compound was first determined by a totally different method. Namely, J. M. Bijvoet succeeded to determine the L-(2R,3R) AC of (+)-tartaric acid by using the anomalous scattering effect of heavy atoms in X-ray crystallographic diffraction experiments [20]. It was fortunate that the AC arbitrarily selected in Fischer’s convention agreed with the results of the X-ray Bijvoet method. Later in the field of chiroptical spectroscopy, the relation between helical structures of biopolymers and chiroptical spectra was rationalized by using the so-called coupledoscillator mechanism. In 1956, W. Moffitt extended the theory to study the OR and CD

E L E C T R O N I C C D E X C I T O N C H I R A L I T Y M E T H O D : P R I N C I P L E S A N D A P P L I C AT I O N S

of proteins [21]. In 1962, I. Tinoco and co-workers applied the theory to the CD of DNAs and oligonucleotides [22]; the same year, J. A. Schellman applied the theory to helical polypeptides [23]. In these studies, the ACs of biopolymers or oligomers were already known through the AC of monomeric units determined by X-ray crystallography. In the field of organic stereochemistry, the coupled-oscillator theory was first applied in 1962 by S. F. Mason to calycanthine, a natural dimeric alkaloid with C2 symmetry [24]. The CD spectrum of calycanthine shows a positive CE at 259 nm and negative CE at 240 nm in the 1 La transition (252 nm) of the aniline chromophores, from which the AC was determined; the AC was later confirmed by X-ray crystallography [25]. It should be noted that this is the first application of the coupled-oscillator mechanism to a chiral organic compound. S. F. Mason and co-workers applied the same method to other chiral compounds, but later it became clear that some compounds were not suited for the coupled oscillator mechanism. For example, the AC of Troger’s base assigned by the coupled-oscillator method [26] was later revised by X-ray crystallography [27]. In 1969, N. Harada and K. Nakanishi reported the dibenzoate chirality rule for determining the AC of chiral glycols [28]. Here the absolute helicity between two benzoate chromophores (i.e., AC of the original glycols) could be unambiguously determined from the bisignate CEs of dibenzoates. This dibenzoate chirality rule was based on the coupled-oscillator mechanism, and it opened a general protocol for determining ACs as the CD exciton chirality method [1, 2]. In the history of the absolute configurational assignment, there were many controversies, and among them the biggest one was raised in 1972–1973 [29]. Namely, it was claimed that the ACs determined by the X-ray Bijvoet method disagreed with those assigned by the exciton coupling mechanism and that the ACs determined by the Bijvoet method had to be reversed because of an error in the Bijvoet theory. If this was true, all organic chemistry textbooks would have to be revised. In 1973, Y. Saito immediately pointed out that there is no error in the theory of the X-ray Bijvoet method [30], and H. H. Brongersma and P. M. Mul experimentally confirmed the Bijvoet method [31]. In the same year, S. F. Mason reported that the dipole velocity treatment of CD led to the correct AC [32]. In 1976, N. Harada reported the synthesis and CD of an ideal compound connecting the X-ray Bijvoet and CD exciton chirality methods (Section 4.4) [33]. It is now established that both methods lead to the same and correct AC.

4.2. OUTLINE AND PRINCIPLE OF CD EXCITON CHIRALITY METHOD The CD exciton chirality method (ECM) has been successfully applied to a variety of natural products and synthetic chiral compounds to determine their ACs. This method enables one to determine the AC of a chiral compound without any reference, that is, it is a nonempirical method [1–7]. For example, the CD and UV spectra of cholest-5ene-3β,4β-diol bis(p-bromobenzoate) 1 are illustrated in Figure 4.2, where UV spectrum shows an intense band of the allowed π –π ∗ transition at 244.0 nm, which is polarized along the long axis of the p-bromobenzoate chromophore [5]. In this region, the CD shows intense negative first and positive second CEs (λext 243.6 nm, ε −30.4: λext 236.2 nm, ε +21.2; A = −51.6) [5]; the CE at longer wavelength is called the first CE, while the shorter wavelength extremum the second CE. The exciton CD shows two CEs of similar intensity but opposite signs (Figure 4.2), which are called “bisignate” CEs. The exciton bisignate CD reflects the “exciton chirality”—that is, helical sense between two electric transition dipole moments (ETDMs) involved in the excitation:

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+40

+20

Br

group i 3β-equatorial

CD

Δε

O

3 O

0

–20

–40 UV

CD 243.6 (–30.4) 236.2 (+21.2) A = –51.6

ε × 10–4

Br

O

H

4 O O

O O

1

O group j 4β-axial

Br

4β-axial group j in rear Br

6 4

UV 244.0 (41,800)

200

300 λ (nm)

250

2

X-ray crystallographic stereoview

3β-equatorial group i in front

0

(a)

(b)

Figure 4.2. (a) CD and UV spectra of cholest-5-ene-3β,4β-diol bis(p-bromobenzoate) 1: UV in 0.3% 1,4-dioxane/EtOH; CD in 10% 1,4-dioxane/EtOH. (b) Negative exciton chirality between long axes of two p-bromobenzoate chromophores: Newman projection and X-ray crystallographic stereoview. (Redrawn from reference 5, with permission.)

(i) If the exciton CD shows negative first and positive second CEs, the two ETDMs constitute a counterclockwise screw sense as in the case of bis(p-bromobenzoate) 1 (Figure 4.2). (ii) If the exciton CD shows positive first and negative second CEs, the two ETDMs constitute a clockwise screw sense. From this relation, the AC of the target compound, namely, cholest-5-ene-3β,4β-diol, can be determined. This is the electronic CD exciton chirality method [1–7]. In the case of bis(p-bromobenzoate) 1, the π –π ∗ transition at 244 nm is polarized along the long axis of the p-bromobenzoate chromophore, and the exciton chirality corresponds to the helicity between the long axes of two chromophores. As illustrated in the Newman projection, the two long axes constitute anticlockwise screw sense generating negative first and positive second CEs. The counterclockwise screw sense between two p-bromobenzoate groups is directly observed in the X-ray crystallographic stereoview in Figure 4.2 [5].

4.2.1. Principles and Nonempirical Nature of Exciton Chirality Method The second example used for explaining the principle of the ECM is 5α-cholestane-2β,3βdiol bis(p-dimethylaminobenzoate) 2 (Figure 4.3). When two identical chromophores i and j , with intense UV π –π ∗ transition (ground state 0 → excited state a), exist in a molecule, two chromophores interact with each other to split the excited state into two energy levels (α and β states), while the ground state (0) remains unsplit [1]. This phenomenon, the exciton coupling or exciton interaction, generates two electronic transitions, from ground state 0 to excited states α and β—that is, transitions 0 → α and 0 → β. The wavefunction, energy, dipole strength, and rotational strength for the α-state

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α−state:

N

wave function, energy, dipole strength, rotational strength,

O group j O H O

H

N

β−state:

2

O group i

5α-Cholestane-2β,3β-diol bis(p-dimethylaminobenzoate) a

0 group i

β α

a

0 0 total system group j

wave function, energy, dipole strength, rotational strength,

⎯ 2) (fiafj0 – fi0fja) yaa = (1/√ E a = Ea – Vij D a = (1/2)(li0a – lj 0a)2 R a = +(1/2)ps0 Rij • ( li 0a × lj0a) yab = (1/√2) (fiafj0 + fi0fja) Eb = Ea + Vij D b = (1/2)(li 0a + lj 0a)2 R b = –(1/2)ps0 Rij • ( li 0a × lj 0a)

interaction energy, Vij = Rij –3{li0a lj0a – 3Rij–2( li 0aRij) (lj0aRij)} If Vij > 0, the a-state is lower in energy than the b-state. α-state, longer wavelength side => 1st Cotton effect. β-state, shorter wavelength side => 2nd Cotton effect.

Figure 4.3. Theoretical summary of the CD ECM.

and β-state are summarized in Figure 4.3, where Vij is defined as the interaction energy between two electric transition moments μi 0a and μj 0a . If Vij is positive, the α-state corresponds to the transition at longer wavelength, while the β-state corresponds to the transition at shorter wavelength. As shown in Figure 4.3, the rotational strength R α of the α-state is opposite in sign to that of the β-state, R β , but their absolute values are equal. Note that the sign and magnitude of R α and R β are governed by the triple product R ij • (μj 0a × μj 0a ) [1]. These equations were next applied to bis(p-dimethylaminobenzoate) 2 in Figure 4.4, where electric transition moments μi 0a and μj 0a of the benzoate chromophores were assigned as shown. Since vectors μi 0a and μj 0a are set in-phase, the interaction energy Vij becomes positive, and hence the α-state is lower in energy than the β-state. Two vectors μi 0a and μj 0a constitute a clockwise screw, and so the resultant vector (μj 0a × μj 0a ) becomes parallel to the distance vector R ij . Therefore the triple product R ij • (μj 0a × μj 0a ) becomes positive, and R α is positive, while R β is negative. This leads to the CD in Figure 4.4b, where the CE at longer wavelength (1st CE) is positive and that at shorter wavelength (2nd CE) is negative [1]. Figure 4.4c shows the UV and CD spectra of bis(p-dimethylaminobenzoate) 2, which has an intense π –π ∗ transition (λmax 307 nm, ε 54,300) polarized along the long axis of the chromophore. The CD spectrum shows positive 1st and negative 2nd CEs in agreement with the theoretical conclusion: 1st CE, λext 320 nm, ε +61.7 and 2nd one, λext 295 nm, ε −33.2. The amplitude of the exciton CD is defined as A = ε1 − ε2 , where ε1 and ε2 are ε values of 1st and 2nd CEs, respectively. In the case of dibenzoate 2, A = +94.9. From these results, the AC of the original glycol is readily determined. In Figure 4.4a, the in-phase combination of vectors μi 0a and μj 0a was considered. But we can theoretically choose another case of in-phase relation and two cases of outof-phase combination. What will happen in these cases? Due to the self-consistency of the exciton CD theory, the theoretical results agree with that in Figure 4.4b; that is, the exciton CD depends only on the mutual absolute arrangements of two long

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μi0a

O O H 2

N O

Vector product μi0a × μj0a

O

+40

O H

Parallel

Rij

group i (1) Interaction energy Vij > 0 (2) Parallel, so R α > 0,and R β < 0

H

O H O

O 3

N +20

2

Δε

(a)

OBz-dma OBz-dma

ε × 10–4

μj0a

group j

N

320 (+61.7)

+60

CD

0 307 (54,300)

in EtOH

Positive 1st Cotton –20

295 (–33.2)

λ –40 Negative 2nd Cotton

6 4 2

UV

0 200

250

300

350

λ (nm)

(b)

(c)

Figure 4.4.

Application of the CD ECM to 5α-cholestane-2β,3β-diol bis(p-dimethyl-

aminobenzoate) 2: CD and UV spectra in EtOH. (Redrawn from reference 28g, with permission.)

axes of benzoate chromophores. In application of the CD ECM for AC determination, it is unnecessary to consider the in-phase or out-of-phase combination of ETDMs. The exciton chirality governing the sign and intensity of CEs is defined as shown in Table 4.1 [1]. As discussed, the nonempirical nature of the CD ECM is easily proved, indicating the simplicity of exciton CD mechanism. Further details of the quantum mechanical molecular exciton CD theory are described in the Section 4.3.

TAB L E 4.1. Definition of Exciton Chirality Qualitative Definition

Quantitative Definition

CEs

Positive exciton chirality

R ij • (μioa × μjoa )Vij > 0

Negative exciton chirality

R ij • (μioa × μjoa )Vij < 0

Positive first (at longer wavelength) and negative second (at shorter wavelength) Cotton effects Negative first (at longer wavelength) and positive second (at shorter wavelength) Cotton effects

Source: Redrawn from reference 28g, with permission.

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121

The qualitative definition of exciton chirality is simple: If two ETDMs constitute a clockwise screw sense, CD shows positive first and negative second CEs, and vice versa. In general, intense exciton CD CEs are observed at the long axis-polarized transition, and the essential points of the ECM are summarized as follows [1]. 1. If the long axes of two interacting chromophores constitute a clockwise screw sense, the CD shows a positive first CE at longer wavelength and a negative second CE at shorter wavelength (Table 4.1 and Figure 4.5). 2. If they constitute a counterclockwise screw sense, a negative first CE at longer wavelength and a positive second CE at shorter wavelength result (Table 4.1 and Figure 4.5). Pertinent features of the exciton CD follow. 1. The intensity of the exciton CD (A value) is inversely proportional to the square of the interchromophoric distance Rij , provided that the remaining angular part is the same [1]. A(= ε1 − ε2 ) ∝ Rij −2 2. The A value of exciton split CD is a function of the dihedral angle between two transition moments. In vicinal glycol dibenzoates, the sign of the exciton split CEs remains unchanged from 0◦ to 180◦ . The qualitative definition shown in Table 4.1 is applicable to a dibenzoate with the dihedral angle of more than 90◦ . The maximum A value is around 70◦ [1]. 3. The A value is proportional to the square of absorption coefficient ε of the chromophore. Therefore, it is advisable to use chromophores undergoing intense π –π ∗ transition. In general, a weak transition along the short axis of chromophores is unsuitable.

Figure 4.5. Exciton coupled CD CEs and UV absorption band. In general, the CD zero-crossing point corresponds to λmax of UV band. (Redrawn from refernece 1, with permission.)

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4. The CEs of α and β states have identical rotational strength of opposite signs, and two CEs are conservative, satisfying the sum rule. Thus the integrated areas of positive and negative CEs are equal. 

Rk = 0

5. Rotational strength R should be origin-independent because it is a physically observable quantity. Equations in Figure 4.3 satisfy the origin-independence of rotational strength.

4.3. THEORY OF EXCITON CD SPECTROSCOPY 4.3.1. CD Spectra and Rotational Strength of CE The rotational strength R, a parameter representing the sign and intensity of a CE, is experimentally obtained from the observed CD spectra as shown in Eq. (4.1) [34]. R = 2.296 × 10−39

 ε(σ )/σ dσ

(cgs unit)

(4.1)

where σ is wavenumber. The rotational strength R is theoretically formulated by Eq. (4.2) as proposed by Rosenfeld [15]. R = Im{< 0|μ|a > • < a|M |0 >}

(4.2)

where Im denotes the imaginary part of the terms in brackets, < > denotes the integration over configuration space, μ and M are operators of electric and magnetic moment vectors, respectively. The dot stands for scalar product of two vectors, 0 and a are wavefunctions of ground and excited states, respectively. Rotational strength R is thus equal to the imaginary part of the scalar product of electric and magnetic transition moments. A Gaussian distribution approximation of a CD Cotton effect curve leads to Eq. (4.3) [1, 34]. ε(σ ) = εmax exp{−((σ − σo )/σ )2 }

(4.3)

where εmax is the maximum intensity of the CE, σo is the central wavenumber of the CE, and σ is half the band width at 1/e peak height of the Gaussian curve. From eq. (4.1) and (4.3), we obtain √ R = 2.296 × 10−39 π εmax σ/σo

(4.4)

From Eqs. (4.3) and (4.4), the CD curve is formulated as √ ε(σ ) = (σo /(2.296 × 10−39 π σ ))R exp{−((σ − σ0 )/σ )2 }

(4.5)

where σ can be evaluated from observed UV–Vis spectra. Provided that rotational strength R is calculated by Eq. (4.2), a CD spectrum can be reproduced by theoretical calculation [1, 34].

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4.3.2. Molecular Exciton Theory of a Binary System with Two Chromophores According to the quantum mechanical exciton theory, in the exciton coupling system composed of two identical chromophores i and j , exciton wavefunctions are expressed by (4.6) and (4.7), where each chromophore undergoes excitation 0 → a [1]: Ground state :

φi 0 ,

φj 0

(4.6)

Excited state :

φia ,

φja

(4.7)

The Hamiltonian operator of the coupling system is formulated as H = Hi + Hj + Hij

(4.8)

where Hi and Hj are the Hamiltonian of groups i and j , respectively, and Hij is the interaction energy term between two groups i and j . The ground-state wavefunction and energy of a binary system are expressed as ψ0 = φi 0 φj 0

(4.9)

E0 = 0

(4.10)

The singly excited state of the binary system splits into two energy levels, α and β states. For the α state, wave function : Energy :

√ ψaα = (1/ 2){φia φj 0 − φi 0 φja } α

E = Ea − Vij

(4.11) (4.12)

where Vij is the interaction energy between two groups i and j and is approximated by the point dipole approximation: Vij = μi 0a μj 0a Rij−3 {ei • ej − 3(ei • eij )(ej • eij )}

(4.13)

where μioa , μjoa , and Rij are absolute values of vectors μioa , μjoa , and R ij , respectively; ei , ej , and eij are unit vectors of μioa , μjoa , and R ij , respectively. For the terms μioa , μjoa , and R ij , see Eqs. (4.18), (4.19), and (4.31), respectively. For the β state, wave function: Energy:

√ ψaβ = (1/ 2){φia φj 0 + φi 0 φja }

(4.14)

E β = Ea + Vij

(4.15)

These equations indicate that the binary system has two electronic transitions, 0 → α and 0 → β, in UV–Vis spectrum. If Vij > 0, the α state is lower in energy than the β state, and therefore the transition 0 → α locates at longer wavelengths, while the transition 0 → β is at shorter wavelengths. The electric dipole moment operator μ of a whole system is defined as μ=



μi =



er is

(4.16)

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where μi is the electric dipole moment operator of group i , e is the elementary charge, and r is is the distance vector of electron s in group i from the origin. The electric transition moment α of the transition 0 → α is formulated as  √ (4.17) < 0|μ|a>α = μo aα = ψo μψ aα d τ = (1/ 2)(μioa − μjoa ) where  μioa =

φio μi φia d τi

(4.18)

φjo μj φja d τj

(4.19)

 μjoa =

Those are electric transition moments of transition 0 → a in groups i and j , respectively. The electric transition moment of the transition 0 → β is similarly expressed as < 0|μ|a>β = μoa β =



√ ψo μψ a β d τ = (1/ 2)(μioa + μjoa )

(4.20)

The magnetic moment operator M of a whole system is formulated as M =



M i = (e/2mc)



r is × p is

(4.21)

where m is the mass of electron, c is the velocity of light, p is is the linear momentum of electron s in group i , and × stands for vector product of two vectors. The magnetic moment operator is further changed as M = (e/2mc)



Ri × pi +



mi

(4.22)

where R i is distance vector of group i from the origin, p i and m i are linear momentum and internal magnetic moment operators of group i , respectively. The magnetic transition moment < a|M |0>α of the excitation 0 → α is calculated as  < a|M |0>α = ψaα M ψo d τ √ = (1/ 2){(e/2mc)R i × p iao + m iao − (e/2mc)R j × p jao − m jao } (4.23) where p iao and m iao are linear momentum and internal magnetic moment of group i , respectively. For the linear momentum of a group, the next equation is useful [35]: p oa = −(2π imc/e)σo μoa

(4.24)

where i is the symbol of imaginary, σo is excitation energy expressed in wavenumber units, and μoa is electric transition moment of transition 0 → a. For group i , p iao = (2π imc/e)σo μioa

(4.25)

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Accordingly, √ α = (1/ 2){i π σo R i × μioa − i π σo R j × μjoa + m iao − m jao }

(4.26)

In a similar manner, the magnetic transition moment of excitation 0 → β is calculated as √ β = (1/ 2){i π σo R i × μioa + i π σo R j × μjoa + m iao + m jao } (4.27) The dipole strength D α of a binary system for the excitation 0 → α is expressed as D α = (1/2)(μioa − μjoa )2

(4.28)

D β = (1/2)(μioa + μjoa )2

(4.29)

Similarly,

Rotational strength R α of the α state is derived from Eqs. (4.2), (4.17), and (4.26): R α = Im{< 0|μ|a>α • α } = (1/2)Im{(μioa − μjoa ) • (m iao − m jao )} + (1/2)π σo R ij • (μioa × μjoa )

(4.30)

where R ij is the interchromophoric distance vector from group i to group j and is defined as (4.31) R ij = R j − R i Similarly, β

R β = Im{< 0|μ|a>β • < a|M |0 >} = (1/2)Im{(μioa + μjoa ) • (m iao + m jao )} − (1/2)π σo R ij • (μioa × μjoa )

(4.32)

In the case of π → π ∗ transition of common molecules, internal magnetic transition moments m iao and m jao are negligible. Therefore, rotational strengths are approximated as: (4.33) R α = +(1/2)π σo R ij • (μioa × μjoa ) R β = −(1/2)π σo R ij • (μioa × μjoa )

(4.34)

These equations indicate that the CEs of α and β states have equal intensity but of opposite signs. Thus exciton CD satisfies the sum rule.  (4.35) RA = R α + R β = 0 The rotational strength is proportional to the triple product of interchromophoric distance and electric transition moments of groups i and j . Therefore, provided that chromophores exhibiting intense π –π ∗ transitions are used, intense exciton CEs are observable. The rotational strengths of exciton CD satisfy the origin-independence as shown in Eqs. (4.31), (4.33), and (4.34).

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4.3.3. Exciton CD of N-mer and Dimer: Quantitative Definition of Exciton Chirality The exciton theory is applicable to UV–Vis and CD spectra of N -mer having N identical chromophores [1]. When N chromophores undergoing intense π –π ∗ transition (0 → a) interact with one another, the excited state splits into N energy levels. The wavenumber σk of k th excitation is formulated as  Cik Cjk Vij (4.36) σk − σo = 2 where coefficients Cik and Cjk are obtained by solving the N th-order secular equation. The rotational strength R k is expressed as R k = −π σo



Cik Cjk R ij • (μioa × μjoa )

(4.37)

For the N -mer, CD curve is formulated as  √ ε(σ ) = {σo /(2.296 × 10−39 πσ )} R k exp{−((σ − σk )/σ )2 }

(4.38)

The Taylor expansion of Eq. (4.38) against σk /σ around σo /σ gives the second term of expansion as √ ε(σ ) = {2σo /(2.296 × 10−39 π σ )} exp{−((σ − σo )/σ )2 }{(σ − σo )/σ }  × R k {(σk − σo )/σ } (4.39) From Eqs. (4.36), (4.37), and (4.39), the CD equation of N -mer is obtained: √ ε(σ ) = {4 π σo2 /(2.296 × 10−39 σ 2 )}{(σo − σ )/σ } exp{−((σo − σ )/σ )2 }        (4.40) × Cik Cjk R ij • (μioa × μjoa ) Cik Cjk Vij It should √ be noted that for α state √ in the case of a binary system, √ the coefficients √ are always 1/ 2 and −1/ 2, and for β state they are 1/ 2 and 1/ 2, for any mutual configuration of two identical chromophores. Therefore, Eq. (4.40) is simplified as √ ε(σ ) = {2 π σo2 /(2.296 × 10−39 σ 2 )}{(σo − σ )/σ } exp{−((σo − σ )/σ )2 } × R ij • (μioa × μjoa )Vij

(4.41)

This is the exciton CD equation of a binary system. The next term of Eq. (4.41), √ {2 π σo2 /(2.296 × 10−39 σ 2 )}{(σo − σ )/σ } exp{−((σo − σ )/σ )2 } represents an anomalous dispersion curve with positive and negative extrema. The sign and intensity of exciton CD depend on the quadruple term R ij • (μioa × μjoa )Vij . Therefore, the term R ij • (μioa × μjoa )Vij is adopted as the quantitative definition of exciton chirality. This term is also expressed as R ij • (μioa × μjoa )Vij = Dioa Djoa Rij−2 eij • (ei × ej ){ei • ej − 3(ei • eij )(ej • eij )} (4.42)

E L E C T R O N I C C D E X C I T O N C H I R A L I T Y M E T H O D : P R I N C I P L E S A N D A P P L I C AT I O N S

where Dioa and Djoa are transition dipole strengths of groups i and j , respectively. From this equation, it is suggested to use chromophores undergoing intense π –π ∗ transition in the UV–Vis spectrum for obtaining intense exciton CD. This equation also indicates that the exciton CD amplitude is inversely proportional to the square of the interchromophoric distance Rij .

4.3.4. Theoretical Simulation of Exciton CD As discussed above, the ECM is simple in mechanism, and exciton CD spectra were simulated by various theoretical methods. There were reported examples of simulation by the DeVoe coupled oscillator method [1, 6, 36], the π -electron SCF-CI-DV MO method [1; See Chapter 5, this volume], and more recent ab initio and related MO methods—for example, TDDFT B3LYP/6-32G(d) [37]. For complex CD spectra and molecules, the TD-HF/6-31G(d), TDDFT B3LYP/6-32G(d), and CAM-B3LYP/6-32G(d) methods would be very useful (see theoretical chapters). The simulations are important for confirming the ACs determined by the ECM, and these theoretical methods provide better understanding of the CD generation mechanism.

4.4. THE CONSISTENCY BETWEEN X-RAY BIJVOET AND CD EXCITON CHIRALITY METHODS These methods are based on totally different physical phenomena, but they should give the same AC for a specific compound. However, it was claimed in 1972 that the ACs determined by X-ray and CD exciton methods disagreed and that the ACs determined by the X-ray Bijvoet method should be revised [29]. This claim was based on the X-ray and CD analyses of compounds (–)-5 and (+)-6 in Figure 4.6, where the CD of the weak 1 Lb transition (∼290 nm) of aniline chromophore polarized along the short axis was analyzed as an exciton couplet. However, this claim was subsequently retracted. Note that the ECM should be applied to an intense UV transition (Section 4.5), but not to a weak UV transition. In 1976, the synthesis and CD spectrum of a chiral cage compound (+)-3 with two anthracene chromophores as an ideal model for ECM were reported [33]; the results unambiguously proved the consistency between X-ray Bijvoet and CD exciton methods (Figure 4.6). Compound (+)-3 was synthesized from diester (+)-4, which was chemically correlated with compounds (−)-5 and (+)-6. The ACs of (−)-5 and (+)-6 had been determined by the Bijvoet method [38]. As expected, compound (+)-3 showed strong exciton-coupled CD CEs at the strong 1 Bb transition of anthracene polarized along the long axis: λext 268.0 nm (ε +931.3), 249.7 (−720.8), A = +1652.1 (Figure 4.6), showing that the strong UV transition gives rise to intense the exciton coupled CD. Since the UV π –π ∗ transition at 267.2 nm is polarized along the long axis of the anthracene chromophore, the exciton split CEs at 268.0 nm and 249.7 nm are generated by the exciton coupling between two ETDMs of anthracene groups. The long axes of the anthracene moieties constitute a clockwise screw sense leading to positive first and negative second CEs, and therefore the AC of compound (+)-3 was determined as shown. This result agrees with that determined by the X-ray Bijvoet method (Figure 4.6) [33]. Another controversy regarding the ACs of clerodin (7) and related diterpenes should be noted. In 1962, the AC of clerodin 7 [39] was determined by the X-ray Bijvoet method, which was opposite to the AC shown in Figure 4.7 [40]. Since this AC was believed to

127

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Figure 4.6.

CD and UV spectra of (6R,15R)-(+)-6,15-dihydro-6,15-ethanonaphtho-[2,3c]pentaphene 3 in dioxane/EtOH, and chemical correlation between compound 3 and related compounds. (Redrawn from reference 33a, with permission.)

(−)-clerodin 7

3-epicaryoptin derivative bis(p-Cl-benzoate) 9

steroidal model 11

Figure 4.7. Correct ACs of (–)-clerodin 7 and related compound 9, and comparison of exciton CD of compounds 9 and 11.

be correct, clerodin 7 had been used as a reference of AC for newly isolated compounds of the clerodane family for many years. For example, in 1974 the AC of 3-epicaryoptin 8 was determined by comparison of CD and chemical correlation with 7 [41]. At the same time, an unexpected result was reported; the CD ECM was applied to 3-epicaryoptin derivative 3,6-bis(p-Cl-benzoate) 9, but the observed positive couplet was opposite to the negative couplet expected from the AC of 9, which was based on the X ray of 7. To explain the discrepancy, it was postulated that one of the benzoate groups is twisted by an intramolecular H bond, generating a positive exciton chirality, and the result was reported as an exception of the CD ECM [41]. To solve the problem of this unexpected discrepancy, the steroidal model compound 11 was synthesized in 1978 [42], because compounds 9 and 11 have the same relative

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configurations at key positions (Figure 4.7). The CD spectrum of 11 showed a positive couplet, concluding that the conformation of the benzoate group was not twisted by an H bond. Since 3,6-bis(p-Cl-benzoate) 9 and 11 showed CD couplets of the same sign, 9 should have the same AC as 11. From the exciton CD and molar rotation data, the ACs of clerodane diterpenes 7 and 8 were reversed [42]. The revised ACs were confirmed by X-ray analysis later [43]. Unfortunately, the incorrect AC of clerodin 7 had been used as a reference of the clerodane diterpene family for about 16 years.

4.5. SUITABLE CHROMOPHORES FOR THE CD ECM AND EXAMPLES It is essential to select suitable chromophores for the application of the CD ECM. The following issues should be considered: (i) intense π –π ∗ transition, (ii) unambiguous direction of ETDM, and (iii) symmetrical structure. Figure 4.8 shows typical chromophores useful for the CD ECM, in which arrows show the ETDM direction leading to exciton coupled CD. In general, the long-axis polarized transitions are suitable for exciton CD, because of the larger UV intensity. (a) Para-Substituted Benzoate Chromophores for Glycols The intramolecular CT or 1 La transition (230–310 nm) of para-substituted benzoate chromophores has been used for determining the AC of many glycols [1, 3]. The intramolecular CT transition is polarized along the long axis of the benzoate chromophore, which is almost parallel to the alcoholic C–O bond. Therefore, the AC of

Chromophores for -OH groups: O X O X = H, Br, OMe, NMe2 230–310 nm O

Ph O

X

N

X = OMe, NMe2 O 300–360 nm

Ph N

270 nm fluorescent

M = 2H, Zn, Mg

For -C=C- groups:

O

N

O

O 260 nm fluorescent

280 nm fluorescent

230 nm fluorescent

Ph

O O

Me2N

MeO

N 305 nm

O 260 nm

O 350 nm

O

420 nm fluorescent

For -COOH groups:

O

Me2N

N Ph

O

For -NH2 groups:

O

O

O 235 nm fluorescent

N M

HN

N

N M

Ph N

N

M = 2H, Zn, Mg Ph 420 nm fluorescent

Figure 4.8. Chromophores useful for the CD ECM, where arrows show the direction of ETDM. (Redrawn from reference 5, with permission.)

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the glycol part can be determined from the exciton CD data. In contrast, ortho- and meta-substituted benzoate chromophores are not suited, because their ETDMs are not parallel to the alcoholic C–O bond. (b) Cinnamate, β-Naphthoate, and Other Chromophores for Glycols These chromophores are characterized by their strong absorption at longer wavelengths [44]. (c) Tetraphenyl-Porphyrin-Carboxylic Acid (TPP-COOH) Tetraarylporphyrins and their zinc and copper analogues deserve special attention as chromophores. They possess a very intense, sharp, and narrow Soret band, which is red-shifted to ∼420 nm and has ε ∼450,000–550,000. These porphyrins and metalloporphyrins belong to the most powerful and versatile CD chromophores [45–47]. One of the first examples for application of porphyrin in structural studies includes the red-tide toxin brevetoxin, where the CD exciton coupling was observed over a long distance of ˚ [45, 47, 48]. A detailed discussion on the application of porphyrins as CD ∼40–50 A reporter groups as well as an account of the theoretical analysis of porphyrin-porphyrin exciton interactions can be found in references 45–47. The Soret band originates from the two degenerate transitions Bx and By (Figure 4.9), which are perpendicular to each other; theoretically the porphyrin Soret band should be considered as a circular oscillator [46, 47]. However, due to the rotational flexibility around the meso porphyrin 5-C-phenyl junction (librational averaging), the transitions Bx and By can be represented by one effective transition moment along the 5–15 axis (Figure 4.9), and the exciton CD reflects the chirality between two effective transition moments. The large ε value and red shift of Soret band above 400 nm where most other chromophores do not absorb make the TPP-COOH extremely useful and versatile chromophore for exciton CD analysis. The typically very intense couplet can be measured with a high S /N ratio at very low concentration; thus it allows reliable studies on a microscale and, as mentioned above, also in cases where a very long-range coupling is involved [45, 48, 49]. Bx

15 N N 5 Ph M N N Effective transition moment

Ph

By X

3 O O

3α,17β

13, M: Zn2+ . UV-Vis: 419 nm ε 550,000 (CH2Cl2) fluorescence: λem 646, Φf 0.10

OR

TPP-COOH

O 17 O

12, M: H, H. UV-Vis: 418 nm ε 440,000 (CH2Cl2) fluorescence: λem 650, Φf 0.12

O

Δε +200 CD

+100

A = +270

0 –100

416 nm (–117) 419 nm (914,000)

–200

419 nm (550,000) monomer

350

1

bis (Zn-TPP) derivation CH2Cl2

UV-Vis

X Rij

14, X = H e = 15,000 Rij = 13.6 Å no coupling

424 nm (+153)

e × 10–6

Ph

400

0 450 λ (nm) 500

15, X = NMe2 e = 28,000 Rij = 13.6 Å A = +21 16, X = TPP e = 440,000 Rij = 24.4 Å A = +193 17, X = Zn-TPP e = 550,000 Rij = 24.4 Å A = +270

Figure 4.9. (Top) UV–Vis, and fluorescence data for TPP-COOH and its derivatives. (Bottom) CD and UV–Vis data of steroidal bis(tetraarylporphyrin) derivatives 16 and 17 together with corresponding benzoate derivatives 14 and 15. (Redrawn from reference 5, with permission.)

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The large steric size of porphyrin chromophores, however, calls for attention when they are introduced at vicinal positions, such as in diols, polyols, diamines, and amino alcohols. The steric repulsion between bulky porphyrins may cause conformational changes upon porphyrin derivatization; therefore additional conformational studies by NMR or molecular modeling are recommended [47]. Figure 4.9 illustrates the striking increase in the A value seen in tetraarylporphyrin (TPP) and its Zn derivative (Zn-TPP) compared to p-dimethylaminobenzoate at the Rij ˚ (Figure 4.9). Other examples for efficient porphyrin–porphyrin CD distance of 24.0 A ˚ can be found [48]. coupling over 40–50 A (d) Benzamide, Phthalimide, and 2,3-Naphthalenedicarboximide Chromophores for Diamines and Amino Alcohols The CD ECM is also applicable to the intramolecular CT band of benzamide groups [1]. The transition is polarized along the long axis of the chromophore. However, in some cases such as N -methyl benzamides, the benzamide moiety exists as a mixture of (E ) and (Z ) isomers, and therefore, the mutual orientation of the ETDMs is uncertain. Thus in these cases, one should be cautious in assigning AC by exciton CD [50]; see Section 4.10 (1). The C2v -symmetrical phthalimide and 2,3-naphthalenedicarboximide chromophores are ideally suited for the ECM application to diamines and amino alcohols, because their long axis-polarized ETDMs are exactly parallel to the amine C–N bond [51, 52]. For example, the 2,3-naphthalenedicarboximide chromophore exhibits an intense 1 Bb transition around 260 nm, which is polarized along the long axis of the chromophore. Figure 4.10 shows the CD and UV spectra of trans-1,2-cyclohexanediyl bis(2,3-naphthalenedicarboximide) (1R,2R)-(−)-18, where the UV 1 Bb transition shows +100 in 10% 1,4-dioxane-EtOH

+50

O –50 Δε

H N O O

CD

–100

H N O (1R,2R)-(–) CD 264.8 (–154.6) 257.5 ( 0.0) 251.9 ( +38.9) UV A = –193.5 UV 259.0 (94,600) 252.2 (97,400)

–150

–200

200

250

300

350

ε x10–4

0

20

O

H

N H N

OO

H 18

(A) NMR: J1-H,2-H = 11.9 Hz

O

O

N

O

15 10

O

N

H O

(B)

5 0

400

λ (nm)

Figure 4.10.

CD and UV spectra of (1R,2R)-(−)-trans-1,2-cyclohexanediyl bis(2,3-naph-

thalenedicarboximide) 18 in 10% 1,4-dioxane/EtOH. (Redrawn from reference 52.)

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two split bands. This split represents the exciton coupling, because the UV spectrum of mono(2,3-naphthalenedicarboximide) shows a single band in this region. The CD showed negative first and positive second CEs (λext = 264.8 nm, ε −154.6; λext = 251.9 nm, ε +38.9; A = −193.5). From the negative A value, a counterclockwise helicity between two long axes of 2,3-naphthalenedicarboximide chromophores was assigned to compound (−)-18, leading to the (1R,2R)-AC [52]. Note that compound (−)-18 can take diequatorial conformer (A) and diaxial conformer (B) as shown in Figure 4.10. In general, conformer (A) is considered to be more stable than conformer (B). However, if the electric repulsion between two polar groups is strong, conformer (B) may become more stable. To confirm the conformational preference of (A), the measurement of 1 H NMR coupling constant J1,2 is crucial. However, since these two protons are equivalent, it is not possible to determine J1,2 by regular 1 H NMR spectroscopy. Hence, the 13 C satellite signal method was used to give J1,2 = 11.9 Hz, indicating that conformer (A) was more stable than (B) [53]. Figure 4.11 illustrates a submicroscale chemical protocol developed for the analysis of sphingosines and dihydrosphingosines isolated from new cell lines. First the NH2 group of d-erythro-sphingosine 19 was blocked as a naphthalimide group yielding a derivative 20. Then the OH groups were converted to 2-naphthoate groups yielding derivative 21 that could be sensitively detected by HPLC, mass spec, CD and fluorescence analyses. The relative and ACs were assigned by comparing the observed CD with the standard CD curves of erythro- and threo-sphingosines/dihydro-sphingosines [54]. (e) Chromophores for Carboxylic Acids and Olefin Compounds The chromophores suitable for chiral carboxylic acids are listed in Figure 4.8. The application of the ECM to olefin compounds is unique. The isolated olefin group shows a π –π ∗ transition below 200 nm, and therefore the exciton method is not applicable in a straightforward manner. However, the double bond can be transformed via olefin metathesis into chromophores (see Figure 4.8) that absorb at longer wavelength, so that the entire exciton couplet can be conveniently measured [55]. (f) Compounds with Preexisting Chromophore that Interfere with Exciton CD: Use of Red-Shifted Chromophores When a natural product has a preexisting chromophore that could interfere with observation of exciton CD, chromophores with a longer wavelength UV λmax than the preexisting chromophore can be used to avoid overlap of CEs. Red-shifted chromophores for derivatization of hydroxyl groups are shown in Figure 4.12. For amino groups, the red-shifted

fluorescent fluorescent

NH2 HO

C13H27

OH D-erythro-sphingosine 19 50 μg

O N O

O N O

λmax 258 nm λem 370 nm

C13H27

HO OH

20

C13H27

O O λmax 234 nm λem 360 nm

O

O 21

Figure 4.11. By a selective two-step microscale chemical derivatization procedure, two different types of chromophores are introduced in D-erythro-sphingosine 19.

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Δe 263 (+25) +20

N O O

chrom-1

O chrom-3

N O chrom-2

O

UV λmax 382 nm (ε 27,000)

+10

CD

O

UV λmax 382 nm (e 34,000) UV λmax 410 nm (e 37,000) RO OR

389 (+16) e × 10–4

Me2N

0 –10 –20

22a 412 274 (58,000) (63,000)

22b 8 455 (–25)

O O-Cin H OAc : 22a, R = H : 22b, R = chrom-3 ester

6 4

H

UV 2 200

300

400

500 λ (nm)

0

Figure 4.12. Red-shifted chromophores and application to taxinine. (Redrawn from reference 57, with permission.)

chromophores, such as Schiff bases and cyanine dyes, are also useful for exciton CD analysis, in particular, when it is desirable to avoid possible interference with other electronic transitions present in the substrate [56]. As shown in Figure 4.12, taxinine derivative α-glycol 22a exhibits an intense CE around 263 nm due to the π –π ∗ transition of the highly strained enone group. In the previous application of the ECM, unsubstituted benzoate chromophores were used where a negative exciton couplet was clearly observed despite the overlap with the enone CE [28a]. However later, to avoid the overlap, a red-shifted chromophore (chrom-3) was used for derivatization to yield ester 22b. As expected, the CD of 22b showed a clearer negative exciton couplet indicating a counterclockwise screw sense between the two hydroxyl groups in full agreement with the previous report of the AC [57].

4.6. THE USE OF PREEXISTING CHROMOPHORES IN NATURAL PRODUCTS FOR EXCITON COUPLING Some natural products already have one or two chromophores such as those shown in Figure 4.13, which can be used in exciton CD to determine their ACs.

Figure 4.13. Exciton CD chromophores found in natural products.

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(a) Substituted Benzene and Polyacene Chromophores for the CD ECM As demonstrated in Section 4.4, the long-axis polarized 1 Bb transition of polyacene chromophores is ideally suited for observing exciton coupled CD, because of large ETDM. The UV data of polyacenes with D2h symmetry are shown in Figure 4.13. In the polyacene systems, there is no ambiguity for determining the long and short axes, and therefore the CD ECM leads to clear-cut conclusions. (b) Conjugated Dienes, Enones, Ene-Esters, Ene-Lactones, and DieneEsters as Exciton CD Chromophores The moieties in Figure 4.13 are useful chromophores for the CD ECM. The transition moment of their π –π ∗ band is almost parallel to the chromophoric long axis. (c) Natural Products with Two Chromophores Showing Exciton CDs The exciton coupling CD mechanism is applicable also to compounds already having two different chromophores, which exhibit long-axis polarized π –π ∗ transitions at different wavelengths—that is, i.e., nondegenerate system. The ACs of some natural products, such as those in Figure 4.14, were established by direct analysis of their CD spectra. In such cases the interaction of at least two preexisting chromophores leads to exciton split CDs. For abscisic acid (23), the opposite AC was once assigned, but it was later revised as shown by several studies. One was the application of exciton CD to the interaction between the enone and diene-carboxylic acid chromophores showing a positive couplet [58]. The case of quassin (24) is unique because of the exciton coupling between two identical preexisting α-methoxy-enone groups [59]. The AC of dendryphiellin F (25) was determined by exciton CDs from the interaction between diene and diene-carboxylate chromophores [60], while that of arnottin II (26) was determined from the dehydrotetralone and phthalide chromophoric interaction [61]. The AC of a derivative of vinblastine 27, a dimeric alkaloid, was originally determined by X-ray crystallography (Figure 4.15) [62]. Experimental and theoretical CD studies were carried out to clarify the CD mechanism of vinblastine and related compounds [63, 64]. The molecule 27 can be considered as containing two moieties, that of cleavamine 27a and that of vindoline 27b, both of which exhibit the intrinsic CD CEs due to their own local chirality [64]. In addition, an exciton-coupled through-space interaction between them takes place (Figure 4.15). To obtain the net exciton CD, the intrinsic CD bands were subtracted from the CD of 27. The resulting “difference CD” appeared as an intense positive couplet around 220 nm (Figure 4.15d), generated by the positive exciton chirality between 1 Bb transition moments of the indole and indoline chromophores at 225 nm and 215 nm, respectively, and by that confirming the (S ) AC at 16’-C.

Figure 4.14. Natural products with two preexisting chromophores showing exciton CD.

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(a)

(c)

27 λ (nm)

(b)

(d)

λ (nm)

Figure 4.15. (a) Vinblastine 27 consists of cleavamine 27a and vindoline 27b. (b) ETDMs of indole and indoline chromophores. (c) The sum CD spectrum (dotted line) = CD(27a) + CD(27b), and CD spectrum of 27. (d) Difference CD = CD(27) − {CD(27a) + CD(27b)}. (Redrawn from reference 64, with permission.)

4.7. SUPRAMOLECULAR APPROACH IN THE ECM: APPLICATION OF PORPHYRIN TWEEZERS The use of tetraarylporphyrins and their metal derivatives as CD chromophores has initiated a new supramolecular approach for the determination of the AC of chiral compounds containing a single stereogenic center and one site for chromophoric derivatization. This group includes various natural products carrying only a single functionality, such as secondary hydroxyl, primary or secondary amino, and carboxyl groups. These compounds are unsuitable for application of the conventional ECM where at least two intramolecularly interacting chromophores are required. The supramolecular approach employs a dimeric zinc porphyrin reagent 31, now commercially available as “Zn-tweezers,” which is capable of forming 1:1 host–guest complexes upon adding a solution of N,N -bidentate conjugate 30, prepared by reacting the chiral substrate 28 with an achiral carrier 29 as shown in Figure 4.16 [65]. The application of the porphyrin tweezers method to (S )-α-(2-naphthyl)ethanol is shown in Figure 4.16b. The formation of 1:1 sandwiched chiral host–guest complex 34

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M N N Zn N N

H chiral XH substrate 28

M L X = O, NH

HO

M L

X

H N

N N Zn N N

NH2

Zn

L H O

:N H

P-1 HH N:

Zn

conjugate 30 (guest)

+ O

O

H

P-2 O

H N carrier 29

O O O O 1:1 host-guest complex 32

Zn porphyrin host 31 “tweezer”

NH2 (a)

+100 M H3C O

P-1

O :N H

P-2

P-1

P-2

H tweezer

M

L

M

L

HH N:

chiral conjugate 33 of (S)-abs. config

+50 Δε 0 –50

host-guest complex 34 –100

preferred conformation

433 nm (+91)

CD A = +170

e × 10–5

L

423 nm (–79)

15 10

422.2

416.6

UV/Vis 400

420

440 λ (nm)

5 0

(b)

Figure 4.16. Porphyrin tweezers method: (a) Preparation of bidentate conjugate 30 from chiral substrate 28 and carrier 29; Formation of a 1:1 host guest complex 32 with Zn-porphyrin tweezers 31. (b) Example of (S)-α-(2-naphthyl)ethanol conjugate 33: two conceivable conformations of complex 34; observed CD spectrum of 34 in methylcyclohexane. (Redrawn from reference 65b, with permission.)

from conjugate 33 proceeds under steric control and leads to positive first and negative second CEs in the Soret region. The origin of the intense exciton CEs is due to a preferred conformer with a clockwise interporphyrin twist, where the larger group L (2-naphthyl) protrudes from the binding pockets in order to avoid unfavourable steric interactions. The interporphyrin twist in the complex is thus dictated by the steric orientation of L (2-naphthyl) and M (methyl) at the stereogenic center of the substrate. When there is no ambiguity in the assignment of L and M groups, the sign of the couplet determines the AC at this center. Recently, a more reliable discrimination of preferred interporphyrin helicity of the host–guest complexes by theoretical analysis of both steric and electronic factors involved in stereocontrolled complexation process has become possible. This analysis relied on molecular mechanics calculations by Merck Molecular Force Field (MMFFs) or OPLS2005 approaches coupled to Monte Carlo-based conformational analysis and quantum mechanical treatment of free conjugates [66–68]. The porphyrin tweezers method is now well established and has allowed successful determinations of AC of some natural products, such as isotomenoic acid 35, an irregular diterpene [69], and bovidic acid 37, an 18-carbon hydroxyfuranoid acid [70] (Figure 4.17). More recently, other types of porphyrin-based tweezers have been developed. Structural changes in the tweezers, such as introduction of various substituents at the aryl groups and in the bridge between the two porphyrins, allow for tuning the complexation ability

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O H OH O

s P-2

15

Zn Isotomenoic acid 35

H O N H

5

O O

MeO P-1 NH2 15′ HO Zn 5′

36

O O

O

H H O 6

OH

9

4

O

P-2 O 5

15

Zn Bovidic acid 37

6

H

N H

15′

N Zn H2

5

O O

P-1

O

5′

38

O O

Figure 4.17. Applications of the porphyrin tweezers method to natural products.

of the tweezers and extension of its application to other types of chiral substrates [67, 71, 72].

4.8. APPLICATION OF THE CD ECM: FUNDAMENTAL EXAMPLES As shown, there exist numerous applications of ECM. In the following, some selected examples of fundamental application are explained.

4.8.1. Exciton Coupling Between Polyacene and Related Chromophores Polyacenes (e.g., naphthalene and anthracene) are ideal chromophores for exciton coupling, because the long and short axes are clearly assigned, and the long-axis polarized transition has a large ETDM, yielding intense bisignate CEs. Chiral 1,1 -binaphthyls are typical atropisomers showing exciton CEs. For example, (S )-1,1 -binaphthyl-2,2 -dimethanol 39 shows intense positive first and negative second CEs (λext 231.3 nm, ε +342.4: λext 224.3 nm, ε −329.0; A = +671.4) in the longaxis 1 Bb transition (λmax 224.4 nm, ε 132,700) (Figure 4.18). The positive A value leads to an (S ) AC [1]. The exciton CD sign depends on the dihedral angle between two naphthalene planes. From the theoretical viewpoint, the exciton CD of 1,1 -binaphthalene compounds undergoes sign changes around 110–120◦ [73]. Therefore, in the application of the ECM, information of the dihedral angle is necessary. In most cases, the dihedral angle is distributed around 90◦ , which was supported by X-ray crystallography [74] and MO calculations. Chiral 1,1 :4 ,1 -ternaphthalene-2,2 -dimethanol (aS,aS )-(+)-40 with three naphthalene groups in positions of axial chirality is a unique atropisomer [75]. Enantiopure compound (+)-40 was prepared by the CSDP acid method. As shown in Figure 4.18, the CD spectrum of (aS,aS )-(+)-40 shows intense negative first and positive second CEs (λext 231.7 nm, ε −333.9: λext 223.4 nm, ε +225.4; A = −559.3) in the long-axis 1 B transition (λ b max 224.0 nm, ε 186,500). In Figure 4.18, chromophores 1 and 2 constitute a counterclockwise screw, and the same negative screw holds for chromophores 2 and 3, because of C2 -symmetry. However, chromophores 1 and 3 have no helicity because the long axes of naphthalene moieties 1 and 3 are almost parallel to each other. Thus the AC of (+)-40 was determined to be (aS,aS ) by the exciton CD method and confirmed by X-ray crystallography of the CSDP ester [76]. The dihedral angle between naphthalene groups ranges over −84.1◦ , −87.2◦ ,

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HOH2C

+300

+200 CH2OH

Δe

+100 Δe 0

CD

(S) HOH2C

CH2OH

–100 224.4 (132,700)

e × 10–4

+200 (S)-[CD(+)231.3]-39

0 CH2OH

chrom 2 –200

15

CH2OH

–200 10 224.3 (–329.0)

–300

5

–400

chrom 3

–400 chrom 1

UV 200

300 λ (nm) 400

0

obsd CD 285.4 ( +21.9) A = –559.3 231.7 (–333.9) 223.4 (+225.4)

e × 10–4

+400 231.3 (+342.4)

(aS,aS)-(+)-40

200

20

(aS,aS)-(+)-40 obsd UV 292.8 ( 24,000) 224.0 (186,500) 250

10

0 300 λ (nm) 350

Figure 4.18. CD and UV spectra of (S)-1,1 -binaphthyl-2,2 -dimethanol 39 (EtOH) and (aS,aS)-(+)-1,1 :4 ,1 -ternaphthalene-2,2 -dimethanol 40 (95% aq. EtOH). (Redrawn from references 1 and 75, respectively, with permission.)

−89.1◦ , and −89.4◦ as determined by the X-ray analysis. That is, three naphthalene chromophores are almost perpendicular to one another. Figure 4.19a shows the CD and UV spectra of (1R,1 S ,2S )-2,2 -spirobi[benz[e] indan]-1,1 -diol diacetate 41 [77]. The exo/endo configuration of two acetate groups was determined by 1 H NMR data showing nonequivalent four methylene protons. Racemic diacetate was enantioseparated by chiral HPLC to give an enantiomer [CD(–)230.2]-41 whose CD and UV spectra are shown in Figure 4.19. In the region of the naphthalene 1 Bb transition (λmax 224.8 nm, ε 172,700), the intense negative first and positive second CEs (λext 230.2 nm, ε −961.5 : λext 221.6 nm, ε +567.1; A = −1528.6) led to the (1R,1 S ,2S ) AC [77]. [6,6]-Vespirene 42 is a unique member of chiral 9,9 -spirofluorene compounds, and its chiroptical activity arises from the 9,9 -spirobifluorene system twisted by the side-chain bridge (Figure 4.19b) [78]. The AC of (−)-42 was determined to be R by the coupled oscillator analysis of its CD spectrum [78, 79]. However, the CD spectrum showed a complex pattern deviated from the ideal exciton bisignate CEs, implying that the 9,9 spirobifluorene chromophores of 42 may be strongly strained. Thus, it was questionable whether the CD ECM is applicable to such a strained system in a straightforward manner. To confirm the AC of compound 42, enantiopure compounds 43 and 44 with two anthracene and naphthacene chromophores, respectively, were prepared (Figures 4.20) [80]. These spiroaromatics are more suited than [6,6]-vespirene 42 for the ECM, because of their less strained structures and clear definition of exciton chirality between two polyacene chromophores. Enantiopure [6,6]-vespirene (−)-42 and compound (R)-(+)-43 were synthesized starting from diester (R)-(+)-45 (Figure 4.20). The UV spectrum of (+)-43 shows an intense 1 Bb transition (λmax 288.6 nm, ε 152,000), which is polarized along the chromophoric long axis. In the 1 Bb transition region, the CD shows intense positive first and negative second CEs (λext 300.5 nm, ε +551.0 and λext 278.5 nm, ε −560.7; A value = +1111.7). The present results unambiguously indicate that the long-axis electric transition moments of the two anthracene chromophores constitute a clockwise screw sense (i.e., positive exciton chirality), leading to the (R) AC [80]. In such spiroaromatics, there is the so-called spiro-conjugation—that is homoconjugation between p orbitals surrounding the spiro quaternary center. It is known

E L E C T R O N I C C D E X C I T O N C H I R A L I T Y M E T H O D : P R I N C I P L E S A N D A P P L I C AT I O N S

(a)

(b)

41

λ (nm)

Figure 4.19. (a) CD and UV spectra of (1R,1 S,2S)-2,2 -spirobi[benz[e]indan]-1,1 -diol diacetate 41 in EtOH. (b) Chiral spiroaromatics. (Redrawn from reference 77, with permission.)

(a)

(b)

λ (nm)

Figure 4.20. (a) Synthesis of [6,6]-vespirene (R)-(−)-42 and chiral spiroaromatics (R)-(+)-43 and (R)-(+)-44 starting from diester (R)-(+)-45. (b) CD and UV spectra of (R)-(+)-43 in EtOH. (Redrawn from reference 80, with permission.)

139

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(5R,12R)-(–)

(5R,12R)-(–)-46

λ (nm)

Figure 4.21. CD and UV spectra of (5R,12R)-(−)-1,15-diethynyl-5,12-dihydro-5,12[1 ,2 ]benzenonaphthacene 46 in EtOH. (Redrawn from reference 84, with permission.)

that in some cases, such spiro-conjugation makes a dominant contribution to the CD spectra [81]. However, in the case of (+)-43, the spiro-conjugation effect is negligibly small, because the observed CD spectrum shows intense conservative bisignate CEs due to the exciton coupling. Bis(naphthacene) compound (R)-(+)-44 also showed intense positive first and negative second CEs leading to the (R)-AC, although the CD curve was complex due to vibronic structures. The AC determination of (R)-(+)-43 and (R)-(+)-44 confirmed the (R)-ACs of dimethyl ester (+)-45 and [6,6]-vespirene (−)-42. The (R)-AC of (−)-42 was later confirmed by X-ray crystallography [83]. (5R,12R)-(−)-1,15-Diethynyl-5,12-dihydro-5,12[1 2 ]benzenonaphthacene (46) is a triptycene derivative having one naphthalene and two phenylacetylene chromophores, with no conformational flexibility due to its cage structure and linear acetylene groups (Figure 4.21). The CD spectrum of (5R,12R)-(−)-46 shows strong exciton CEs (λext 245.5 nm, ε −138.2 : λext 215.0 nm, ε +113.6; A = −251.8) in the UV absorption region (λmax 241 nm, ε 75,000). Clearly the CEs originate from the coupling between the longaxis polarized 1 Bb transition (λmax 220.2 nm, ε 107,300) of naphthalene and the long-axis polarized 1 La transition (λmax 234.2 nm, ε 15,000) of phenylacetylene [84]. The long axes of the naphthalene and one phenylacetylene moiety constitute a negative exciton chirality. Similarly, a negative helicity is found between the naphthalene and the other phenylacetylene. On the other hand, the long axes of two phenylacetylenes are parallel to each other, indicating nil exciton chirality. Thus, the total exciton chirality is negative, leading to the (5R,12R) AC of (−)-46 [84, 85]. This absolute configurational assignment is in line with the chemical correlation results [84].

4.8.2. Application of the CD ECM to Acyclic 1,2-Glycols and Polyols The CD exciton chirality method has been applied to dibenzoates or bis(2-anthroates) of acyclic 1,2-glycols, which show typical bisignate CEs as exemplified in Figures 4.22

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Δε R

ε x 10–4

273 (+97) +90 OChrom CD +60 Chrom = p-BrBz H OChrom A = +190 or 2-anthroyl +30 47 first CD, (+) 0 second CD, (–) Exciton Chirality: –30 H3C OChrom zero –60 OChrom OChrom H OChrom 258 –90 253 OChrom H R OChrom ChromO 15 (147,000) Chrom = (–93) R H 2-anthroyl H H H H H 10 (S)-48 R H H OChrom [47A] [47B] UV 5 in CH3CN J (trans) = 6.8 ~ 8.4 Hz, [47C] J (gauche) = 3.6 Hz 0 200 250 300 350 λ (nm)

Figure 4.22. Applications of the CD exciton method to acyclic terminal 1,2-glycols. (Redrawn from reference 87, with permission.)

50

λ (nm)

51

λ (nm)

Figure 4.23. Application of the CD ECM to acyclic internal 1,2-glycols with threo-configuration. (Redrawn from reference 86.)

and 4.23 [86, 87]. Acyclic dibenzoates or bis(2-anthroates) can rotate around the bond connecting two benzoates or 2-anthroates, and hence the CD sign depends on the conformational equilibrium. Based on the exciton CD and the conformational analysis by 1 H NMR, the AC of acyclic 1,2-glycols can be determined (Figures 4.22 and 4.23).

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In terminal acyclic 1,2-glycols, diester 47 {bis(p-Br-benzoate) [86] or bis(2anthroate) [87]} can adopt three rotational conformers 47A, 47B, and 47C (Figure 4.22); here conformer 47B is unstable due to two gauche relations among three bulky groups. In contrast, because conformers 47A and 47C have only one gauche relationship between two bulky groups, they are more stable and dominate the equilibrium. The stable conformer 47A has a positive exciton chirality between two chromophores, while in conformer 47C the two chromophores are trans, and hence no exciton chirality is generated. Thus the CD of diester 47 reflects the positive exciton chirality of 47A. The 1 H NMR coupling constants {J (trans) = 6.8–8.4 Hz, J (gauche) = 3.6Hz} support this conclusion. The CD of (S )-1,2-propanediol bis(2-anthroate) 48 shows intense exciton CEs, from which the AC was assigned (Figure 4.22) [87]. Similarly, the CD ECM is applicable to internal 1,2-glycols with threo-configuration (Figure 4.23) [86, 87]. For example, diester 49 {bis(p-Br-benzoate) or bis(2-anthroate)} adopts three rotational conformers 49A, 49B, and 49C, in which conformers 49B and 49C are unstable because of three gauche relationships. Conformer 49A with two gauche relations between bulky groups dominates the equilibrium. Conformers 49A and 49B have positive and negative exciton twists between two chromophores, respectively, while in conformer 49C two chromophores are in the transrelationship, and therefore no exciton chirality is generated. The preference of 49A is supported by the large 1 H NMR coupling constant {J (trans) = 6.1–8.7 Hz}. After all, the CD spectrum of diester 49 reflects a positive exciton chirality of conformer 49A. For example, (2S,3S )-2,3-butanediol bis(p-Br-benzoate) 50 exhibits bisignate CEs of positive exciton chirality and an 1 H NMR coupling constant {J (trans) = ∼6.1 Hz}, from which the AC can be determined (Figure 4.23) [86]. The above relationship between the AC and exciton CD CEs holds for most internal 1,2-glycols. However, if a glycol has polar or extremely bulky groups (R1 and R2 ), the equilibrium is changed; groups R1 and R2 adopt a trans-relation to diminish the electric repulsive force or steric repulsion, and conformer 49B becomes dominant. The preference of 49B is supported by 1 H NMR coupling constant {J (gauche) = 2.9–4.1 Hz}. The CD spectrum of (2R,3R)-diethyl tartrate bis(p-Br-benzoate) 51 shows a negative exciton couplet reflecting the preference of 49B [86], where the ethyl ester groups are trans as confirmed by 1 H NMR coupling constant {J (gauche) = 2.9 Hz}. If the groups R1 and R2 are identical, the 1 H NMR vicinal coupling constant between two methine protons cannot be measured because of the same chemical shifts. In such cases, the 13 C satellite band method is useful to determine the Jvic value [86, 88]. In erythro-1,2-glycols, the determination of AC is more difficult. When the two groups R1 and R2 are identical, the glycol is a meso-isomer and hence achiral. If they are different, the glycol is chiral. The exciton CD CEs of erythro-diester are weak, and they depend on the equilibrium of the rotational conformations. Thus assignment of ACs requires further analysis by other methods. Noteworthy, the AC of 1,3-acyclic polyols can be determined much easier and in more straightforward manner due to a better discrimination between CD of 1,3syn/1,3-anti diols bis(p-Br-benzoates) or bis(p-methoxycinnamates). An acyclic anti 1,3-bis(acylate) adopts a planar zigzag form in its most stable conformer and exhibits a typical CD exciton couplet corresponding to the sign of the screw sense between the two gauche-oriented chromophores, while the syn-analogue also in most stable zigzag conformation has almost parallel p-Br-benzoate or p-methoxycinnamate chromophores that exhibit negligible coupling [89–91].

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4.8.3. Application of the ECM to Compounds Containing a Single Suitable Chromophore: Nondegenerate System The exciton coupled CD is observable even in a nondegenerate system composed of two different chromophores, which undergo different electronic excitations. The first example of the nondegenerate exciton CD used for determining the AC of a chiral compound is the case of chromomycin A3 (52), (Figure 4.24). The AC of 52 was determined in the very early stage of the development of the CD ECM [92]. The first strategy for determining the AC of 52 was to apply the dibenzoate chirality method to glycol derivative (53). However, benzoylation of glycol 53 yielded monobenzoate 54 due to the steric hindrance. This unexpected result led to a general protocol to apply the CD ECM to nondegenerate systems [92]. The CD spectrum of monobenzoate 54 showed intense bisignate CEs (λext 270 nm, ε −19.9: λext 230 nm, ε +16.8; A = −36.7), which are stronger than those of glycol 53 (λext 270 nm, negative: λext 220 nm, positive) as seen in Figure 4.24 [1, 2]. The CD data of 54 imply that the bisignate CEs originate from the interaction between the long-axis transition of benzoate (λmax 230 nm, ε 14,000) and the long-axis 1 Bb transition of naphthalenoid chromophore (λmax 270 nm, ε 57,200), where the naphthalenoid 1 Bb transition is red-shifted due to the conjugation with a carbonyl group. If this mechanism is true, the following can be expected. If a proper benzoate group is introduced whose long-axis transition is close to the naphthalenoid 270 nm, the exciton CD would be enhanced, because the exciton theory tells us that the exciton coupling is more effective when two transitions are close to each other in energy. Hence the p-methoxybenzoate chromophore (λmax 256 nm, ε 18,000) was chosen to yield monobenzoate 55, the CD of which showed much intense bisignate CEs as expected (λext 271 nm, ε −70.6: λext 250 nm, ε +34.0; A = −104.6) (Figure 4.24). This result not only verified the exciton mechanism of nondegenerate systems, but also established the absolute configurational assignment. Since the first CE is negative and the second positive, the long axes of two chromophores constitute a counterclockwise screw, leading to the AC as shown in Figure 4.24 [2, 92]. This assignment was later confirmed by chemical correlation [93].

+40

250 (+34.0) 55

R = p-MeO-C6H4CO- HO

H

OMe OH O OH

+20 Δe 0

OH OH O 54

R = C6H5CO-

–20

H

MeO OH 52

MeO

MeO

R1

OMeO

H

OR OH O

O O

53, R = H 54, R = Bz 55, R = p-MeOBz

Me

–40

53

R=H in EtOH

–60

271 (–70.6)

–80 200

300

λ (nm)

MeO MeO H

H O

O H H O O OH O Me Me O Me H

54, R1 = H 55, R1 = OMe

400

Figure 4.24. Preparation of benzoate 54 and p-methoxybenzoate 55 of chromomycin A3 derivative: CD spectra of p-methoxybenzoate, benzoate, and alcohol derivatives. (Redrawn from reference 1, with permission.)

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OR

+40 R=H λext 226 nm, Δe +14.8

+30

H R = Bz λext 235 nm, Δe +34.0 220 nm, Δe –14.3

+20 +10 Δe 0

MeO 56, R = H 57, R = Bz

in EtOH

Figure 4.25. CD spectra of

Me O O

–10

17-dihydroequilenin 3-methyl ether (56) and 17-benzoate (57). (Redrawn from reference 92, with

17

–20

H 300

λ (nm)

MeO

400

57

permission.)

To confirm the nondegenerate exciton method further, the exciton method was applied to equilenin derivative 17-benzoate (57) (Figure 4.25) [2, 92]. The CD of benzoate 57 shows intense bisignate CEs around 230 nm (λext 235 nm, ε +34.0: λext 220 nm, ε −14.3; A = +48.3), while alcohol 56 exhibits a positive CE (λext 226 nm, ε +14.8). It is thus clear that the exciton CD of benzoate 57 originates from the interaction between long-axis 1 Bb transition of naphthalenoid chromophore (λmax 230 nm) and the long-axis transition of benzoate (λmax 230 nm). The positive exciton couplet agrees with the AC as shown in Figure 4.25. These results corroborated the methodology of nondegenerate exciton coupling. The nondegenerate ECM is applicable also to the conjugated diene–benzoate system as exemplified in Figure 4.26, where the CD and UV of 3-methylenecholest-4-ene-6β-ol benzoate (58) is shown (λext 242.0 nm, ε −30.8: λext 225.0 nm, ε +39.1; A = −69.9) [1]. The long-axis polarized π –π ∗ transition of the s-trans diene appears at 234 nm (ε 20,000), which matches the long-axis polarized benzoate transition at 230 nm (ε 15,300). These ETDMs constitute a counterclockwise screw generating negative first and positive

(a)

(b)

225.0 (+39.1) +40

58 H

H +20 Δε 0

CD

in EtOH

OBz

H

58

e × 10–4

200

–20

242.0 (–30.8) 235.0 (33,800)

–40

300

OBz-p-Cl 59 Me

O O

2

UV 200

4

λ (nm)

0

H O

H

CD in MeOH λext 247 nm, Δe –24.4 λext 224 nm, Δe +23.0 A = –47.4

H

Figure 4.26. (a) CD and UV spectra of 3-methylenecholest-4-en-6β-ol benzoate (58). (b) CD data of 3-oxocholest-4-en-6β-ol p-chlorobenzoate (59). (Redrawn from reference 1, with permission.)

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second CEs. The exciton coupling between conjugated diene and benzoate chromophores determine the AC of diene–alcohol compounds. The nondegenerate ECM was applied to the conjugated enone–benzoate system, 3-oxocholest-4-en-6β-ol p-chlorobenzoate (59) (λext 247 nm, ε −24.4 : λext 224 nm, ε +23.0; A = −47.4) (Figure 4.26) [59]. The π –π ∗ transition of conjugated enone (λmax 241 nm, ε 16,600) couples with the p-chlorobenzoate transition (λmax 240 nm, ε 21,400) to generate negative first and positive second CEs, stemming from the counterclockwise screw sense.

4.8.4. UV λmax Separation of Two Different Chromophores versus Exciton CD As described above, the exciton coupling is the most effective in a degenerate system having two identical chromophores. On the other hand, it is interesting to know how the exciton CD decreases, when the difference between UV λmax values of two chromophores increases. To clarify the effect of UV λmax separation on the exciton CD, we carried out the CD calculation by the exciton theory and also synthesized steroidal model compounds having two different p-substituted benzoate chromophores (Figures 4.27). Figure 4.27a shows the CD calculation result how the exciton CD decreases in intensity, when the separation between two λmax values increases [1]. The important aspect is that even when two chromophores undergo excitations at 230 nm and 310 nm, respectively, their interaction provides observable bisignate CEs, whose signs are governed by the exciton chirality between two ETDMs. The observed CD spectra of steroidal model compounds agree well with the calculated curves. Thus the ECM is applicable to nondegenerate systems, in which two λmax values are much separated. Based on this

223.0 (+15.7)

R=H

230 nm–230 nm

(1)

300 λ (nm) 350

200

238.5 (–15.2) 300 λ (nm)

200

200

250

300

R = Cl 350

230 nm–250 nm

(3) 200

300 230 nm–260 nm

(4) 200

300 230 nm–280 nm

(5) 200

250

200

300

350

229.5 (+14.5)

R = OMe

350 200

230 nm–257 nm 300

250 249.5 (–10.4)

350

350

O O

350

250

230 nm–240 nm

242.3 (–18.2)

O O

232.5 (+11.2)

230 nm–310 nm

(6)

350

227.0 (+16.8)

230 nm–240 nm

(2)

230 nm–230 nm

R = NMe2 R 230 nm–310 nm 350

(a)

200

250

312.0(–3.7)

350

(b)

Figure 4.27. (a) Calculated exciton CD curves, when changing λmax of two chromophores. (b) Observed CD spectra of cholest-5-ene-3β,4β-diol 3-benzoate 4-p-substituted benzoates in EtOH. (Redrawn from reference 1, with permission.)

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mechanism, the CD allylic benzoate method was developed, as will be discussed in the next section.

4.8.5. Allylic Benzoate Exciton Method for Determining the AC of Allylic Alcohols

e × 10–4

0 CD

Δε –5

229.5 (–8.72) –10

(a)

229.0 (+11.45) +10

2 BzO

228.9 (16,400)

H 60

(b)

OBz

BzO CD

+5 Δε 0

61

1

60

200

250 λ (nm) 300 (a)

BzO 0

2

228.5 (13,100)

1 UV

e × 10–4

The chiroptical method for determining the AC of allylic alcohols was first developed as the Mills’ rule [94] and the Brewster’s benzoate rule [95], in which the AC was correlated with optical rotation. Later the benzoate sector rule was proposed by Harada and Nakanishi to correlate the AC with CD CEs at 230 nm, where the position of the C=C double bond against the benzoate chromophore was a key factor to govern the CD CE [96]. As an extension of this concept and based on the nondegenerate exciton CD mechanism, the allylic benzoate exciton method was developed for determining the AC of allylic alcohols. Figure 4.28a shows the CD and UV spectra of cholest-4-en-3β-ol benzoate 60, where a negative CE is seen at the long-axis polarized UV band (230 nm) [1, 97]. The mechanism of this CE is interpreted as follows. The C=C double bond undergoes an allowed π –π ∗ transition around 190 nm polarized along its long axis. This transition couples with the long-axis transition of benzoate chromophore at 230 nm; and by this nondegenerate exciton coupling, the negative first CE is observed around 230 nm. On the other hand, it is difficult to observe the expected positive second CE, because the π –π ∗ band of C=C double bond locates below 200 nm. Since the long axes of two chromophores constitute a counterclockwise screw sense, the benzoate CE becomes negative as the first CE of the non-degenerate exciton coupling. Another stereoisomer, cholest-4-en-3α-ol benzoate 61, exhibits a positive CE around 230 nm, reflecting the positive exciton chirality between benzoate and C=C double bond chromophores (Figure 4.28b). Note that the CD intensity of axial allylic benzoate is generally larger than that of equatorial allylic benzoate, as exemplified in Figure 4.28 [1, 97]. Allylic benzoate 60 undergoes a negative CD below 210 nm, which is opposite to the expected positive second CE around 190 nm. A similar phenomenon is observed in the case of allylic benzoate 61. These results may originate from the participations of the

H 61

UV 200

250 λ (nm) 300

0

(b)

Figure 4.28. (a) CD and UV spectra of cholest-4-en-3β-ol benzoate 60 in EtOH. (b) CD and UV spectra of cholest-4-en-3α-ol benzoate 61 in EtOH. (Redrawn from references 97 and 1, respectively, with permission.)

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benzenoid 1 B transition (around 200 nm) of benzene chromophore and the weak π –σ ∗ transition of the C=C double bond chromophore. Despite such complexity, the 230-nm CE reflects solely the allylic benzoate chirality, which is useful for determining the AC of allylic alcohols [1, 97]. More recent studies led to a significant advance in application of allylic benzoate method to homoallylic alcohols, amines, and other enes by the use of microscale cross metathesis [98, 99]. By applying the microscale cross-metathesis protocol the double bond can be transformed into more suitable for coupling chromophores, such as styrene or p-substituted analogues, so the entire CD couplet can be observed and used for an AC determination. The introduction of fluorescent styrene provides an additional benefit, since the CD can be measured in emission by the more sensitive fluorescent detected CD (FDCD) method [98b, 99].

4.9. RECENT APPLICATIONS OF THE CD EXCITON CHIRALITY METHOD The following are the recent interesting application examples of the CD ECM for determining the ACs of chiral natural and synthetic compounds. (1) ACs of Ciguatoxin and Related Compounds Intense exciton coupled CDs are useful for comparison of CD data with those of a reference compound as exemplified below. The AC of C5 in CTX4A (62), a ciguatoxin precursor, was determined by the use of the exciton coupled CD spectra as summarized in Figure 4.29 [100]. The AB ring fragment (64) of CTX4A was stereoselectively synthesized, and its p-bromobenzoate 65 exhibits the exciton split CEs. It is obvious that these CEs originate from the exciton coupling between conjugated diene in the C5 side chain and C11 p-bromobenzoate, and these two chromophores constitute a clockwise screw sense (Figure 4.29). The CD spectrum of CTX4A tris(p-bromobenzoate) 63 also shows the exciton split CEs, which was interpreted as follows. Although there are six possible interactions among four chromophores in 63, the coupling between 1,3-diene and C11 p-bromobenzoate makes a dominant contribution, because the remaining ones are weak due to the remote distances. This interpretation was confirmed by the CD data of 65. The ACs of CTX4A and ciguatoxin (CTX) were thus determined by comparison of the exciton CD CEs of 63 and 65. The ACs of the CTXs were later confirmed by total syntheses [101].

Me CTX4A (62), R = H 63, R = OBz-Br-p

H 5

O

H

H

A 11 O O H H ORH H

H

Me H OR O H 47 O O O M O H H H H O H Me Me H Data of 63, CD (MeOH) λext 246 nm (Δe +32) 230 nm (Δe –28)

H Me RO O H HO

O O H H

32

H

H

A 5

O H H

O

H O

11

H OR

O

64, R = H 65, R = OBz-Br-p Data of 65, CD (MeOH) λext 242 nm (Δe +25) 225 nm (Δe –14)

Figure 4.29. ACs of ciguatoxin precursor CTX4A (62) and related compounds, along with their CD data.

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(2) AC of Urothion The AC of acyclic terminal 1,2-glycol was determined by the ECM as follows. To determine the AC of urothion (66), a yellow pteridine pigment isolated from human urine, the compound was subjected to desulfurization yielding 67, which was converted to tris(p-chlorobenzoate) 68 (Figure 4.30) [102]. An authentic sample of (R)-67 was synthesized starting from d-glucose. Since the [α]D values of diols (S )-67 and (R)-67 were too small to assign their ACs by comparison, tris(p-chlorobenzoates) (S )-68 and (R)-68 were prepared and their CD spectra were compared. The CD spectrum of (R)-68 was opposite in sign to that of (S )-68, thus leading to the (R)-AC of urothion 66. The bisignate CEs at 247 and 228 nm are mainly caused by the exciton coupling between the two benzoate groups in the side chain. According to the ECM applied to acyclic terminal 1,2-glycols (Section 4.8.2), the positive first CE leads to the S configuration, which agrees with that obtained by comparison of CD spectra. It should be noted that the intense exciton CEs are thus useful for determining the AC by comparison of chiroptical data. (3) AC of Cephalocyclidin A, a Five-Memberd Ring cis-α-Glycol The ECM was applied to the five-membered ring 1,2-cis-glycol system. The unprecedented pentacyclic structure of cephalocylidin A (69) was elucidated by X-ray crystallographic, 1 H-NMR, and CD methods [103]. To determine the AC, 2,3-bis(p-methoxycinnamate) (70) was synthesized, which showed bisignate CEs of negative exciton chirality (Figure 4.31). The observed exciton CD is weak, reflecting the small dihedral angle of cis-glycol moiety in a five-membered ring. The AC of compound 69 was determined as shown. It should be advised that in cases with small dihedral angle between two hydroxyl groups, the use of more symmetrical chromophore such as p-dimethylaminobenzoate or p-bromobenzoate would be suitable for obtaining unambiguous results.

O HN H2N

N

H OR

O SCH3

N N

HN

OH

S H

RHN

OR

N N

N

OH

(S)-68, CD (EtOH), λext 247 nm (Δe +8.0) 228 nm (Δe –3.0) UV (EtOH) λmax 241 nm (e 43,600)

(S)-67, R = H (S)-68, R = Bz-p-Cl

urothion (R)-66

Figure 4.30. Urothion and exciton CD data.

O

O

H H 3 OO 2 OHO

OH

HO

2 3

HO O 69

MeO N MeO

70

N O OO

Compound 70, CD (CH3OH) λext 325 nm (Δε –6.6), 283 nm (Δε +5.8)

O O 9 O 1 H

OAcO

HO H

NOEs

Compound 71, CD (CH3CN) λext 270.7 nm (Δe +20.3) 227.8 nm (Δe –18.1)

71

Figure 4.31. ACs of cephalocyclidin A 69 and dihydro-β-agarofuran sequiterpene 71 as determined by the CD ECM.

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(4) AC of Dihydro-β-Agarofuran Sequiterpene Dihydro-β-agarofuran sequiterpene 71 is unique because the natural product itself contains cinnamate and benzoate chromophores at C1 and C9 in an ideal 1–3 transrelationship for exhibiting exciton CEs (Figure 4.31) [104]. The CD spectrum of 71 shows positive first and negative second CEs, from which the AC was unambiguously determined as shown. (5) AC of Strevertenes This is an interesting example of the exciton CD due to the interaction between conjugated pentaene and p-dimethylaminobenzoate chromophores [105]. The relative stereostructures of strevertenes A (72) and G (73), antifungal macrolides, were determined by X-ray crystallography of compound 73, where the pentaene moiety adopts all transconfiguration and almost planar conformation as shown in Figure 4.32. To determine the AC of compound 72, the CD ECM was applied as follows. As the UV λmax of the pentaene chromophore is located around 330 nm, p-dimethylaminobenzoate (λmax = 311 nm) was selected as an exciton coupling partner with a red-shifted absorption suitable for coupling with the pentaene moiety. Thus, methyl ester 74 was benzoylated to give a mixture of mono-benzoates, which was separated by reverse-phase HPLC. All possible six mono-benzoates were isolated, and the esterification positions were assigned by 1 H NMR spectra. Of these benzoates, 15-p-dimethylaminobenzoate (75) was suitable for application of the ECM, because the allylic position generates a clear exciton chirality (Figure 4.32). The difference CD spectrum {CD(75) − CD(74)} between 15-benzoate 75 and alcohol 74 is shown in Figure 4.32, where the exciton coupling between pentaene and p-dimethylaminobenzoate chromophores generates intense positive first and negative

336 (+37.6)

O

OH

HO

O

R1 OR2

Strevertene A (72): R1 = COOH, R2 = H methyl ester (74): R1 = COOMe, R2 = H derivative (75): R1 = COOMe, R2 = Bz-p-NMe2

C6

C4

C3

C5

Δε

H16 O

C14 H15

C7

+145°

+20 N

0 Diff. CD = CD(75) – CD(74)

in MeOH

C10

C9

354 (+18.8)

O

C11 C8

C12 O7 C29 C13 C1 C14 O9 O2 C16 O1 C20 C18 C22 C15 C24 C27 C17 C19 O8 C25 C23 C21 C31 C26 C28

H3CO2C

O6

O5

O4

O3 C2

+40

–20

303 (–21.4) UV(75) UV(74)

–40

e × 10–5

OH OH OH

320

336 353

1

in MeOH

C30

Strevertene G (73) : R1 = CH2OH, R2 = H 200

250

300 λ (nm)

350

400

Figure 4.32. ACs of strevertenes A (72) and G (73), X-ray crystallographic stereoview of (73), difference CD spectrum {CD(75) − CD(74)}, and UV spectra of (75) and (74). (Redrawn from reference 105, with permission.)

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second CEs. The positive A value indicates that the long axes of both chromophores constitute a clockwise screw sense as shown in Figure 4.32, where the trans-antiperiplanar relation between H-15 and H-16 was assigned by the 1 H NMR coupling constant (J15,16 = 9.2 Hz). The ACs of 15-benzoate 75 and natural products 72 and 73 were thus determined [105]. (6) AC of Phomopsidin The example shows an exciton CD due to the interaction between remote diene-ester and p-nitrobenzoate chromophores. The CD spectrum of phomopsidin 76, a marinederived fungal metabolite, shows only one very weak CE at 266 nm associated with the diene-carboxylic acid chromophore at 6-C with an intense UV absorption at 266 nm (Figure 4.33a) [106]. To determine the AC, alcohol 76 was converted to p-nitrobenzoate 77, which exhibited bisignate CEs due to the exciton coupling between diene-ester and p-nitrobenzoate. From the positive first CE, the AC having a clockwise helicity was determined. (7) AC of Spiroxin A, a Bis-Acetophenone Fungal Metabolite In this application, red-shifted chromophores were used to prevent the overlap of CEs. Spiroxin A (78) is a bis-acetophenone with a spiroketal moiety that locks the two conjugated chromophores (Figure 4.33b) [107]. The relative stereochemistry had previously been established by NMR. Spiroxin A 78 exhibits a complex CD in the 200 to 280 nm region, which was difficult to interpret. To determine the AC, two phenolic hydroxyl groups were esterified with retinoic acid because the UV band of all-trans retinoic acid ester (λmax 356 nm, ε 39,500) is well red-shifted from the absorption of the existing chromophore. However, while spiroxin A bis(retinoate) (79) did not exhibit useful exciton couplet in the retinoic ester region, the difference CD between bis(retinoate) 79 and spiroxin A 78 provided a clear-cut negative exciton couplet that allowed for the AC assignment [107]. (8) AC of Pinellic Acid The CD allylic benzoate method was applied to pinellic acid 80, a long-chain allylic alcohol, to determine the AC as shown in Figure 4.34 [108]. The relative configuration COOR1

(a)

O

(b) 76, R1 = R2 = H 77, R1 = CH3, R2 = p-NO2Bz

ax

OR

spiroxin A 78, R = H CI spiroxin A bis(retinoate) 79, R =

O

O

77

H

CD (MeOH), λext 271 nm (Δε +22.4) λext 244 nm (Δε –7.9) UV (MeOH), λmax 264 nm (ε 35,000)

6 11

eq H R2O

O

O O OR O

Difference CD = CD (79) – CD (78), λext 385 nm (Δε –17.3), 331 (+17.4)

Figure 4.33. (a) CD and UV data of phomopsidin methyl ester p-nitrobenzoate 77. (b) Spiroxin A 78 and CD data.

OR4 12 9 13 R1O 10 OR3 pinellic acid 80, R1 = R2 = R3 = R4 = H O

OR2

81, R1 = CH3, R2 = p-BrBz, R3 & R4 = acetonide

Figure 4.34. Pinellic acid 80 and exciton CD.

81, J9,10 = 7.0 Hz CD (CH3OH), λext 245 nm (Δe +6.9), 221 (+2.13), 209 (+5.7)

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of three chirality centers was determined by NOE experiments of methyl ester-acetonide, from which the syn configuration of the 12-C/13-C vicinal diol was assigned. The acetonide was then converted to p-bromobenzoate 81, the 1 H NMR spectrum of which indicated an antiperiplanar relationship between the 9 and 10 protons (J9,10 = 7.0 Hz). The CD of the allylic p-bromobenzoate showed a positive CE at λext 245 nm (ε +6.97), indicative of the S configuration at 9-C. This predicted the AC of pinellic acid to be either (9S,12S,13S ) or (9S,12R,13R). The remaining question was solved by a stereospecific synthesis of both diastereomers. The comparison of spectral data with those of the authentic samples indicated that the AC of the natural product was (9S,12S,13S) as shown. (9) AC of Phorboxazole The CD allylic benzoate method was applied to determine the AC of allylic alcohol moiety as follows. The AC of phorboxazole A (82) was determined as shown by total synthesis except for the configuration of 38-C (Figure 4.35) [109]. Although the AC at the 38-C allylic alcohol had originally been assigned as R by application of the Mosher MTPA method, there was an anomaly in the NMR δ data. The threo and erythro model compounds (83 and 84) were synthesized from (S )-malic acid, and hence the ACs of 33C, 35-C, and 37-C were assigned as shown. To determine the AC of 38-C by the allylic exciton method, these alcohols were converted to 2-naphthoate esters (85 and 86). The NMR coupling constants J38,39 = 9.6 Hz for 85 and J38,39 = 9.2 Hz for 86 indicate that these two protons are in trans-relationship in their stable conformations. Threo ester 85 exhibited a negative CE at λext 234 nm (ε −9.2), indicating a negative twist between the naphthoate and the allylic double bond. In contrast, erythro product 86 showed a positive CE at λext 234 nm (ε +15.1) indicating a positive helicity. Thus the ACs of 83 and 84 were determined as shown. The comparison of the NMR coupling constant J37,38 of 82 with those of 85 and 86 led to the AC of natural product 82 as shown in Figure 4.35 [109]. (10) AC of Gymnocin-B The experiments for the AC determination of gymnocin-B 87, a cytotoxic marine natural product with the largest 15-rings polyether skeleton isolated so far, are very revealing. They demonstrate the effectiveness of porphyrin chromophore to serve as chiroptical probe for AC of remote stereogenic centers residing in a very flexible substrate, available only in a few hundred micrograms (Figure 4.36) [99, 110b]. The compound has two hydroxyl groups at 10-C and 37-C, but it was difficult to clearly assign the helicity between the two remote and sterically hindered OH groups, because of the conformational flexibility arising from the presence of seven-membered rings.

OH

O

phorboxazole A 82, J37,38 = 7.9 Hz

N O

OCH3 OCH3 Br

35

39 38

37

H OH

O

OH

O

O

N O

O O

OCH3

83, R = H n-C4H9

39 38

84, R = H

35 37

H OR

O

n-C4H9 OMe

39

38

OCH3 35 37

H O OMe OR

threo-85, R = 2-naphthoyl J37,38 = 7.0 Hz, J38,39 = 9.6 Hz

erythro-86, R = 2-naphthoyl J37,38 = 3.7 Hz, J38,39 = 9.2 Hz

CD (CH3CN) λext 234 nm (Δe –9.18)

CD (CH3CN) λext 235 nm (Δe +15.1)

Figure 4.35. Phorboxazole A 82 and allylic benzoate method.

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OR H H 37 RO H O Me H H H H H O H 10 O O O H I H J H K C D E F G B O O H O L O H A H H O O H O Me Me 5 Me H H H H Me H O M Me N O H O H O O 55 Gymnocin B 87, R = H H 54 O bis(TPP-cinnamate) 88 NHN O NHN R= CD (MeOH)

29°

15 10

10′

20 5

15′ 20′

5′

C5/Ph rotation

10-TPPcin K (ax) J

λext 419 nm, Δe +11 λext 414 nm, Δe –15

37-TPPcin (eq)

28.7 Å

Figure 4.36. Gymnocin B 87, the lowest-energy conformation of its 10,37-bis(TPP-cinnamate) derivative 88 obtained by Monte Carlo/MMFF94s, and CD data of 88. (Redrawn from reference 110b, with permission.)

Triphenylporphyrin-cinnamate chromophores were introduced into 10-OH and 37-OH by acryloylation/cross-metathesis under microscale conditions. The obtained diester 88 showed a clear exciton split CD, positive first and negative ˚ apart (Figure 4.36). After extensecond CEs, even though the two porphyrins are ∼30 A sive conformational analysis of the derivative by the MMFF94s/Monte Carlo calculation, the (10S,37S) AC was assigned to the derivative 88. The CD curve of 88 calculated by the DeVoe’s coupled oscillator method for the Boltzmann-weighted conformers agreed well with the observed CD spectrum. The AC of gymnocin B 87 was thus determined as shown [99, 110b]. (11) AC of Axially Chiral Binaphthoquinones The exciton CEs of 1,2 -binaphthyl derivative are well suited for AC determination than the CEs of binaphthoquinone as shown below. The AC of (–)-8 -hydroxyisodiospyrin 89, a naturally occurring bi(naphthoquinone), was determined by the synthesis of the opposite enantiomer (S )-(+)-89 (Figure 4.37) [111]. The AC of a synthetic intermediate was determined by X-ray analysis, and the intermediate was then converted to binaphthalene 90, with its CD showing intense exciton coupled CEs. From the positive sign of the couplet, an S configuration was assigned to 90, which was further converted to (S )-(+)89. The AC of the natural product was determined to be (R)-(−)-89. Thus the ACs of these compounds were confirmed by the CD ECM [111]. The CD spectrum of (S )-90 shows intense exciton CEs, while (S )-(+)-89 exhibits two positive and one negative CEs around 360–260 nm, but their ε values are much smaller than those of 90, and the CD curve deviates from the ideal pattern of the exciton coupling. Thus, to determine the ACs by the exciton method, it is important to select the

O

OMe OMe

OH

(S)-(+)-89 (S)-90 MeO MeO MeO

OMe OMe

225 nm (Δε –60.0)

CD (1,4-dioxane)

O O

CD (CH3CN) λext = 239 nm (Δε +46.7), HO

λext = 356.9 nm (Δε +6.9), O

298.5 nm (Δε +11.2), 263.8 nm (Δε –23.2)

OH

Figure 4.37. ACs and CD data of axially chiral binaphthalene and binaphthoquinone. Numerical CD data were obtained from the spectra reported in reference 111.

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most appropriate chromophores—that is binaphthalene rather than binaphthoquinone as exemplified in this case. (12) AC of Pre-anthraquinones The example shows an intense exciton coupling between naphthalene–ketone and anthraquinone. The ACs of atropisomeric pigments 91 and 92 were determined by spectroscopic methods including ECM (Figure 4.38) [112]. Atropisomer 91 exhibits intense negative first and positive second CEs at 272 nm and 251 nm, respectively, thus leading to an AC with negative helicity between long axes of two aromatic chromophores. The AC at the 3 position was deduced by chemical correlation; the reductive cleavage of 93 yielded (R)-torosachrysone methyl ether with known AC. Pigment 92 exhibits weak bisignate CEs compared to 91, because the two aromatic chromophores are connected by two σ bonds, and hence the dihedral angle between two long axes is close to 180◦ . (13) AC of Spiroleptosphol Figure 4.39 shows an interesting example of triol tribenzoate (97) where the AC has been successfully determined in the presence of three exciton interactions. Spiroleptosphol (93), a γ-methylidene-spirobutanolide, exhibited cytotoxicity against P388 murine leukemia and HeLa human cervix carcinoma (Figure 4.39) [113]. The relative stereostructures of compound 93 and spiroleptosphol C (94) were determined by NMR spectroscopy and/or by X-ray crystallography [114]. Compound 93 was converted to dibenzoate 96, which exhibited typical exciton CEs of negative exciton chirality leading to a counterclockwise helicity between two benzoate chromophores at the 6- and 7-positions (Figure 4.39). The AC of 93 was thus unambiguously determined as shown [114]. Triol 93 was also converted to tribenzoate 97, the CD of which showed intense positive first and negative second CEs [114]. These CD data are interpreted as follows: The exciton chirality between 4- and 6-benzoates is clockwise, and that between 4- and 7-benzoates is also clockwise, while that between 4- and 6-benzoates is anticlockwise. The total exciton chirality becomes thus positive and leads to positive first and negative second CEs, confirming the AC of triol 93. (14) AC of Leucettamol A, α,ω-Bifunctionalized Sphingolipid The intense exciton CEs are useful for amplifying the chiroptical properties of natural products with very weak optical rotation as exemplified below, where the deconvolution ECM was also useful for AC determination. Leucettamol A (98) was isolated as a marine natural product exhibiting a variety of biological activities. The relative configuration of 2-amino-3-hydroxy end groups was determined to be erythro by NOE experiments of a

OMe OH O

OMe OH O

(–)-92

(+)-91 3'

3'

MeO

CD (MeOH), λext 272 nm (Δε –159.3) 251 nm (Δε +158.8) UV (EtOH) λmax 274 nm (log ε 4.50)

OH O HO

OH O

OMe

MeO

OH O HO

OH O

OMe

Figure 4.38. Pre-anthraquinones and CD data.

CD (CHCl3), λext 286 nm (Δε +14.4) 257 nm (Δε –8.2) UV (EtOH) λmax 278 nm (log ε 4.36)

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O

O 4

O HO

12

OH 17 R

6 HO 7

spiroleptosphol (93), R = H spiroleptosphol C (94), R = OH

O RO

4

O

OH

O O

6

RO 7

O (95), R = H (96), R = Bz

4 6

(97)

BzO 7

O

H

O O

6

OBz

O

7 H O

OH R O

CD (MeOH) of (96) λext 238 nm, Δe –18.9 222 nm, Δe +10.9

O O

H

(96), R = side chain

(93)

O BzO

H 6

H4O R O

7 H O

CD (MeOH) of (97) λext 238 nm, Δe +38.4 220 nm, Δe −18.1 204 nm, Δe −6.4

(97), R = side chain

Figure 4.39. Determination of the absolute stereochemistry of spiroleptosphol (93) by the CD ECM. The CD data of (97) were obtained from the reported figure.

bis-oxazolone derivative. Compound 98 was originally assigned to be racemic because it did not exhibit any measureable optical rotation [115]. To reinvestigate the AC of leucettamol A 98, it was catalytically reduced to give perhydro-derivative 99, which was then converted to N,N ,O,O  -tetrabenzoyl derivative 100. The CD spectrum of compound 100 showed bisignate CEs due to the exciton coupling between benzoate/benzamide chromophores (Figure 4.40) [116]. Since the 2,3-N,Odibenzoyl chromophores are remote from 28,29-N,O-dibenzoyl chromophores, the simple additivity of exciton coupled CD is applicable. Erythro-101, selected as a model and prepared from (2S )-alanine, exhibited a negative exciton couplet (Figure 4.40) [117]. The simulated CD curve of (ent-erythro-101 + ent-erythro-101) agreed well with the observed CD of (erythro / erythro)-100 (Figure 4.40), but other combinations—for example (threo-102 + threo-102) and (ent-erythro-101 + threo-102)—disagreed with the observed CD of 100. The ACs of 100 and hence 98 were unequivocally determined to be (2R,3S,28S,29R). Thus leucettamol A is optically active; redetermination of the specific rotation of 98, averaged over 10 measurements, gave [α]D = −3.8±0.1 (c 4.4,

OH

NH2

NHBz 3

OH leucettamol A (2R,3S,28S,29R)-(–)-98 NHR

OR

99: R = H

100: R = Bz

NH2 OR

OBz erythro-101

CD (MeOH) λext = 235 nm, Δe = –5.6 λext = 220 nm, Δe = +1.6

NHR NHBz

erythro l erythro-100: obsd CD (MeOH), λext = 238 nm, Δe = +10.3, λext = 222 nm, Δe = –2.8 simulated CD based on (ent-erythro-101 + ent-erythro-101): λext = 235 nm, Δe = +11.3, λext = 220 nm, Δe = –3.2

OBz threo-102

CD (MeOH) λext = 237 nm, Δe = +3.0 λext = 221 nm, Δe = –3.5

Figure 4.40. ACs and CD data of leucettamol A (98) and related compounds.

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MeOH). The deconvolution exciton CD method is thus useful for determining the AC of dimeric sphingolipids. (15) AC of 11-Deoxydiaporthein A by the Exciton Allylic Benzoate Method The AC of allylic alcohol was determined by ECM and X-ray analysis as shown below. 11-Deoxydiaporthein A (103) was isolated from a marine fungus [118], and its relative stereostructure was determined by NMR. To determine its AC, compound 103 was converted to benzoate (104), the CD spectrum of which showed a positive CE (λext = 230 nm, ε +5.8), reflecting a clockwise helicity between the long axes of benzoate and olefin chromophores (Figure 4.41a). The R configuration at 7-C was determined by the CD allylic benzoate method. The AC determined by CD was confirmed by X-ray crystallography of a single crystal of compound 103 obtained by recrystallization from chloroform. Interestingly, the crystal contained chloroform molecules as crystal solvent, and based on the strong anomalous scattering effect of chlorine atoms, the AC of 103 was established [118]. (16) AC of Cortistatin A This is an example of a natural product whose AC was determined by the exciton coupling of its two preexisting trans-diene and isoquinoline chromophores. Cortistatin A (105), an anti-angiogenic steroidal alkaloid, was isolated from a marine sponge. The relative stereostructure of 105 was elucidated by 2D-NMR (COSY and NOESY) and confirmed by X-ray as shown in Figure 4.41b. Interestingly, compound 105 itself exhibited bisignate CEs of negative exciton chirality, leading to the AC as shown [119]. Compound 105 has a conjugated diene (UV λmax = ∼234 nm) and a C17 isoquinoline (UV λmax = ∼220 nm), which couple to generate exciton CEs. The data indicate that the long axes of the two chromophores constitute a counterclockwise screw in the conformation shown in Figure 4.41, leading to the AC shown. (17) AC of trans-Acenaphthene-1,2-diol The ECM is applicable to glycols with 120◦ dihedral angle as follows. Chiral transacenaphthene-1,2-diol (106) and related compounds were prepared by baker’s yeastmediated reduction, and the AC of (−)-trans-106 was determined to be (1S,2S) by the CD ECM [120]. Diol (−)-106 (97% ee) was converted to bis(p-dimethylaminobenzoate) (+)-107, which exhibited positive first and negative second CEs. The negative exciton

OH

H

O 7 OR

OH OH

11-deoxydiaporthein A (103), R = H AC of (103) by X-ray of crystal (103)/CHCI3 (a)

(104), R = Bz CD λext = 230 nm, Δe = +5.8

OH

11 17

HO O N

N

H H N

H

cortistatin A (105) relative structure of (105) by X-ray

H CD of (105) λext 237 nm, Δe = –17 217 nm, Δe = +35

17S

(b)

Figure 4.41. (a) AC of 11-deoxydiaporthein A (103) as determined by the CD allylic benzoate and X-ray methods. (b) AC of cortistatin A (105) as determined by X-ray and ECM methods.

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CD couplet led to the (1S,2S) AC as shown in Figure 4.42a. When reporting the CD data, the intensity should be provided in ε units, not in raw θ /m◦ units, otherwise it is impossible to judge the intensities of the observed CEs. (18) AC of Kolokoside A Aglycone The ECM is useful for the AC determination of cyclic 1,2-glycols as exemplified below. The AC of kolokoside A (108), a triterpenoid glycoside, was determined by the CD ECM (Figure 4.42b) [121]. The aglycone was esterified to give 2,3-bis(pdimethylaminobenzoate) (109), whose CD spectrum showed negative first and positive second. Thus the (2R,3R) AC of the aglycone was determined. (19) AC of Dinemasone B This is an example of a cyclic trans-1,2-glycol. The AC of dinemasone B (110), a bioactive metabolite from fungi, was determined by the CD ECM [122]. Glycol 110 was converted to bis(p-bromobenzoate) (111), which exhibited a negative exciton CD. The AC of 110 was thus assigned as shown in Figure 4.42c. (20) AC of Oligonaphthalenes The following are unique chiral oligonaphthalenes whose ACs were determined by porphyrin–porphyrin coupling at very long distances (Figure 4.43) [123]. These chiral oligomers were synthesized from chiral (S )-binaphthyl derivative by repeating the oxidative coupling giving the diastereomeric products—that is, 4-mers, 8-mers, and 16-mers. For example, the coupling reaction of (S,S,S )-4-mer yielded diastereomeric (S,S,S,S,S,S,S )-8-mer and (S,S,S,R,S,S,S )-8-mer. To determine their ACs, the CD ECM using tetraphenylporphyrin (TPP) carboxylic acid was applied, because the Soret band (λmax = 420 nm) of TPP-carboxylic ester is far separated from the naphthalenoid UV bands. It has been previously reported that the exciton CD method using TPP-esters was applicable to remote hydroxyl groups, where the interchromophoric distance R ranges ˚ [47, 48]. around 50 A Two terminal phenol groups of diastereomers were esterified to yield bis(TPP-ester) 112 and 113. When applying the exciton method to these systems, it is important to elucidate the dihedral angle between naphthalene moieties. The X-ray crystallographic

N

N

N

H

HOOC O

O

O

H

O

O O

O

O O

(1S,2S)-(+)-trans-107, 97%ee CD (MeOH)

N

H

CD (CH3CN)

(a)

OH O

O O O

109

Kolokoside A aglycone bis(p-dimethylaminobenzoate)

λext 329 nm, postive λext 308 nm, negative

O

O

Br 111

Br Dinemasone B, bis(p-bromobenzoate) CD (CH3CN)

λext 320 nm, Δe = –22 λext 296 nm, Δe = +13

λext 252 nm, Δe = –45.3 λext 235 nm, Δe = +22.9

(b)

(c)

Figure 4.42. Application of ECM and ACs: (a) (1S,2S)-(+)-trans-acenaphthene-1,2-diol; (b) kolokoside A aglycone; (c) dinemasone B.

E L E C T R O N I C C D E X C I T O N C H I R A L I T Y M E T H O D : P R I N C I P L E S A N D A P P L I C AT I O N S

(S,S,S,S,S,S,S,S,S,S,S,S,S,S,S)-114,

(S,S,S,S,S,S,S,S,S,S,S,S,S,S,S)-114, UV (CHCI3) λmax 420.0 nm, e = 756,000 CD (CHCI3) λext 434 nm, Δe = –2.8 418 nm, Δe = +2.7

n = 7, R = 66 Å HN N

H N

N O

O

OO

OO

OO O

O

(S,S,S,S,S,S,S)-112, n = 3 UV (CHCI3) λmax 420.0 nm, e = 725,000 CD (CHCI3) λext 428 nm, Δe = –10.1 418 nm, Δe = +12.6

n (S,S,S,S,S,S,S)-112, n = 3 O

O

O

O O

OO

O

OO

O

O O

OO

O

O

O

(S,S,S,R,S,S,S)-113, n = 3 UV (CHCI3) λmax 420.0 nm, e = 755,000 CD (CHCI3) λext 428 nm, Δe = +10.7 418 nm, Δe = –11.1

Figure 4.43. Exciton CD data and the AC of oligonaphthalenes.

analyses of some derivatives and the CONFLEX-MM2 calculation indicated the average dihedral angle to be around 89.4◦ ∼90.0◦ , that is a right angle. Thus, it is predicted that if bis(TPP-ester) 8-mer takes an (S,S,S,S,S,S,S ) configuration, the dihedral angle between two terminal TPP-ester groups becomes −90◦ . That is, it is calculated 90◦ × 7 = (360◦ × 2) − 90◦ . Thus a negative exciton couplet is predicted. If bis(TPP-ester) 8-mer takes an (S,S,S,R,S,S,S ) configuration, the dihedral angle between two terminal TPP-ester groups becomes +90◦ , because 90◦ × 6 − 90◦ = (360◦ ) + 90◦ . That is a positive exciton couplet is predicted. As listed in Figure 4.43, bis(TPP-ester) 8-mer 112 exhibited negative first and positive second CEs, while bis(TPP-ester) 8-mer 113 exhibited an opposite couplet. Thus the observed CD curves are mirror images of each other. Thus, an (S,S,S,S,S,S,S ) configuration was assigned to 112 and an (S,S,S,R,S,S,S ) configuration was assigned to 113. The ECM method is applicable to a more remote diol diester—for example bis(TPP-ester) 16-mer 114, where two chromophores are separated at ∼66 ˚ but still gave an observable exciton CD. From the sign of the first CE, an A, (S,S,S,S,S,S,S,S,S,S,S,S,S,S,S ) AC was assigned to 16-mer 114 (Figure 4.43) [123]. (21) AC Assignment of Acetylene Alcohols by the CD ECM The combination of Sonogashira reaction and ECM enables the AC determination of chiral terminal acetylene alcohols as shown below. Enantiopure acyclic acetylene alcohols are employed as chiral synthons for bioactive compound syntheses. It is generally difficult to determine the ACs of acyclic acetylene alcohols, but the 1 H NMR anisotropy method using MαNP acid ester has been developed for enantioresolution of racemic alcohols and simultaneous determination of AC. The CD ECM is also useful for determining ACs of acetylene alcohols. A method for determining the ACs of terminal acetylene alcohols was developed from the exciton CD due to the interaction between p-methoxyphenylacetylene (λmax 252 nm) and p-methoxybenzoate (λmax 257 nm) [124]. For example, acetylene alcohol (+)115 was converted by a Sonogashira reaction to p-methoxyphenylacetylene alcohol (−)116, which was esterified giving benzoate (−)-117 (Figure 4.44). The CD spectrum of (−)-117 showed exciton bisignate CEs (Figure 4.44). The negative A-value led to an (R)-AC for (−)-117, consistent with the result from the 1 H NMR anisotropy method. This method is thus useful for determining the ACs of terminal acetylene alcohols [124].

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158

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

+20 CD

H OH

(R)-(–)-117

–10 –20

obsd CD 266.0 (–27.9) 246.2 (+21.0)

–30

A = –48.9 UV

e x 10–4

+10 Δe 0

300

(R)-(–)-116

CH3O

OCH3 252 nm

obsd UV 258.2 (41,500)

250

(R)-(+)-115

4

H O

O

(R)-(–)-117

2 CH3O

in EtOH 200

H OH

257 nm

350

Figure 4.44. A scheme for the AC determination of terminal acetylene alcohol by combination of the Sonogashira reaction and the CD ECM: CD and UV spectra of 1-(4-methoxyphenyl)1-dodecyn-3-ol 4-methoxybenzoate (R)-(−)-117 in EtOH. (Redrawn from reference 124, with permission.)

(22) ACs and Exciton CD of Unique 1,3-Diethynylallene Compounds The ACs of allene compounds can be determined by the ECM as exemplified below. Allene compounds are unique chiral synthons devoid of chirality centers, and they have been employed for the syntheses of various chiral compounds. Allene (M )-(−)-118 is one of such compounds, the AC of which was determined as follows. Compound (−)-118 was converted to 1,3-bis{(4-dimethylaminophenyl)ethynyl}allene (−)-119, with typical intense exciton split CEs (Figure 4.45) [37, 125]. The negative A value indicated that two identical chromophores of (4-dimethylaminophenyl)ethynyl olefin constitute a counterclockwise sense, and thus an (M )-AC was assigned to allene (−)-119. It should be noted that the dihedral angle between two (4-dimethylaminophenyl)ethynyl groups is 90◦ due to the allene skeleton, which satisfies the requirement of an ideal exciton CD mechanism. The CD spectral curves of (M )-(−)-119 as calculated by TDDFT and π -electron SCF-CI-DV MO methods were in good agreement with the observed spectrum confirming the above assignment by the ECM [37]. These absolute configurational assignments were consistent also with the X-ray analysis and chemical correlation results [125].

H i-Pr3Si (M)-(–)-118

N N

(M)-(–)-119 (e.r. > 91:9) CD (hexane) λext 328 nm, Δε = –77.9 287 nm, Δε = +37.2

(M)-(–)-119

Figure 4.45. Exciton CD of 1,3-diethynylallene derivative.

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4.10. EXAMPLES REQUIRING CAUTION AND THEORETICAL ANALYSIS OF EXCITON CD The following are examples, where cautious considerations of CD were necessary. That is, the observed CD spectra could not be interpreted by the exciton coupling mechanism in a straightforward manner. (1) AC of Antitumor Antibiotic AT2433-A1 with a Secondary Amino Group To determine the AC of antitumor antibiotic AT2433-A1 (120), amino sugar bis(p-Brbenzoyl) derivative (121∗ ) was derived from the natural product (Figure 4.46). Its CD spectrum showed a negative couplet leading to the AC as shown [126]. However, it was later pointed out that this assignment was wrong as explained below [50]. To clarify the reasons for the wrong assignment, the authentic samples 121 and 122 were synthesized from a starting material with known AC. Surprisingly, the CD of 121 showed a weak positive exciton couplet, while that of 122 showed a strong negative one. The 1 H NMR of 121, a benzamide derivative of the secondary amine, indicated the presence of (Z ) and (E ) amide isomers, where the exciton chirality is negative and positive, respectively. Since the CD contributions cancel in some extent, the sign and intensity of observed CD are governed by those of the prevailing (E ) amide. On the other hand, the CD of the primary amine derivative 122 reflects straight the AC because of its (Z ) conformation. Therefore, when the ECM is applied to secondary amines, the analysis of (E ) and (Z ) conformations is critical. The AC of the secondary amine in natural product 120 was confirmed by the total synthesis of a related compound [50]. (2) Anomalous CD CEs of 1,1 -Biphenanthryl Compounds Enantiopure 2,2 -dimethoxy-1,1 -biphenanthryl (aR)-(+)-123 (Figure 4.47) was synthesized by oxidative coupling of 2-phenanthrol, followed by enantioresolution, where its AC was determined by the axial chirality recognition method [127]. It was expected that

CH3 N O

O

O

CI OH

O O HN CH3 OH

p-BrBzN CH3

N

N H O

OH OCH3

OCH3

O

p-BrBzO p-BrBzN

p-BrBzN Me

OBz-p-Br

R

121*(AC originally assigned) CD (CH3CN), λext 249 nm (negative CD) 219 nm (positive CD)

AT2433-A1 (120)

O H Ar N O Ar Me O H

Ar O H OCH3

121, (Z )-amide negative chirality

O Ar

H

N O Me O H

O

Ar H Ar

OCH3

121, (E)-amide positive chirality

O H N O H O H

OCH3

OBz-p-Br

121, R = Me CD (CH3CN), λext 251 nm (Δe +5.5) 219 nm (Δe –4.4)

O H OCH3

122, (Z )-amide negative chirality

122, R = H CD (CH3CN), λext 252 nm (Δe –33.4) 234 nm (Δe +12.6)

Figure 4.46. Application of the ECM to secondary amine. Numerical CD data were obtained from the spectra reported in reference 50.

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+200

(aR)-(+)-123 +100 CD Δe

(aR)-(+)-125

OCH3

OCH3

(aR)-(–)-124

OCH3

OCH3

e x 10–5

0

(aR)-(–)-124

(aR)-(+)-125

–100 2 OCH3 –200

200

OCH3

UV

250

1

300

350 λ (nm)

0

(aR)-(+)-123

(aR)-126

Figure 4.47. Chemical correlation of 1,1 -biphenanthryl derivative (aR)-(+)-123 and related compounds, along with their CD and UV spectra. (Redrawn from reference 127, with permission.)

the CD spectrum of (aR)-(+)-123 should show a negative exciton couplet around the 1 Bb transition of phenanthrene chromophore, because the two long axes of phenanthrene groups constitute an anticlockwise screw sense as illustrated in Figure 4.47. However, compound (aR)-(+)-123 showed positive and negative CEs at 274 nm 258 nm, respectively, disagreeing with the expectation. The anomalous CD results led to the reinvestigation the ACs of (+)-123 and related compounds. Starting from (aR)-(+)-1,1 -binaphthyl-2,2 -diol, compound (aR)-(−)-124 was synthesized, and it was easy to convert (aR)-(−)-124 to the target compounds (aR)-(+)-123 and (aR)-(+)-125 with a binaphthyl chromophore (Figure 4.47). The CD spectrum of (aR)-(+)-125 showed intense exciton CEs (λext 239.8 nm, ε −197.1; λext 227.8 nm, ε +133.3; A = −330.4) reflecting a negative helicity between two long axes of naphthalene moieties, which confirmed the (aR)-AC of (+)-125. Compound (aR)(−)-124 also exhibited exciton CEs (λext 249.6 nm, ε −112.6; λext 236.4 nm, ε +60.5; A = −173.1), but the A value decreased to about half. That is, the conjugation of the naphthalene chromophore with a double bond diminished the exciton CD intensity, because the corresponding ETDM deviated from the long axis of the naphthalene chromophore [127]. In contrast, compound (aR)-(+)-123 exhibited positive and negative CEs (λext 274.2 nm, ε +38.5; λext 258.0 nm, ε −52.5; A = +91.0) (Figure 4.47). These results confirmed that the CEs of 1,1 -biphenanthryl derivative (+)-123 are opposite in sign to those of 1,1 -binaphthyl derivative (+)-125 despite the same ACs. Furthermore, the CD shape of (+)-123 is complex, and the A value is about 1/4 compared to that of (aR)-(+)125. Additionally, more intense negative and positive CEs were observed around 220 nm. To gain insight into the anomalous CD behavior of compound (aR)-(+)-123, the CD and UV spectra of 1,1 -biphenanthryl (aR)-126 were calculated by the π -electron SCF-CI-DV MO method (for this MO method, see Chapter 5, this volume). The UV

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calculation of phenanthrene chromophore revealed its complexity due to the presence of another electronic transition polarized along the short axis around 255 nm in addition to the intense long axis-polarized 1 Bb transition around 260 nm. Therefore, in (aR)-126, four ETDMs interact with one another, giving rise to positive first and negative second CEs. The simulated CD and UV spectra agreed well with the observed; the (aR)-AC of (+)-123 was confirmed also by the MO calculation [127]. It should be emphasized that the CD ECM itself is correct, but the electronic transitions of compounds (aR)-(+)-123 and (aR)-126 are complex, and therefore the simple and qualitative application is not valid for these compounds. In general, symmetrical chromophores (e.g., linear polyacenes such as naphthalene, anthracene, etc.) are more suitable for the CD ECM than the less symmetrical ones such as nonlinear condensed aromatics (e.g., phenanthrene).

4.11. CONCLUSION As discussed above, the CD ECM is useful for determining the ACs of various chiral compounds. The exciton coupling between two or more chromophores generates exciton split and intense bisignate CEs that reflect the helicity between ETDMs (positive or negative exciton couplet). The AC of the compound can be unambiguously determined from the sign of the couplet. In general, the exciton couplet CDs due to through-space chromophoric interaction are much stronger than the CEs of isolated chromophores, such as those due to ketone n → π ∗ , benzenoid π → π ∗ , and conjugated diene or enone π → π ∗ transitions. Their unique bisignate shapes facilitate the recognition of an exciton couplet. The CD ECM is readily proved by the quantum mechanical exciton theory as described, and therefore it is classified as a nonempirical method. Thus the ACs of chiral compounds can be determined by the exciton CD method without any reference compound. It was established that both X-ray Bijvoet and CD exciton chirality methods give the same AC, although assignments are based on totally different phenomena. However, the unambiguous determination of AC by ECM requires a very careful selection of the appropriate chromophores. It is critical that this selection takes into account not only the structural and conformational features of the chiral substrate, but also other basic requirements of this method. We hope that this chapter clarifies the main aspects of the CD exciton chirality method and provides useful guidelines for its application in stereochemical analysis.

ACKNOWLEDGMENTS The authors thank the co-workers in these studies, whose names are listed in references, and Dr. George A. Ellestad, Department of Chemistry, Columbia University, for his valuable suggestions. We are very grateful to JASCO Co., for their continuing instrumental and technical support.

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5 CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS: THEORETICAL DETERMINATION OF THE ABSOLUTE STEREOCHEMISTRY AND EXPERIMENTAL VERIFICATION Nobuyuki Harada and Shunsuke Kuwahara

5.1. INTRODUCTION Electronic circular dichroism (ECD) is very useful for characterization of chiral organic compounds with π -electron chromophores. That is, ECD enables one to determine the absolute configurations (ACs) of various natural products and chiral synthetic compounds by the use of appropriate CD methods, exemplified by the CD exciton chirality method [1–5]. In general, chiral compounds containing a chiral conjugated π -electron chormophore such as conjugated diene and enone exhibit medium CD Cotton effects. These chromophores contained in chiral compounds naturally adopt twisted conformations falling in the category of the inherently dissymmetrical chromophore. The observed CD Cotton effects are generally governed by the helicity of the diene or enone moiety, from which the absolute configuration can be determined. In some cases, however, the allylic group makes a contribution to the CD, and hence the observed CD does not agree with the chromophore helicity. On the other hand, compounds containing further extended and conjugated π -electron chromophores exhibit much more intense CD Cotton effects, as will be discussed in this chapter. In these cases, the CD Cotton effects are mostly governed by the helicity or twisted structure of the π -electron chromophore itself. Therefore, the CD spectra of these systems can be calculated by the π -electron approximation such as the π -electron self-consistent-field / configuration interaction / dipole velocity molecular orbital (SCFCI-DV MO) method [6–8]. In fact, we have determined the ACs of various natural products and chiral synthetic compounds by the use of the π -electron SCF-CI-DV MO method. In this chapter, the principle and applications of this method are explained in detail. Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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To confirm the ACs as determined by the theoretical method, chiral model compounds and/or natural products themselves were synthesized in enantiopure forms. In such cases, the CSDP acid method and/or MαNP acid method are very useful for enantioresolving racemic compounds into enantiopure derivatives, and the methods simultaneously enable one to determine the ACs by X-ray crystallography and/or by 1 H NMR anisotropy [9–12]. The CD spectra of the synthesized model compounds were compared with those of the compounds in question. By these experimental studies, the theoretical method was established to lead to the correct absolute configurational assignments. Besides the theoretical method, the combination of CD spectroscopy and X-ray crystallographic analysis with an internal reference is also reliable for determining the ACs of various chiral compounds. This method has been applied to various natural products, chiral spiro compounds, light-powered chiral molecular motors, chiral C60 fullerene bis-adducts, and so on which led to the unambiguous assignment of ACs as described in this chapter. In the case of light-powered chiral molecular motors, the motor rotation mechanism and dynamics were also clarified by CD spectroscopy together with 1 H NMR spectroscopy. CD spectroscopy is thus useful not only for studying chiral stereochemistry, but also for the static and dynamic behavior of natural products and chiral synthetic functional compounds. In this chapter are described the research results carried out mostly by the authors’ group.

5.2. THEORETICAL CALCULATION OF CD AND UV SPECTRA BY THE π -ELECTRON SCF-CI-DV MO METHOD The CD and UV spectra of an extended π -electron system can be calculated by the π electron SCF-CI-DV MO method, where the rotational strength Rba and dipole strength Dba are expressed as follows [6]. Rba = 2(ψa |∇|ψb )(ψa |r × ∇|ψb )μB 2 /(π σba )

(5.1)

Dba = 2(ψa |∇|ψb ) μB /(π σba )

(5.2)

2

2

2

where ∇ is the del operator, r is a distance vector, μB is the Bohr magneton, and σba is the excitation wavenumber of the transition a → b. The z -axis components of the electric and magnetic transition moments are formulated, respectively, as [6] (ψa |∇|ψb )z =



(Cra Csb − Csa Crb )cos Zrs

bonds

(ψa |r × ∇|ψb )z =



(Cra Csb − Csa Crb )(Xrs cos Yrs − Yrs cos Xrs )

(5.3) (5.4)

bonds

cos Zrs = (Zr − Zs )/Rrs

(5.5)

Xrs = (Xr + Xs )/2

(5.6)

where Cra is the coefficient of atomic orbital r in the wavefunction ψa ; is the expectation value of a dipole velocity ∇rs , which is directed along the bond rs in the direction r → s; Xr , Yr , and Zr are the x , y, and z coordinates of an atom r, respectively; and Rrs is the interatomic distance between atoms r and s. The x and y components of the electric and magnetic transition moments can be similarly calculated.

169

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

In the π -electron SCF-CI-DV MO method, the following standard values of atomic orbital parameters are proposed: for sp2 carbon, Z (C) = 1.0, W (C) = −11.16 eV, ˚ = −2.32 eV, (C–C, 1.388 A) ˚ = 4.70 × (rr|rr)(C) = 11.13 eV, β(C–C, 1.388 A) 107 cm−1 ; for ether oxygen, Z (O) = 2.0, W (O) = −33.00 eV, (rr|rr)(O) = 21.53 eV, β(C–O) = −2.00 eV, (C–O) = 6.00 × 107 cm−1 ; for sp 2 nitrogen, Z (N) = 1.0, W (N) = −14.12 eV, (rr|rr)(N) = 12.34 eV, β(C–N) = −2.32 or −2.55 eV, (C– N) = 4.70 or 5.17 × 107 cm−1 [1]. The electric repulsion integral (rr|ss) was approximated by the Nishimoto–Mataga equation. The resonance integral β and del value were calculated by the use of following equations, respectively [1]: ˚ β(1.388 A) ˚ cos θ β = [S /S (1.388 A)]

(5.7)

˚ ˚ = [(empirical, 1.388 A)/(theoretical, 1.388 A)] × (theoretical) cos θ

(5.8)

where θ is a dihedral angle. The overlap integral S and (theoretical) were calculated on the basis of the Slater orbitals. The configuration interactions between all singly excited states were included. The curves of the component CD and UV bands were approximated by the Gaussian distribution [13], ε(σ ) =



εk exp[−{(σ − σk )/σ }2 ]

(5.9)

k

ε(σ ) =



εk exp[−{(σ − σk )/σ }2 ]

(5.10)

k

where σ is half the bandwidth at 1/e peak height. The σ value of 2500 cm−1 was used as a standard value [1].

5.3. SOME ESTABLISHED EXAMPLES OF THE π -ELECTRON SCF-CI-DV MO METHOD The following are some examples of the application of the π -electron SCF-CI-DV MO method applied to various chiral natural products and synthetic chiral compounds with extended π -electron chromophores. These examples were already explained in reference 3, and hence the summary of the results (i.e., comparison of observed and calculated CD and UV–Vis spectra, absolute stereostructures, and experimental verification by Xray crystallography and/or by synthesis) are briefly described. The exciton CD studies of chiral spiroaromatics of 9,9 -spirobifluorene skeleton are described in Chapter 4 of this volume.

5.3.1. Absolute Configuration of (+)-1,8a-Dihydro-3,8-dimethylazulene Chiroptically active 1,8a-dihydro-3,8-dimethylazulene (+)-(1) was isolated from the cell culture of the liverwort Calypogeia granulata Inoue (Figure 5.1) [14]. The labile intermediate 1 with a unique 1,8a-dihydroazulene skeleton shows very intense chiroptical activity, [α]D + 1164 and intense CD Cotton effects as shown in Figure 5.1, suggesting

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Δe 314.0 (+19.7) +20

CD

0

H e × 10–4

–20

–40 235.2 (–47.4)

(8aS)-(+)

3

227.5 (25,600) –60 Obsd in hexane

2

UV 1 308.5 (5,400)

200

Figure 5.1. CD and UV spectra of naturally occurring (8aS)-(+)-1,8a-dihydro-3,8dimethylazulene (1) in hexane. (Redrawn from

0

300 λ (nm)

reference 15, with permission.)

Δe 219 (+46.2) H +40

(8aR)

CD

e × 10–4

+20

0

–20

219 (27,300) 313 (–13.9)

Calcd

UV

3

2

313 (9,900) 1

Figure 5.2. CD and UV curves of (8aR)-1,8a-dihydroazulene 2 calculated by the 200

300 λ (nm)

0

π -electron SCF-CI-DV MO method. (Redrawn from reference 15, with permission.)

171

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

a strongly twisted conjugated tetraene system. Therefore, it is reasonable to consider that the chiroptical activity of 1 is mainly due to the twist of the π -electron chromophore. To determine the AC of 1 theoretically, we carried out the calculation of the CD curve of 1,8a-dihydroazulene (2) on the basis of the π -electron framework approximation, using the SCF-CI-DV MO method, where its AC was arbitrarily chosen to be (8aR) (Figure 5.2) [15]. The theoretically calculated CD and UV curves agree well with the observed CD and UV spectra except for the sign of the CD ε values (compare Figures 5.1 and 5.2). That is, the observed CD curve of compound 1 is almost a mirror image of the curve calculated for the model compound (8aR)-2. Accordingly, the AC of the labile biosynthetic

Br

OCH3

O

OCH3

O O

O

H

(8aS)-(+)-4

(1S,8aS)-(+)-3

CH3O (1S,3aR,4S,7R,8aS)-(+)-5 X-ray

Scheme 5.1. A synthesis of the model compound (1S,8aS)-(+)-3.

+20

321.0 (+5.7) CD

0 Δe –20

–40

221.3 (–24.5)

3

e × 10–4

OCH3

(1S,8aS)-(+) –60

223.2 (23,700) 2 Obsd in EtOH

UV 324.3 (6,000)

1

Figure 5.3. CD and UV spectra of (1S,8aS)-(+)200

300 λ (nm)

0

1,8a-dihydro-1-methoxy-8a-methylazulene (3) in EtOH. (Redrawn from reference 15, with permission.)

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intermediate (+)-1 was theoretically determined to be (8aS ). This conclusion was proved experimentally by the synthesis of model compounds, as described in the following. As a chiral model compound, (1S,8aS)-(+)-(3) was selected because the angular position 8a is blocked by a methyl group, and hence it resists the oxidation to azulene. The model compound was synthesized (Scheme 5.1) [15, 16], starting from the enantiopure Wieland–Miescher ketone (S )-(+)-(4) [17] via an intermediate bromide (+)-5, the AC of which was confirmed by the Bijvoet method in X-ray crystallography [15, 16]. The CD and UV spectra of (1S,8aS)-(+)-3 are shown in Figure 5.3; the CD curve of (1S,8aS )-(+)-3 is quite similar, in both sign and shape of Cotton effects, to that of dihydroazulene (+)-1. Therefore, it was proved experimentally that the natural product (+)-1 has 8aS absolute configuration. Thus the present results verify the theoretical determination of the absolute configuration of (+)-1 discussed above.

5.3.2. Circular Dichroism and Absolute Stereochemistry of Chiral Troponoid Spiro Compounds The SCF-CI-DV MO method has been successfully applied to a chiral troponoid spiro compound (6) as follows (Figure 5.4) [18]. Racemic spiroacetal (±)-6 could be enantioseparated by chiral HPLC of (+)poly(triphenylmethylmethacrylate). In the HPLC, the first-eluted fraction gave an enantiomer (−)-6, [α]D −4700, which shows the CD and UV spectra as illustrated in Figure 5.4. To determine the absolute stereochemistry of (−)-6, we calculated the

Δe

Obsd OO

+100

287 (+80.4)

N

+50

N

(S)-(–) e × 10–4

CD

0

–50

285 (23,500)

3 398 (–45.3)

–100

2

MeOH UV

378 (7,900) 1

Figure 5.4. CD and UV spectra of troponoid 300

400 λ (nm)

500

spiro compound (S)-(−)-6 in MeOH. (Redrawn from reference 18, with permission.)

173

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

CD spectra of (S )-6 by applying the π -electron SCF-CI-DV MO method, where the absolute configuration was arbitrarily chosen as S . The calculated (calcd) CD and UV spectra shown in Figure 5.5 are in a good agreement with the observed (obsd) spectra. Accordingly, the absolute stereochemistry of (−)-6 was theoretically determined to be S . The present conclusion is in line with the X-ray crystallographic results of a related compound [19].

5.3.3. Absolute Stereochemistry of the Halenaquinol Family Marine Natural Products The π -electron SCF-CI-DV MO method for calculation of CD spectra was next applied to the determination of the AC of the compounds of the halenaquinol family (Chart 5.1) [20–23]. To determine the absolute configuration of halenaquinol (+)-7, we first planned to apply the CD exciton chirality method [21] to the interaction between the naphthalene and benzoate chromophores. During the synthetic studies of a pertinent benzoate derivative 8, we obtained a naphthalene–diene compound (−)-9 (Chart 5.1) [24], which surprisingly exhibited much stronger CD Cotton effects than other halenaquinol derivatives did (Figure 5.6). The result clearly indicates that the major part of the CD Cotton effects originates from the π -electron chromophore composed of the naphthalene–diene moiety, which is twisted by the angular methyl group at the 12b position. Therefore, the twisted

Δe

Calcd OO

+100

289 (+76.3)

N

N

+50

(S)

e × 10–4

CD

0

–50

3

284 (23,500)

–100

2 UV

394 (–106.9) 1

Figure 5.5. CD and UV curves of spiro 300

400 λ (nm)

500

troponoid compound (S)-6 calculated by the π -electron SCF-CI-DV MO method. (Redrawn from reference 18, with permission.)

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HO

1

2

O

12

10

OR

CH3O

OSi

CH3O

4 7

HO

4

OCH3 O

O O

3

CH3O

OBz

CH3O

(12bS)-(+)-7

O CH3O

CH3O

8

(–)-9

7

6

O

(12bS)-10

Chart 5.1. Halenaquinol (7) and related compounds.

naphthalene–diene moiety is an ideal system for the determination of the absolute stereochemistry by applying the π -electron SCF-CI-DV MO method. As a model compound for the theoretical calculation of CD spectra, we adopted the molecule (12bS )-10, which has the essential part of the π -electron system of naphthalenediene compound 9. The absolute configuration of 10 was arbitrarily chosen as 12bS for the calculation, and the molecular geometry of the model compound was calculated by molecular mechanics [25]. The theoretical calculation of the CD and UV spectra of (12bS )-10 by the π electron SCF-CI-DV MO method afforded the curves illustrated in Figure 5.7 [24]. The

229 (+40.9) +40

OSi

CH3O

OCH3 O CH3O

+20 Δe

(12bS)-(–) 338 (+6.4)

CD

e × 10–4

0

Obsd in MeOH –20

218 (42,000) 301 (–23.3)

UV

4

324 (27,000)

2

Figure 5.6. CD and UV spectra of 0 200

300

400 λ (nm)

helanaquinol trans-methoxy diene derivative (3R,4R,12bS)-(−)-(9) in MeOH. (Redrawn from reference 24b, with permission.)

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

+40

223 (+35.5)

175

CH3O

O CH3O

+20

(12bS )

CD

Δe

378 (+3.3)

248 (–5.7)

–20

e × 10–4

0

Calcd

219 (40,300)

322 (–22.4)

4

349 (29,900) UV 2

Figure 5.7. CD and UV curves of the model compound 200

300

(12bS)-10 calculated by the π -electron SCF-CI-DV MO method. (Redrawn from reference 24b, with permission.)

0

400 λ (nm)

+100

CH3O

+50

CH3O

O (12bS )

D × 1036 cgs unit

CD

0

Calcd

R × 1040 cgs unit

–50

30 UV 20 10

200

300

400 λ (nm)

0

Figure 5.8. Calculated rotational and dipole strengths of the model compound (12bS)-10. (Redrawn from reference 24b, with permission.)

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theoretically simulated CD curve is in good agreement with the observed curve of (−)-9. It is thus evident that the basic pattern of the CD and UV spectral curves, including the sign, position, intensity, and shape of the bands, was well reproduced by the calculation. Since the absolute configuration of the model compound 10 is set as 12bS, the comparison of the present calculated and observed CD data leads to the unambiguous determination that the naphthalene–diene compound 9 has the 12bS absolute configuration. Accordingly, the absolute stereochemistry of halenaquinol (+)-7 was theoretically determined to be 12bS . To clarify the applicability of the present theoretical method to such a complex system, we analyzed the composition of the apparent CD and UV bands [24b]. As shown in Figure 5.8, there are nine major electronic transitions that contribute to the CD and UV bands. The first and second transitions with weak positive rotational strength at 374.5 and 351.6 nm, respectively, generate the weak positive Cotton effect at 378 nm (Figure 5.8). Furthermore, the third transition with an intense negative rotational strength at 324.4 nm results in the negative Cotton effect at 322 nm, and the sixth transition with a strong positive rotational strength contributes mainly to the intense positive Cotton effect at 223 nm. The correspondence between the component transitions and the apparent CD is thus clear. Therefore, the present analysis makes the absolute configurational determination of the halenaquinol compounds more reliable. Theories and theoretically obtained results should be proved experimentally. We succeeded in the first total synthesis of (+)-halenaquinol 7 and related natural products starting from (8aR)-(−)-Wieland–Miescher ketone [26–29]. The CD and UV spectra of the compounds synthesized were, of course, identical to those of the natural products. By these total syntheses of halenaquinol family compounds, we have proved, in an excellent way, that their absolute configurations theoretically determined were correct [26].

5.3.4. Atropisomerism of Natural Products: CD and Absolute Stereochemistry of the Biflavone, 4,4  ,7,7 -Tetra-O-methylcupressflavone Atropisomers are chiral compounds devoid of a chirality center. Those compounds are unique because the rotation about a single bond connecting two bulky moieties is sterically hindered, and hence their rotational conformers are sufficiently stable to be resolved into enantiomers. A natural product of biflavone, 4,4  ,7,7 tetra-O-methylcupressuflavone (11), is one of such atropisomers (Figure 5.9). The CD spectrum of biflavone (−)-11 shows strong bisignate Cotton effects of positive first and negative second signs at 400–300 nm (Figure 5.9). These Cotton effects look like an exciton split CD; therefore, one may assign the positive exciton chirality—specifically, clockwise screw sense of P -helicity—to this atropisomer. In fact, during the stereochemical studies of this flavone, the aS absolute stereochemistry (or P -helicity) had initially been assigned to (−)-11. However, such a careless application of the exciton chirality method leads to the erroneous assignment of the AC as

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

+50

177

Obsd 362.0 (+25.6)

267.5 (+21.3) Δe

CD

e × 10–4

0

OH O

CH3O

O

–50

OCH3 10 OCH3

326.2 (–54.4) O

CH3O

225.8 (51,800)

UV OH O (aR)-(–)

273.0 (41,400)

5 324.2 (40,900)

in EtOH

200

300

0

400 λ (nm)

+50

Calcd

Figure 5.9. CD and UV spectra of 4,4 ,7,7 -tetra-O-methylcupressuflavone (aR)-(−)-11 in EtOH. (Redrawn from reference 30, with permission.)

359.7 (+28.6)

263.2 (+21.7) Δe

CD

OH O

CH3O –50

e × 10–4

0

O

317.5 (–45.0)

OCH3 10 OCH3

226.8 (78,300)

CH3O 322.6 (66,200)

O

OH O (aR)

5

UV

Figure 5.10. CD and UV curves of 0 200

300

400 λ (nm)

(aR)-4,4 ,7,7 -tetra-O-methylcupressuflavone 11 calculated by the π -electron SCF-CI-DV MO method. (Redrawn from reference 30, with permission.)

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

described below [30]. We calculated the CD and UV spectra of biflavone (−)-11 by the π -electron SCF-CI-DV MO method and came to the conclusion that the correct absolute stereochemistry of (−)-11 is aR (or M -helicity). The absolute stereochemistry of a model compound for the calculation was arbitrarily chosen as (aR). The structure of atropisomer (aR)-11 was calculated by molecular mechanics (MMP2) to generate the stable conformation, where the calculated dihedral angle between two flavone moieties was 91◦ . The CD and UV spectra of (aR)-11 were calculated by the π -electron SCF-CI-DV MO method (Figure 5.10). The calculated CD and UV curves are in excellent agreement with the observed curves, including sign, intensity, and position of bands. Based on these results, the absolute stereochemistry of biflavone (−)-11 was unambiguously determined as aR (or M helicity) [30]. There are two nonempirical methods for determining the AC of chiral compounds; one is the X-ray Bijvoet method, and the other is the theoretical CD method including the exciton chirality method. These two methods are based on totally different phenomena, but they should come to the same AC for the same compound. In the case of the biflavone (−)-11, there had been considerable confusion in the stereochemical studies. After publication of our assignment of (aR) absolute configuration based on theoretical CD studies [30], the opposite AC, namely (aS ), by X-ray crystallography was reported [31]. Which determination is more reliable? Most people may support the determination by X-ray analysis. However, we were confident about our assignment by the theoretical CD calculation, because of the nonempirical nature of the method. To solve such a problem, we proved the absolute stereostructure by the total synthesis of the natural enantiomer. We designed a synthetic route, where the absolute stereochemistry of an intermediate was determined by X-ray crystallography, and we succeeded in the total synthesis of the natural atropisomer (−)-11 [32, 33]. The CD and UV spectra of the synthetic sample (aR)-(−)-11 were identical to those of the natural sample. Therefore, it was concluded that the absolute stereochemistry of natural biflavone (−)-11 is (aR). Thus our theoretical determination of the absolute stereochemistry of biflavone 11 by the π -electron SCF-CI-DV MO method was thus proved experimentally by the total synthesis of natural atropisomer 11.

5.4. CD SPECTRA AND ABSOLUTE STEREOSTRUCTURES OF UNIQUE CHIRAL OLEFINS: DISCOVERY AND DEVELOPMENT OF LIGHT-POWERED MOLECULAR MOTORS There are various kinds of chiral compounds devoid of chirality centers. Those compounds cannot take a planar structure because of strong steric hindrance. Some examples of these compounds are chiral olefins, (E )-1,1 ,2,2 ,3,3 ,4,4 -octahydro-4,4 biphenanthrylidene (12) and its (Z )-isomer (13) as shown in Chart 5.2. Olefins 12 and 13 can exist as chiral compounds, and they have been actually resolved into enantiomers by chiral HPLC using a chiral stationary phase [34]. The CD spectra of these olefins showed intense Cotton effects reflecting their twisted π -electron chromophores. However, their absolute configurations have remained undetermined. To solve this problem, we carried out the theoretical calculation of their CD spectra by the π -electron SCF-CI-DV MO method, synthesis of enantiopure compounds, and the experimental determination of their absolute configurations as follows [35].

179

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

8

8 8

8

10

5

10

5

10

1

1 3

5

1

1

3

[CD(+)239.0](M,M)-(E)-12

10

5

[CD(–)239.0](P,P)-(E)-12

3

3

[CD(+)238.1](M,M)-(Z)-13

[CD(–)238.1](P,P)-(Z)-13

Chart 5.2. Absolute stereochemistry of unique chiral olefins, (E)-1,1 ,2,2 ,3,3 ,4,4 -octahydro-4,4 biphenanthrylidene (12) and its (Z)-isomer (13).

5.4.1. Synthesis of Enantiopure Chiral Olefins 12 and 13, and Their CD Spectra During our calculation of CD and UV spectra by the π -electron SCF-CI-DV MO method, we realized that the reported CD ε values [34] are too small compared to the calculated values. To obtain reliable CD and UV data, we synthesized the enantiopure target compounds. According to the reported procedure [34], the racemic olefins, trans-(±)-12 and cis-(±)-13 were synthesized as shown in Scheme 5.2. The relative stereostructures of trans-olefin 12 and cis-olefin 13 were determined by 1 H NMR spectroscopy and then confirmed by the X-ray crystallographic analysis of trans-olefin 12 [35] as illustrated in Figure 5.11. The molecular framework of this compound is thus nonplanar and strongly twisted, supporting that this molecule can take a chiral form. Next the enantioseparation of racemic trans-olefin (±)-12 by chiral HPLC was attempted. We found that hydrocarbon 12 could be completely resolved into enantiomers using a chiral stationary phase of (+)-poly(triphenylmethylmetacrylate) under the reverse phase condition using MeOH as eluent and a column temperature of 3◦ C. To remove a small amount of the polymer of the chiral stationary phase, which was present as a contaminant, the fraction of each enantiomer was purified by HPLC (ODS-C18 , MeOH). From the first-eluted fraction, enantiopure olefin [CD(+)239.0]-(E )-12 was obtained, and its 1 H NMR spectrum was identical to of racemate (±)-12. The CD and UV spectra of the first-eluted trans-olefin [CD(+)239.0]-(E )-12 are shown in Figure 5.12, where the UV spectrum shows a broad band at 329.8 nm, which

8 8 10

5

1 O 14

10

5

+ 1

3

3 (±)-(Z)-13 (±)-(E)-12

Scheme 5.2. Preparation of racemic olefins, (E)-1,1 ,2,2 ,3,3 ,4,4 -octahydro-4,4 -biphenanthrylidene (12) and its (Z)-isomer (13).

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Figure 5.11. ORTEP drawing of racemic trans-olefin, (E)-1,1 ,2,2 ,3,3 ,4,4 -octahydro-4,4 -biphenanthrylidene (±)-12. (Redrawn from reference 35, with permission.)

+100 A = +211.5

239.0 (+58.2)

Δe

e × 10–4

0

CD –100 214.2 (−153.3) 216.2 (82,800)

10 (M,M)-(E)

–200 Obsd in MeOH

5

UV

200

250

300 λ (nm)

350

400

0

Figure 5.12. CD and UV spectra of the first-eluted trans-olefin [CD(+)239.0]-(E)-12 in MeOH. (Redrawn from reference 35, with permission.)

181

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

may be assigned to the 1 La transition of naphthalene chromophore. In the corresponding region, the CD spectrum shows a broad positive Cotton effect of medium intensity (λext 331.8 nm, ε +26.0). On the other hand, in the 1 Bb transition region, the UV spectrum shows an intense broad band (λext 232.2 nm, ε 61,800 and λext 216.2 nm, ε 82,800), and the CD spectrum shows intense positive and negative Cotton effects (λext 239.0 nm, ε +58.2 and λext 214.2 nm, ε −153.3): The amplitude A value between the peak and trough is +211.5. Such intense CD Cotton effects clearly indicate that the π -electron system of trans-12 is strongly twisted. The enantioseparation of cis-olefin (±)-13 was next examined, and we found that the reverse-phase HPLC used for trans-olefin (±)-12 was not useful. Instead, the chiral HPLC using (+)-poly(triphenylmethylmetacrylate) and hexane as eluent was effective; cis-olefin (±)-13 was partially separated into enantiomers at 3◦ C. To obtain the enantiopure olefin, the first-eluted fraction was recycled five times. Since we found the unexpected thermal racemization of cis-olefin 13 at room temperature, as will be discussed later, the CD and UV spectra were immediately measured after HPLC separation. Figure 5.13 shows the CD and UV spectra of the first-eluted cis-olefin [CD(+)238.1]-(Z )-13 in hexane. The first-eluted cis-olefin [CD(+)238.1]-(Z )-13 exhibits a broad UV band at 301.9 nm (ε 11,300) at the 1 La transition of naphthalene chromophore. In the corresponding region, the CD spectrum shows a broad weak negative Cotton effect

238.1 (+189.7)

+200

A = +429.0

CD

+100 Δe

e × 10–4

0

–100

–200 223.5 (–239.3)

10

(M,M)-(Z)

223.0 (73,700) –300 Obsd in hexane

5

UV

Figure 5.13. CD and UV spectra of the 200

250

300 λ (nm)

350

400

0

first-eluted cis-olefin [CD(+)238.1]-(Z)-13 in hexane. (Redrawn from reference 35, with permission.)

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

(λext 339.0 nm, ε −12.3). In the 1 Bb transition region, the UV spectrum shows an intense broad band (λext 223.0 nm, ε 73,700), while the CD spectrum shows very intense positive and negative Cotton effects (λext 238.1 nm, ε +189.7 and λext 223.5 nm, ε −239.3): The amplitude A value between the peak and trough is +429.0. The intense CD data thus indicate that the π -electron system of cis-13 is also strongly twisted.

5.4.2. Absolute Stereochemistry of Chiral Olefins trans-12 and cis-13 as Determined by the Calculation of CD and UV Spectra Using the SCF-CI-DV MO Method To determine the absolute stereochemistry of chiral olefins 12 and 13, we next calculated the CD and UV spectra by the π -electron SCF-CI-DV MO method. As a model compound for the calculation, the (M,M)-(E )-enantiomer 12 was arbitrarily chosen, and the atomic coordinates were obtained by the MOPAC AM1 calculation. The calculated CD and UV spectra of trans-olefin (M,M)-(E )-12 are shown in Figure 5.14 [35]. As seen in figures 5.12 and 5.14, the CD and UV spectra of trans-olefin 12 were reproduced well by the calculation. In the 1 La transition around 300 nm, the positive CD band was obtained by calculation, which agreed with the observed CD, although its intensity was smaller than the observed one. In the 1 Bb transition around 200–250 nm, +100 240.4 (+87.9)

0 Δe –100

e × 10–4

CD

–200 219.3 (–256.0)

10 223.2 (94,400) –300

(M,M)-(E)

Calcd 5

UV A = +343.9

Figure 5.14. CD and UV spectral curves of 200

250

300 λ (nm)

350

400

0

trans-olefin (M,M)-(E)-12 calculated by the π -electron SCF-CI-DV MO method. (Redrawn from reference 35 with permission.)

183

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

the intense positive and negative CD Cotton effects were obtained by calculation. The sign and shape of Cotton effects agreed well with those of observed spectrum, although the calculated intensity was stronger. Therefore, the absolute stereochemistry of the firsteluted trans-olefin [CD(+)239.0]-(E )-12 was clearly determined to be (M,M) by the theoretical calculation. The first-eluted enantiomer is designated as [CD(+)239.0]-(M,M)(E )-12 [35]. The CD and UV spectra of cis-olefin (M,M)-(Z )-13 were similarly calculated by the π -electron SCF-CI-DV MO method as shown in Figure 5.15. When comparing with Figure 5.13, it was clear that the CD and UV spectra of cis-olefin 13 were also wellreproduced by the calculation. In the 1 La transition around 300–370 nm, the negative CD band was obtained by calculation, which agreed with the observed CD, although its intensity was again larger. In the 1 Bb transition around 200–250 nm, the intense positive and negative CD Cotton effects were obtained by calculation. The sign and shape of the Cotton effects agreed well with those of the observed spectrum, although the calculated intensity in this case was weaker. Therefore, the absolute stereochemistry of the first-eluted cis-olefin [CD(+)238.1]-(Z )-13 was clearly determined to be (M,M) by theoretical calculation. Thus the absolute stereochemistry of the first-eluted enantiomer is designated as [CD(+)238.1]-(M,M)-(Z )-13 [35].

+100 232.6 (+76.7)

0

Δe

10 CD e × 10–4

–100

215.5 (–158.0) 211.9 (57.600) –200

(M,M)-(Z)

5

Calcd A = +234.7

UV

Figure 5.15. CD and UV spectral curves of 200

250

300 λ (nm)

350

400

0

cis-olefin (M,M)-(Z)-13 calculated by the π -electron SCF-CI-DV MO method. (Redrawn from reference 35, with permission.)

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5.4.3. Unexpected Thermal Racemization of cis-Olefin 13 During the studies discussed above, we observed that chiral cis-olefin 13 underwent an unexpected thermal racemization at room temperature. We had first considered that if one of these chiral olefins undergoes the racemization, it must be trans-olefin 12, because of less steric hindrance. In cis-olefin 13, two naphthalene moieties overlap with each other as seen in the X-ray stereostructure (Figure 5.16), which generates a severe steric hindrance, and therefore it is difficult to image the racemization. However, it was confirmed that cis-olefin 13 really undergoes thermal racemization, which was monitored by CD spectrum as illustrated in Figure 5.17. The thermal racemization of cis-olefin 13 was also measured by the magnetization transfer experiment of 1 H NMR spectroscopy. On the other hand, it was clarified that trans-olefin 12 does not undergo racemization at room temperature. To obtain the enantiopure cis-olefin 13 and to measure its CD spectrum, we carried out the HPLC separation at lower temperature. That is, the chiral HPLC column was cooled at −30◦ C during the enantioseparation, and the CD spectrum was measured at −50◦ C as illustrated in Figure 5.18, where the observed CD intensity was corrected for volume contraction. The CD intensity of cis-13 in Figure 5.18 is larger than that in Figure 5.13. It is thus important to measure the CD spectrum of the enantiopure sample. The reaction mechanism of the thermal racemization of cis-olefin 13 was later clarified by theoretical calculation [37], where the (M, P)-(Z ) isomer was included as an intermediate. This mechanism indicates that two naphthalene moieties slip by each other. This is the critical reaction step in the light-powered molecular motor discussed below.

Figure 5.16. ORTEP drawing of racemic cis-olefin, (Z)-1,1 ,2,2 ,3,3 ,4,4 -octahydro-4,4 biphenanthrylidene (±)-13. (Redrawn from reference 36, with permission.)

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

185

+200 0h

Racemization of

1h

+100

2h Δe

(M,M)-cis

3h 4h 5h

in hexane at room temp.

0 % 100 UV λmax 222.8 nm –100

CD CD λext 238.1 nm

50

t1/2 = 1.2 h –200

0 200

250

Figure 5.17. Decrease of CD intensity of cis-olefin 0

300 λ (nm)

2

4

6 h 350

[CD(+)238.1]-(M,M)-(Z)-13 in hexane due to the thermal racemization at room temperature. (Redrawn from reference 36 with permission.)

5.4.4. Experimental Determination of Absolute Stereochemistry of trans-Olefin 12 and cis-Olefin 13: Use of the Internal Reference of Absolute Configuration in X-Ray Analysis The absolute stereostructures of trans- and cis-olefins were theoretically determined by the calculation of CD and UV spectra using the π -electron SCF-CI-DV MO method as described above. But the authors believe that the theoretically determined results have to be proved experimentally. That is, the problem is now how to prove the absolute stereochemistry of 12 and 13 experimentally. To solve this problem, we adopted the following strategy. At first we thought to synthesize derivatives containing a heavy atom like Br or S and to carry out X-ray crystallography for determining the absolute configuration using the X-ray Bijvoet method. However, all attempts of the synthesis were unsuccessful. It was then decided to introduce an internal reference of the absolute configuration—that is a methyl group in a chiral position, as shown in compounds 15 and 16 (Chart 5.3). As the starting material for the synthesis, racemic cis-alcohol (±)-17 was selected, and it was enantioresolved by the CSDP acid (camphor-sulfonyl-dichloro-phthalic acid) method [9–12] as shown in Scheme 5.3. Cis-alcohol (±)-17 was esterified with CSDP

186

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

239.6 (+222.2)

+200 Δe

CD

+100

282.5 (+11.9)

e × 10–4

0 338.0 (–14.0) –100 256.8 (–80.1) 10 –200 (M,M)-cis

224.0 (–281.3)

–50.0°C

–300

222.8 (71.900) in hexane 5 UV 301.9 (11,300)

300

200

400

Figure 5.18. CD and UV spectra of cis-olefin

0

[CD(+)238.1]-(M,M)-(Z)-13 in hexane at −50◦ C. (Redrawn from reference 36, with permission.)

λ (nm)

8 8

H CH3

10

5

10

5

1 1

3

H3C

[CD(–)237.2]-(3R,3'R)(P,P)-(E)-15

H

3

H CH3

H3C

H

[CD(–)238.0]-(3R,3′R)(P,P)-(Z)-16

Chart 5.3. Dimethyl-substituted chiral olefins 15 and 16 useful for determining absolute configurations.

acid (1S,2R,4R)-(−)-18 to yield a diastereomeric mixtures of esters, which was easily separated by HPLC on silica gel. The second-eluted ester (−)-19b was obtained as a solid, which was recrystallized from EtOAc giving large prisms suitable for X-ray crystallography. The AC of the second-eluted ester (−)-19b was unambiguously determined to be (3S, 4S ) by the heavy atom effect of Cl and S atoms and also by the use of the camphorsultam moiety as an internal reference of the AC (Figure 5.19).

187

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

Cl

Cl Cl

Cl Cl N S O

+ OH CH3

O

N S O O

COOH

(1S,2R,4R)-(–)-18

+ O

O

H3C

O

(±)-17

OO

Cl N S O

O

O H3C

O

(3S,4S)-(–)-19b, X-ray

(3R,4R)-(+)-19a

Scheme 5.3. Enantioresolution of alcohol (±)-17 by the CSDP acid method.

Figure 5.19. ORTEP drawing of the second-eluted CSDP ester (3S,4S)(−)-19b. (Redrawn from reference 38, with permission.)

The AC of the first-eluted CSDP ester (+)-19a was, therefore, assigned as (3R,4R). The LiAlH4 reduction of the first-eluted CSDP ester (3R,4R)-(+)-19a yielded enantiopure cis-alcohol (3R,4R)-(+)-17, which was then oxidized to give enantiopure ketone (3R)-(−)-20 (Scheme 5.4). McMurry coupling reaction of ketone (3R)-(−)-20 yielded the desired dimethyl trans-olefin (−)-15, which was purified by repeated HPLC under normal-phase and reverse phase conditions affording enantiopure sample, [CD(−)237.2](3R,3 R)-(P, P)-(−)-15 ([α]D −446.2). The large negative optical rotation value of the product (−)-15 indicates that no racemization occurred during the McMurry reaction.

Cl Cl

S O

N O

OO H3C

O

H CH3

HO

O CH3

(3R,4R)-(+)-17 (3R,4R)-(+)-19a

CH3 (3R)-(–)-20

H3C H [CD(–)237.2]-(3R,3′R)(P,P)-(E)-15

Scheme 5.4. Synthesis of dimethyl trans-olefin [CD(–)237.2]-(3R,3 R)-(P, P)-(−)-15.

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

The relative and absolute stereochemistry of dimethyl trans-olefin (−)-15 was determined by X-ray crystallography as follows. Recrystallization of the product (−)-15 from MeOH afforded prismatic crystals, one of which was subjected to X-ray crystallographic analysis, and the stereostructure was determined as shown in Figure 5.20 [38]. Since compound (−)-15 is just a hydrocarbon containing no heavy atom, the AC of (−)-15 could not be determined by the X-ray analysis. However, it has two methyl groups at chiral positions, and therefore the (3R,3 R) configuration was used as an internal reference of the AC. The absolute helicity of the chiral olefin part was thus determined as (P, P ) from the ORTEP drawing in Figure 5.20. The CD and UV spectra of dimethyl trans-olefin (3R,3 R)-(P, P)-(E )-(−)-15 were next measured as shown in Figure 5.21, where the CD spectrum shows a negative Cotton effect at 237.2 nm. Hence the enantiomer is designated as [CD(–)237.2]-(3R,3 R)-(P, P)(E )-(−)-15. The UV spectrum of (−)-15 is similar to that of trans-olefin [CD(+)239.0]-(M,M)(E )-12. On the other hand, the CD spectra of [CD(−)237.2]-(3R,3 R)-(P, P)-(E )-(−)-15 is also similar to that of [CD(+)239.0]-(M,M)-(E )-12 in position, shape, and absolute intensity, but opposite in sign (compare Figures 5.12 and 5.21). These results clearly indicate that the dimethyl groups in (−)-15 do not change the molecular conformation too much, and that the absolute helicity of the chiral olefin part in [CD(+)239.0]-(E )-12 is (M,M). The absolute stereochemistry of trans-olefin [CD(+)239.0]-(M,M)-(E )-12 as determined previously by the theoretical calculation of CD spectrum was thus confirmed in an experimental manner. To synthesize dimethyl cis-olefin (3R,3 R)-(Z )-16, enantiopure dimethyl trans-olefin [CD(–)237.2]-(3R,3 R)-(P, P)-(E )-(−)-15 was irradiated by a high-pressure mercury lamp using a Pyrex glass filter to yield dimethyl cis-olefin 16 (Scheme 5.5), the CD spectrum of which showed an intense negative Cotton effect at 238.0 nm. Therefore, the enantiomer was designated as [CD(−)238.0]-(3R,3 R)-(Z )-16. The helical sense of the naphthalene–double bond–naphthalene moiety of [CD(−)238.0]-(3R,3 R)-(Z )-16 was first studied by 1 H NMR spectroscopy and it was finally determined by X-ray crystallography as follows. We first obtained single crystals of racemate (±)-16, which were subjected to X-ray analysis, affording the ORTEP drawing as shown in Figure 5.22.

Figure 5.20. ORTEP drawing of dimethyl trans-olefin [CD(–)237.2](3R, 3 R)-(P, P)-(E)-(−)-15. (Redrawn from reference 38, with permission.)

189

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

217.8 (+148.5) +150 H CH3 +100 CD

H3 C H

+50 (3R,3′R)-(P,P)-(E)

Δe

e × 10–4

0

–50 10 237.2 (–92.5) A = –241.0 –100 218.4 (85,700) 5 UV

Obsd in MeOH

Figure 5.21. CD and UV spectra of dimethyl 200

250

300

350

400

0

trans-olefin [CD(–)237.2]-(3R,3 R)-(P, P)-(E)-(−)-15 in MeOH. (Redrawn from reference 38, with permission.)

λ (nm)

H CH3 hν

H3C H

[CD(–)237.2]-(3R,3′R)(P,P)-(E)-15

H

CH3

H 3C H

[CD(–)238.0]-(3R,3′R)(P,P)-(Z)-16

Scheme 5.5. Synthesis of dimethyl cis-olefin [CD(–)238.0]-(3R,3 R)-(P, P)-(Z)-16.

From the ORTEP drawing, the relative stereochemistry of (±)-16 was determined as (3R ∗ ,3 R ∗ )-(P ∗ , P ∗ )-(Z ). Since the 1 H NMR spectrum of chiral olefin [CD(−)238.0](3R,3 R)-(Z )-16 was identical with that of racemate (3R ∗ ,3 R ∗ )-(P ∗ , P ∗ )-(Z )-(±)-16, the absolute helicity of chiral olefin was determined as (P, P ). The absolute stereochemistry of dimethyl cis-olefin [CD(−)238.0]-(3R,3 R)-(P, P)-(Z )-16 was thus unambiguously determined. Later, we obtained single crystals of chiral dimethyl cis-olefin [CD(–)238.0](3R,3 R)-(P, P)-(Z )-16, and the same AC was determined from the X-ray crystallographic analysis [39].

190

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Figure 5.22. ORTEP drawing of dimethyl cis-olefin (3R∗ ,3 R∗ )-(P ∗ , P ∗ )-(Z)-(±)-16. (Redrawn from reference 38, with permission.)

+400 223.4 (+334.0)

+200

CD

e × 10–4

H3 C H

H CH3

Δe

(3R,3′R)-(P,P)-(Z) 0

10

238.0 (–226.9)

–200

A = –560.9 5

222.4 (76,500)

UV

–400

Obsd in hexane

Figure 5.23. CD and UV spectra of dimethyl 200

250

300 λ (nm)

350

400

0

cis-olefin [CD(–)238.0]-(3R,3 R)-(P,P)-(Z)-16 in hexane. (Redrawn from reference 38, with permission.)

191

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

The CD and UV spectra of [CD(–)238.0]-(3R,3 R)-(P, P)-(Z )-16 is shown in Figure 5.23. As in the case of trans-olefin 12 and dimethyl trans-olefin 15, the CD and UV spectra of dimethyl cis-olefin [CD(−)238.0]-(3R,3 R)-(P, P)-(Z )-16 are very similar to those of cis-olefin [CD(+)238.1]-(M,M)-(Z )-13 in position, shape, and absolute intensity, but opposite in sign (compare Figures 5.13 and 5.23). Therefore, the absolute stereochemistry of cis-olefin [CD(+)238.1]-(M,M)-(Z )-13 previously determined by the theoretical calculation of CD was confirmed experimentally. The X-ray crystallographic method using an internal reference of absolute configuration is thus very useful for the absolute configurational assignment of various chiral compounds. It is interesting that the CD spectrum of dimethyl cis-olefin [CD(–)238.0]-(3R,3 R)(P, P)-(Z )-16 did not show a decrease in intensity at room temperature, unlike the case of cis-olefin [CD(+)238.1]-(M,M)-(Z )-13. That is, dimethyl cis-olefin 16 does not racemize at all, because the two methyl groups block the racemization process.

5.4.5. Unique Photo- and Thermo-chemical Behavior of Chiral Dimethyl Olefin: First Discovery and Development of a Light-Powered Chiral Molecular Motor Further studies of the photo- and thermo-chemistry of chiral dimethyl olefins 15 and 16 led to the first discovery of a light-powered chiral molecular motor as described below. During the photochemical studies of chiral dimethyl trans-olefin (−)-15, we found the formation of another product, yellow-colored dimethyl trans-olefin (+)-21 as shown in Scheme 5.6, although olefins (−)-15 and (+)-16 are colorless. Later it was clarified that the product (+)-21 was not directly formed from (−)-15 but from dimethyl cis-olefin (+)-16, and this photochemical step is reversible [40]. The structure of yellow-colored dimethyl trans-olefin (+)-21 was first studied by 1 H NMR spectrum, where two methyl groups appeared at δ 0.31 ppm, implying that the high field shift is due to the anisotropy effect by a neighboring naphthalene ring. These NMR data suggested the structure of (3R,3 R)-(M,M)-(E )-21, in which two methyl groups are placed at the equatorial position. The relative stereochemistry of olefin 21 was confirmed by X-ray crystallography of racemate (±)-21 as shown in Figure 5.24, where the two equatorial methyl groups are in contact with the naphthalene rings, causing a strong steric hindrance between methyl and naphthalene moieties. This effect makes olefin (+)-21 unstable, and also affects the π electron framework to change its color. This is the major reason why olefin 21 is yellow. Figure 5.25 shows the CD and UV spectra of the yellow dimethyl trans-olefin (3R,3 R)-(M,M)-(E )-(+)-21 together with those of colorless dimethyl trans-olefin

H CH3

H CH3

hn



hn H 3C H (3R,3′R)-(P,P)-(E)-(–)-15 with two axial methyl groups

H CH3

H 3C H

(3R,3′R)-(P,P)-(Z)-(+)-16 with two axial methyl groups

H3C

H

(3R,3′R)-(M,M)-(E)-(+)-21 with two equatorial methyl groups

Scheme 5.6. Photochemical interconversion between chiral dimethyl olefins (−)-15, (+)-16, and (+)-21.

192

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Figure 5.24. ORTEP drawing of yellow colored dimethyl trans-olefin (3R∗ ,3 R∗ )-(M∗,M∗ )-(E)-(±)-21. (Redrawn from reference 40, with permission.)

+200 H CH3

+100

CD

H3C

H

(3R,3′R)-(M,M)-(E)-(+)

e × 10–4

Δe 0

H CH3

–100

10

H3C H UV

5

–200

Figure 5.25. CD and UV spectra of

(3R,3′R)-(P,P)-(E)-(–)

200

300

400 λ (nm)

0

yellow-colored unstable dimethyl trans-olefin (3R,3 R)-(M,M)-(E)-(+)-21 in EtOH together with those of colorless stable (3R,3 R)-(P, P)-(E)-(−)-15 in EtOH. (Redrawn from reference 40, with permission.)

193

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

(3R,3 R)-(P, P)-(E )-(−)-15. It should be noted that in the UV–Vis spectrum of (3R,3 R)-(M,M)-(E )-(+)-21, the 1 La transition of the naphthalene chromophore is largely red-shifted at 320–420 nm, causing the yellow color. In the corresponding region, the CD spectrum shows a broad positive Cotton effect reflecting the inversed (M,M) helicity, while olefin (3R,3 R)-(P, P)-(E )-(−)-15 exhibits a negative Cotton effect in the 1 La transition region. In the 1 Bb transition region around 200–270 nm, the UV spectrum shows two absorption bands. On the other hand, the CD spectrum shows intense but complex Cotton effects as shown in Figure 5.25, reflecting the strongly twisted π -electron system. The absolute stereochemistry of the unique third isomer (3R,3 R)-(M,M)-(E )-(+)-21 was unambiguously determined. It should be noted that the internal reference method of absolute configuration is thus applicable to the X-ray analysis of racemic compounds. As shown in Scheme 5.6, the photochemical step between stable dimethyl cis-olefin (+)-16 and unstable dimethyl trans-olefin (+)-21 was reversible, as expected for olefin compounds. However, it was surprising that the step between stable dimethyl trans-olefin (−)-15 and stable dimethyl cis-olefin (+)-16 was irreversible. That is, the photochemical conversion from stable dimethyl trans-olefin (−)-15 to stable dimethyl cis-olefin (+)-16 occurred, but the reverse reaction did not proceed. Why? To solve this problem, we postulated the reaction scheme as shown in Scheme 5.7, where trans-olefin (−)-15, cis-olefin (+)-16, and trans-olefin (+)-21 were renamed trans-isomer (−)-22a, cis-isomer (+)-22c, and trans-isomer (+)-22d, respectively. As discussed above, it was observed that the photochemical isomerization between stable cis-isomer (+)-22c and unstable trans-isomer (+)-22d was reversible, but unstable transisomer (+)-22d underwent thermal isomerization to stable trans-isomer (−)-22a. It was assumed that the unstable cis-isomer (3R,3 R)-(M,M)-(Z )-22b must exist as a primary

hn

Δ hn

H

H

CH3

CH3

H3C

H

(3R,3′R)-(M,M)-(Z)-22b

H3C

H

H Δ

CH3

H3C H

(3R,3′R)-(P,P)-(Z)-(+)-22c

(3R,3′R)-(P,P)-(E)-(–)-22a

hn H

CH3 hn

CH3 H

(3R,3′R)-(M,M)-(E)-(+)-22d

Scheme 5.7. The cyclic reaction scheme of photo- and thermo-chemical conversions of unique dimethyl olefins.

194

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

product of the photochemical conversion of (−)-22a, and the reverse reaction from 22b to (−)-22a may occur. However, if the isomer 22b is extremely unstable, the formed isomer 22b immediately and irreversibly converts to stable cis-isomer (+)-22c. Therefore, the total reaction from (−)-22a to (+)-22c becomes irreversible in agreement with the observed results [41]. In fact, we succeeded in detecting the unstable isomer (±)-22b in the photochemical reaction of (±)-22a at −60◦ C by 1 H NMR spectroscopy (Figure 5.26) [41]. Later, we realized that this system makes a unidirectional molecular motor rotation around the central double bond [42]. That is, when looking at the molecule from the left side, the naphthalene moiety on the left rotates counterclockwise against the naphthalene moiety on the right-upper side. The photochemical step makes the rotation in both directions, but the thermal step rotates only counterclockwise. The reaction 22a → 22b → 22c → 22d thus makes the 360◦ rotation in the counterclockwise direction, and the motor returns to the starting place 22a. Therefore, the molecular motor can make a continuous rotation under photoirradiation and heating, where the direction of the motor rotation is governed by the molecular chirality. The photochemical energy is thus converted to the mechanical rotation of the molecule, and this was the discovery of the first light-powered molecular motor [42].

5.5. A NEW MODEL OF LIGHT-POWERED CHIRAL MOLECULAR MOTOR WITH HIGHER SPEED OF ROTATION The chiral olefins shown in Scheme 5.7 ideally satisfy the requirements of molecular motor, but its rotation was not fast, because the fourth rotation step (i.e., thermal reaction Aromatic Part

ppm

8.25

(3R*,3R*)-(P*,P*)-trans stable

8.00

7.75

7.50

7.25

7.00

6.75

7.75

7.50

7.25

7.00

6.75

irradiation at –60.0 °C after 1 day

ppm

8.25

8.00

NMR detection of unstable dimethyl cis-olefin in CD2 Cl2 : ∗, unstable cis-olefin (3R∗,3 R∗ )-(M∗ ,M∗ )-(Z)-22b; ◦, stable trans-olefin (3R∗ ,3 R∗ )-(P ∗ , P ∗ )-(E)-22a. (Redrawn from reference

Figure 5.26. 41.)

1H

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

195

22d → 22a), needs higher temperature and hence is slow, because of the severe steric hindrance between methyl group and naphthalene moiety. To make a faster molecular motor, we improved the structure as follows. A new model of chiral molecular motor 23 with higher speed of rotation was designed as shown in Chart 5.4, where the six-membered rings in molecular motor 22 were replaced by five-membered rings to diminish the steric hindrance between methyl group and naphthalene moiety [43, 44].

5.5.1. Synthesis, CD Spectra, X-ray Structure, and Absolute Stereochemistry To synthesize the new chiral molecular motor, we adopted the strategy shown in Scheme 5.8. Racemic cis-alcohol (±)-24 was esterified with CSDP acid, giving a diastereomeric mixture of esters, which was easily separated by HPLC on silica gel [43]. One of the advantages of the CSDP acid method is that CSDP esters tend to give single crystals suitable for X-ray crystallography with high probability [9–12]. In fact, the second-eluted CSDP ester (−)-cis-25b was obtained as single crystals by recrystallization from hexane/EtOAc. The single crystal was subjected to X-ray analysis, and the absolute stereostructure was determined by the use of CSDP acid moiety as an internal reference and also by the heavy atom effect (Figure 5.27). That is, the (1S,2S ) absolute configuration was assigned to (−)-cis-25b. The absolute configuration of the first-eluted ester was naturally determined as (1R,2R). To recover alcohol, the second-eluted CSDP ester (1S,2S )-(−)-cis-25b was hydrolyzed with KOH/MeOH yielding enantiopure cis-alcohol (1S,2S )-(+)-24. Cis-alcohol (1S,2S )-(+)-24 was next oxidized to yield enantiopure ketone (S )-(+)26. The product was then subjected to the McMurry coupling reaction with TiCl3 and LiAlH4 in THF giving dimethyl trans-olefin (2S,2 S)-(E )-(−)-23a (colorless prisms, yield 21%) and dimethyl cis-olefin (2S,2 S)-(Z )-(−)-23c (pale yellow prisms, yield 5%) as shown in Scheme 5.8. The relative stereochemistry of racemate (±)-23a was determined to be (2S ∗ ,2 S ∗ )∗ (M ,M ∗ )-(E ) by X-ray crystallography as shown in Figure 5.28. Since the 1 H NMR spectrum of chiral trans-olefin (−)-23a was identical to that of racemate (2S ∗ ,2 S ∗ )-(M ∗,M ∗ )(E )-(±)-23a, the absolute stereochemistry of (−)-23a was unambiguously determined to be (2S,2 S)-(M,M)-(E ).

8

CH3

H

5

2 1

1

2

H CH3

5 8

[CD(–)257.8]-(2S,2′S)(M,M)-(E)-23a

CH3

H

H CH3

[CD(–)270.0]-(2S,2′S)(M,M)-(Z)-23c

Chart 5.4. A new model of chiral molecular motor with higher speed of rotation.

196

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Cl

Cl

Cl

Cl

H3C

N

N

+

S

OH

O

S O

COOH

O

O

O (1S,2R,4R)-(–)-18

(±)-24

O

+ O

O

H3C (1R,2R)-(–)-cis-25a

Cl Cl N S

O

O

O

O

(1S,2S)-(–)-cis-25b

O

HO

H3C

CH3

(1S,2S)-(+)-cis-24 (1S,2S)-(–)-cis-25b, X-ray

H

CH3 +

O

CH3

H

H

H

CH3

CH3

CH3

(S)-(+)-26 [CD(–)257.8]-(2S,2′S)(M,M)-(E)-(–)-23a

[CD(–)270.0]-(2S,2′S)(M,M)-(Z)-(–)-23c

Scheme 5.8. Synthesis of chiral dimethyl olefins (−)-23a and (−)-23c.

Figure 5.27. ORTEP drawing of the second-eluted CSDP ester (1S,2S)-(−)-cis-25b. (Redrawn from reference 43, with permission.)

197

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

Figure 5.28. ORTEP drawing of dimethyl trans-olefin (2S∗ ,2 S∗ )-(M∗ ,M∗ )-(E)-(±)-23a. (Redrawn from reference 43, with permission.)

It was surprising to see the CD spectrum of (−)-23a, which showed several complex negative Cotton effects in the 1 Bb transition region at 200–270 nm (Figure 5.29). The CD pattern is much different from that of previous chiral six-membered olefins. On the other hand, in the 1 La transition region at 300–400 nm, a broad positive Cotton effect was observed. Since the CD spectrum showed a negative Cotton effect at 257.8 nm, the enantiomer was designated as [CD(–)257.8]-(2S,2 S)-(M,M)-(E )-(−)-23a.

obsd CD 365.8 ( +16.7) 349.6 ( +18.2) 295.8 ( –10.5) 257.8 (–140.0) 247.8 ( –57.1) 226.6 (–100.2) 214.2 (–109.6)

200 CD Δe

H

CH3

e × 10–4

0

–100 CH3 –200

H

[CD(–)257.8]-(2S,2′S)(M,M)-(E) obsd UV 367.6 (25,600) 352.0 (25,900) 243.6 (39,200) 216.4 (87,700)

UV

200

10

in MeOH

300

400 λ (nm)

5

Figure 5.29. CD and UV spectra of stable dimethyl trans-olefin

0 500

[CD(–)257.8]-(2S,2 S)-(M,M)-(E)-(−)-23a in MeOH. (Redrawn from reference [43], with permission.)

198

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

The stereochemistry of the other olefin (−)-23c was determined to be (2S,2 S)(M,M)-(Z )-(−)-23c by 1 H NMR analysis and also by the fact that the UV irradiation of trans-olefin (−)-23a yielded cis-olefin (−)-23c. The CD and UV spectra of cis-olefin (−)-23c are shown in Figure 5.30, where in the 1 La transition region at 350–400 nm a broad negative Cotton effect was observed. On the other hand, in the 1 Bb transition region at 200–290 nm, strong negative and positive Cotton effects were obtained. Since the CD Cotton at 270 nm was negative, this enantiomer was fully designated as [CD(–)270.0](2S,2 S)-(M,M)-(Z )-(−)-23c. For the cis-olefin [CD(–)269.8]-23c, the absolute stereochemistry had been previously assigned by the Feringa group as (2R,2 R)-(P, P)-(Z )-23c by comparison with the CD spectrum of the six-membered ring compound [CD(–)238.0]-(3R,3 R)-(P, P)-(Z )-16 in Figure 5.23. They considered that the pattern of negative (270.0 nm)/positive (232.0 nm) bands of [CD(–)269.8]-23c was similar to that of the negative (238.0 nm)/positive (223.4 nm) bands of six-membered cis-olefin 16 [45]. Since their assignment was thus opposite to ours, it was concluded that such comparison of CD spectra led to the erroneous assignment [43].

5.5.2. Light-Powered Chiral Molecular Motor with Higher Speed of Rotation: Isolation or 1 H NMR Detection of the Unstable Motor Rotation Isomers and Their CD Spectra The new chiral olefins with five-membered ring systems worked as a light-powered chiral molecular motor with higher speed of rotation as shown in Scheme 5.9. To clarify the

100

obsd CD 379.2 ( –6.5) 304.2 ( –21.5) 291.8 ( –23.9) 270.0 (–159.6) 232.0 (+116.2) 223.8 ( –21.0) 215.4 ( +42.7) 210.2 ( +30.5)

CD

Δe

e × 10–4

0

–100

CH3 –200

in MeOH

UV

200

H

H

CH3

[CD(–)270.0]-(2S,2′S)(M,M)-(Z) obsd UV 369.6 (15,300) 330.4 ( 7,000) 305.8 ( 8,200) 294.4 ( 6,500) 254.2 (28,200) 221.4 (72,100)

300

400 λ (nm)

10

5

Figure 5.30. CD and UV spectra of stable 0 500

dimethyl cis-olefin [CD(−) 270.0]-(2S,2 S)(M,M)-(Z)-(−)-23c in MeOH. (Redrawn from reference 43, with permission.)

199

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

hn

Δ hn

H

CH3

CH3

CH3

H

H

CH3

[CD(+)279.2]-(2S,2′S)(P,P)-(Z)-23b

H CH3

Δ hn

[CD(–)257.8]-(2S,2′S)(M,M)-(E)-(–)-23a

H

CH3

H

H CH3

[CD(–)270.0]-(2S,2′S)(M,M)-(Z)-(–)-23c hn

H

Scheme 5.9. Rotation scheme of a

CH3

light-powered chiral molecular motor of five-membered ring type rotating with a higher speed.

[CD(+)269.0]-(2S,2′S)(P,P)-(E)-23d

motor rotation mechanism, we first tried to isolate the unstable cis-olefin 23b as follows [44]. A solution of the stable trans-olefin 23a in CH2 Cl2 was irradiated with UV light at 312 nm at −78◦ C, and the reaction mixture was subjected to HPLC (ODS, MeOH) at −40◦ C. The desired unstable cis-olefin 23b was obtained as a yellow powder of the second-eluted fraction, and the structure of 23b was determined by 1 H NMR spectra measured at −30◦ C. To avoid the thermal isomerization, the CD spectrum of the unstable cis-olefin (2S,2 S)-(P, P)-(Z )-23b was measured in MeOH at −32.5◦ C as illustrated in Figure 5.31, where very complex and intense Cotton effects were observed in the 1 Bb transition region (200–300 nm), reflecting the strongly twisted π -electron structure. In addition, a weak

Δε +100 CD +50

H H CH3 CH3 [CD(+)279.2]-(2S,2′S)(P,P)-(Z)

0

–50 in MeOH at –32.5°C –100

–150 200

300

obsd CD 400.6 ( +8.8) 279.2 (+100.6) 261.0 ( –71.3) 233.0 (–144.1) 221.6 ( +70.9) 400

λ (nm)

Figure 5.31. CD spectrum of the unstable 500

cis-olefin [CD(+)279.2]-(2S,2 S)-(P, P)-(Z)-23b in MeOH at −32.5◦ C. (Redrawn from reference 44, with permission.)

200

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

positive broad Cotton effect appeared at 350–450 nm, and the strong red-shift of the electronic transition caused the yellow color of this unstable motor rotation isomer 23b. Since the unstable cis-olefin (2S,2 S)-(P, P)-(Z )-23b shows an intense positive CD band at 279.2 nm, its AC was fully designated as [CD(+)279.2]-(2S,2 S)-(P, P)-(Z )-23b. We also attempted to isolate the other unstable motor rotation isomer 23d in a similar manner. A solution of the stable cis-olefin (−)-23c in MeOH was irradiated with UV light at 330 nm at −78◦ C for 18 s. The photochemical reaction was monitored by CD spectroscopy performed at −62◦ C to find that the reaction had reached a photoequilibrium state between 23c and 23d. The equilibrium ratio was determined to be 23d/23c = 93 : 7 by 1 H NMR spectra measured at −60◦ C. The extremely unstable trans-olefin (2S,2 S)-(P, P)-(E )-23d shows intense and complex CD Cotton effects in the 1 Bb transition region (200–290 nm), reflecting the strongly twisted π -electron structure, while at 300–450 nm a negative broad CD band was observed (Figure 5.32). Since the unstable trans-olefin 23d shows a positive CD band at 269.0 nm, its AC was designated as [CD(+)269.0]-(2S,2 S)-(P, P)-(E )-23d.

5.5.3. Light-Powered Chiral Molecular Motor with Higher Speed of Rotation: Dynamics of Motor Rotation Studied by CD Spectroscopy To clarify the motor rotation mechanism, the photochemical and thermal reactions of olefin 23 were studied by CD and 1 H NMR spectroscopy as follows [44]. (1) The Photochemical First Motor Rotation Step. A solution of stable transolefin (2S,2 S)-(M,M)-(E )-(−)-23a in MeOH was irradiated with UV light at 312 nm at −78◦ C, and the change was monitored by CD measured at −25◦ C (Figure 5.33). The photochemical reaction was thus very fast and reached photoequilibrium after 20.5 s of irradiation. The 23b/23a ratio at the final stage was 94:6. The reverse reaction 23b → 23a was similarly studied by CD spectroscopy, where a solution of unstable cis-olefin (2S,2 S)-(P, P)-(Z )-23b in MeOH was irradiated with

+150 Δε H

+100 CD CH3

+50

H

[CD(+)269.0]-(2S,2′S)(P,P)-(E)

0

obsd CD 386.0 ( –35.0) 269.0 ( +52.4) 255.4 ( +41.4) 240.0 ( –7.9) 230.4 (+137.1) 220.2 ( –30.2) 214.8 ( +67.7)

–50 in MeOH at –62.0 °C –100

200

CH3

300

400 λ (nm)

500

Figure 5.32. CD spectrum of the unstable trans-olefin [CD(+)269.0]-(2S,2 S)-(P, P)-(E)-23d (93%) in MeOH at −62.0◦ C; the sample contained some of the stable cis-olefin (2S,2 S)-(M,M)-(Z)-23c (7%); the ratio was determined by 1 H NMR spectroscopy. (Redrawn from reference 44, with permission.)

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

Δε 233.0 nm

201

in MeOH –25 °C

+100

7

+50 2

1

0

1 2

1, 0.00 sec 2, 2.62 sec 3, 5.09 sec 4, 7.06 sec 5, 10.37 sec 6, 20.50 sec 7, unstable

7

–50

–100 1

7 220

240

260

280

300

Figure 5.33. CD spectral change due to the photoisomerization of the stable trans-olefin (2S,2 S)-(M,M)-(E)-23a into the unstable cis-olefin (2S,2 S)-(P, P)-(Z)-23b on UV irradiation in MeOH at 312 nm at −78◦ C, as monitored by CD at

320

λ (nm)

−25◦ C. (Redrawn from reference 44, with permission.)

visible light (430 nm) at −78◦ C. After 65 sec irradiation, the reaction 23b → 23a was complete. (2) The Thermal Second Motor Rotation Step. The thermal reaction 23b → 23c was also monitored by CD spectroscopy, where a solution of unstable cis-olefin (2S,2 S)-(P, P)-(Z )-23b in MeOH was kept at 14.8◦ C and CD spectra were measured at intervals of 1 h (Figure 5.34). Based on the Arrhenius and Eyring plots, the dynamics data of the thermal molecular motor rotation step 23b → 23c were determined. The data obtained by CD spectroscopy agreed well with those by 1 H NMR spectroscopy.

Δε 13

+100

in MeOH 14.8 °C

1

+50 0 13

–50 –100

1, 2, 3, 4, 5, 6, 7,

2 1

–150

233.8 nm 220

240

260

280 λ (nm)

0.0 h 1.0 h 2.0 h 3.0 h 4.0 h 5.0 h 6.0 h 300

8, 7.0 h 9, 8.0 h 10, 9.0 h 11, 10.0 h 12, 11.0 h 13, stable cis 320

Figure 5.34. CD spectral change due to the thermal isomerization of the unstable cis-olefin (2S,2 S)-(P, P)-(Z)-23b into the stable cis-olefin (2S,2 S)-(M,M)-(Z)-23c at 14.8◦ C. (Redrawn from reference 44, with permission.)

202

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

(3) The Photochemical Third Motor Rotation Step. A solution of stable cisolefin (2S,2 S)-(M,M)-(Z )-(−)-23c in MeOH was irradiated with UV light at 330 nm at −78◦ C giving unstable trans-olefin (2S,2 S)-(P, P)-(E )-23d, and the change was monitored by CD at −60◦ C (Figure 5.35). The photochemical reaction was also very fast and reached photoequilibrium after 23.0 s of irradiation. The 23d/23c ratio at the final stage was 93:7. The low-temperature CD spectra (−60◦ C) are very useful for studying the photodynamics of extremely unstable motor rotation isomer. (4) The Thermal Fourth Motor Rotation Step. The thermal reaction 23d → 23a was also monitored by CD spectroscopy as follows; CD spectra of the solution 23d/23c (93:7) in MeOH was measured at −19.1◦ C at intervals of 1 h (Figure 5.36). The thermal step 23d → 23a occurred even at subzero temperatures like −19.1◦ C, indicating that the fourth motor rotation is much faster than that of six-membered ring motor described above. This five-membered ring molecular motor thus rotates very fast as predicted. From the Arrhenius and Eyring plots, the dynamics data of the thermal fourth molecular motor rotation step 23d → 23a were determined. The molecular motor rotation dynamics data are summarized in Table 5.1. (i) The first photochemical rotation step 23a → 23b is much faster under the conditions of CD measurement than under the conditions of 1 H NMR measurement, because of the photoirradiation efficiency. That is, the speed of the photochemical rotation step essentially depends on the photoirradiation conditions. As the motor can rotate backward (e.g., 23b → 23a), the direction of motor rotation has to be controlled by choosing the optimal wavelength. Thus, the motor rotates forward on UV irradiation at 312 nm, reaching photoequilibrium in 20 s with the ratio 23b/23a = 94 : 6. (ii) The second step of motor rotation 23b → 23c is thermally controlled, and the dynamics data obtained by 1 H NMR and CD methods are similar. (iii) The third photochemical rotation step 23c → 23d was again faster under the conditions of CD measurement, where the motor rotates forward on UV irra-

Δε in MeOH

–60 °C

+100 1 5

+50 0 5

3

–50 –100 1

–150

1, 0.00 sec 2, 0.69 sec 3, 1.86 sec 4, 4.22 sec 5, 13.78 sec

270.0 nm 220

240

260

280 λ (nm)

300

320

Figure 5.35. CD spectral change due to the photoisomerization of the stable cis-olefin (2S,2 S)-(M,M)-(Z)-23c into the unstable trans-olefin (2S,2 S)-(P, P)-(E)-23d on UV irradiation in MeOH at 330 nm at −78◦ C, as monitored by CD at −60◦ C. (Redrawn from reference 44, with permission.)

203

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

Δε in MeOH

–19.1 °C

+50

1

0

1, 2, 3, 4, 5, 6, 7, 8,

–50

8

–100

258.2 nm 220

240

260

280

0.0 h 1.0 h 2.0 h 3.0 h 4.0 h 5.0 h 6.0 h stable trans 300

320

λ (nm)

Figure 5.36. CD spectral change due to the thermal isomerization of the unstable trans-olefin (2S,2 S)-(P, P)-(E)-23d into the stable trans-olefin (2S,2 S)-(M,M)-(E)-23a at −19.1◦ C. (Redrawn from reference 44, with permission.)

TAB L E 5.1. The Molecular Motor Rotation Dynamics Data as Monitored by 1 H NMR and CD Methods Motor Rotation Forward rotationa 23a → 23b, hν, 312 nmb Backward rotationa 23b → 23a, hν, 430 nmb Forward rotationc 23b → 23c, thermal Forward rotationa 23c → 23d, hν, 330 nmb Backward rotationa 23d → 23c, hν, 430 nmb Forward rotationc 23d → 23a, thermal

a

1

H NMR 400 MHz in CD2 Cl2 15 min 23b/23a = 91 : 9 4 min 23b/23a = 0 : 100 Ea = 20.7 H = = 20.1 S = = −6.17 R = 0.999, 0.999 12 min 23d/23c = 96 : 4 60 min 23d/23c = 25 : 75 Ea = 17.1 H = = 16.5 S = = −9.23 R = 0.999, 0.999

CD in MeOH 20.5 s 23b/23a = 94 : 6 90 s 23b/23a = 0 : 100 Ea = 21.4 H = = 20.8 S = = −6.30 R = 0.999, 0.999 23 s 23d/23c = 93 : 7 90 s 23d/23c = 20 : 80 Ea = 16.8 H = = 16.3 S = = −12.6 R = 0.975, 0.974

Time to photoequilibrium. Ratio at photoequilibrium. c Activation energy Ea and activation enthalpy H = in kcal mol−1 unit: activation entropy S = in cal K−1 mol−1 unit; the value of correlation coefficient R for Arrhenius and Eyring plots, respectively. Source: Adapted from reference [44], with permission. b

204

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

diation at 330 nm, reaching the photoequilibrium state in 23 s with the ratio 23d/23c = 93 : 7. (iv) The fourth thermal rotation step 23d → 23a was similarly monitored by 1 H NMR and CD methods, but in this case the CD study was difficult because of the instability of compound 23d. However, it should be noted that both methods gave similar values of kinetic parameters as seen in Table 5.1. The activation energy of the fourth thermal step was much lower than that found for the motor of sixmembered ring type, and hence the new motor rotates much faster than the old one.

5.5.4. Continuous Rotation of the New Light-Powered Chiral Molecular Motor Studied by CD Spectroscopy Continuous rotation experiments were carried out as follows: (i) For the first rotation step, a solution of the enantiopure stable trans-olefin 23a in n-pentanol was irradiated with UV light at 312 nm at −78◦ C for 30 s; (ii) for the second rotation step, the solution was heated at 120◦ C for 20 s; (iii) for the third rotation step, the solution was irradiated with UV light at 330 nm at −78◦ C for 30 s; (iv) for the fourth rotation step, the solution was heated at 120◦ C for 10 s. After each operation, the CD spectrum of the solution was measured at −50◦ C, and the CD intensity at 275 nm was plotted. One cycle of operations (namely, 360◦ rotation of motor) took 90 s under these conditions. Figure 5.37 shows the CD plot for 10 cycles of rotation, indicating that this new molecular motor rotates continuously and is durable for such operations.

5.6. ABSOLUTE CONFIGURATION OF CHIRAL C60 -FULLERENE CIS-3 BISADDUCTS DETERMINED BY X-RAY CRYSTALLOGRAPHY AND CD SPECTROSCOPY The fullerene C60 is a symmetrical and achiral molecule. However, an addition reaction at two chiral positions of the C60 skeleton (e.g. a cis-3 addition) makes the π -electron 1

2

3

4

5

6

7

8

9

10 cycles

+60 +40 +20 Δε 0 –20 –40 –60 –80 –100

Figure 5.37. Continuous rotation of the 0

200

400

600

Time (sec)

800

new molecular motor 23 as monitored by CD. (Redrawn from reference 44, with permission.)

205

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

system in fullerene chiral. Synthetic and absolute configurational studies of various chiral fullerene cis-3 bisadducts have been carried out by many research groups as listed in Chart 5.5 [46]. Compound [CD(–)288]-27 was synthesized as the first chiral cis-3 bisadduct by using a chiral tether, and its AC was tentatively assigned as (R, R, f,s A) {≡ (R, R, f C ), old nomenclature} on the basis of MM2/Monte Carlo calculations, because it was assumed that the product formed should be the most energetically stable diastereomer. Therefore, the stereochemistry of the most stable diastereomer calculated was assigned as shown in Chart 5.5 [47]. In a similar manner, the AC of compound [CD(+)281]-28 was determined as shown by assuming that the product formed should have the most energetically stable stereostructure. Thus the diastereomeric structure (S,S,f,s A) was assigned as the most stable one by molecular mechanics calculation [48]. In addition, the CD spectrum of compound (S,S,f,s A)-28 was calculated by the π electron SCF-CI-DV MO method to compare with the observed CD spectrum [49]. By comparison of the data, the AC of bisadduct [CD(+)281]-28 was determined to be (S,S,f,s A). Later, the same AC was assigned by applying the CD exciton chirality method to a related compound to confirm the previous assignment of 28 [50].

O

O

O

H

H

H

O O

O

(R,R,f,sA)-[CD(–)288]-27* energy calculation (1996)

O

B

O

O

B

H

CH3O O

O

H3C CH3 H H

O

O

O

OCH3

O

O

O

EtO

OEt

(S,S,f,sA)-[CD(+)281]-28 energy calculation (1997) CD calculation (1998) Exciton CD (2000)

(S,S,f,sC)-[CD(+)284]-29* energy calculation (1997–8) revised (2003)

H3CO H H OCH3

H3CO H H OCH3

O

(f,sC)-[CD(−)287]-30 comparison of CD (1999)

O O

O

O O

O

O

O O

O

O

O

O

O

EtO

OEt

EtO

OEt

(S,S,f,sA)-[CD(+)281]-31a 1H NMR analysis (2002)

(S,S,f,sC)-[CD(−)281]-31b 1H NMR analysis (2002)

Chart 5.5. Previously reported chiral C60 -fullerene cis-3 adducts together with their CD data and absolute configurations, which are designated by the new systematic nomenclature (f,s C and f,s A). Our studies described here suggested that the ACs of compounds 27 and 29 should be revised.

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The AC of cis-3 bisadduct [CD(+)284]-29 was tentatively assigned as shown in Chart 5.5 by calculation of the stable diastereomeric structures and their energy levels, because the tether part was synthesized from (2S,3S )-butanediol, and the stereostructure (S,S,f,s C ) was calculated to be the most stable isomer [51]. Compound [CD(–)287]-30 has no chirality center in the tether moiety, and therefore its AC was determined to be (f,s C ) by comparison of CD spectrum with that of compound [CD(+)281]-(S,S,f,s A)-28 [52]. That is, the CD spectra of [CD(–)287]-30 and [CD(+)281]-(S,S,f,s A)-28 were opposite to each other. Regarding the ACs of these chiral fullerene derivatives, a serious problem was raised as follows. Among compounds 27–30, their tether moieties are different from each other, but the remaining C60 chiral chromophores with the cis-3 bisadduct pattern are the same or mirror images of each other. As listed in Table 5.2, however, the CD spectrum of (R,R,f,s A)-27 is opposite to that of (S,S,f,s A)-28, although they have the same (f,s A) AC of the fullerene moiety. On the other hand, compounds (S,S,f,s A)-28 and (S,S,f,s C )-29 have the opposite ACs in the fullerene part, but they exhibited similar CD spectra as seen in Table 5.2. These results strongly indicated that some absolute configurational assignments were wrong. To solve this problem, a different strategy was taken as follows. In the previous syntheses, only one diastereomer of two possible products was isolated and it was assumed to be the most stable diastereomer. This strategy brought some ambiguity in the determination of AC. To overcome these difficulties, we selected a tether with a more flexible conformation to yield two possible disatereomeric products in the synthesis. That is, we thought that it was relatively easy to determine the relative stereochemistry by comparing the 1 H NMR data of two diastereomers [53]. We were able to synthesize the two possible diastereomers [CD(+)281]-31a and [CD(–)281]-31b starting from (2S,3S )-(−)-2,3-butanediol, and these diastereomers were separable by HPLC on silica gel (Chart 5.5). Their CD spectra were almost mirror images of one another, reflecting the opposite chirality of the π -electron system in the two C60 skeletons. Careful analysis of the 1 H NMR data (i.e., chemical shift and coupling constant) led to the absolute configurational assignments, (S,S,f,s A)-[CD(+)281]-31a and (S,S,f,s C )-[CD(–)281]-31b [53]; these results thus confirmed the AC of (S,S,f,s A)[CD(+)281]-28 reported previously by the Diederich and our groups [48–50]. Although the new assignment based on the 1 H NMR analyses of two diastereomers was more reliable than the previous ones using only one diastereomer, we wanted to confirm our results by X-ray crystallography.

TAB L E 5.2. Reported CD Data and ACs of Chiral Fullerene cis-3 Bisadducts Compound

27

28

29

30

AC CD λ (nm) ε CD λ (nm) ε References

(R,R,f,s A)a 720.0 +4.69c 288.0 −75.0c 47

(S,S,f,s A) 706.0 −37.0 281.0 +89.0 48–50

(S,S,f,s C )b 737.0 −36.3 284.0 +60.6 51

(f,s C ) 726.0 +26.7 287.0 −73.2 52

a The

revision of AC was later suggested; see the discussion below. was later revised [51]. c Values are 1/1000 of the ε values reported in reference 47, which are too large. b AC

207

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

Although it was known that most fullerene derivatives were obtained as amorphous solids, we attempted to get single crystals of various chiral cis-3 bisadducts, and we finally succeeded in obtaining single crystals of diethyl ester [CD(+)280]-32, which was previously synthesized by the Diederich group [50]. As seen in Scheme 5.10, bisadduct [CD(+)280]-32 was prepared starting from (2R,3R)-(−)-2,3-butanediol, the moiety of which would be useful as the internal reference of absolute configuration in X-ray crystallography. The product [CD(+)280]-32 was recrystallized from chloroform/hexane (1:1), giving extremely thin, red plate crystals with a thickness of 1–2 μm, which were too thin for conventional X-ray diffractometers [54]. Therefore, the X-ray diffraction experiment was carried out with extremely strong synchrotron radiation at the SPring-8 in Hyogo ˚ space group P 21 (#4), R = 0.180. Although (Japan): X ray, 22.00 keV, λ = 0.5633 A, the final R value remained large, the AC of bisadduct [CD(+)280]-32 was unambiguously determined as (f,s A) by using the (2R,3R) absolute configuration of the tether moiety as an internal reference (Figure 5.38). Thus the use of the internal reference method in X-ray crystallographic analysis is very useful for unambiguous determination of AC [54].

H3C H H CH3 HO

H3C H H CH3

O

O

EtO

O

O

H3C H H CH3 O O O O

O OEt

O

OH

(2R,3R)-(–)2,3-butanediol

O OEt EtO

O

(2R,3R)-tether

Scheme 5.10. Synthesis of chiral cis-3 bisadduct (R,R,f,sA)-[CD(+)280]-32

(R,R,f,s A)-[CD(+)280]-32.

a

Figure 5.38. Absolute stereo-structure of the C60 fullerene cis-3 bisadduct (R,R,f,s A)[CD(+)280]-32 (top) and projection along b-axis

o

c Projection along b-axis

(bottom). (Redrawn from reference 54, with permission.) (See insert for color representation of the figure.)

208

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

The CD and UV–Vis spectra of bisadduct (R,R,f,s A)-32 are shown in Figure 5.39, where the CD spectrum shows an intense positive Cotton effect (ε +93.7) at 280 nm. In addition, compound (R,R,f,s A)-32 exhibited an anomalously large optical rotation [α]28 D +3950 (c = 0.0214, CHCl3 ). Therefore, its AC was designated as (R,R,f,s A)-[CD(+)280]-(+)-32 [54]. Based on these X-ray and CD results, the ACs of C60 fullerene cis-3 bisadducts were rationalized as follows: cis-3 derivatives showing a positive CD band around 280 nm should have the (f,s A) absolute configuration, while cis-3 compounds showing a negative CD around 280 nm should have the (f,s C ) absolute configuration. Therefore, our previous assignments of (S,S,f,s A)-[CD(+)281]-31a and (S,S,f,s C )-[CD(−)281]-31b were corroborated by this study. The assignment of (S,S,f,s A)-[CD(+)281]-28 by Diederich and co-workers was also confirmed. However, it was concluded that the AC of [CD(−)288]27 should be revised to be (R,R,f,s C ) [54]. In a similar manner, revision of the AC was suggested so that cis-3 bisadduct [CD(+)284]-29 should have the (S,S,f,s A) absolute configuration. We found unique phenomena in the CD and UV–Vis spectra as follows. Compound (R,R,f,s A)-[CD(+)280]-(+)-32 exhibits a very weak absorption band at 706.2 nm (ε = 338); this band is due to the forbidden π –π ∗ transition as a result of the small ε value. In the corresponding region, the CD spectrum shows an intense negative Cotton effect at 701.5 nm (ε −36.3). The curve of g value (g = ε/ε) was calculated as illustrated in Figure 5.39, where the maximum value found was g = −0.110 at 697.0 nm [54]. This g value is much larger than that of n–π ∗ forbidden transition of chiral ketones and that of

+0.10

+100

280.0 (+93.7) CD +0.05

+50

701.5 (–36.3) 0 Δe/e

Δe 0

–50

–100

–150

ε × 10–4

10

5

220

obsd CD g-value 701.5 (–36.3) 639.5 (–10.0) 697.0 (–0.110) 593.0 (+5.6) 486.5 (+21.5) g-value 424.5 (–20.1) 697.0 (–0.110) 412.0 (+3.0) 398.0 (–13.3) 635.5 (–0.0191) 378.5 (–32.4) 593.0 (+0.00752) 339.0 (+75.8) 490.0 (+0.0130) 313.0 (+37.5) 425.5 (–0.00717) 280.0 (+93.7) 380.5 (–0.00425) 263.0 (–151.2) 343.0 (–0.00298) 232.0 (–47.9) 706.2 (338) obsd UV UV 706.2 (338) 643.6 (517) × 100 316.5 (37100) 254.5 (106600) 300

400

500 λ (nm)

600

700

–0.05

–0.1

–0.15

Figure 5.39. CD and UV–Vis spectra and g-value curve of cis-3 bisadduct (R,R,f,s A)[CD(+)280]-(+)-32 in ClCH2 CH2 Cl: CD and

800

UV–Vis, top curve; g value (g = ε/ε), bottom curve. (Redrawn from reference 54, with permission.)

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

209

the π –π ∗ allowed transition of other compounds. For example, the n –π ∗ transition of (R)-(+)-3-methylcyclohexanone showed g = +0.03 at 298 nm; π –π ∗ , (+)-hexahelicene, g = +0.007 at 325 nm [55]; π –π ∗ , exciton coupling CD of (2S,3S )-butanediyl bis(4bromobenzoate), g = +0.00035 at 252 nm. A similar large g value was also observed for bisadduct (S,S,f,s A)-[CD(+)281]-31a: g = −0.126 at 696 nm [54]. Why does this transition of chiral cis-3 fullerene make such a large g value? The phenomenon could be interpreted as follows: The π –π ∗ transition is electronically forbidden as discussed above, but is magnetically allowed, because molecular orbitals (MOs) involved are spherical, reflecting the spherical shape of fullerene skeleton. Therefore, the transition contains a lot of angular momenta, thus yielding a large magnetic moment and generating an intense CD Cotton effect. The g-value thus becomes large in this transition [54].

5.7. ABSOLUTE STEREOCHEMISTRY AND CD SPECTRA OF AN ALLENO-ACETYLENIC MACROCYCLE The alleno-acetylenic tetrameric macrocycle (P, P, P, P)-(−)-33 is a unique chiral compound devoid of any chirality center, in which each allene moiety takes a P helicity, and hence the compound takes a D4 symmetric structure as illustrated in Figure 5.40 [56, 57]. Chiral macrocycle (P, P, P, P)-(−)-33 was first synthesized by Diederich and coworkers starting from tert-alcohol 34 as shown in Scheme 5.11 [56], where racemic alcohol (±)-34 was resolved as camphanate esters. The absolute configuration of alcohol (R)-(−)-34 was determined by X-ray crystallographic analysis of its camphanate ester, where the camphanate group was used as an internal reference of the absolute configuration [58]. The other enantiomer (S )-34 was converted to chiral allene derivative (P )-(+)-35 via a rearrangement reaction. The obtained chiral alleno-acetylene (P )-(+)35 was then dimerized, followed by deprotection, to yield a chiral dimer (P, P)-(+)-36, [α]D 20 +506 (c 1, CHCl3 ), the absolute configuration of which was determined by X-ray crystallographic analysis of bis[Si(iso-Pr)3 ] derivative 37 of the other (M,M)-enantiomer series, where the anomalous dispersion effect of silicon atoms was used [59]. The further dimerization–cyclization of bis(acetylene) (P, P)-(+)-36 furnished the target chiral macrocycle (P, P, P, P)-(−)-33, [α]D 20 −770 (c 1, CHCl3 ), the relative crown configuration of which was determined as shown by X-ray analysis of racemate (±)-33 (Scheme 5.11) [57]. The absolute stereochemistry of macrocycle (P, P, P, P)-(−)-33 was thus unambiguously determined by X-ray crystallography.

Figure 5.40. A novel unique chiral alleno-actylenic (P,P,P,P)-(–)

macrocycle (P, P, P, P)-(−)-33 and its crown stereostructure. (Redrawn from reference 56, with permission.)

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HO

OH

H H (S)-34

(P)-(+)-35

abs. config. by X-ray of camphanate ester of (R)-34

R

R

(P,P)-(+)-36: R = H abs. config. by X-ray of Si(iso-Pr)3 derivative of (M,M)-series

(P,P,P,P)-(–)-33 relat. config. by X-ray of (+)-33 –

Scheme 5.11. Synthesis of macrocycle (P,P,P,P)-(−)-33 and absolute configurational assignment by X-ray crystallographic analyses of related derivatives.

It is interesting that macrocycle (P, P, P, P)-(−)-33 shows extremely intense CD Cotton effects as illustrated in Figure 5.41; for example, the positive CD band at 253 nm has an intensity of ε = +790, which is about 100 times larger than that of monomer (P )-(+)-35 and ≈ 8 times larger than that of dimer (P, P)-(+)-36. The CD spectrum of macrocycle (P, P, P, P)-(−)-33 is thus unique and a good example for CD studies.

+800 CD

(P,P,P,P)-(–) e × 10–5

+400 Δe 0 –400

3

–800 2

UV

1

Figure 5.41. CD and UV–Vis spectra of enantiopure macrocycle (P, P, P, P)-(−)-33 (thick

200

300 λ (nm)

0 400

line) and CD spectra of (M, M, M, M)-(+)-33 (thin line) in hexane. (Redrawn from reference 56, with permission.)

211

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

The UV spectrum of (P,P,P,P)-(−)-33 shows three maxima of medium intensity around 275–375 nm, which were assigned to the vibronic structure of conjugated acetylene groups because of the vibronic interval of ≈ 2100 cm−1 (Figure 5.41). The three UV bands around 275–375 nm were thus assigned due to a single π –π ∗ transition of medium intensity, but not due to three different π –π ∗ transitions. On the other hand, a very intense UV band is seen at 245 nm (ε 210,000), which was assigned to an allowed π –π ∗ transition [56]. In the region of 270–350 nm, the CD spectrum of (P, P, P, P)-(−)-33 shows three negative extrema corresponding to the UV vibronic structure, while a very intense positive Cotton effect is observed in the region of 230–270 nm (Figure 5.41). The g values (g = ε/ε) of these Cotton effects were calculated to give interesting data as follows: g = approximately −0.007 to −0.008 for the Cotton effects in the region of 270–350 nm; g = approximately +0.004 for the intense Cotton effect at 253 nm. These data clearly indicate that the CD bands in the region of 270–350 nm have a large magnetic transition dipole moment contribution, and the transition is magnetically allowed. On the other hand, the CD band at 253 nm has a large electric transition dipole moment contribution, indicating the character of electric allowed transition [56]. To give insight into the CD mechanism of macrocycle (P, P, P, P)-(−)-33 and also to determine its absolute stereochemistry in a theoretical manner, the CD and UV spectra were calculated by the ZINDO MO method. As illustrated in Figure 5.42, the basic pattern of the CD curve including the sign, amplitude, and position of Cotton effects, but not the vibronic structures around 270–350 nm, was reproduced well by the ZINDO calculation. The (P,P,P,P ) absolute stereochemistry of macrocycle (−)-33 was thus determined by the MO calculation of the ZINDO level, and the theoretical absolute configurational assignment was consistent with the experimental one [56]. The calculation results show that there are three major electronic transitions as shown in Figure 5.42. The negative CD bands at 270–350 nm are due to the S1 transition, while the positive CD band at 253 nm is due to two degenerate S2 and S3 transitions. The S1 transition is very unique, since its large magnetic transition dipole moment (MTDM) is perpendicular to the ring plane of the macrocycle and is oriented upward, as seen in the

MTDM

+800 +600 +400

R × 1037 cgs unit

Δe

S2,S3 ETDM

+2.0

transition S1

+200

+1.0

0 –200

0

Figure 5.42. Comparison of the observed CD

–1.0

spectrum of (−)-33 (thick line) with the CD curve of (P, P, P, P)-33 (thin line) calculated by the ZINDO MO method, where the graphic inserted

obsd CD –400 S1

–600 200

–2.0

calcd CD

300 λ (nm)

–3.0 400

above shows the electric transition dipole moment (ETDM) and magnetic transition dipole moment (MTDM) of the transition S1 in the geometry of the compound. (Redrawn from reference 56, with permission.)

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

graphic inserted in Figure 5.42. This large MTDM is generated by the cyclic movement of an electron along the macrocycle ring during the electronic transition. At the same time, the S1 transition generates a small electric transition dipole moment (ETDM), which is also perpendicular to the ring plane, but is oriented downward. Therefore, MTDM and ETDM are antiparallel to each other and take nonzero values, generating an intense negative CD band at the S1 transition. The ETDM and MTDM of the S2 transition are placed in the macrocycle plane and oriented parallel to each other generating a positive CD band (Figure 5.42). Both ETDM and MTDM take nonzero values, which is the main reason for the intense CD at the S2 transition. The S3 transition has a similar character to that of the S2 transition, generating an intense positive CD. The ETDMs of S2 and S3 transitions are perpendicular to each other reflecting the D4 symmetric structure of macrocycle 33. This is the reason that the S2 and S3 transitions are degenerate. The mechanism of intense CD of macrocycle (P, P, P, P)-(−)-33 was thus clarified even by the MO calculation of ZINDO level [56]. A similar result was obtained by the more advanced MO method, that is, the Coulombattenuated hybrid exchange-correlation functional (CAM-B3LYP), supporting the CD mechanism discussed above [57].

5.8. CONCLUSION As discussed above, the ACs of various chiral compounds with extended π -electron system, including natural products and synthetic compounds, have been theoretically determined on the basis of the calculation of their CD spectra by the π -electron SCF-CIDV MO method. The ACs theoretically assigned were proved experimentally by X-ray crystallographic analyses using an internal reference of AC, and/or by the total synthesis of natural enantiomers. The combination of X-ray crystallography and CD spectroscopy is thus very reliable for determining ACs. In addition, in the case of the light-powered chiral molecular motors, CD spectroscopy is useful for clarifying the motor rotation mechanism and dynamics. Therefore, the CD methodology discussed here is a promising and powerful tool for determining the ACs of various chiral compounds with an extended and twisted π -electron chromophore.

ACKNOWLEDGMENTS The authors sincerely thank the co-workers of the studies described here for their contributions, whose names are listed in references, and Dr. George A. Ellestad, Department of Chemistry, Columbia University, for his valuable suggestions.

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CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

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27. N. Harada, T. Sugioka, H. Uda, T. Kuriki, J. Org. Chem. 1990, 55 , 3158–3163. 28. N. Harada, T. Sugioka, H. Uda, T. Kuriki, M. Kobayashi, I. Kitagawa, J. Org. Chem. 1994, 59 , 6606–6613. 29. N. Harada, T. Sugioka, T. Soutome, N. Hiyoshi, H. Uda, T. Kuriki, Tetrahedron Asym. 1995, 6 , 375–376. 30. N. Harada, H. Ono, H. Uda, M. Parveen, N. U-P. Khan, B. Achari, P. K. Dutta, J . Am. Chem. Soc. 1992, 114 , 7687–7692. 31. F.-J. Zhang, G.-Q. Lin, Q.-C. Huang, J. Org. Chem. 1995, 60 , 6427–6430; Additions and corrections in J. Org. Chem. 1996, 61 , 5700. Later, the authors changed to the (aR) absolute configuration; G.-Q. Lin, M. Zhong, Tetrahedron Lett. 1997, 38 , 1087–1990. 32. N. Harada, H.-Y. Li, T. Nehira, M. Hagiwara, Enantiomer 1997, 2 , 353–358. 33. H.-Y. Li, T. Nehira, M. Hagiwara, N. Harada, J. Org. Chem. 1997, 62 , 7222–7227. 34. B. Feringa, H. Wynberg, J. Am. Chem. Soc. 1977, 99 , 602–603. 35. N. Harada, A. Saito, N. Koumura, H. Uda, B. de Lange, W. F. Jager, H. Wynberg, B. L. Feringa, J. Am. Chem. Soc. 1997, 119 , 7241–7248. 36. N. Harada, A. Saito, N. Koumura, D. C. Roe, W. F. Jager, R. W. J. Zijlstra, B. de Lange, B. L. Feringa, J . Am. Chem. Soc. 1997, 119 , 7249–7255. 37. R. W. J. Zijlstra, W. F. Jager, B. de Lange, P. T. van Duijnen, B. L. Feringa, H. Goto, A. Saito, N. Koumura, N. Harada, J. Org. Chem. 1999, 64 , 1667–1674. 38. N. Harada, N. Koumura, and B. L. Feringa, J. Am. Chem. Soc. 1997, 119 , 7256–7264. 39. N. Koumura, N. Harada, Enantiomer 1998, 3 , 251–253. 40. N. Koumura, N. Harada, Chem Lett. 1998, 1151–1152. 41. N. Koumura, Ph.D. Thesis, Tohoku University, March 1999. 42. N. Koumura, R. W. J. Zijlstra, R. A. van Delden, N. Harada, B. L. Feringa, Nature 1999, 401 , 152–155. 43. T. Fujita, S. Kuwahara, N. Harada, Eur. J. Org. Chem. 2005, 4533–4543. 44. S. Kuwahara, T. Fujita, N. Harada, Eur. J. Org. Chem. 2005, 4544–4556. 45. M. K. J. ter Wiel, R. A. van delden, A. Meetsma, B. L. Feringa, J. Am. Chem. Soc. 2003, 125 , 15076–15086. 46. For the nomenclature of regioisomeric fullerene derivatives, see: (a) A. Hirsch, I. Lamparth, H. R. Karfunkel, Angew. Chem. 1994, 106 , 453–455; Angew. Chem. Int. Ed. Engl . 1994, 33 , 437–438; (b) for the nomenclature of chiral fullerene derivatives, see: C. Thilgen, A. Herrmann, F. Diederich, Helv. Chim. Acta 1997, 80 , 183–199; (c) for a new and systematic nomenclature for fullerenes (IUPAC Recommendations 2002), see W. H. Powell, F. Cozzi, G. P. Moss, C. Thilgen, R. J.-R. Hwu, A. Yerin, Pure Appl. Chem. 2002, 74 , 629–695. 47. E. Nakamura, H. Isobe, H. Tokuyama, M. Sawamura, Chem. Commun. 1996, 1747–1748. 48. J.-F. Nierengarten, T. Habicher, R. Kessinger, F. Cardullo, F. Diederich, V. Gramlich, J.-P. Gisselbrecht, C. Boudon, M. Gross, Helv. Chim. Acta 1997, 80 , 2238–2276. 49. H. Goto, N. Harada, J. Crassous, F. Diederich, J. Chem. Soc. Perkin Trans. 2 1998, 1719–1723. 50. R. Kessigner, C. Thilgen, T. Mordasini, F. Diederich, Helv. Chim. Acta 2000, 83 , 3069–3096. 51. (a) M. Taki, S. Sugita, Y. Nakamura, E. Kawashima, E. Yashima, Y. Okamoto, J. Nishimura, J. Am. Chem. Soc. 1997, 119 , 926–932; (b) N. Taki, Y. Nakamura, H. Uehara, M. Sato, J. Nishimura, Enantiomer 1998, 3 , 231–239; (c) revised assignment: Y. Nakamura, K. O-kawa, J. Nishimura, Bull. Chem. Soc. Jpn. 2003, 76 , 865–882. 52. T. Ishi-i, K. Nakashima, S. Shinkai, A. Ikeda, J. Org. Chem. 1999, 64 , 984–990. 53. K. Yoshida, S. Osawa, K. Monde, M. Watanabe, N. Harada, Enantiomer 2002, 7 , 23–32. 54. S. Kuwahara, K. Obata, K. Yoshida, T. Matsumoto, N. Harada, N. Yasuda, Y. Ozawa, K. Toriumi, Angew. Chem. Int. Ed ., 2005, 44 , 2262–2265.

CD SPECTRA OF CHIRAL EXTENDED π-ELECTRON COMPOUNDS

55. S. F. Mason, Molecular Optical Activity and the Chiral Discrimination, Cambridge University Press, Cambridge, 1982. 56. J. L. Alonso-G´omez, P. Rivera-Fuentes, N. Harada, N. Berova, F. Diederich, Angew. Chem. Int. Ed . 2009, 48 , 5545–5548. 57. P. Rivera-Fuentes, J. L. Alonso-G´omez, A. G. Petrovic, P. Seiler, F. Santoro, N. Harada, N. Berova, H. S. Rzepa, F. Diederich, Chem. Eur. J . 2010, 16 , 9796–9807. 58. M. K. J. ter Wiel, S. Odermatt, P. Schanen, P. Seiler, F. Diederich, Eur. J. Org. Chem. 2007, 3449–3462. 59. J. L. Alonso-G´omez, P. Schanen, P. Rivera-Fuentes, P. Seiler, F. Diederich, Chem. Eur. J . 2008, 14 , 10564–10568.

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6 ASSIGNMENT OF THE ABSOLUTE CONFIGURATIONS OF NATURAL PRODUCTS BY MEANS OF SOLID-STATE ELECTRONIC CIRCULAR DICHROISM AND QUANTUM MECHANICAL CALCULATIONS ´ and Karsten Krohn Gennaro Pescitelli, Tibor Kurtan,

6.1. INTRODUCTION Natural products represent a rich source of therapeutically useful compounds. About 70% of the drugs marketed in the 1982–2007 period was more or less directly derived from natural products, especially in the field of anticancer drugs [1]. At the same time, the portion of chiral drugs patented as a single enantiomer has increased sharply in recent years [2], mostly as a consequence of the regulatory prescriptions concerning the stereochemical characterization of new drugs [3]. Isolation and identification of new chemical compounds from natural sources, including elucidation of their absolute stereochemistry, has therefore important consequences in many disciplines. It is hard to believe that a rather fundamental aspect of chemistry—that is, the assignment of absolute configuration (AC)—was established only in 1951 with the Xray diffraction experiment of Bijvoet et al. [4] on NaRb (+)-tartrate. The observation of anomalous dispersion has remained unsurpassed as the most reliable means for assigning absolute configurations, though with its well-known limitations. In the last decade, a valid alternative has been offered by quantum mechanical (QM) calculations of chiroptical properties such as electronic circular dichroism (ECD), vibrational CD (VCD), and Raman optical activity (ROA). Thanks to the development of computer technology, QM calculations have become accessible at a higher level of sophistication and their reliability has increased significantly. The computational approach for assigning ACs is based on the comparison of experimental and calculated ECD, VCD, or ROA spectra and has certain advantages over X-ray structure elucidation, including its practicability and wider scope. Its main limitations are the appearance of significant CD or ROA bands and (at some extent) the molecular size. As far as electronic CD (ECD) is concerned, the Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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compound must show a significant ECD spectrum in the commonly accessible spectral range (above 185 nm). This is, however, not uncommon with natural products, most of which contain at least a conjugated moiety leading to distinct ECD spectra. Every molecular calculation is necessarily size-dependent, and demanding computational methods may be restricted to small systems. However, ECD spectra of increasingly larger and complex molecular assemblies have been treated by high-level methods in recent years [5]. The most serious drawback of the computational approach is related to the reliability of the input structure, an issue that will be extensively discussed in the following sections because it represents the main reason for the development of the solid-state ECD/TDDFT (time-dependent density functional theory) approach described in the present chapter.

6.2. ASSIGNING ABSOLUTE CONFIGURATIONS THROUGH ECD CALCULATIONS 6.2.1. Conformation and Configuration Whenever a molecular property is predicted by theory and used for comparison with the experiment, it is crucial to employ a correct input structure. “Correct” means it must represent as faithfully as possible the true structure (or structures) responsible for the observed property. In particular, chiroptical data such as ECD, VCD, and ROA spectra are extremely sensitive to the overall molecular geometry in terms of both conformation and absolute configuration. Configurational and conformational elements are often strictly intertwined, and chiroptical approaches usually determine only one of them in the knowledge of the other [6, 7]. There are spectacular examples in the literature where two slightly different conformations of a compound (with fixed AC) led to almost mirrorimage computed ECD spectra: In other words, regarding their chiroptical parameters, two conformers behaved as two enantiomers [8]. Generally speaking, any solution CD spectrum amounts to the sum of contributions from all populated conformations, and the set of input structures to be considered in the calculation must be representative of the whole conformational ensemble [6]. As a consequence, when ECD calculations are applied to deduce absolute configurations, they must rely on an independently established conformational picture, which is gained through the use of other spectroscopic and/or theoretical means. Modern NMR techniques play a major role in deducing solution conformations, in particular when they provide data sensitive to the three-dimensional structure such as NOE effects and scalar J -couplings [9, 10]. In challenging cases represented by very flexible compounds, assistance by molecular modelling may be indispensable. A conformational analysis is normally started with a rapid computational procedure, based on Monte Carlo or molecular dynamics approaches at a low level of theory, such as molecular mechanics (MM) [11]. These conformational search routines provide a set of structures that are further optimized at a higher level of theory, usually density functional theory (DFT) or other ab initio methods. Geometry optimizations provide structures with respective (internal) energies, thereafter used to estimate the population of each calculated conformer. Calculated geometries must be checked against NMR data by considering H–H distances versus observable NOEs, as well as H/H and C/H dihedrals versus measured J -couplings [10]; when necessary, 13 C chemical shifts may be calculated and compared with the experimental set [9]. After a reliable set of input structures has been generated with an initial arbitrary AC, ECD calculations must be run on all minima within a certain energy threshold (2–3

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kcal/mol)—that is, with significant population (say, >3–5%) at the working temperature (normally, 298 or 300 K). Thereafter, a weighted average of all computed ECD spectra is estimated according to the Boltzmann weights at the working temperature. Reliable populations can be obtained by single-point calculations at a higher calculation level than that used for geometry optimizations, for example, using larger basis sets. Furthermore, internal energies should be corrected with zero-point vibrational and entropy terms to afford true free energies. Finally, the weighted average ECD is compared with the experimental ECD spectrum: If the agreement is good with either the calculated ECD (for the initially assumed AC) or its mirror image (i.e., for the opposite AC), the configuration may be assigned. The outlined procedure, first developed by Bringmann and co-workers [12], has been used frequently in recent years to assign the AC of natural products, in particular by employing QM semiempirical [7, 13] and TDDFT calculations [14, 15]. Several approximations are often used, the most drastic of which are the neglect of solvent and vibronic effects on geometries and calculated ECD. Treatment of solute–solvent interactions, in both geometry optimization and CD calculation steps, is possible by adopting a suitable solvent model (which increases the computational time) [16]. Inclusion of vibronic effects is a rather complicated process and remains still restricted to some models or small molecules [17]. Provided that the calculation method employed for ECD calculations is efficient, the crucial point of the above procedure lies in the generation of the input structure(s). In fact, the conformational analysis may be both computationally demanding and prone to inaccuracy. The major sources of error lie in the prediction of relative energies, as well as in the possible overlooking of one or more significant conformers. Finally, since the CD calculation must be run on each calculated conformer, flexible molecules may represent very difficult cases to handle.

6.2.2. The Origin of the Solid-State ECD/Computational Approach X-ray analysis of crystalline natural products offers a twofold advantage to surmount the difficulty just described in the generation of the input structure for ECD calculations. First, in the crystals, the molecular conformation is fixed and univocal (unless polymorphs occur); second, its structure can be determined with high accuracy by diffraction experiments. In the course of a screening for novel bioactive compounds from natural sources, Krohn and co-workers investigated a Phomopsis sp. and isolated (+)-phomoxanthone A (1, Figure 6.1) [18]. The relative configuration of the chirality centers and axial chirality element was established by X-ray single-crystal analysis (Figure 6.1), while the ECD spectrum served for the assignment of the absolute configuration. Atropisomeric biaryl compounds like 1 show intense ECD spectra dominated by the exciton coupling (see Section 6.2.3) between the two aromatic chromophores, and the exciton-coupled spectra are easily correlated with the absolute stereochemistry [19]. Following the computational procedure outlined in the previous section, the authors first performed a conformational analysis with MMFF and AM1 methods [20], which afforded eight low-energy conformers within 11 kJ/mol with arbitrarily assumed (aS , 5R, 6R, 10aR, 5 R, 6 R, 10a R)-(+)-1 absolute configuration. They were used as input for ECD calculations with a semiempirical method using the BDZDO/MCDSPD program package [21]. The calculated spectra were then weighted with their respective Boltzmann populations and summed to obtain a weighted-average ECD spectrum, which reproduced the experimental solution spectrum. Surprisingly, however, when the X-ray geometry was used as input for

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Figure 6.1.

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(1) in solution (CH2 Cl2 and methanol/CH2 Cl2 4:1) and in the solid state (KCl disc). (b) Calculated Boltzmann-weighted average ECD spectrum over eight low-energy AM1 structures, as well as calculated ECD spectrum using the X-ray geometry (shown on the top). All calculations run with the BDZDO method.

BDZDO calculations, the resultant spectrum showed a better agreement with the experimental one. Clearly, the comparison between calculated and experimental properties is more justified when they refer to the same geometry. Therefore, the ECD spectrum was also recorded in the solid state using the KCl pellet technique (described in Section 6.3.2) and, as expected, the match between this latter spectrum and that calculated using the X-ray geometry was improved. In this way the idea was born to use X-ray coordinates as input data for ECD calculations for future characterization of chiral nonracemic natural products. It was immediately clear that the major advantage of the method would lie in skipping the conformational analysis step and its related uncertainties, with consequent time-saving and increased reliability.

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6.2.3. The Choice of the Computational Method After its first application to phomoxanthone A, the major improvement of the approach based on solid-state ECD has consisted in a different choice of the standard computational method employed, which was switched from the semiempirical BDZDO method to TDDFT. Some specific applications to large molecules and/or molecules containing multiple aromatic chromophores have been dealt with alternative computational methods such as ZINDO or even the semiclassical coupled oscillator DeVoe’s one. In this section, we will briefly discuss the choice of the computational method for solid-state ECD calculations [22]. The reader is also referred to the many chapters of Volume 1 especially devoted to the topic of simulations of ECD spectra [23]. ECD calculations with high-level quantum mechanical (QM) methods are nowadays fully practicable for moderately large organic molecules and metal complexes [24–27]. Reliable ECD predictions require theoretical methods that take electron correlation into account and use of large basis sets. Among the many possible ab initio methods employed for excited states calculations, time-dependent density functional theory (TDDFT) has emerged in recent years as one of those leading to the best accuracy/cost compromise [26, 28] (it must be noted that many DFT functionals contain adjusted parameters and are not strictly “ab initio”). Although DFT functionals are usually designed to reproduce thermochemical data [11, 29], hybrid functionals such as B3LYP, BH&HLYP, and PBE0 [30, 31] predict with high accuracy transition energies and rotational strengths. Several commonly employed DFT functionals have well-recognized drawbacks, especially a poor description of some loosely localized states, such as charge-transfer, diffuse, and Rydberg states, which may be alleviated using some of the new long-range functionals [32–34]. TDDFT arises from a perturbative approach to DFT, and therefore it is intrinsically more accurate in predicting low-lying excited states [35]. Apart from these issues, the scope of TDDFT calculations is practically unlimited. Thus, when we had to choose a general and reliable method for the calculation of solid-state ECD spectra, the choice of TDDFT was almost obvious, and now we refer to this approach as the solid-state ECD/TDDFT approach [22]. Semiempirical quantum mechanical methods rely on strong simplifications, which include ignoring core electrons and neglecting differential overlap (NDO) [36]. They are much faster than ab initio methods and may be helpful when dealing with complex molecules and simple supramolecular aggregates. Various approximation schemes have been purposely developed for spectroscopic simulations, such as CNDO/S (complete NDO) and ZINDO/S (Zerner’s intermediate NDO). They have been parameterized in order to describe aromatic and heteroaromatic chromophores and, for ZINDO, some transition metals. Both methods reproduce well ECD spectra dominated by “strong” mechanisms of optical activity [37], such as the exciton coupling between aromatic rings, like in biaryls, and the inherent chirality of twisted π -electron systems [7, 38]. The accuracy of semiempirical methods in predicting high-lying electric-dipole forbidden transitions is comparatively much poorer [39]. Another problem with semiempirical methods is related to the two gauge formulations (length and velocity) used for calculating rotational strengths. Unless using gauge-independent methods, dipole-length (DL) and dipolevelocity (DV) values for rotational strengths are always different [40]. The difference is related to basis set completeness; therefore using, for example, TDDFT with double- or triple-ζ quality basis sets including polarization functions leads to substantially equivalent DL and DV rotational strengths. By contrast, semiempirical methods often employ minimal basis sets and very large and unpredictable discrepancies may be obtained. Finally, there are cases where the ECD pattern is dominated by the so-called exciton coupling mechanism [19, 41, 42]. It arises when two or more chromophores, allied

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with strong electric-dipole-allowed transitions, are close in the space and arranged in a skewed fashion with respect to each other. In this condition the coupling between the two transition dipoles generates a strong bisignate ECD signal, called an exciton couplet. Analysis of exciton-coupled ECD spectra is often straightforward, as witnessed by the countless applications of the exciton chirality method in the AC assignments of organic compounds, including natural products [6, 19, 41, 42]. On a quantitative ground, excitoncoupled ECD spectra may be simulated by some techniques that may be grouped under the name of semiclassical methods, such as DeVoe’s approach. For a comprehensive description of this method, we refer the reader to the original papers [43] and to recent reviews and applications [27, 44]. Provided that the chromophores under considerations are known and characterized, DeVoe-type calculations are extremely fast and applicable to systems containing even dozens of chromophores. Therefore, it would be a method of choice to estimate the ECD of large supramolecular aggregates in the coupled-oscillator approximation.

6.3. THE SOLID STATE ECD/TDDFT APPROACH: METHODOLOGY AND SCOPE 6.3.1. Principle The essence of the procedure for assigning absolute configurations by means of the solid-state CD/TDDFT method consists of measuring the solid-state ECD spectrum of a microcrystalline sample and comparing it with the spectrum calculated using the Xray geometry as input structure [22]. The main advantage of the solid-state approach, with respect to similar procedures based on solution ECD calculations, is that it does not require a conformational analysis and therefore it is computationally fast and avoids the difficulties connected to conformational searches and geometry optimizations [6b]. Moreover, the experimental and calculated ECD spectra refer to the very same geometry, implying a good agreement between theory and experiment and a reliable assignment. It is of vital importance that an artifact-free experimental solid-state ECD spectrum has to be measured (see Section 6.3.2). Furthermore, the solid-state ECD spectrum must be devoid of bands intrinsic to the solid state—for example, arising from intermolecular interactions in the crystals [45, 46]. A step-by-step formulation of the solid-state CD/TDDFT approach is the following: 1. Isolation of the natural product and determination of its constitution and relative configuration [22]. 2. Growing crystals for X-ray analysis. 3. X-ray single-crystal diffraction analysis. 4. Measurement of microcrystalline solid-state ECD spectrum as KCl pellet, as well as of solution ECD spectra in one or more solvents. 5. Generation of the input geometry for ECD calculations (with initial arbitrary AC), by optimizing hydrogen atoms of the X-ray structure. 6. Calculation of rotational strengths with the TDDFT method, possibly employing various combinations of functionals and basis sets. 7. Generation of the ECD spectrum as a sum of Gaussians. 8. Comparison of the experimental solid-state (and solution) ECD spectrum with the TDDFT-calculated one.

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The reason for recording both solid-state and solution ECD spectra is that their comparison is useful to reveal the presence of unexpected bands in the solid-state ECD spectrum. Bands much stronger than anticipated, or bands appearing in unexpected positions of the spectrum, may be due to measurement artifacts (Section 6.3.2) or be allied to solid-state intrinsic ECD effects (Section 6.5). In point 5, it is stated that the input geometry for ECD calculations is generated from the X-ray one upon optimization of the hydrogen atoms. Hydrogen atoms are often not accurately located using X-ray data because of low scattering power, distorted electron density, and large librations. In the process of structure refinement, hydrogen atoms are generated in positions determined by distance and angle constraints relative to the heavy atoms they are attached to. The SHELXL routine for structure refinement [47] adopts a “riding” model based on default C–H distances that, for some reason, are much shorter than real ones and would introduce unwanted errors in the calculated ECD spectra. Thus a preliminary DFT optimization of hydrogen atoms is run with B3LYP/6-31G(d), leaving all other atoms frozen, which usually produces geometries whose Y–H bonds (Y = C,O,N) are longer by 10–15% than the input ones. Although librations of carbon, oxygen, and nitrogen atoms are usually much smaller than for hydrogen, their effect may also lead to a slight underestimation of, for example, C–C, C–O, and C–N bond lengths by X-ray diffraction measurements [48]. In our experience, the discrepancies between Xray geometries and DFT-optimized ones (using the X-ray geometries as input structures and keeping all dihedral angles frozen) are very small, because C–C, C–O, and C–N bond lengths may vary within ±2%. Possible exceptions are compounds with a compact polycyclic structure, for example, containing fused or spiro-linked five-membered rings, where many bond lengths are strictly correlated to each other (see compounds 4 and 15 in Chart 6.1) [49, 50]. In these cases, we observed that relieving the bond lengths by means of DFT geometry optimizations was beneficial for a better agreement between experimental and computed solid-state ECD spectra, but never decisive for assigning the absolute configuration. Concerning point 6, it is clear that the choice of a proper DFT functional and basis set is crucial for the success of the method. One of the advantages of the solid-state approach is that the time saved in the generation of the input structure may be devoted to testing different combinations of functionals and basis sets to look for the best agreement with the experimental spectrum. According to our experience on several compounds with diverse structures, the three hybrid functionals B3LYP [29], PBE0 [31], and BH&HLYP [30], with increasing fraction of exact (Hartree–Fock) exchange, can be used to handle most common situations and often result in calculated ECD spectra in very good agreement with experimental ones. Usually, the spectra calculated with B3LYP and PBE0 are quite similar to each other, and they differ from BH&HLYP for a systematic wavelength shift (the direction depends on the nature of transitions involved). To improve the predictions of energies and transitions dipoles allied with charge-transfer, diffuse, and Rydberg states, use of the Coulomb-attenuated version of B3LYP, known as CAMB3LYP, is advisable [34]. In our hands, however, BH&HLYP has demonstrated to be capable of solving the same kinds of problems efficiently. It is remarkable that this “halfand-half” functional is included in the most recent versions of computational packages “for backward-compatibility only,” but its usefulness is indisputable [51]. As for the basis sets, use of the largest possible basis set is recommended for many reasons, some of which have been outlined above [26, 40]. On a practical ground, a split-valence basis set including a reasonable set of polarization functions and a minimum set of diffuse functions would be sufficient in most cases. Our favorite in the field is Ahlrich’s triple-ζ

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basis set TZVP [52], whose set of flexible polarization functions somehow counterbalances the lack of diffuse functions. When inclusion of these latter seemed necessary, we used the well-known Dunning’s correlation-consistent aug-cc-pVDZ set [53], or the less popular ADZP [54], or else aug-TZVP, obtained by augmenting TZVP with the set of most diffuse functions taken from aug-cc-pVDZ. In almost all cases analyzed thus far, however, use of, for example, aug-TZVP versus TVZP improved the general agreement between experimental and calculated spectra, without being decisive for the configurational assignment. In point 7, the set of calculated rotational strengths as a function of frequency (in other words, a stick plot) is converted in a more handy ECD spectrum by applying a broadening or band-shape. To each rotational strength is associated a band-shape function, usually of Gaussian or Lorentzian type, with intensity proportional to the absolute rotational strength value. A sum of all bands is then evaluated to generate a full ECD spectrum. Such a procedure requires the selection of a band-width parameter σ that is normally established on an empirical ground, selecting the value providing the best fit with the experimental spectrum in the more relevant spectral region(s). Expressing the rotational strengths in 10−40 cgs units and ε in the common M−1 · cm−1 units (where M is molarity, mol · L−1 ), the ECD spectrum calculated as sums of Gaussians in the wavenumbers (˜ν in cm−1 ) domain is [55]      Ri v˜i v˜ − v˜i 2 exp − . (6.1) ε(˜ν ) = 0.0247 σi σi i

If computed transition wavelengths are systematically shifted with respect to experimental ones, a wavelength correction may be applied to better compare computed and experimental spectra. In the so-called UV correction, one looks for the match between computed and experimental UV–vis spectra and then applies the same shift to ECD ones [7]. The comparison between the experimental solid-state ECD spectrum and the TDDFT-calculated one (point 8) is clearly the decisive step. The advantage of using full predictions of ECD spectra with respect to other kinds of treatments such as the exciton chirality approach is that the former provide a full ECD spectrum extending on a more or less wide wavelength range, rather than focusing on a single spectral feature. When the experimental ECD spectrum is well-structured—that is, when it contains several distinct bands—this offers the chance for a critical evaluation of the calculation results going beyond a mere comparison of band signs. This “quality check” may be very important to assess the reliability of the calculation method employed and may point, if necessary, to the need of testing further ones.

6.3.2. Solid-State CD Measurements Solid-state ECD spectra can be measured by different techniques described in several reviews [22, 45, 46, 56, 57]. The microcrystalline pellet or disc method is the most frequently used technique and was adopted as the standard in our solid-state ECD/TDDFT protocol. The crystalline sample is mixed and powdered with a suitable matrix such as KBr, KCl, or CsI, and the microcrystalline powder is pressed to produce a translucent glassy disc. KBr can be used for ECD measurements only above 220 nm, because of its UV cutoff. The use of KCl is less common in the literature, despite the fact that KCl can be used down to 180 nm and its handling is not different from KBr. The shortwavelength range extension may be crucial for the solid-state ECD analysis of natural

A B S O L U T E C O N F I G U R AT I O N O F N AT U R A L P R O D U C T S B Y S O L I D - S TAT E E C D

products containing only weak chromophores with high-lying transitions, such as alkene, ester, or anhydride groups (see compounds 7, 13, and 14 in Chart 6.1). Detailed procedures of pellet preparation are reported in several articles [58, 59]. In our solid-state ECD measurements of natural products, the disc is prepared by grinding and mixing ≈ 180–250 mg of KCl (≥99.999% Fluka, preheated at 100◦ C) and 30–250 μg of sample (depending on the chromophore) with the aid of a Perkin–Elmer vibrating mill equipped with a stainless steel ball for 5 min. The mixture is then pressed under vacuum at 10 tons with a Perkin–Elmer press for 5–10 min to provide a translucent disc. To decrease diffused reflections at grain boundaries, the sample and the matrix must be finely powdered and mixed to provide homogeneous distribution. Elaborated grinding is necessary because the intensity of the scattered light is proportional to 6th power of the particle diameter. The lowest possible sample amount providing acceptable ECD spectra is generally used to decrease the effect of absorption flattening [60] and assure linearity with sample concentration [58]. Because KCl is hygroscopic, measurements are carried out right after the preparation of the disk by mounting it on a rotatable holder placed as close as possible to the detector. Normally, solid-state ECD data are reported as ellipticity φ in mdeg units. However, they can be normalized to ε when necessary, provided that the approximate dimensions of the pellet are known. It is well established that solid-state ECD measurements are easily contaminated by artifacts due to linear dichroism (LD) and linear birefringence (LB) allied with macroscopic sample anisotropies in the sample [56, 61, 62]. These artifacts have both rotation-dependent and rotation-independent contributions, whose presence may be ascertained by, respectively, sample rotation around the incident-light axis (or z axis) and flip (180◦ rotation) around the vertical y axis [61, 62]. However, averaging the various spectra obtained by z -rotation and y-flip is not sufficient for obtaining artifact-free ECD spectra. As clearly pointed out by Kuroda and Shindo, the only proper way to extract true ECD data from a raw spectrum with LB and LD contributions consists of recording ECD, LB, and LD signals simultaneously and applying a specific protocol based on Mueller matrix formalism [56, 61]. Recording ECD, LB, and LD spectra is possible with a dedicated chiroptical spectrophotometer (Jasco J-800KCM) [61]. Using commercially available ECD spectrophotometers, at least LD data can be recorded, and simultaneous ECD/LD measurement should always be performed whenever possible on solid samples. In our protocol, various ECD spectra are usually recorded upon stepwise 90◦ rotations around the z axis as well as 180◦ flip around the y axis, to exclude the presence of both rotation-dependent and -independent contributions from macroscopic anisotropies. In most cases, the spectra showed negligible changes with rotation or flip [22]. When some influence of rotation around z axis was noticed, it consisted of a periodic baseline shift leading to minor differences between spectra (Figure 6.2). Solution spectra in various solvents are always recorded to be compared with solid-state ones to further exclude the presence of spectral artifacts in solid-state spectra (Figure 6.2).

6.3.3. Applicability The most important prerequisite of the solid-state ECD/TDDFT approach is the availability of X-ray geometries from single-crystal diffraction. One may question why to measure and calculate an ECD spectrum once the X-ray geometry is known. This is because the configurational assignment by X-ray anomalous scattering effect is subjected to important limitations that do not apply to the solid-state ECD method. When crystals belonging to noncentrosymmetric space groups exhibit anomalous scattering, the differences observed in Friedel pairs intensities may be used to extract

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60

60

40

20

0

–20

–40

0° 90° 180° 270°

40

φ (mdeg)

Δε (M–1cm–1)

Solid-state ECD spectra (KCI disc), disc rotation

Solution ECD spectrum (CH3CN)

20

0

–20

200

225

250 275 λ (nm)

300

325

350

–40

200

225

250

275

300

325

350

λ (nm)

Figure 6.2. Comparison between solution (left) and solid-state ECD spectra (right) measured on KCl pellets upon rotations around the incident light z axis. The sample is bis(4-bromobenzoate) of palmarumycin M1 (29b) discussed in Section 6.6.

phase information and assign absolute configurations. Such a difference is, however, rather small, and it is measurable only in the presence of one or more atoms whose absorption edge is close to the X-ray wavelength. The scattering factor responsible for the magnitude of the anomalous dispersion effect is in fact both atom- and wavelength-dependent, and it is almost negligible for light elements (up to O). Although a single F or even O atom may suffice for measuring the anomalous dispersion effect, excellent data collection should be performed with well-defined single crystals at low temperatures, recording at least a full set of Friedel pairs and using CuKα radiation. A statistical survey of Cambridge Structural Database (CSD) [63] clearly reveals the scope of the anomalous dispersion method to assign absolute configurations. The version of the CSD updated to March 2010 contains ≈ 8000 compounds in chiral space groups flagged with “absolute configuration.” However, only 586 consist of H, C, O, and N atoms, and 51 consist of H, C, O, N, F, amounting overall to less than 8% on the total. Even in the presence of a heavy scatterer, assignment of the absolute structure by X-ray analysis is not trivial. Two literature surveys that were reported around 25 years apart [64] revealed “many unsatisfactory features in the original publications,” including incorrect space groups and insufficient Friedel coverage leading to great uncertainty in some of reported configurations. It must also be stressed that a large majority of natural products contains only H, C, O, and N atoms. Of the around 226,500 entries comprised in the Dictionary of Natural Products as of June 2010 [65], only 15,500 (less than 7%) contain heteroatoms other than O and N. In summary, there is much space available for application of the solid-state ECD method for assigning absolute configurations of natural compounds. A major issue associated with solid-state ECD spectra is that intermolecular interactions between molecules closely packed in the crystals may give rise to non-negligible contributions to the spectrum [45, 46]. Any phenomenon of this kind cannot be predicted by a calculation run on a single molecule. The impact of crystalline intermolecular effects on the solid-state ECD/TDDFT method will be discussed in Section 6.5.

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6.4. THE SOLID-STATE ECD/TDDFT APPROACH: EXAMPLES OF APPLICATIONS The solid-state ECD/TDDFT approach has been applied thus far to 17 natural products (Chart 6.1), secondary metabolites of fungi, often endowed with biological activities such as antibiotic, antifungal, and anti-inflammatory [15, 49, 50, 66–76]. These compounds exhibit a great structural variability and contain different chromophores, fully or partially unsaturated rings, flexible saturated rings or chains, and centers of chirality in diverse O

O

O HO

OH

OH COOCH3

H3C

HO

O O

Globosuxanthone A (2)

O OHO

OCH3 OH

O

H O

O

O O Microsphaeropsone A (8)

O

3,16-Diketoaphidicolan (6)

O H Sinularolide B (5)

OH

O

H

O

O HO

HO

O

O HOH2C

O

HO

O Massarilactone E (4)

OH O Ascochin (3)

O

OH O

Viburspiran (7)

O

OH

H

O

O

O

OH

O

HO

H

HO O

O

MeO

O

OH

O Curvulone A (9)

O

O

O

α,β-Dehydrocurvularin (10) O

OCH3

OH

O

OH

OH

Fusidilactone B (14)

O Tetrahydropyrenopherol (13)

H3C H3CO O RO

OH

O O

N Macropodumine B (12)

H

O

HO

O

OH

O

H

O

OH

Blennolide A (11)

H

H3C

O

OH

O

O

CH3

O

H O O

Papyracillic acid A (R = H, 15a) and methyl acetal (R = CH3, 15b)

H3CO

O

Hypothemycin (16)

O OHOH

O

O 1β,10β-Epoxydesacetoxymatricarin (17)

Chart 6.1. Natural products whose AC has been assigned by means of the solid-state ECD/TDDFT approach.

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spatial relationships. In all cases, the absolute configuration could be established thanks to a good agreement between the experimental and calculated solid-state ECD spectra. In the following, some relevant cases will be discussed in detail to exemplify the adopted procedure and stress its scopes and limitations [22]. After phomoxanthone (1) described above, the first case investigated with the solidstate ECD/TDDFT approach was globosuxanthone A (2, Chart 6.1) extracted from Microdiplodia sp. and obtained in a crystalline form suitable for X-ray analysis [68]. Globosuxanthone A is a dihydroxanthenone with potent antitumor activity, also isolated from Chaetomium globosum [77]. ECD spectra of 2 were recorded in solution (methanol and a tertiary solvent mixture) and in the solid state as a KCl pellet (Figure 6.3). The three spectra were roughly consistent, but they displayed some differences probably related to the conformational freedom around the ester and diol moieties. Most importantly, however, the solid-state ECD spectrum did not show any extra band with respect to the solution ones and both the signs and relative intensities of the major bands were preserved. This observation pointed to the essentially intramolecular origin of the solidstate ECD spectrum, meaning that intermolecular couplings in the crystal lattice did not give rise to apparent contributions. Starting from the X-ray geometry of 2 and assuming (1R,2R) configuration, hydrogen atoms were re-optimized with DFT using B3LYP/631G(d). As a result, C–H and O–H bond lengths increased by 15% on the average, demonstrating the necessity of this preliminary optimization. TDDFT and ZINDO calculations were tested in ECD calculations, employing in the first case various hybrid functionals (B3LYP, PBE0, and BH&HLYP) and TZVP basis set. Both B3LYP/TZVP and PBE0/TZVP calculations led to a good agreement with the experimental spectrum above 250 nm in terms of position, sign, and (to some extent) relative intensity of bands, including a couple of shoulders in the 300- to 330-nm range (Figure 6.3). The BH&HLYP functional reproduced the sign sequence but with a less satisfying general agreement. On the contrary, ZINDO performed very poorly, which was not unexpected in view of the

Δε (M–1cm–1), φ (mdeg), and R (10–39 cgs)

8 6

Experimental CD in CH3OH solution

4

Experimental solid-state CD (KCl disc)

O OH COOCH3

OH O HO Globosuxanthone A (2)

2 0

C3

O2 C6

–2

C2 C1

C5

C7

Calculated CD on X-ray geometry Calculated R

–4

C4

C12 C10 C11

C8

–6

O5

C13 C14

C9

O1 07 C15

04

–8

O3

200

250

300 λ (nm)

350

O6

400

Figure 6.3. Experimental ECD spectra of (1R,2R)-(−)-globosuxanthone A (2) in methanol solution and in the solid state (KCl disc), as well as ECD spectrum calculated with B3LYP/TZVP on the solid state geometry (shown on the right). Vertical bars represent calculated rotational strengths.

A B S O L U T E C O N F I G U R AT I O N O F N AT U R A L P R O D U C T S B Y S O L I D - S TAT E E C D

molecular and electronic structure. In fact, the most plausible mechanism of optical activity responsible for the moderately intense ECD spectrum of 2 is the second-sphere chirality [78] provided by the chiral ring on the conjugated chromophore (which includes the planar diene). Based on the results obtained with TDDFT calculations, the absolute configuration of globosuxanthone A was assigned as (1R, 2R)-(−)-2 [68]. The conclusion was reached that TDDFT, with a proper choice of the functional and a sufficiently flexible basis set, would grant in subsequent cases a wide applicability with a reasonable computational time. In particular, since the conformational analysis step is skipped and the ECD calculation needs to be run on a single structure, various functionals (and possibly basis sets) may be tested to look for the best agreement with the experiment in terms of overall spectral appearance, which can be taken as an indication of the reliability of the configurational assignment. Essentially the same procedure was followed for successive compounds 3–17 (Chart 6.1) isolated from natural sources, the absolute configurations of which were assigned by means of the solid-state ECD/TDDFT approach. These included (4S )-(+)ascochin (3), isolated from the fungus Ascochyta sp. from the plant Meliotus dentatus, exhibiting antifungal and algicidal activity [69]; (4S , 5R, 6S , 7R, 10R)(+)-massarilactone E (4), isolated from Coniothyrium sp. associated with Artimisia maritima [49]; (1R, 2R, 3R, 12S , 13R)-(−)-sinularolide B (5), a cytotoxic compound isolated from the soft coral Lobophytum crassum [71]; (4R, 5R, 8S , 9S , 10S , 12R)-(−)-3,16-diketoaphidicolan (6), extracted from the endophytic fungus Phoma sp. isolated from Aizoon canariense [76]; and (1R, 2S , 4R, 5R, 6R, 7R, 8S )-(+)-viburspiran (7), a new octadride member of maleic anhydride natural products, extracted from the endophytic fungus Cryptsporiopsis sp., isolated from Viburnum tinus [74]. A somewhat peculiar case is represented by (1R, 2R)-microsphaeropsone A (8), the first natural compound with dihydrooxepino[2,3-b]chromen-6-one skeleton, isolated from Microsphaeropsis sp. from the bush Lycium intricatum. Calculated ECD spectra using the solid-state geometry for 8 showed a great variation with the functional employed, a situation occurring sometimes with complicated chromophores which calls for special caution in the interpretation of results. Although at least BH&HLYP/TZVP calculations reproduced the experimental solid-state ECD spectrum satisfactorily, the assignment was substantiated by means of vibrational CD [79], following the recommendation to use diverse chiroptical techniques to assign the absolute stereochemistry in ambiguous situations [80]. The VCD spectrum of 8 was measured in solution (CDCl3 ) and compared with the Boltzmann-averaged calculated spectrum using B3LYP/6-31G(d) on three DFT-optimized low-energy structures, including SCRF-PCM solvent model for chloroform [73]. More recently, a series of curvularin derivatives with 12-membered lactone ring skeleton belonging to the polyketide family was extracted from the fungus Curvularia sp. 6540, isolated from the marine red algae Gracilaria folifera. All compounds showed antibacterial, antifungal, and antialgal activity, and they included two new compounds, (10S ,15R)-(−)-curvulone A (9, Chart 6.1) and (11R,15R)-(−)-curvulone B, and two known curvularins with unusual (15R) configuration, namely (11R,15R)11-hydroxycurvularin and (10E ,15R)-(+)-10,11-dehydrocurvularin (10) [75]. For compounds 9 and 10, crystals suitable for X-ray analysis were obtained and thus the solid-state ECD/TDDFT approach was applied. In both cases, the absolute configuration assignment was confirmed by independent methods (chemical correlation and X-ray analysis) [75, 81]. Compound 10 was especially interesting because it crystallized in two different forms, depending on the solvent employed (CDCl3 versus wet CH3 OH/CH2 Cl2 ). The

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two X-ray geometries showed large discrepancies in the conformation of the flexible lactone ring, and, interestingly enough, the ECD spectra calculated with TDDFT (B3LYP/TZVP) on the two X-ray structures were also very different (Figure 6.4). The solid-state ECD spectrum measured on the crystals obtained from CDCl3 (type A) was well-reproduced by the TDDFT-calculated spectrum using the respective geometry. The above results suggested that the solid-state ECD/TDDFT approach may be well employed for crystalline materials exhibiting polymorphism, provided that the crystal form used for the solid-state ECD measurement is known and the corresponding molecular structure is determined [75]. Another large collection of natural compounds was obtained from Blennoria sp., an endophytic fungus from the succulent Carpobrotus edulis, which led to eight compounds related to the known secalonic acids [72, 82]. Besides secalonic acid B (18, Chart 6.2), a powerful fungicide and algaecide, a series of new monomeric and a mixed dimer derivatives were found, named blennolides (Chart 6.2). These compounds represent the long-awaited monomeric units of the dimeric secalonic acids, in particular the isomeric hemisecalonic acids B and E (or blennolides A and B, 11 and 19). Their rearrangement products 20–22 (blennolides D–F) are structurally unique new natural products, where a highly substituted γ -lactone moiety is linked to a dihydrobenzopyranone. In blennolide G (23), the usual ergochrome monomer is linked to the deoxy analogue of rearranged monomer 20, extending the secalonic acid family with a novel heterodimer. The structure and the relative stereochemistry of blennolide A (11) were confirmed by single-crystal X-ray analysis, while the absolute configuration was determined as

OH

Δε (M–1cm–1) and φ (mdeg)

25 Experimental solid-state CD (KCl disc, type A crystals)

20 10

HO

Calculated CD on X-ray geometry (type A)

H CH3 α,β-Dehydrocurvularin (10) O

Calculated CD on X-ray geometry (type B)

5

O

O

A

0 B –5 200

250

300 350 λ (nm)

400

450

Figure 6.4. Left: Experimental solid-state ECD spectrum of (15R)-(+)-10,11-dehydrocurvularin (10) recorded using crystals isolated from CDCl3 (type A), as well as ECD spectra calculated with B3LYP/TZVP on the X-ray structures of (15R)-10 for the crystals isolated from CDCl3 (type A) and a mixture of wet CH3 OH and CH2 Cl2 (type B). Right: Overlapped solid-state X-ray geometries of (15R)-10 for type A and B crystals (dark and light structures, respectively).

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O

HO

OMe O

OH

OH

O

O

OH

OH

OH

OH

O H

2

OH

O

O

MeO

O

OH

MeO

Secalonic acid B (18)

OH

O

OH

O

O

O O H

O

MeO

Blennolide B (19)

OH

O

O

O

O

Blennolide D (20) x OMe O OH

H O O

Blennolide E (21)

O

OH

OH

O

9

O

H

OH

2

MeO

OH 9

O

O

MeO

O O

Blennolide F (22)

O

O

OH O

Blennolide G (23)

MeO

O

OH

Chart 6.2. Blennolides extracted from Blennoria sp. [72, 82]. Blennolide A (11) is shown in Chart 6.1.

(5S ,6S ,10aR)-(+)-11 after application of the solid-state CD/TDDFT approach. The situation for blennolides D and E (20 and 21) was more challenging because their Xray structures were not available. The overall stereochemistry of 20 and 21 could be established only by means of a combination of several spectroscopic (NOESY, heteronuclear 3 JC,H couplings, ECD) and computational techniques (MM conformational searches, DFT geometry optimizations, TDDFT calculations). In particular, molecular modeling results were essential to rationalize observed NOEs around the rotatable C2–C9 bond [72]. The family of blennolides offered a striking evidence of the advantage provided by the X-ray crystal structure for establishing both relative and absolute stereochemistry. A further confirmation of this latter point is provided by the two analogue macropodumines B and C (12 and 24, Figure 6.5 and Figure 6.6, respectively), belonging to the family of Daphniphyllum alkaloids, a group of fused-heterocyclic fungal metabolites with significant medicinal properties. Macropodumine B (12) shows an almost unique structural feature for a natural compound: It is in fact a zwitterion containing a rare cyclopentadienyl anion and an iminio counterion (Figure 6.5). Compounds 12 and 24 were isolated from the Chinese medicinal plant D. macropodum, and the solid-state structure of 12 was determined by X-ray analysis [83]. The absolute configuration of macropodumines B and C was established by comparison of their ECD spectra with TDDFT-calculated ones, using the solid-state protocol for macropodumine B (12) and the corresponding solution protocol for macropodumine C (24). In practice, the two compounds offered the option for a direct comparison between the two methods. For macropodumine B (12), the solid-state ECD/TDDFT approach led to a calculated CD spectrum (B3LYP/TZVP) in very good agreement with the experimental solid-state one (KCl disk, Figure 6.5). Other functional/basis set combinations (using BH&HLYP and ADZP) did not improve the observed agreement. After a moderate computational effort (>>

5′ O

O

O

O

Favored conformation I

Unfavored conformation II

Predicted positive CD exciton couplet

Predicted negative CD exciton couplet

Figure 7.7. Macrocyclic 1:1 host–guest complex formed between guest and host. (Reproduced by permission of The Royal Society of Chemistry [16, 41].)

7.3.2.3. Practical Application of the Pfeiffer Effect for Analyzing Chiral Diamines. Recently, Anslyn took advantage of Pfeiffer-related phenomena to develop a rapid assay of enantiomeric excess. Chiral diamines were added to racemic Cu(I) or Pd(II) complexes, resulting in CD spectra corresponding to metal-to-ligand charge transfer (MLCT) bands of the metal complexes [45, 46]. An instrument interfaced to a robotic 96-well plate allowed rapid and convenient measurement of the CD spectra of the compound library. Linear discriminate analysis of the CD spectra then determined the identification, concentration, and enantiomeric excess of the diamines. This study represents a practical application of a chiroptical sensor technique. 7.3.2.4. Anion-Controlled Switching of Amide Complexes. There are several interesting examples of chiroptical metalloswitches triggered by interaction with

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OCH3 O

1.3 nm

0.3 nm

+2 H• (CF3SO3H)

2X

NO3–

2X

N * H OCH3

X X



–2 H N

NO3–

N

X: H2O, CH3CN or CF3SO3– “Extended-Λ-form”

H N

N*

H2L5

“Extended-Δ-form”

N* H

N

N*

OCH3

O OCH3

O H3C

“Contracted-Λ-form”

N

H N

CH3

O

H2L6

535 nm Contracted-Λ

Δε (dm3mol–1cm–2)

1

Extended-Λ

0.5

0

–0.5 Extended–Δ 400

600

800

1000

λ (nm)

Figure 7.8. Stretching and inverting dual motions of the CoII complex. Crystal structures CD spectra of [Co(L5)](left, • for CD) and [Co (H2 L5) (CF3 SO3 ) (H2 O)] (CF3 SO3 )–(CHCl3 ) (middle, ), as well as DFT-optimized structure of [Co(H2 L5)(NO3 )]+ (right, ), are illustrated [50]. (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.)



anions. Interest in such systems is heightened because supramolecular recognition of anions developed later than that of cations, and the abundance of potential anionic analytes in biology and other areas. Yano et al. [47] reported chiral inversion induced around a seven-coordinated cobalt center by interaction between sugars and sulfate anions. New cage-type cobalt(II) complexes that consist of N -glycosides from mannose-type aldoses and tris(2-aminoethyl)amine (tren), [Co((aldose)3 tren)]X2 • nH2 O (X = Cl− , Br− ), and [Co((aldose)3 tren)]SO4 • nH2 O exhibited C3 helical configuration inversion around the Co(II) center. The CD spectral characteristics of [Co((aldose)3 tren)]X2 • nH2 O changed dramatically with the addition of sulfate anions, and even inverted at high sulfate concentrations, suggesting ion pair formation which was confirmed by a crystal structure. When sulfate ion is embedded into the cavity of the sugar hydroxyl groups, the complex adopts a  configuration, while the complex with the halogen anion exhibits a  configuration. When the sulfate anion approaches the sugar complex, the electrostatic attraction between the doubly negative and positive charges of the sulfate anion and complex cation causes the hydrogen bonds between the ligands to be interrupted and brings about a chiral inversion due to the sulfate embedding into the large complex cavity. Reversibility was exhibited when the sulfate ions were removed and replaced with halide ions. Miyake et al. [48] established that the helicity of a chiral tetradentate ligand (ligand L6 in Figure 7.8) chelated to Co(II) was readily inverted by the addition of nitrate anion. Preliminary studies suggest that two molecules of nitrate serve to invert the helicity

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of the ligand. Chelation of the first equivalent to the Co(II) center displaces the two tertiary nitrogens of the bound ligand, while the second equivalent of nitrate disrupts hydrogen bonding of the amide to solvent [49]. Circular dichroism studies indicated that the initial Co(II) complex exhibited a positive CD signal in the range of the d –d transition (around 530 nm). Upon gradual addition of Bu4 NNO3 the d –d transition the CD response changes from positive to negative. These early findings by Miyake led to the synthesis of a chemical device designed to exhibit dual mode motions [50]. This time, a modified version of chiral tetradentate ligand (ligand L5 in Figure 7.8) including 2,5-dimethoxybenzene moieties attached through amide linkages to the terminals of the ligand was employed. An acid–base reaction of the corresponding cobalt complex triggers an interconversion of coordinating atoms between amide nitrogen atoms and amide oxygen atoms, which causes a stretching (extension/contraction) molecular mode. Inversion of helicity (again from  to ) after addition of five equivalents of Bu4 NNO3 accounts for the second device mode. CD studies of the [Co(L5)] complex in CH3 CN/CHCl3 = 1/9 exhibit positive signals at 433 nm and 918 nm and negative signals at 474 nm, 607 nm, and 1100 nm, which correspond to the contracted -form. Two equivalents of CF3 SO3 H (to form [Co(H2 L5)(CF3 SO3 )(H2 O)](CF3 SO3 ) • (CHCl3 ) then caused a rapid signal shift from 0 to positive in the 530-nm region (∼ 5 s) which indicated a switch to the extended -form. The helicity inversion caused by addition of five equivalents of Bu4 NNO3 gave rise to a negative CD signal around 530 nm. The similarity of this CD signal shift to the original H2 L6 ligand study supports the assertion that helicity is changed in the device. CD signals remained consistent after many deprotonation/protonation cycles, proving that robust reversibility was established. Such a kinetically labile Co(II) complex provides for a dynamic dual mode switch that could potentially be required for sophisticated supramolecular switching devices. Recently, pentapeptide chains were combined in such a chirality-switchable Co(II) complex. The peptide chains experienced helix inversion following the reconfiguration of the octahedral metal center upon addition of the NO3 − anion stimulus (Figure 7.9) [51]. Similar peptide helix inversion by nitrate anion was shown to occur in analogous NiII and ZnII complexes. Selection between ZnII , CoII , or NiII allowed tuning of the rate of the inversion process to occur on a timescale from milliseconds (ZnII ) to hours (NiII ). The estimated half-lifetime (log τ1/2 ) of these metallo-peptide complexes showed a linear correlation with the water exchange lifetime of the aqueous metal cations.

P O O NO3– O O N M M O O Λ Helicity Δ Inversion

4

M Rapid

O N OM O Chirality Δ Transfer

log(t1/2)

P

Ni(II)

2 Co(II) 0 Zn(II)

–2 Λ, P-form

Δ, P-form

Δ, M-form

–8

–7

–6 log(τ)

–5

–4

Figure 7.9. (Left) Helicity inversion around a metal center and sequential chirality transfer to the pentapeptide helical tubes (-Aib-Phe-Aib-Phe-Aib-OCH3 ). (Right) Linear relationship between half-lifetime (t1/2 ) of helicity inversion and cation water exchange lifetime (τ /s) [51]. (Reproduced by permission of the American Chemical Society.)

D Y N A M I C S T E R E O C H E M I S T RY A N D C H I R O P T I C A L S P E C T R O S C O P Y

Δε a b1

N S

R R

N R H

c1, d1 He1 g1, h1 R N f1 i1, j1 R i2, j2 R S N f2 g2, h2 N H e2 c2,d2

λ acetonitrile

N

H

Water Δε

b2 a

L7 (RRRR) (RSRS)

λ

Figure 7.10. (Left) Structures of one of the chiral macrocycle isomer L7(RRRR)(RSRS) . (Right) Solvent induced reversible helicity inversion with accompanying CD spectra [54]. The top spectra show the change in ellipticity over time for the compound on the left upon dissolution in acetonitrile; the bottom spectra are for the compound on the right in water. (Copyright American Chemical Society. Reproduced with permission.)

7.3.2.5. Solvent-Controlled Switching of Metal Complexes. Solvent can also induce significant changes in chiroptical response in metal-based systems, either as a result of general differences in polarity or nonspecific solvation or as a result of coordination of solvent in the inner coordination sphere of a metal complex. In a novel study, the Lisowski group has examined chiroptical switches involving lanthanide complexes of chiral hexaazamacrocycles [52, 53]. The hexaazamacrocycle L7 [54] shown in Figure 7.10 was designed to complex large lanthanides such as Yb(III) and Eu(III). Upon addition of Yb(NO3 )3 • 5H2 O in acetonitrile, it was observed that the chiral ligand L7 wrapped around the Yb in a helical -form corresponding to the (R, R, R, R)-(S, R, S, R) L7 isomer. Crystal structure studies of [YbL7(NO3 )2 ]2 -[Yb(NO3 )5 ](NO3 )4 • 5CH3 CN show an improper torsion angle C2–C4–C15–C17 of −13.3◦ , which is unusually high for a lanthanide(III) hexaazamacrocycle complex. Solvation of the same complex in water, though, leads to ligand reorganization presenting a sharp shift in helicity as evidenced by an improper torsion angle C2–C4–C15–C17 of 87.2◦ for the (R, R, R, R)-(S, S, S, S ) isomer. CD studies confirm helicity inversion by solvent effects, demonstrating quantitative conversion in 144 hours. The proposed mechanism of inversion involves an initial exchange of hydrate into a 10-coordinate metal inner sphere, which is followed by slow ligand reorganization into an 8-coordinate sphere. Lisowski argues that the “squeezed” (R, R, R, R)–(S, S, S, S ) isomer is more capable of accommodating smaller water axial ligands whereas the “open” (R, R, R, R)–(S, R, S, R) isomer preferentially binds the bulkier nitrate ligand in the axial position [54]. The study as a whole represents a rare case of reversible solvent induced helicity inversion for a metal-based complex. Recently, Muller, Lisowski, and co-workers [55] reported that a similar but larger chiral nonaazamacrocyclic amine wraps around the lanthanide(III) ions to form enantiopure helical complexes. The NMR and CD spectra show that kinetic complexation product of the (R, R, R, R, R, R) isomer prefers the (M )-helicity. However, the preferred helicity of the thermodynamic product is M for the early lanthanide(III) ions and P for the late lanthanide(III) ions. In solution, the late lanthanide(III) complexes slowly invert their helicity from the kinetically preferred M to the thermodynamically preferred P . The Mamula group reported the diastereoselective self-assembly of the enantiomerically pure pinene-bipyridine-based receptor, (−) or (+) L-, in the presence of Ln(III) ions

263

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Ln3+

Ln3+ N CH3OH

N

COO– (+)-L

CH3CN

CH3CN CH3CN + H2O

tris-Ln[(+)-L]2

tetra-Ln4[(+)-L]9

Figure 7.11. Divergent self assembly leading to the synthesis of interconverting trinuclear [Ln3 {(+)-L}6 (μ3-OH)]2+ and tetranuclear [Ln4 {(+)-L}9 (μ3-OH)]2+ complexes [56]. (Reproduced by permission of the American Chemical Society.)

(Figure 7.11) [56]. Upon exposure to La, Pr, Nd, Sm, Eu, Gd, and Tb ions in dry acetonitrile, it forms a C3 -symmetrical, pyramidal tetranuclear species with the general formula [Ln4 (L)9 (μ3 -OH)](ClO4 )2 ) (abbreviated as tetra-Ln4 L9 ). Three metal centers shape the base: an equilateral triangle surrounded by two sets of helically wrapping ligands with opposite configurations. The tetranuclear structure is completed by a capping, helical unit LnL3 whose chirality is also predetermined by the chirality of the ligand. The sign and the intensity of the CD bands in the region of the π –π * transitions of the bipyridine are highly influenced by the helicity of the capping fragment LnL3 . In methanol, it selfassembles to give the trinuclear species [Ln3 (L)6 (μ3 -OH)(H2 O)3 ](ClO4 )2 ) (abbreviated as tris-LnL2 ). The two related superstructures can be interconverted. As is shown by the CD evolution in Figure 7.12, in pure dry acetonitrile, pure tris-LnL2 disassembles and reorganizes gradually to form tetra-Ln4 L9 . If a certain amount of water is added, tris-LnL2 can be reassembled quantitatively. Water stabilizes the trinuclear species to the detriment of the tetranuclear ones. Reducing the amount of water by molecular sieves leads to the tetranuclear species. However, the number of these reversible cycles is limited due to partial decarboxylation of the ligand in the presence of water. Recent reports from Nitschke describe a Cu(I) based solvent-triggered molecular switch [57]. The initial synthesis of the chiral Cu(I) complex in methanol resulted in an equal mixture of both P - and M -diastereomers which was characterized by a weak circular dichroism spectrum bearing similarities to that of the free ligand. A featureless CD spectrum in the region of the MLCT band further established that there was no net diastereomeric excess formed. A stark contrast was then encountered when the Cu(I) complex was dissolved in dichloromethane-d2 and the CD spectrum revealed a positive CE in the MLCT region. Combined studies of CD and NMR suggest that the Cu(I) complex (Figure 7.13) fully converts to the P -diastereomer in nonpolar dichloromethane. Similar studies in DMSO then showed that the M -diastereomer of the complex (Figure 7.13) exists in 20% excess, setting the stage for a reversible metal-based chiroptical molecular switch. The solvent-induced conformational exchange was reasoned to be dominated by hydrogen bonding effects. A weakly polar solvent such as dichloromethane only weakly

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300 pure tetra-Pr4L3

180 min 115 min

Δε (M–1 cm–1)

200

75 min

45 min

100 15 min 10 min

0 5 min

–100

pure tris-Pr[L]2 260

280

300 λ (nm)

320

340

360

Figure 7.12. Time-dependent evolution of the CD profile of tris-Pr[(+)-L]2 in CH3 CN [56]. (Reproduced by permission of the American Chemical Society.)

Figure 7.13. Postulated structures in DMSO (left, M predominating) and CH2 Cl2 (right, P exclusively) [57]. (Reproduced by permission of the Royal Society of Chemistry.)

interacts with the hydroxyl groups of the ligand, allowing for intramolecular hydrogen bonding. Such hydrogen bonding serves to rigidify the structure and lock the complex into the P conformation. Polar solvents such as DMSO, though, interact strongly with the ligand hydroxyl group and push the hydroxyl groups apart, leading to a preference for the M conformation. The authors hypothesize that such a reversible solvent-triggered complex could serve as a means to control stereoselectivity in future metal-catalyzed reactions.

7.3.3. Redox-Triggered Systems The rich coordination chemistry literature offers many avenues for entry into the design of redox-sensitive metal complexes that display rich chiroptical spectra. Redox-active metal ions themselves often show useful electronic spectral changes. However, changes in CD spectra of the organic ligand are also very useful, particularly in complexes that display CD exciton chirality. 7.3.3.1. Iron Translocation in Triple-Stranded Helical Complexes. Shanzer and co-workers [58] reported the first published example of a redox-mediated chiroptical redox switch. The system was based on chemical triggering of iron translocation in

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Fe2+

+e–

Fe3+

–e–

(a)

O N

N H

(b)

H N CH3

OH N O

O

O N H

N N 3

Figure 7.14. Tripodal ligand containing two binding sites and the redox-switched chirality of its iron complexes [58]. (Reprinted by permission from Macmillan Publishers Ltd. Copyright 1995.)

triple-stranded helical complexes (Figure 7.14). The design accommodated a single metal ion in one of two sites, either a “hard” binding N3 O3 cavity presenting three hydroxamate moieties or a “soft” N6 -cavity with three bipyridyl ligands. Chemical reduction of Fe(III) to Fe(II) induced the metal to translocate from the hydroxamate binding site to a bipyridyl site, because the “softer” Fe(II) favored the site with more nitrogen ligands. Redox switching of the complex was induced by reduction with ascorbate and oxidation with ammonium persulfate. Pronounced differences in UV–vis and CD spectra were observed corresponding to changes in absorbance associated with Fe(II) versus Fe(III) electronic spectra. A split CD spectrum in the UV region was observed that was three times more intense for the Fe(II) state, suggesting exciton interactions involving the bipyridyl moieties. Reduction was rapid, and oxidation gave the Fe(III) absorbance spectrum after a few minutes (several hours were required to achieve the original Fe(III) CD spectrum). The fact that metal exchange did not occur between control compounds with single metal binding sites suggested intramolecular translocation reaction. Variation of the structure resulted in significantly different translocation rates. 7.3.3.2. Chiroptical Tripodal Ligands. Three-armed, or tripodal, ligand–metal complexes have been found to offer particularly rich stereodynamic behavior, especially when coupled with exciton chirality analysis. The development of redox-triggered chiroptical switches in the Canary laboratory began with the observation that tripodal, N4 ligands form stable coordination complexes with divalent metal cations [59, 60]. In the case of Zn(II) and Cu(II), the ligand, otherwise conformationally mobile with many conformations, wraps around the metal ion to form a propeller-like complex. In ligands with a single stereogenic center on one of the tripod arms, the helicity of the propeller formed by the

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planes of the heterocycles is dictated by this stereocenter. A number of crystallographic structures [61], with few exceptions, established the relationship between the chiral carbon center and the propeller configuration [62]. ECCD established the preponderance of a single propeller conformation in solution, and it tested whether the same configuration was present relative to the carbon center as had been observed in solid-state studies [63]. It was confirmed that Cu(II) and Zn(II) complexes showed ECCD spectra consistent with solid-state propeller-like structures. This method allowed the assignment of the absolute configuration of secondary amines from the sign of the observed excitant couplet. Furthermore, the sign of the couplet discloses the sense of the propeller twist in solution. The dependence of CD exciton chirality upon the strength of the electronic transition moment, the proximity of the coupled transitions, and the angle between them led to the development of several interesting chiroptical molecular switches. An on/off system was studied involving a tripodal ligand containing three quinoline moieties [64]. The tris(quinoline) compound in Figure 7.15 forms a coordination complex with Cu(II) (8) involving the coordination of four nitrogen atoms and affording an exceptionally intense split CD spectrum that results from the additive effect of three ECCD couplets in one molecule. Reduction to the Cu(I) complex in the presence of strongly coordinating thiocyanate ion gave dissociation of one quinoline arm. This resulted in a much weaker ECCD spectrum due to two factors: (1) the dissociation of one quinoline reduces the number of ECCD couplets from three to one, and (2) the less sterically crowded environment around the copper ion allows unwinding of the ligand and reduces the magnitude

S C N N

S C N N N

+e–

CuII H

Cu I H

–e–

N

CH3

N CH3

N (a)

200

66000

100

33000

Δε 0

0 [Θ]

–100

–33000

–200

–66000

–300

–99000

–400

–132000

CuI –165000 CuII –600 –198000 200 210 220 230 240 250 260

0 [Cu(I)]

OFF

–100 –200

Δε

8

–500

N

N

–300 –400

[Cu(II)] –500

ON 0

1

2

3

4

5

Reversibility at 240 nm

λ (nm)

(b)

(c)

Figure 7.15. On/off chiroptical molecular switch. (a) One-electron reduction results in dissociation of an arm of the tripodal ligand. (b) CD spectra of Cu+ and Cu2+ complexes. (c) oxidation and reduction cycles with ascorbate and persulfate [64]. (Reproduced by permission of Wiley-VCH.)

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

of the dihedral angle and therefore diminishes the amplitude of the ECCD couplet. The overall effect is a very large difference in ECCD amplitude between Cu(I) and Cu(II) states. Dependence of the ECCD amplitude on the counterion supported the structural assignment [65]. The complex is highly reversible chemically upon oxidation of the Cu(I) complex with ammonium persulfate and reduction of the Cu(II) complex with sodium ascorbate. Temperature-dependent 1 H NMR studies of this system led to the conclusion that the two arms lacking the chiral carbon center are in rapid equilibrium between associated and dissociated states at room temperature, but slow on the 1 H NMR timescale at low temperature [66]. The arm containing the chiral carbon center, however, remains coordinated. Such tripodal ligands were found to act as chemosensor molecules by virtue of their ability to torque a nematic into a cholesteric liquid crystalline phase increased upon complexation with copper ion [67]. Changes in overall shape of the complexes induced by different metals and counterions were transferred sensitively to the supramolecular level, observed by proportionate changes in the degree of twisting. Redox changes (Cu(I)/Cu(II)) also gave large changes in twisting power. The handedness of the induced cholesteric phase was related to the stereochemistry of the ligand. Interestingly, a direct correlation was observed between helical twisting power and ECCD amplitude, consistent with each technique responding proportionately to the relative twist of the planes of the nitrogen heterocycles. Another related complex containing two chiral carbon centers within a piperidine ring (9) was reported (Figure 7.16) [68]. In this case, the rigidity of the ligand provided control as to which chair form of the piperidine was adopted. In the Cu(I) oxidation state, the ligand adopts a relatively stable cyclohexane chair conformation, with two equatorial and one axial substituent. This conformation places one pyridine moiety remote from the metal ion, but this is accommodated by the lower coordination number of the Cu(I) ion. In the Cu(II) state, strong binding to the higher-coordination number ion brings all three pyridines into association, which forces the piperidine to adopt a higher-energy chair with two axial and one equatorial substituents. The CD spectrum of the Cu(II) complex showed the largest amplitude of any complex in this series, but the Cu(I) spectrum did not give an exciton chirality spectrum. In this case, the Cu(I) structure was characterized by a series of 1 H NMR experiments. In these studies, CD exciton chirality served as a tool to gauge not only the configuration of the propeller conformation but also the degree of twist of the molecule. Relatively few spectroscopic probes are available to report 3D molecular geometry, so it may be expected that this technique should be broadly applicable for the characterization of solution species [16]. Systematic exploration of amino acid derivatives by Canary and co-workers [69, 70] led to the discovery of a molecule that inverts helicity and CD couplet sign upon one-electron redox change [71]. A ligand derived from the amino acid methionine forms a tetradentate complex with Cu(II) involving three nitrogen atoms and a carboxylate (Figure 7.17). In this system, the propeller twist of the molecule is dictated by the asymmetric carbon center by virtue of a gearing mechanism between the methine and methylene carbon atoms, and it can be visualized when viewing down the bond between the tertiary amine nitrogen atom and the Cu(II) ion. Upon reduction to Cu(I), the ligand reorganizes and the sulfide moiety replaces the carboxylate, which is expected due to the preference of Cu(I) for this type of coordination. The reorganization requires a pivot about the bond between the tertiary nitrogen atom and the asymmetric carbon atom. This pivot destroys the gear previously mentioned; to retain the geared conformation, the

D Y N A M I C S T E R E O C H E M I S T RY A N D C H I R O P T I C A L S P E C T R O S C O P Y

269

X N

CuI

N

N

X

H

H CuII HN

N H

N

N

N X = sovent 9

800 600 400

Free ligand CuI complex CuII complex CuI complex oxidized CuII complex reduced ZnII complex

Δε

200 0 –200 –400 20

12 8 4

200

210

220

230 240 λ (nm)

250

260

0 270

ε × 10–4

16

Figure 7.16. Redox-triggered inversion of one chair form of a piperidine ring into the other chair and corresponding CD (top) and UV–vis (bottom) spectra [68]. (Reproduced by permission of the American Chemical Society.)

two methylene carbon groups flip, which, in turn, inverts the helical orientation of the two quinoline moieties and, therefore, the exciton chirality spectrum. The CD spectrum appears to give mirror images for the Cu(I) versus Cu(II) complexes. The switching was reversible with cyclical additions of ascorbate and ammonium persulfate. Crystallographic data supported the structural assignments [72]. The Cu(I)/Cu(II) complexes of other tripodal ligands also give inversion of the CD spectrum including derivatives of methioninol and S -methylcysteine [73]. 7.3.3.3. Redox-Controlled Molecular Flipper Based on a Chiral Cu Complex. Copper redox chemistry has also been explored in other ligand platforms for redox-dependent chiroptical effects. A molecular bipaddled flipper based on a tetradentate chiral Cu complex was reported whose paddling motion could be controlled

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

(a)

(b) 40

N O CuII H N

H

Ar

H N ArO CO2-H CH3SCH2

H

N

S

+e– –e–

I

Cu N

N -O C 2 H

N

H

–60

[Cu(I)] [Cu(II)]

Cu

5

0

4

–100

3 2

II

Cu –200

(c)

7 6

I

100 Δε239

Ar

H –20 –40 –80

CO2–

S

Ar

CH3SCH2

N

20 0

0

1

2

3

ε × 10–4

X

Δε

+



1 210 220 230 240 250 260 λ

n

Figure 7.17. Redox-induced inversion of helicity. (a) As a result of the presence of gearing among the three arms of the tripod near the sterically crowded tertiary amine of the ligand, a pivot about a C–N bond results in the inversion of the propeller. (b) CD and UV–vis spectra of Cu+ and Cu2+ oxidation states. (c) chemical cycling with ascorbate and persulfate [71]. (Reproduced by permission of the American Association for the Advancement of Science.)

N (R) (R) N (R)

CH3

(R) N

CuI N

[Δ-10]+ +e–

[Λ-11]+ +e–

–e–

–e–

Figure 7.18. Crystal structure of [-10]+ (top left) and DFT structures of [-11]+ (top right), [-12]2+ (bottom

CH3

Δ-10PF6 [Δ-12]2+

[Λ-13]2+

left), and [-13]2+ (bottom right) [74]. (Reproduced by permission of the American Chemical Society.)

by reversible oxidation of the metal center (Figure 7.18) [74]. The isomeric pair of Cu(I) complexes -[CuI ((NR , NR , R, R)-L)]PF6 (-10PF6 ) and -[CuI ((NS , NS , R, R)-L)]PF6 (-11PF6 ) interconvert, a slight preference for -11PF6 , (Keq = 1.3), which can be monitored by time-dependent CD starting with a pure -10PF6 in CH2 Cl2 (Figure 7.19a). The amplitude of the Cotton effects decreased with time and eventually rested at smaller amplitudes with opposite signs within a couple of hours. The inversion of the chirality of the aliphatic N atoms resulted in the inversion of helicate chirality. The mechanical motion undergone by -10PF6 and -11PF6 could be switched on/off by reversible metal oxidation and reduction electrochemically or chemically. An oxidation experiment of species -10PF6 with AgBF4 was performed at different times of the isomerization process and the CD of the resulting Cu(II) species (-12PF6 and/or 13PF6 ) recorded (Figure 7.19b). The spectra varied, depending on when the oxidant was added, which corresponded to the degree of [-10]+ /[-11]+ isomerization. However, when AgBF4 was added to a pure -10PF6 sample, all of the -10PF6 was oxidized to -12PF6 and no isomerization to -13PF6 or -11PF6 was observed. The transition

271

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7 3

40

CD (mdeg)

CD (mdeg)

80

0 –40

t = 30

t = 123

t=0

–7

× 10

–3

–80 –120 235

0

t = 123

t=0 t = 30

335

435 λ (nm) (a)

535

–1 235

436

635

835

λ (nm) (b)

Figure 7.19. (a) CD monitoring of the -10PF6 /-11PF6 isomerization reaction in CH2 Cl2 . (b) CD spectra of the oxidized -10PF6 /-11PF6 couple with AgBF4 at different isomerization times yielding [-12]2+ at t = 0 min and mixtures of [-12]2+ and [-13]2+ at t > 0 min [74]. (Reproduced by permission of the American Chemical Society.)

metal integrated into this device acts as a redox switch that permits one to start/stop the motion at will. 7.3.3.4. Redox-Switchable Pt-Bridged Cofacial Diporphyrins via Carbon– Metal σ Bonds. In one of several porphyrin-containing systems, Shinokubo, Osuka, and co-workers [75] reported the construction of a Pt(IV)-bridged cofacial diporphyrin architecture and its dynamic helical conformational change by reduction of the bridge to Pt(II) (Figure 7.20). Two stable Pt-C σ bonds supported by the pyridyl groups brought two porphyrin macrocycles to be in close proximity in each of these two complexes. The platinum bridge offers conformational flexibility to the complexes due to the susceptibility of platinum toward redox reaction. These complexes also exhibit helical chirality. Reduction of M spiral of 14M mainly yielded the P spiral enantiomer of 15P . The Pt(IV) complex 14M exhibits exciton coupling in both UV–vis and CD, while there is no exciton coupling in the Pt(II) complex 15P . 7.3.3.5. Redox-Triggered Porphyrin Tweezers. Recently, a redox-triggered porphyrin tweezer was reported in an attempt to develop materials with optical properties in the visible region of the electromagnetic spectrum [76]. As shown in Figure 7.21, bis(porphyrin) methioninol derivative (16) gave a strong ECCD couplet upon metallation with Cu(II). The free ligand and Cu(I) complex did not give ECCD. The absence of an ECCD couplet in the Cu(I) complex was rationalized as resulting from relatively weak association of the metal under the conditions studied. The Cu(II) complex, however, showed very strong amplitude, affording an on/off chiroptical molecular switch. Other, nonchiral electrochemically responsive dimeric porphyrin systems have been reported where the redox changes occurred within the porphyrin moieties [77]. 7.3.3.6. Redox-Controlled Dinuclear Ruthenium-Based Switches Monitored by Electronic Near-IR CD. A system showing strong changes in near-infrared (NIR) CD spectra was reported recently [78]. NIR techniques are of interest for several reasons, including the benefit of lower incident light energy on organic materials and greater transparency of NIR light in biological applications. Building on earlier studies of organic-based systems [79–81], the Wang laboratory studied dinuclear ruthenium complexes with 1,2-dicarbonylhydrazizo bridging ligands , -17 and , -17

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

N N

2e–

N Ni

N

CI

N N

N

N

N Ni

Ni

N

N

N N

CI N

N

Ni

N N

N

14M spiral

15P spiral

200

Δε (M–1cm–1)

100

0

–100 14M –200

15P

–300

–400 300

400

500

600

700

800

Wavelength (nm)

Figure 7.20. (Top) Reduction of the M spiral Pt(V) complexe 14M result in P spiral Pt(II) complex 15P. (Bottom) CD spectra. [75]. (Reproduced by permission of the American Chemical Society.)

(Figure 7.22) that are highly electrochromic with absorption bands near 500, 900, and 1200–1600 nm. Ligand-centered transitions in the UV region and redox-sensitive MLCT bands in the visible region dominate the CD spectra shown in Figure 7.22. A prominent band near 1115 nm observed in the Ru(II)/Ru(III) state, due to metal–metal charge transfer (MMCT), did not give a strong Cotton effect in the CD spectrum. The Ru(III)/Ru(III) state gave a strong MLCT band at 900 nm that gave a relatively strong Cotton effect in the CD spectrum. Reversible redox switch behavior was demonstrated by monitoring the CD signal at 890 nm and cycling up to seven times electrochemically between the Ru(II)/Ru(II) and Ru(III)/Ru(III) states. A variety of systems have thus been examined for redox-active metal ion triggered chiroptical molecular switches. The mechanisms reported involve translocation of a metal

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N N C N N

Cu(CIO4)2

N HN

NH4SCN

NH N

N N

Cu

N

N

SCN

OH H

N HO HCu N N

16 N N 2

SCH3

SCH3

300 3eq of Cu(II) and NH4NCS free ligand

200 Δε

100 0 –100 –200

A

–300 0,16 0,14 0,12 0,10 0,08 0,06 0,04 0,02 0,00

360

390

360

390

420

450

480

420

450

480

λ (nm)

Figure 7.21. Redox-triggered reorientation of porphyrins [76]. (Reproduced by permission of the American Chemical Society.)

ion, changes of lability of ligand rearrangement, or inner sphere ligand rearrangement resulting from change in coordination number or hardness of the metal. The changes in amplitude of observed CD spectra can be dramatic, even leading to complete inversion of the sign of the ECCD couplet.

7.3.4. Photochemically Triggered Chiral Metal Switches Among many interesting studies, the Aida group used ECD to characterize a redoxtriggered system in which chemical or photoreduction of a chiral cerium bisporphyrinate double-decker complex resulted in racemization by acceleration of the porphyrin ligand

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n+

N

N

HN

Ru

N O

N N

N

Pr

N

O N

Ru

NH

Pr

N N

3×10 2×10

5

RuII/RuII RuII/RuIII RuIII/RuIII

1×105 0 –1×105 –2×105 –3×105

300

400 500 600 Wavelength (nm)

Molar Ellipticity (deg x cm2/dmol)

Molar Ellipticity (deg x cm2/dmol)

Λ, Λ-17 5

700

3×104 RuII/RuII RuII/RuIII RuIII/RuIII

2×104 1×104

0 –1×104 –2×104 –3×104 600

800

1000

1200

1400

Wavelength (nm)

(a)

(b)

Figure 7.22. CD spectra of , -isomer of a diruthenium complex 17 at different oxidation states [78]. (Reproduced by permission of the Royal Society of Chemistry.)

rotation. They further showed that oxidation of a chiral zirconium complex resulted in deceleration of acid-induced racemization [82]. 7.3.4.1. Azobenzene-Based Molecular Scissors. The Aida group carried out the synthesis of other complex light-triggered chiroptical molecular switches. Life-sized scissors having a handle, pivot, and blades inspired the preliminary design of a pair of molecular “scissors” [83]. The chemical equivalents to these three units were found to be azobenzene as the handle, ferrocene as a pivot, and phenyl groups as the blades (Figures 7.23a and 7.23c). The operation of the molecular scissor is quite elegant. Under standard conditions, the azobenzene handle is predominantly in the trans state leading to “closed” blades. Under irradiation of UV light, the azobenzene undergoes isomerization to the cis isomer, which then causes a slight rotation of the cyclopentadienyl rings of the ferrocene pivot. This finally moves the attached phenyl rings away from one another, leading to an “open” scissor state. The scissors’ chirality (due to the planar 1,1 ,3,3 -tetrasubstituted ferrocene) allows both open and closed states to be seen using circular dichroism (Figure 7.23b). The authors explain that the trans-to-cis isomerization of [CD(−)280]-trans-18 upon UV-irradiation (λ = 350 nm) after 180 s gave rise to CD spectral changes at 240–300 nm due to the major adsorption of the tetraarylferrocene unit. Upon irradiation with visible light (λ > 400 nm), a reverse spectral change occurred, where the system quickly reached a photostationary state in 15 s. Effective reversibility was also exhibited by the system upon sequential irradiation with UV and visible light.

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+2.0

Handle Pivot

N N

Fe 18 (a)

Δε

+1.0 0.0

–1.0

trans-18 10 sec 20 sec 60 sec 180 sec

–2.0 235 260 285 310 335 360 λ (nm) (b)

Blade

Azobenze Strap

(c)

Figure 7.23. (a) Structural representation of azobenzene controlled ‘‘molecular scissors.’’ (b) CD spectral changes of trans-18 upon irradiation with UV light. (c) Graphic conceptualization of the ‘‘molecular scissors’’ [83, 86]. [Reproduced by permission of the American Chemical Society (a, b) and the Royal Society of Chemistry (c).]

7.3.4.2. Host-Controlled Guest Chirality. Further research into Aida’s molecular scissors proved that they could be applied to the field of host–guest chemistry [84]. When metallated porphyrins were attached to the 4-position of the phenyl blades, it was found that a diisoquinoline guest was able to chelate to the zinc porphyrin units. Upon irradiation of the host–guest complex with UV light (λ = 350 ± 10 nm), the trans-azobenzene unit again isomerizes to the cis-isomer, causing a long-distance conformational twist of the diisoquinoline guest (Figure 7.24). The guest molecule (19) in solution is initially achiral due to its conformational freedom; but when added to the host molecule (trans-20), it binds in a nonplanar CD-active chiral geometry. Overlap of CD bands (275–350 nm) from the host molecule required that differential CD spectra be used to examine the motion of the guest (Figure 7.24b). Irradiation with UV light caused the Cotton effects at 270–350 nm of the guest (19) to diminish and then vanish. It was reasoned that the disappearance of the CD band is caused by the guest molecule being forced into a nearly planar state when bound to the cis-isomer of the host compound. Sequential irradiation of host–guest complex (19 • trans-20) with UV and visible light proved that the complex was controllably reversible (Figure 7.24c). This represents the first instance of a molecular machine causing chirality manipulation in a controllable and reversible manner. 7.3.4.3. Chirality Transfer via Ternary Complex. Recently, Aida and coworkers [85] have created many similar compounds incorporating the molecular scissor as a basis for more elaborate and complex systems. Such systems include a ternary compound, which includes a pyridine-appended dithienylethene derivative as a photochromic module that can again be used to transfer conformational information with UV and visible light as a trigger [85]. Extension of the pivotal ferrocene has also been adopted in reversible self-locking compounds shown in Figure 7.25. In the presence of trans1,2-bispyridine ethylene, the zinc–porphyrin moieties coordinate intramolecularly with the anilines to “lock” the molecule internally [86]. UV light is then used to isomerize to the cis-1,2-bispyridine ethylene that is then capable of coordinating to the zinc porphyrin units, “locking” the molecules externally. The process is again shown to be reversible by alternating UV and visible light irradiation. Such discoveries by Aida and co-workers could help to controllably transmit chiral and mechanical information through long molecular distances.

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N Ar N Zn N N Ar

Ar

(a)

N Zn N N N

N

Ar

N

Ar N

19

N

Vis

N N Zn

N

N

N

UV

N

Fe

Ar

Fe

19

N N

N Zn N N Ar

Trans-20

Ar

Cis-20 19·Cis-20

19·Trans-20 100

(b)

[19]/Trans-[20]

Δε

50

0.0 0.3 0.6 1.0 2.0

0

–50

–100

250

300

350

400

450

500

Wavelength (nm) 6.0

(c) Δε

4.5 3.0 1.5

NN N Zn NN

0

Δε

150

N

NN Zn NN

100 50

[trans-20]

[trans-20] + [cis-20]

0 1.00 0.75 0.50 N N

0.25 0.00

0 10 20 30 40 50 60 70 80 90 Times (s)

Figure 7.24. (a) Photoisomerization of a 1:1 complex of molecular pedal 20 with rotary guest 19 (19 • 20). (b) CD spectral changes of trans-20 upon titration with 19. (c) CD visualization of the motions of guest-binding molecular pedals 19•(+)-20 and 19•(−)-20 triggered by light [84]. (Reprinted by permission from Macmillan Publishers Ltd: Copyright 2006.)

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H2 N

NH2

N

N N Zn N

N

N N Zn N

N

UV N N N Zn

N N N Zn N

Vis

trans-22

N

N

N N H2 Internally Double-locked 21

NH2 Externally Locked 21 in 21⊃cis-22

Figure 7.25. Structures of internally double-locked 21 and externally locked 21 ⊃ cis−22, and the self-locking operation in response to photochemical isomerization of 22 [86]. (Reproduced by permission of the Royal Society of Chemistry.)

7.4. DYNAMIC STEREOCHEMISTRY MONITORED BY VCD VCD spectra have been applied to study transition-metal complexes since the pioneering work by Nafie and co-workers [8, 13, 87] VCD spectroscopy was applied to monitoring in situ the photoinduced rewind of supramolecular helices in a liquid crystal (Figure 7.26) [11]. A room-temperature liquid crystal, ZLI-1132, was doped with a chiral Cr(III) complex -[Cr(acac)2 (2C12)] (acac = acetylacetonate; 2C12 = 4, 4 -didodecyloxyated dibenzoylmethanate). The selective reflection wavelength λc = np (n is the average refractive index, p is the pitch length of an induced helix) of the nematic phase was determined to be 5.3 μm. At this wavelength, circularly polarized light reflects from or passes through the sample when it has the same or opposite sense of the induced helix, respectively. Under the illumination of UV light (365 nm), the photoracemization of the Cr(III) complex rewound helices in the chiral nematic phase. In response to this, the VCD spectrum of the system exhibited the transient change. Figure 7.26 shows the time course of the VCD spectrum recorded every 30 min. The peak at 1610 cm−1 increased intensity for the initial 1 h. The change reflected the elongation of the pitch maintaining the relation of λ/λc > 1. The peak underwent a drastic change at 1.5 h: the spectral shape transformed from a Gaussian to a biphasic one, which indicated the relation of λ/λc = 1 was fulfilled at this stage. After 2 h, the peak returned to a Gaussian shape with a negative sign, indicating the relation of λ/λc < 1. Reflecting the further elongation of the helical pitch, the position of a biphasic peak shifted toward the longer wavelength. When the VCD spectrum is regarded as a memory signal for the photoresponsive events in this liquid-crystalline system, it shows high signal-to-noise ratio (S/N) since it changes the sign as well as the intensity. The spectral change conveys the information of time memory because the position of the biphasic shaped peak shifts toward the longer wavelength on continuing irradiation. It

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C12H25O O O

O O

O

Cr

Cr O

O O C12H25O

6h 5.5h 5h 4.5h 4h 3.5h 3h 2.5h 2h 1.5h 1h 0.5h 0h

OC12H25

O O

O O

Δ Cr(acac)2(2C12) Λ

OC12H25

1800

1600

1400 1200 Wavenumber (cm–1)

1000

Figure 7.26. VCD spectra of a chiral nematic sample of ZLI-1132 doped with 0.538 mol% -[Cr(acac)2 (2C12)] at various times after UV light (365 nm) irradiation [11]. (Reproduced by permission of Taylor and Francis.)

shows extremely stable memory since the racemization process is accompanied by an increase of entropy, thus irreversible.

7.5. DYNAMIC STEREOCHEMISTRY MONITORED BY FDCD AND CPE Fluorescence-detected circular dichroism (FDCD) is a method that can measure the CD response by detection in emission if the chromophore is also fluorescent. This method was originally developed by Tinoco and co-workers [88, 89] and studied intensively more recently by Berova, Nakanishi, and co-workers [90–92]. While conventional CD measures the difference in a sample’s absorption of left- and right-circularly polarized light, FDCD measures the difference in fluorescence intensity upon excitation by leftand right-circularly polarized light. Since it is usually true that the excitation spectrum of a fluorophore parallels its absorption, the same circular dichroic information should be able to be extracted from both processes if the artifacts related to undesired fluorescence anisotropy are eliminated by more advanced instrumentation [92]. FDCD has been shown to be more sensitive than absorption CD [90, 93], analogous to the fact that fluorescence spectroscopy is more sensitive than the UV–vis absorption method because fluorescence suffers no background interference from the incident light. Raw FDCD data measured by a JASCO circular dichroism system equipped with FDCD attachment and with the fluorescence detector placed at 90◦ to the excitation beam (i.e., 90◦ to the CD detector) is recorded in two channels [90]. They represent excitation spectra and correspond to the difference in emission F (FL − FR ) and the total emission (FL + FR ) resulting from differential absorption of left- and right-circularly polarized light, respectively. Typically, the data are converted to CD spectra by established methods, which gives a normal CD spectrum if fluorescence polarization is negligible: The FDCD and normal CD of zinc complex of chiral tripodal ligand 23 match perfectly. An adaptation of the FDCD technique can provide a unique and powerful new strategy for sensor applications by using the F , that is, (FL − FR ), component of FDCD data directly, without conversion to CD. To distinguish this new approach from traditional FDCD and to avoid confusion, this method was named differential circularly polarized fluorescence excitation (CPE) [17], although no new instrument is required and all of the advantages and nature of FDCD still pertain. This is different from circularly polarized luminescence (CPL) because CPL is the differential spontaneous emission of left- and right-circularly polarized light and reflects the structural properties of the excited

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state, while CPE is still an indirect reflection of the structural properties of the ground electronic state. The theoretical basis of CPE can be derived from long-established Eq. (7.1) [90]. F =

θ · (FL + FR ) · ln 10 . 33 · 2 · (10A − 1) · k

(7.1)

If A = AL − AR ≤ 0.1 and A/A ≤ 0.1, total emission (FL + FR ) should be proportional to fluorescence induced by nonpolarized light, that is, FL + FR = k2 · F = k2 · F · I 0 · (1 − 10−A ),

(7.2)

Therefore Eq. (7.1) can be simplified as shown in Eq. (7.3), where K is a constant, which incorporates all other constants and F is the fluorescence quantum yield. F =

θ · F · I 0 θ · F · I 0 · k2 · ln 10 = K · . 33 · 2 · 10A · k 10A

(7.3)

Materials with higher ellipticity θ and higher fluorescence quantum yield F will lead to an even larger F . Substances lacking either fluorescence or CD properties will not be observed. Shown in Figure 7.27 are the CD and CPE (F) responses of a chiral piperidine compound (23) to Zn2+ [17]. Apparently, FDCD and CPE may be used to monitor the chirality switching in such metal complexes.

N

N

N

N H

H 23

20 15

0.4 μM incremental 0 μM Zn2+

5

5 ΔF (V)

θ (mdeg)

10

0 –5

–10

5

Zn2+ 5.2 μM Zn2+

Zn2+

0 μM Zn2+ 0.4 μM incremental 5.2 μM Zn2+

–15 200 220 240 260 280 300 320 340 λ (nm) (a)

–5

0 μM Zn2+ 0.4 μM incremental

10 15

Zn2+ 5.2 μM Zn2+ 20 200 220 240 260 280 300 320 340 λ (nm) (b)

Figure 7.27. Spectral responses of 4.8 μM (R,R)-23 to 0–5.2 μM Zn(II) in acetonitrile. (a) CD. (b) CPE (700V, 81 deg, filter: 360 nm) [17]. (Reproduced by permission of the American Chemical Society.)

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6 3+

Me

Ph

4

HN R

O

O N Me

N H

N

N

N

Ln

N

N

N

O NH Ph

(SSS)-Δ-[Ln·L25]3+

(IL − IR)

N

2 0 480

Ln = Eu, Gd, or Tb

−2

25a: R = H 25b: R = COOMe

−4

530

580

630

Me

Figure 7.28. (Left) CPL spectra for (SSS)--[Tb.L

Wavelength (nm)

25b 3+

] (solid curve) and in the presence of BSA (broken curve). (Right) Chiral lanthanide metal–ligand complex used to bind human or bovine serum albumin in ‘‘drug site II’’ [18]. (Reproduced by permission of the Royal Society of Chemistry.)

7.6. DYNAMIC STEREOCHEMISTRY MONITORED BY CPL Circularly polarized luminescence (CPL), the anisotropic emission of circularly polarized light originated from nonpolarized excitation, is the emission analogue to CD. The sign and magnitude of CPL are affected by the degree of helical twist of the complex, the nature of the ligand field, and other factors. In this context, excited Ln(III) ions can be considered as “spherical” emitters and avoid the problems associated with anisotropy that can complicate some chiroptical analyses [94]. CPL reflects the time-averaged local helicity around the lanthanide(III) ion. The Parker group has recently utilized the chiral environment of drug site II of serum albumin to induce helicity inversion in complexes of terbium and europium (III) [18]. It was found that chiral complex (S , S , S )--[Tb.L25 ]3+ changed helicity to (S , S , S )--[Tb.L25 ]3+ upon addition of human or bovine serum albumin. Convincing data was supplied by circularly polarized emission (Figure 7.28). When the -isomer is exposed to BSA or HSA, there is an inversion of the sign of emission and 35% reduction of the signal intensity. The authors explain that the emission spectra “are consistent with the inversion of the helicity of the complex in the protein-bound form” [95]. Parallel experiments were run using the -isomer, but no change in emission spectra was found. These results give one of the few immediately biologically relevant examples of a metal-based chiroptical molecular switch. The system could potentially allow protein association to be tracked in vitro in real time.

7.7. SOLID-STATE METAL-BASED CHIROPTICAL SWITCHES 7.7.1. Pressure-based switches Pressure also has been reported to induce chiroptical responses in chiral metal complexes. In solution, high pressure can provide a powerful solvent effect since dispersive interactions depend strongly on density changes. In the solid state, crystal packing plays an additional role. The effect of pressure on circular CD spectra of the octahedral chiral -, -, and (, )tris{O, O -bis[(+)(S )-2-methylbutyl]dithiophosphate}Cr(III)

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D Y N A M I C S T E R E O C H E M I S T RY A N D C H I R O P T I C A L S P E C T R O S C O P Y

300

(Δ,Δ) − Cr[(S)(S)Mebdtp]3

200

S

Me O P O Me

O

Me

P S

S

Me O

O P

Δ − (S,S)(S,S)(S,S)

S M

S S

S

S

M S

1.7

Me

P O Me O Me

S

S P

S

Me O O Me

Me O P O Me

Δ − (S,S)(S,S)(S,S)

CD/mdeg

Me O

100 0

1.2

−100 −200

0.2 GPa

−300 400

500

600 λ (nm)

700

800

CD spectra at different pressures of solid -tris{O, O -bis[(+)(S)-2 -methylbutyl]dithiophosphate}Cr(III) and proposed ,  conversion mechanism [96]. (Reproduced by permission of Taylor and Francis.)

Figure

7.29.

complexes was studied in the pressure range 0–2.5 GPa (Figure 7.29) [96]. Results on polycrystalline samples dispersed in nujol show a pressure-induced -to- inversion of configuration at the metal center above 1.2 GPa, which was suggested to arise from differential crystal packing in the solid-state structure of the diasteromeric complexes. The -form is confirmed to be the most favored crystal packing among different ligand conformations of the chiral complex under high pressure. When the applied pressure exceeded 2.5 GPa, the CD band obtained from polycrystalline Nujol samples of chiral  and -tris-[cyclic O,O , 1(R), 2(R)-dimethylethylene dithiophosphato]chromium (III) complexes inverted from negative to positive, which demonstrated inversion from the -form to the -form by means of pressure [97, 98]. To minimize artifacts, the spectra were obtained from average data from rotating the diamond anvil cell (DAC) around its optical axis, and the reference spectrum was normalized outside the absorption region of the sample. The cycle was reversible as demonstrated by applying repeating pressure cycles. However, the transition pressure varied and was dependent on the amount of -diastereomer present in the sample. Mechanistic explanation of the pressure induced chirality inversion could involve bond breaking or trigonal twisting around the metal center. It would be interesting to see if other solid-state data could be obtained to test the mechanistic hypothesis and exclude artifacts.

7.7.2. Temperature-Induced Dynamic Stereochemistry The compound α-Ni(H2 O)6 · O4 and its selenate derivative exhibit chirality only in the solid state. The Kuroda group observed a remarkable reversible sign inversion of CD in the 3 A2g → 3T1g (P) Ni(II) d –d transition at near liquid nitrogen temperatures, although the crystal structure hardly changes from 300 to 100 K (Figure 7.30) [99]. The change in Ni2+ electronic states at low temperatures might have altered the relative magnitude of the opposite sign first- and second-order rotational strengths.

7.7.3. Photo-induced Switching Switching of molecular chirality under photoirradiation was studied in a cobaloxime complex crystal using CD (Figure 7.31) [100]. The (S -alkyl)(S -base) crystal was irradiated using two different wavelength bands, one with 439–499 nm covering the LMCT transition and the other with 640–900 nm covering the triplet d –d transition of Co(III). After irradiation with either wavelength band, the solid was dissolved in methanol and the changes in its CD spectrum were recorded. Excitation of the d –d transition of the Co(III) ion appeared to be much more effective in inducing the chirality change than

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800 600

3

CD (mdeg)

296 k

A2g→3T1g(P)

3A →3T (F) 2g 1g

400 200 0 –200 300

83 k 400

500

600

700

Wavelength (nm) (a) 200

400 300

CD (mdeg)

CD (mdeg)

100

@384 cm

P41212 (0.062 cm)

200 100 0 –100

Cooling Heating

0 –100 –200

P41212 (0.06 cm)

–200

–300

–300 –400 0

–50

–100

–150

–200

–400

0

–50

–100

–150

Temperature(°C)

Temperature(°C)

(b)

(c)

–200

Figure 7.30. (a) Observed CD spectra of the same α-Ni(H2 O)6 · SO4 single crystal (P43 21 2, 0.062-mm thickness) at different temperatures. (b) CD signal at 384 nm plotted against temperature for the enantiomorphous α-Ni(H2 O)6 · SO4 single crystals. : P43 21 2 (0.62 mm thickness); : P41 21 2 (0.60 mm thickness). (c) Temperature dependence of the CD values of P41 21 2 crystal on cooling () and on heating (•) [99]. (Reproduced by permission of Elsevier.)

excitation of the ligand–metal charge transfer band, although the latter is more effective in breaking the Co–C bond that initiates the chirality switching. The chirality change versus irradiation time showed a step-like behavior suggesting that chirality switching of molecules occurred in correlation with their nearest neighbors. The same group made direct observation of a photoinduced chirality change or switching in the alkyl ligand of the cobaloxime complex in the hydrated and nonhydrated crystals of the cobaloxime complex by direct CD measurements in the solid phase in Nujol-mull and KBr pellets [101]. The CD spectra of the two crystal forms showed clear differences. Additional CD peaks in the spectra of the nonhydrated crystals seemed to arise from exciton splitting of the charge-transfer band. Photoirradiation induced chirality change or switching in the alkyl part of the molecule, but not in the crystal structure. The CD spectra well reflect such behavior.

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(R-Alkyl)(S-Base)

(S-Alkyl)(S-Base)

O

O

H3C

CH3 hν * H O H O O N N Co N N O H O

H * CH3 O H O O N N Co N N O O H

H3C

H3C * HH2 H

H3C * NH2 H

(a) 100

0

–10 200

(S/R-Alkyl)(S-Base) 300

(S-Alkyl)(S-Base)

400 500 Wavelength (nm) (b)

600

75

25

50

50

25

75

(R-AlkyI) (%)

0

(R-Alkyl)(S-Base) (S-AlkyI) (%)

CD (mdeg.)

10

700 0 0

5 10 15 20 25 Irradiation time (hours)

100 30

(c)

Figure 7.31. (a) Molecular structures of a pair of diastereomers of cobaloxime complex that can be converted to each other by photoisomerization. (b) CD spectra of (S-alkyl)(S-base), (R-alkyl)(Sbase), (S/R-alkyl)(S-base) cobaloxime complexes in 1-mM methanol solution. (c) Time variation of photoinduced chirality change in the cobaloxime complex crystals of (S-alkyl)(S-base), (R-alkyl)(Sbase), and (S/R-alkyl)(S-base) under constant irradiation of light with wavelength of 640–900 nm [100]. (Reproduced by permission of the American Institute of Physics.)

7.8. CONCLUSIONS The future of metal-based chiroptical switches is bright, given the high degree of control available, a multitude of triggering mechanisms, and powerful chiroptical spectroscopy tools available for analysis. With the large number of recently discovered systems, these compounds and materials derived from them could potentially be used for applications including optical displays, complex molecular electronics, chiral resolution, and catalysis. The Pfeiffer effect and metal ion templated synthesis provided early chemistry relevant to more recently developed metal-based chiroptical switches. Environmentresponsive switches have been developed using a large variety of metals and ligands triggered by pressure, counterion alteration, light, and solvent changes. Redox triggered switches have been explored primarily using a tripodal ligand motif. Diazobenzeneferrocene systems were designed to reliably switch the conformations of a set of “molecular scissors,” which were then used in an array of interesting and complex supramolecular machines. Polymer systems have been explored illustrated by the use of metal dopants to cause chiroptical changes in oligothiophene polymers. The studies in this area have

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provided much stimulating new chemistry and exemplify the power of modern molecular design and solution characterization techniques. There is no doubt that there are many more opportunities to develop even more imaginative systems. Many applications for these materials have been discussed, especially in the areas of electronics and sensors, and several of the available systems are poised to make a genuine contribution. Although early phenomena were studied by ORD, electronic circular dichroism experiments were used in nearly all experiments to analyze the conformational changes of the chiral compounds. Although other analytical techniques such as NMR are used to study these systems, it is readily apparent that CD experiments provide accurate and dependable read-out for chiral metal-based switches. The exciton chirality method has been particularly useful as a result of the fact that it gives a sizable and interpretable signal. Indeed, few other spectroscopic measurements give a direct report of three-dimensional shape as exciton chirality does for the orientation of chromophoric units. However, care should be taken in the assignment of CD data as arising from exciton coupling. Newer chiroptical spectroscopic methods are beginning to contribute to this field. The first reports of systems employing NIR-CD, which offers low-energy measurement, have appeared. FDCD can provide very sensitive detection if precautions are taken to avoid artifacts. FDCD or CPE may offer more specific information since it may arise from a subset of transitions compared to CD. VCD offers the possibility to probe vibrational phenomena as illustrated in studies of memory in liquid crystalline switches. All of these newer methods are ripe for further development in chiroptical switch detection strategies. It is also high time for computational methods coupled with chiroptical spectroscopy to play a greater role in not only characterization but also design of these systems. Most metal-based chiroptical switches reported to date were studied in solution, but many applications of chiroptical molecular switches involve the solid phase where chiroptical spectra are more difficult to interpret. Fortunately, the development of solid phase characterization tools and accompanying theory is progressing. In this regard, computation has resulted in renewed interest in ORD and other classic methods due to the possibility of making structural conclusions by matching experiment with theory.

ACKNOWLEDGMENTS We are grateful to the National Science Foundation (CHE-0848234) for generous support of our work in this area. ZD thanks Research Corporation for Science Advancement and the donors of the American Chemical Society Petroleum Research Fund for support of this work.

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8 CIRCULAR DICHROISM OF DYNAMIC SYSTEMS: SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY Angela Mammana, Gregory T. Carroll, and Ben L. Feringa

8.1. INTRODUCTION Chiral systems that undergo controlled dynamic processes including switching the conformation of molecules and the self-assembly of complex structures permeate molecular biology [1]. Studying these phenomena in model synthetic or semisynthetic systems holds great promise in gaining a better understanding of complex and highly organized biological systems. The creation, amplification, and control of chirality [2] is a fundamental issue in chemical biology [3]. Hence, exploring some of the basic pillars regarding dynamic chiral systems at the molecular and supramolecular level, particularly those that undergo conformational switching upon given particular stimuli, provides a strong groundwork by which to develop paradigms to guide forays into the hinterlands of biomolecular and materials sciences. Refining our knowledge regarding conformationally switching molecules and assemblies may provide guiding principles for gaining a deeper understanding of enzyme processes, molecular recognition and self-assembly, the mechanisms behind biological molecular machines [4, 5] and possibly clues regarding the speculative areas of the origins of homochirality and prebiotic structures [3]. Additionally, the study of switchable molecules and assemblies has the potential to provide knowledge innovation applicable to developing new molecular level technologies related to information storage, transport, and optics [6–8]. In this chapter we will explore molecular systems that undergo changes in chiral conformation and configuration upon thermal, chemical, photochemical, or mechanical stimuli. A preview of the kinds of systems we will examine is presented in Figure 8.1. CD spectroscopy is a method “par excellence” to study dynamic chiral systems at different hierarchical levels ranging from molecules to the supramolecular and macromolecular scale. Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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(a)

(b)

(c)

Figure 8.1. Dynamic chirality at the molecular and supramolecular level detected by CD spectroscopy. (a) A chiral molecule can direct achiral molecules to self-assemble into chiral supramolecular structures. (b) A chiral molecular switch or motor undergoes conformational changes that include inversion of molecular helicity. (c) Chiral molecules can self-assemble into chiral supramolecular structures, the chirality of which is determined by the enantiomer in excess. (See insert for color representation of the figure.)

Our survey will emphasize supramolecular systems [9–12]. Chemists have made considerable strides in the ability to create and control covalent bond formation in molecules with a high degree of efficiency, selectivity, and control of chirality, enabling the creation of numerous unique structures. Although the number of reactions that chemists have developed greatly exceeds that utilized by nature, the natural molecular world, constructed over billions of years of evolution, is vastly more complex than synthetic systems. Nature’s qualitative hegemony can be attributed to its mastery of supramolecular chemistry. Supramolecular structures rely on the formation of intermolecular bonds through a variety of interactions including electrostatic, dispersive, hydrophobic, hydrogen bonding, π -stacking, adsorption, or simply entrapment. A variety of molecular spaces that can host a guest molecule and form a supramolecular complex include cyclodextrins, zeolites, buckminsterfullerenes, DNA, micelles, various aggregates, and even transient solvent cages [13]. Our understanding of the intermolecular (noncovalent) bond is much less advanced in comparison with covalent bond formation. Biology has utilized molecular recognition and self-assembly to develop the most complex molecular systems known. As chemistry moves forward in the twenty-first century, a more precise understanding of intermolecular interactions will enable greater control over the properties of self-assembled materials. Supramolecular structures are comprised of two or more molecules forming weak bonds. The noncovalent nature of the interaction allows for greater flexibility of the molecular constituents in comparison with covalent structures; however, polyvalent interactions allow for the stabilization of supramolecular species through the cooperation of many weak interactions [14]. Akin to the advancement of traditional organic and inorganic chemistry, much research has been performed in order to gain an understanding of the dynamics, conformations, and

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stability of supramolecular structures. Among the various aspects of molecular chemistry that has a supramolecular analogue, chirality is of fundamental importance, particularly in regard to chemical biology. The same principles regarding chirality at the molecular level can be conceptually extended to the supramolecular level. A supramolecular system is chiral if the noncovalent units comprising the system are arranged in an asymmetric manner wherein its mirror image is nonsuperimposable, even if the constituents comprising the structure are achiral. A number of systems have been reported that demonstrate the formation and amplification of supramolecular chirality from achiral molecules. Two current principles regarding chirality at the supramolecular level include the sergeant-andsoldiers [15, 16] and majority-rules [17] effects. In brief, a sergeant-and-soldiers effect involves a small amount of chiral material that enforces a chiral structure on an assembly composed predominantly of achiral molecules which is dictated by the chirality of the sergeant. The majority-rules effect states that in a chiral but nonracemic assembly of two enantiomers, the one in the greatest amount will dictate the chirality of the system. CD spectroscopy provides an invaluable tool in elucidating the underlying themes of molecular and supramolecular chiroptical switching [18]. We will focus on some specific examples in which CD spectroscopy is used to interrogate molecules and assemblies that undergo reversible changes in chirality.

8.2. THERMAL SYSTEMS Modification of chirality through thermal processes is a well-known phenomenon, the most widely studied systems being biomacromolecules that lose their helical secondary structure upon melting [19, 20]. Similarly, synthetic systems show thermoresponsive supramolecular chirality. An organogel-based chiroptical system that reversibly assembles achiral porphyrin molecules into a chiral supramolecular assembly by a thermally controlled aggregation/deaggregation process was realized through the coassembly of glutamic diamide gelators, L1 or D1, and a tetra-alkyl-substituted porphyrin, TPPOC12 H25 (Figure 8.2) [21]. A very well-known property of many porphyrins is the ability to self-assemble under certain conditions, giving rise to two possible types of aggregates: edge-to-edge (J-aggregates) and face-to-face (H-aggregates). TPPOC12 H25 itself does not gelate; however, co-mixing with the gelator in DMSO followed by cooling the sample resulted in a supramolecular gel showing a positive exciton-type CD signal with a crossover at 443 nm and a positive Cotton effect with a maximum at 402 nm, in accordance with the Soret band absorption of J- and H-aggregates, respectively. Using a gelator of opposite chirality resulted in the reverse CD signal. The minimum ratio of gelator to porphyrin that displayed an ICD was 30:1 gelator:porphyrin. As more gelator was added, the signal was increased until a maximum was achieved at a ratio of 150:1. The induced chirality was attributed to assembling the porphyrin in a chiral environment. When porphyrins without long alkyl chains were used (i.e., TPPOH and TPPMe), an ICD could not be obtained, indicating that the cooperative assembly of the porphyrin is necessary for transmitting chirality. Furthermore, when TPPOC12 H25 and L1 were co-gelled in toluene, no ICD was obtained. The UV–vis spectra indicated that the porphyrin does not aggregate in toluene, whereas in DMSO both J- and H-aggregates were formed, indicating that aggregation of the porphyrin is essential for its chiral coassembly with the gelator. Upon melting the gel the CD signal was lost, but was regained upon cooling. The cycle could be repeated several times without a loss of signal.

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NH RO

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C18H37 O

O O

Mol. Ellip. (104)

HN

Gel

40 0

Solution

–40 –80 350

400

450 500 550 Wavelength (nm)

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Figure 8.2. A supramolecular chiroptical switch comprising achiral porphyrins (top left) that form gels upon co-assembly with a chiral gelator (bottom left). The chiral assembly can be switched on and off by adjusting the temperature as confirmed by CD spectroscopy. On the right, CD spectra of a mixture of achiral porphyrins (90 μM) and gelator (13 mM) in DMSO are shown. At high temperature the compounds do not gel and a CD signal is not obtained. Cooling the solution results in the formation of a chiral gel. The gel displays an exciton-type CD signal with a crossover at 443 nm and a positive Cotton effect at 402 nm, corresponding to the Soret band of J- and H-aggregates, respectively. (Reproduced by permission of The Royal Society of Chemistry [21].)

Temperature does not always show a simple relationship to the formation or disappearance of chiral structures. In order to understand the effect of temperature on the chiral amplification of dynamic supramolecular polymers, a simple and well-studied building block, trialkylbenzene-1,3,5-tricarboxamide, which assembles by triple-hydrogen bonding, was employed (Figure 8.3) [22]. Both sergeant-and-soldiers and majority-rules experiments were performed. A fast dynamic equilibrium exists between monomers and hydrogen-bonded stacks, allowing for modified self-assembled structures to form within one minute of mixing external components into the solution. Sergeant-and-soldiers experiments confirmed that (S )-TABTC could induce chirality in aggregates of achiral TABTC [23]. Similarly, the system was shown to follow the majority-rules principle. As the opposite (S )-TABTC enantiomer is mixed into the solution of the (R)-TABTC, the CD spectrum weakens. At 0% ee the CD disappears. As the ee is further increased to 40%, the intensity of the CD signal reaches a maximum. The authors studied the temperature dependence of the CD intensity at 223 nm as a function of fraction of sergeant (Figure 8.4a) and as a function of enantiomeric excess (Figure 8.4b). Similarly, the temperature dependence of the net helicity as a function of fraction of sergeant and enantiomeric excess was studied (Figures 8.4C and 8.4D). The phenomena were quantified by

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Figure 8.3. On the top left is presented the structure of a discotic molecule based on benzene1,3,5-tricarboxamide (TABTC). The R substituents can be achiral (TABTC) or chiral [(R)-TABTC or (S)-TABTC]. When R is chiral, self-assembly results in chiral supramolecular polymers. On the right a proposed right-handed supramolecular helix is presented (note that the side chains were replaced by methyl groups for clarity). (Reproduced by permission of the American Chemical Society [22].)

calculating the free energy penalties associated with helix reversal (HRP) in a stack and the introduction of a chiral monomer into a stack of its unpreferred helicity (mismatch penalty, MMP). For both sergeant-and-soldiers and majority-rules experiments, the HRP is associated with the disruption of three hydrogen bonds. In contrast, the MMP has a different physical meaning for the two types of experiments. In the sergeant-and-soldiers experiment, the MMP corresponds to the incorporation of a chiral sergeant into a stack of achiral molecules of its unpreferred helicity. In the majority-rules experiment the MMP is associated with the incorporation of one chiral enantiomer into the helix formed by the opposite enantiomer. The strength of the noncovalent interactions decreases with temperature; however, even at elevated temperatures long stacks composed of 100 monomers were predicted for this cooperative self-assembling system. The HRP was found to change very little with temperature; however, the MMP was found to decrease due to a slight increase of the intermolecular distance which reduces unfavorable steric interactions. The effect of temperature on the MMP value explains why the degree of chiral amplification is reduced for the sergeant-and-soldiers system while it is enhanced for the majority-rules system. A lower MMP reduces the authority of the sergeant in the former case. In the latter case a lower MMP makes it easier for the minor enantiomer to join the helix dictated by the major enantiomer. Consequently, for the sergeant-and-soldiers experiment, upon increasing temperature a higher fraction of sergeant is required in order to obtain a homochiral system. On the contrary, for the majority-rules experiment, a lower ee is required in order to obtain a homochiral system.

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Net helicity (–)

(c) Net helicity (–)

Fraction of sergeant (–)

0.8

0.20

Fraction of sergeant (–)

0.2 0.4 0.6 0.8 Enantiomeric excess (–)

1.0

0.6 0.4 0.2 0 0.0

10°C 20°C 40°C 50°C

0.2 0.4 0.6 0.8 Enantiomeric excess (–)

1.0

Figure 8.4. Effect of temperature on the CD signal on chiral supramolecular assemblies of benzene-1,3,5-tricarboxamide monomers containing either varying amounts of a chiral sergeant that induces chirality into the assembly of achiral soldiers or a mixture of two enantiomers at various ratios [22]. (a) CD intensity at 223 nm as a function of fraction of sergeant at 10◦ C, 20◦ C, 40◦ C, and 50◦ C. (b) CD intensity at 223 nm as a function of enantiomeric excess at 10◦ C, 20◦ C, 40◦ C, and 50◦ C. (c) Net helicity as a function of fraction of sergeant at 10, 20, 40 and 50◦ C. (d) Net helicity as a function of enantiomeric excess at 10◦ C, 20◦ C, 40◦ C, and 50◦ C. (Reproduced by permission of the American Chemical Society [22].)

8.3. PHOTOACTIVE SYSTEMS Systems that can be addressed by light offer many advantages over systems requiring thermal or chemical stimuli. Light provides a clean, traceless, and noninvasive reagent that leaves behind no byproducts. Second, photochemical reactions are localized to the chromophoric functionalities that absorb at the wavelength employed, allowing for highly specific transformations to occur within a molecule [24]. Finally, the use of light allows for spatially directed transformations of materials through the use of well-established photolithographic techniques [25]. Many photoactive overcrowded alkenes have been shown to contain helical structures that give rise to CD signals [26]. A particularly interesting class of overcrowded alkenes behave as molecular rotary motors [27]; that is, one-half of the molecule can undergo continuous 360◦ unidirectional rotation relative to the other half. Changes in the helicity of the motor during the stages of the rotary process make CD spectroscopy an invaluable tool in characterizing the rotary motion. The overcrowded alkene in Figure 8.5, (P , P )-trans1, contains two aromatic halves connected by a photoisomerizable double bond [28]. Each half also contains a stereogenic center in a pseudoaxial configuration, which is crucial for obtaining unidirectional rotation. The helical nature of the molecule is reflected in the sign

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+400 Meax

≥ 280 nm

Meeq

≥ 380 nm

+200

Meeq

(P, P)-trans-1

(M, M)-cis-2 20°C

60°C

Meeq ≥ 380 nm Meax Meeq

Δε (1mol–1 cm–1)

Meax

0

≥ 280 nm Meax –400

(M, M)-trans-1

(a) (b) (c) (d)

–200

(P, P)-cis-2

220

240 λ (nm)

260

280

Figure 8.5. Rotary cycle of a light-driven molecular motor. A combination of photochemical and thermal isomerizations results in a net 360◦ rotation. Each of the four isomers has a distinct P- or M-helicity and a unique CD signal [28]. The CD spectrum of the initial motor at the start of the cycle, (P, P)-trans-1, is shown on the right (a). Upon absorption of a photon, the motor undergoes trans–cis isomerization to form (M,M)-cis-2, which displays an inversion of the CD signal at 217 nm (b). Thermal isomerization generates (P, P)-cis-2, which shows an inversion of the CD signal at 217 nm (c) in comparison with (M, M)-cis-2. A second photochemical isomerization inverts the CD signal at 217 nm and forms (M, M)-trans-1 (d). The original CD spectrum (a) is restored upon thermal isomerization to generate the starting conformation, (P, P)-trans-1.

of the CD spectrum at 217 nm (Figure 8.5). Upon absorption of a photon, the molecular motor undergoes trans–cis isomerization to form (M , M )-cis-2. CD spectroscopy reveals that the resulting cis motor has inverted helicity relative to the trans. The photochemical isomerization is accompanied by a change of the stereogenic center to a pseudoequatorial orientation, which is more unstable than the original pseudoaxial orientation. The motor undergoes a thermodynamically favorable thermal isomerization and forms (P , P )-cis2, which restores the more stable pseudoaxial conformation and inverts the helicity as reflected in the CD spectrum. The large free energy change provided by the thermal isomerization results in an irreversible conformational change, preventing the motor from rotating in the opposite direction. A second photochemical isomerization followed by thermal isomerization regenerates the initial CD spectrum, indicating the initial stage of the rotary cycle. A key challenge in applying the motor to exert nanomechanical-like forces is to demonstrate the rotational motion of the motor while anchored to a macroscopic surface such as a solid substrate (Figure 8.6). Appending the motor to a solid macroscopic surface puts limitations on the characterization options compared to the traditional solution-phase measurements because both (a) a smaller quantity of molecules is present (typically approximately 1014 molecules per cm2 in monolayers [11]) and (b) the analytical methods are limited to techniques that are applicable to the solid state. Although the use of

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S

Rotor Axle Stator O

Legs

O O

O

n

Au Surface

S

n S

2 CD (mdeg)





0 –2 200

240

280 λ (nm)

320

Figure 8.6. Assembly of thiol-terminated light-driven rotary molecular motors on a semitransparent gold film provides a monolayer of chiroptical material that can be analyzed with CD spectroscopy. The CD signals invert between positive and negative bands, corresponding to changes in the helicity of the molecules comprising the monolayer upon the application of photons and thermal energy. The initial spectrum (solid black) inverts (dotted black) after irradiation with UV light (λmax = 365 nm) at room temperature. After heating the surface (70◦ C, 2 h) the spectrum inverts again to restore the original (solid gray). A second dosage of photons inverts the signal (dotted gray). Heating brings the rotors back to the original orientation relative to the substrate [30]. (See insert for color representation of the figure.)

CD spectroscopy to analyze monomolecular layers of organic molecules is rare [29], it provided an invaluable tool in characterizing the rotary motion of molecular motors attached to a semitransparent gold film [30]. In order to use CD spectroscopy, only a very thin layer of gold could be used in order to minimize the optical absorbance of the system. Therefore, 5 nm of gold was deposited onto both sides of an aminosilane-coated quartz substrate. Despite the low amount of material present in monolayer systems, the motor provides a strong enough CD signal to demonstrate rotary motion, as evidenced by the inversion of the CD spectra upon given photochemical and thermal stimuli (Figure 8.6). In addition to providing evidence that the motor can access the four stages of the rotary cycle, CD spectroscopy was used to uncover the proper length of spacer required to minimize quenching of the photochemical isomerization by the gold film. When spacers of eight atomic units were used, the CD signals did not change sign upon irradiation; however, when the motor contained spacers of 16 atoms, the gold-mounted chromophore was able to undergo photoinduced isomerization followed by thermal helix inversion. In addition to controlling the helicity of the chromophore, the overcrowded alkene can also exert intramolecular control over the helicity of a polymer. The stages of the rotary process have been shown to influence the twist sense of helical poly(hexyl isocyanate) (PHIC) when attached to the end-terminus of the macromolecule (Figure 8.7) [31]. Poly(isocyanates) (PIC) are stiff helical polymers that exist as a racemic mixture of P - and M -helices in the absence of an asymmetric influence [32, 33]. X-ray studies ˚ A similar on poly(n-butyl isocyanate) have revealed an 8/3 helix with a pitch of 5.14 A. helical structure is maintained in solution [32, 34, 35]. Chiral perturbations can favor the

SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

Figure 8.7. A single light-driven molecular motor attached to the end-terminus of poly(hexyl isocyanate) (PHIC) is used to control the twist sense of the polymer. The trans isomer of the motor end-group exerts no chiral induction, allowing an equal probability for the P and M helices to form. Photochemical isomerization to the cis form induces a preferred handedness to the polymer backbone. Thermal isomerization inverts the handedness. Restoring the motor to its original trans form brings the polymer solution back to a racemic mixture with no preferred twist sense. (Reprinted by permission of John Wiley & Sons, Inc. [31].)

presence of one helical twist over the other. For example, when a PIC contains chiral repeat units, the two diastereomeric helices, which have the same stereogenic configuration in the repeat units, can have a different energy, making one helix more favorable over the other. Many studies have shown that PICs containing chiral repeat units give rise to CD spectra that indicate that the backbone assumes a preferred helicity [36–38]. A rather striking example is the preference for one helicity from the subtle asymmetric presence of a deuterium in place of a hydrogen atom [33, 35]. The resulting PHIC is optically active and displays a CD spectrum with a band at approximately 250 nm in the region where the recurring amide groups of the backbone absorb. The preference for one helicity is attributed to cooperative effects among the repeat units which amplify a slight energetic preference for one helix. The use of a chiral solvent can also bias the P - or M -helicity [39]. The preparation of PHIC with the presence of a molecular motor at the end-terminus of the macromolecule provides an example in which the helical twist sense can be reversibly controlled [31]. A molecular motor containing a benzamide functionality in the lower half was used to initiate the polymerization of n-hexyl isocyanate from the benzamide’s sodium salt. The use of a molecular motor as the initiator results in a PHIC with a chiral environment at the α-chain end of the polymer that can influence the twist-sense of the macromolecule for certain stages of the rotary cycle in which the helical end-group can interact with the repeat units. In the trans conformation the upper naphthalene shows no detectable interaction with the polymer backbone, and so the helix has no bias (Figure 8.8). No detectable excess of P - or M -helicity is revealed by CD spectroscopy because the signal of the motor-PHIC polymerized from an enantiomerically pure motor matches the signal of the enantiomerically pure motor alone. Photoisomerization of the motor to the cis configuration results in an increase in the intensity of the CD signal and is attributed to an induced preference for one helicity of the polymer. The induced helicity can be attributed to the encroaching naphthalene rotor, which imposes a chiral environment on the nearest repeat unit and favors one helicity over the other. Cooperative interactions along the chain would then amplify the chirality, resulting in a preferred helical twist of the polymer. After thermal

297

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

step 1

step 2

polymer: R N PIM = 50:50 Bz

365 nm

stable (2'S)-(M)-trans-2-PHIC (R = PHIC) stable (2'S)-(M)-trans-3 (R = COCH3)

R polymer: N excess M helicity Bz

unstable (2'S)-(P)-cis-2-PHIC (R = PHIC) unstable (2'S)-(P)-cis-3 (R = COCH3)

R polymer: N excess P helicity Bz stable (2'S)-(M)-cis-2-PHIC (R = PHIC) stable (2'S)-(M)-cis-3 (R = COCH3)

(b)

(a)

(c)

4

4

2

2

2

0 –2 –4

θ (mdeg)

4 θ (mdeg)

θ (mdeg)

Δ

hn

0 –2

–4

–4 220

280 λ (nm)

340

0 –2

220

280 λ (nm)

340

220

280 λ (nm)

340

Motor-polymer Motor (control)

Figure 8.8. The helicity of motor-terminated poly (hexyl isocyanate) (PHIC) can be followed with CD spectroscopy (Et2 O, −20◦ C). The CD spectra of the motor without PHIC (R = COCH3 ) and the motor attached to PHIC (R = PHIC) are shown. (a) In the trans form of the motor the CD spectra of the motor and motor polymer are the same, reflecting the lack of preferred helicity in the polymer backbone. (b) Photochemical isomerization (UV lamp, λmax = 365 nm) to the cis form induces a preferred handedness to the polymer helix, which is reflected in an increase in the intensity of the CD signal relative to the motor alone. (c) Thermal isomerization (20◦ C, 30 min) inverts the CD spectrum, indicative of a helix inversion. Reprinted by permission of John Wiley & Sons, Inc. [31].

isomerization the CD spectrum of the motor-PHIC is inverted and more intense than the motor alone. The change in the CD implies that the upper-half rotor remains close enough to the polymer backbone to maintain influence over the helical twist; however, the rotor is now on the opposite side of the polymer and induces the reverse twist. Photochemical and thermal isomerization bring the motor back to the starting state in which the polymer has no preferred handedness. The changes in the helicity of both the motor and polymer can be followed with CD spectroscopy (Figure 8.8). Recent follow-up experiments show that these kinds of systems can be used to control the pitch of cholesteric liquid crystals [40] and form interesting toroidal morphologies when dried on a solid substrate [41]. Similarly, incorporating photoisomerizable molecules into the backbone of a poly(isocyanate) can reversibly switch the helical sense of the polymer. The azobenzene chromophore, which can be reversibly photochemically switched between cis and trans isomers (and thermally isomerized from the cis to trans form), has a large body of literature related to its use as a photoswitch [42, 43]. A PIC containing chiral azobenzene pendant groups in the repeat units, AzoPIC, was shown to induce a preferred helicity when the chromophore was in the trans conformation (Figure 8.9) [44]. Photoisomerization to the cis isomer resulted in a reversal of the CD spectrum as shown in Figure 8.9. The dashed curve represents the polymer after irradiation and displays the mirror image of the spectra of the polymer before irradiation, indicating that the direction of the helicity was reversed. It was found that in order to induce a preferred helical twist the chiral group must be linked to the same phenyl ring of the azobenzene

SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

Figure 8.9. A poly(isocyanate) (PIC) copolymer with repeat units that contain an azobenzene pendant group bearing a chiral chain displays a CD signal (THF, 0.5 mg/mL). Photoisomerization of the azobenzene unit reverses the sign of the CD signal. (Reproduced by permission of the American Chemical Society [44].)

as the isocyanate backbone. Variation of the location of the stereogenic center allowed the dominant direction of the helicity to be controlled. A variety of azobenzene PICs were synthesized, and their response to photoisomerization was found to depend on the stereogenic center [45]. The various systems synthesized showed different behavior in response to irradiation. Isomerization from the trans to the cis isomer in some polymers was shown to lead to an increase in the chiral interaction, detected by an increase in the CD spectrum, while in other polymers a decrease in the interaction was deduced based on an attenuation of the CD signal. Additionally, strong changes in the optical rotation were observed for some of the polymers during photoisomerization. Photoisomerization of azobenzene chromophores has been shown to affect the chirality of other helical systems as well. For example, a foldamer, a small oligomer that adopts a secondary structure, was designed by incorporating azobenzene into the core of an oligo(meta-phenylene ethynylene) derivative [46]. In the cis form of the azobenzene the foldamer can obtain a helical conformation showing a bisignate CD signal (Figure 8.10). Photoisomerization to the trans form denatures the helix because the coordinates of the foldamer components compromise the propensity to form a stable helical structure. An attenuation of the CD signal upon thermal isomerization from the trans to the cis form was attributed to depletion of the helical conformation through unfolding. Regeneration of the cis form by photo- or thermal isomerization restores the initial helical structure and is accompanied by the regrowth of the initial CD signal. Photoswitchable molecules have also been shown to modify the conformation of proteins in a reversible manner [47]. Such changes can be monitored by CD spectroscopy. For example, spiropyran modified poly(l-glutamate) (SPPGA) (Figure 8.11) has been shown to be effective in inducing such changes [48]. Spiropyran can exist as a neutral spiro form or as a zwitterionic merocyanine form [49]. The two states contain a considerably different geometry and polarity. SPPGA was shown to undergo conformational changes upon switching between the two forms. When the peptide-appended switch is in the merocyanine form (MEPGA), the polypeptide assumes a random coil conformation. Photoisomerization to SPPGA allows the polypeptide to undergo a transition to an α-helix. In hexafluoro-2-propanol, the spiro form thermally converts to the merocyanine form with a half-life of 2.5 h at 25◦ C, regenerating the disordered conformation. The

299

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CO2Tg

Tg

O

O

O

O

O

O

O

O

OMe

H 6

O N N

O

O

O

O

O

O

OMe

H 6

20

CO2Tg helix

θ (mdeg)

10 0 −10

hν, Δ



−20 250

325 λ (nm)

400

Random coil

Figure 8.10. A photoswitchable foldamer composed of an azobenzene core bearing two oligo(meta phenylene ethynylene) pendant groups. The cis form of the switch can be accessed by irradiation with UV light (λmax ∼ 365 nm). The CD spectrum of the cis form is shown (acetonitrile, 5.6 × 10−6 M) and has been attributed to the foldamer obtaining a helical structure. Thermal isomerization to the trans form disrupts the chiral structure and shows a decrease in the CD signal. (Reprinted by permission of John Wiley & Sons, Inc. [46].)

changes in the conformation of the polypeptide manifest as changes in the CD spectrum. The characteristic negative CD signal of an α-helix with minima at 208 and 222 nm is generated and increases during irradiation. Subsequently, the negative CD signal becomes smaller in magnitude as SPPGA converts to MEPGA in the dark. UV–vis and fluorescence measurements indicate that the merocyanine form of the switch dimerizes, which is the proposed driving force for the distortion of the structure. Dithienylethenes (DET) provide another example of an often exploited photoswitch (Figure 8.12) [50]. The dithienylethene unit can undergo reversible photochemical ringopening and closure reactions upon absorption of a photon of the appropriate wavelength. The two forms of the switch absorb at sufficiently different wavelengths to allow for a particular state to be selected through the use of conventional lamps emitting UV and visible light. The open form of the switch absorbs in the UV region of the electromagnetic spectrum, while the closed form of the switch absorbs in both the UV and visible region. DET-1o can be reversibly photochemically closed to form DET-1c, and reopened to form DET-1o without fatigue for at least five cycles, and possesses a thermal stability that prevents the ring-opening and closure reactions from occurring in the dark. In the open form the switch exists as a dynamic structure that rapidly interconverts between a P - and M -helicity. Photochemical ring closure locks the switch in equal amounts of the RR and SS enantiomers; however, the chirality can be controlled by photochemical switching in a chiral environment as will be discussed below.

301

SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

NO2

dark N H (CH2)2 O CO (CH2)2 N H

CH

O

NO2

N+ (CH2)2 O CO

hν COOH

(CH2) 2

(CH2)2

N H

C H

N H

CO

SPPGA

CH

N H

–O

COOH (CH2)2 C H

CO

MEPGA

–20

–210

230 λ (nm)

light

–10 dark

[Θ]·10–3

0

250

Figure 8.11. A spiropyran-modified PGA (poly(L-glutamate)), SPPGA, undergoes a ring opening reaction in the dark to the merocyanine form of the dye, MEPGA. Formation of MEPGA is accompanied by a distortion of the helical structure of the peptide (lower right) which is reflected in a change in the CD spectrum (lower left). Top curve (positive signal), solid line: MEPGA in hexafluoro-2-propanol before irradiation. Bottom curve (negative signal), solid line: SPPGA is generated after irradiation with sunlight. Intermediate spectra, dashed lines: thermal isomerization from SPPGA to MEPGA over a time period of 8 h. (Reproduced by permission of the American Chemical Society [47, 48].)

A dithienylethene photochromic unit functionalized with (R)-1-phenylethylaminederived amides (Figure 8.12) self-assembles into supramolecular structures through hydrogen-bond formation [51]. The stereogenic center causes the assembly to form a helical fiber. At room temperature, DET-1o forms a gel in organic solvents such as toluene, benzene, and hexane. Utilizing photochemical processes that control the molecular conformation of the switch and using thermal processes that control the macroscopic aggregation, it is possible to realize four supramolecular chiroptical states of the gel (Figure 8.13). The aggregated molecules form helical fibers and show a CD band at approximately 320 nm (Figure 8.14). Only the negative half of the exciton band is shown because the positive half is obscured by the solvent, which in this case is toluene. The CD signal of the aggregate is attributed to locking of a selected molecular helicity, M or P , of the open form of the switch when it is confined in the self-assembled structure. The enantiomeric (S )-1-phenylethylamine-derived DET-1o forms an aggregate that shows the opposite CD signal. The chirality of the stereocenters at the hydrogen-bonding components of the molecule determines the selection of the helical conformation of the

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

H N

S O

H H

S

O

DET-1o

Vis H N

S

UV

Vis

UV

H N

S

O

M – DET- 1o

P – DET- 1o

O (S,S) – DET- 1c

(R,R) – DET- 1c

DET-1c

Figure 8.12. A dynamically helical photoswitchable dithienylethene chromophore containing chiral amides can be photochemically switched between an open, DET-1o, and closed, DET-1c, form. The open form of the switch interconverts between two helical conformations. The helicity of the open form during photochemical ring-closure determines the stereochemistry of the two stereogenic centers on the photoswitchable unit of the molecule. The amides allow the molecule to self-assemble into chiroptical fibers [51].

Sol 1

Gel (α) 1

Gel (β) 1 Vis

Vis UV Gel (α) 2 (PSS)

UV

Δ

Sol 2 (PSS)

Gel (β) 2 (PSS)

Figure 8.13. Scheme of the aggregation and switching processes of a DET-1 gel (1–4 mM, toluene), which can access four chiroptical states. Upon cooling an isotropic solution of the open form of DET-1 (Sol 1), a stable Gel (α) 1, with a P-helicity, is obtained. It is possible to reversibly close and open the central ring of DET-1, cycling between the stable Gel (α) 1 and the metastable Gel (α) 2 (PSS) with high diastereoselectivity (96% DE) and P-helicity, by irradiating with UV light (313 nm) and visible light (> 420 nm), respectively. Note that during the photochemical step the helicity of the gel is preserved; however, the photochemical ring-opening or ring-closure changes the rigidity and chirality (fixed or dynamic) of the central unit and as a consequence the stability of the chiral aggregate. Heating of the metastable Gel (α) 2 (PSS) leads to an isotropic solution of 2 [sol 2 (PSS)], which, upon cooling, results in stable Gel (β) 2 (PSS) with M-helicity. The thermal processes (50◦ C required to fully melt gel) irreversibly convert the gel from a metastable to a stable aggregate with an inversion of helicity. Again, the photochemical step is reversible and occurs with retention of the supramolecular chirality on going from the stable Gel (β) 2 (PSS) to the metastable Gel (β) 1, and vice versa. Finally, heating of the metastable Gel (β) 1 gives the isotropic solution of DET-1 (sol 1) closing the cycle shown [51].

core, M or P , during aggregation. The CD signal disappears when the aggregate is melted by heating to 50◦ C (Figure 8.15) and reaches a maximum at temperatures below 0◦ C. The attenuation of the CD bands correlates with changes in the molar fraction of DET-1o existing as a free monomer compared to the amount aggregated as measured by NMR. When completely dissolved, DET-1o photochemically cyclizes with no diastereomeric

303

SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

–100

0

(mdeg)

(mdeg)

200

–200

0

–400

–100

–600

–200

300

350 400 Wavelength (nm) (a)

450

300

400 500 600 Wavelength (nm)

700

(b)

Figure 8.14. (a) CD spectra of stable gel DET-1o obtained by cooling a hot solution of DET-1o (1.8 mM) in toluene (solid line) and an unstable gel of DET-1o obtained by photochemically ringopening (λ > 420 nm) a stable gel of DET-1c (3.6 mM) (dotted line). The dashed line corresponds to DET-1o (0.35 mM) in solution and shows that when DET-1o is not aggregated, it does not produce a CD spectrum. (b) CD spectra of an unstable gel of DET-1c with 96% DE obtained by irradiating a stable gel of DET-1o (3.6 mM) (solid line), a stable gel of DET-1c with 96% DE obtained by heating (100◦ C) and cooling (0◦ C) the aforementioned unstable gel of DET-1c (dashed line) and a gel of DET-1c with no DE obtained by photochemical ring-closure (λ = 313 nm) of DET-1o and cooling (dash–dotted line) [51].

Figure 8.15. Temperature dependency (−15◦ C to 70◦ C) on the intensity of the CD band of DET1o at 320 nm. The extent of aggregation as probed by NMR and the %DE during photochemical cyclization of DET-1o to DET-1c decrease with increasing temperature in correlation with the attenuation of the CD signal [51].

excess (DE); however, in the gel form, DET-1o undergoes photochemical cyclization to DET-1c with 96% DE. The DE correlates with the intensity of the CD and the molar fraction of aggregated DET-1o. In the closed form the chirality of the methyl substituents at the photochromic core are locked. The aggregate of DET-1c can be photochemically ring-opened to regenerate the aggregate of DET-1o.

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Aggregation of a solution of DET-1c containing 0% DE forms a gel that gives a similar CD spectrum obtained upon photochemical ring closure of the aggregate of DET-1o. NMR reveals that the aggregate contains only one diastereomer of the closed switch. Interestingly, the diastereomer of DET-1c that gels is opposite to that formed upon stereoselective photocyclization of DET-1o in the aggregated state. Melting an aggregate of DET-1c formed by photochemical ring closure of an aggregate of DET1o, followed by cooling to regenerate the gel, results in an aggregate with the opposite helicity of that present after photochemical ring closure. The results suggest that in the open form, the chirality of the peripheral amide groups dictates the chirality of the selfassembled aggregate. However, in the closed form the chirality of the central photoactive part of the switch dictates the thermodynamically most stable helical conformation of the aggregate. Photochemical ring closure in the gel results in a metastable aggregate of DET-1c. Melting of the gel and re-cooling is necessary in order to access the more thermodynamically stable form of the supramolecular fiber. Similarly, when a stable aggregate of DET-1c is formed, photochemical ring opening forms a metastable aggregate of DET-1o. The CD signal of the metastable aggregate inverts upon successive heating and cooling. In addition to studies of switch DET-1, switch DET-2 (Figure 8.16), which differs from switch DET-1 by the presence of two methylene units between the outer phenyl rings and the stereogenic center, can also form chiral gels [52]. Interestingly, the gels formed by DET-2 have the opposite chirality of those formed by DET-1. The combination of fixed stereogenic centers in the hydrogen bonding units and a dynamic helicity that can be switched “on” and “off” allows for a four-state switching system in which molecular chirality and supramolecular chirality communicate. The self-assembling system described shows how the molecular and supramolecular chirality in a chemical system can influence each other. The self-assembling DET system described above was further shown to amplify chirality in aggregates of the isostructural, achiral switch DET-3o, shown in Figure 8.16 [52]. While both DET-1o and DET-2o can form chiral gels, DET-3o, which lacks a stereocenter, forms an achiral aggregate. Photochemical ring closure of the gel results in equal amounts of the RR and SS isomers. However, the chirality of DET-1o or DET-2o can induce DET-3o to aggregate in a chiral

H N O

H N n

H N

S

S

n

n

H N

S

O

O

H N

S

H N O

O

S

O

DET-1o n = 0 DET-2o n = 2

DET-3o (M)

DET-3o (P)

UV Vis

UV Vis

UV Vis

S

S

O O DET-1c n = 0 DET-2c n = 2

H N n

H N

S O

H N

S O

DET-3c (SS)

H N

S O

H N

S

H N

S O

DET-3c (RR)

Figure 8.16. Structure of photoresponsive organogelators for dynamic chiral selection and amplification. The compounds aggregate via hydrogen bond formation. Irradiation with UV (λmax = 313 nm) and visible (λ > 420 nm) light [52] produces photochemical ring-closure and ring-opening reactions. DET-3o lacks a stereocenter and forms achiral aggregates; however, in the presence of DET-1o or DET-2o, DET-3o aggregates in a chiral manner as shown in Figure 8.17 [52].

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SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

manner. When DET-3o is coassembled with DET-1o or DET-2o, a supramolecular chiral aggregate results, with the chirality transferring and propagating to achiral DET-3o. When DET-3o is coassembled with DET-1o or DET-2o, the resulting CD spectrum shows a more intense signal compared to DET-1o or DET-2o assembled alone (Figure 8.17), indicating that DET-3o coassembles with its chiral analogue and that the selected helicity of the chiral switch is imparted to the achiral switch. The chirality induced in DET-3o was locked by photochemical ring closure and shown to proceed with 94% ee of DET-3c. As the ratio of DET-3o increases, the intensity of the CD signal decreases and correlates with a decrease in ee. The transfer to and amplification of molecular chirality in DET3o by DET-1o or DET-2o is in line with previous sergeant-and-soldiers systems. The contrasting effects of DET-1o and DET-2o, which differ only in the presence or absence of two pairs of methylene units, show how subtle differences in molecular structure can influence both the resulting molecular and supramolecular properties of the system. The dithienyl systems described above utilize switches containing an inherent chirality. The resulting chiral supramolecular structures in turn influence the chirality of the molecules constituting the assembly. In order to initiate the chirality transfer, a stereogenic center needs to be present within the constituents. It is also possible to induce chirality in an achiral DET by using an external helical template. dsDNA provides a well-studied, chiral nanoscale building block that affords a high level of control over the structure [53, 54] and possesses charge-transport capabilities [55]. Its use as a scaffold for building new classes of organic materials merits attention [56]. Among the number of ways to functionalize dsDNA, electrostatic binding provides perhaps the simplest approach [57]. The construction of a DET switch bearing two primary amines provided a suitable candidate for binding studies (Figure 8.18) [58]. Molecular models show that the amines can access coordinates that closely match the locations of negative charge density on the DNA base pairs due to the phosphate groups. Similar to the DET switches described above, both DET-4o and DET-4c do not display CD spectra when dissolved in solution. However, addition of a poly(dGdC)2 2+3 150

CD (mdeg)

100

2

50 0 –50 –100

1 1+3

–150 300

320

340

360

380

400

Wavelength (nm)

Figure 8.17. CD spectra of chiral gels of DET-1o (1.3 mM, toluene) (solid line 1, negative band), DET-2o (1.2 mM, toluene) (solid line 2, positive band) and coassemblies of the achiral DET-3o (1 equiv.) with the respective chiral switch DET-1o (dotted line 1 + 3) or DET-2o (dotted line 2 + 3). In both cases the addition of DET-3o increases the CD intensity of gels containing DET-1o or DET-2o. (Reproduced by permission of the American Chemical Society [52].)

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UV O

S

Vis

HN

NH H2N

O

O

S

DET-4o

NH2

S

S

H2N

+

O HN

NH

NH2

DET-4c

DET-4o



+ –

dG

dC

Figure 8.18. A photoswitchable chiroptical DNA complex. At the top is shown the photoequilibrium between the open (DET-4o) and closed (DET- 4c) forms of a dithienylethene molecular switch that contains pendant ammonium groups to confer water solubility and allow the switches to bind electrostatically to the polyanionic backbone of DNA when the amine is protonated. Photochemical ring closure was accomplished through the use of a UV lamp (λmax = 365 nm) using a 340-nm cutoff filter. Photochemical ring opening was performed with visible light using a 520-nm cutoff filter. Molecular models (created using Hyperchem®) show that the distance between the terminal ammonium functionalities closely resembles the distance between the anionic phosphate groups of a guanosine (G)–cytosine (c) base pair [58]. (See insert for color representation of the figure.)

oligonucleotide to a solution containing DET-4o or DET-4c results in an ICD corresponding to the switch (Figure 8.19). The chirality of the DNA double helix is transmitted to the orientation of the switches comprising the supramolecular complex. Additionally, the CD signal corresponding to the DNA attenuates, indicating that both components modify the structure of the other. The intensity of the CD grows until the amount of switch is approximately 79% the amount of base-pairs. The results are similar to studies regarding the binding of simple mono- and divalent cations to DNA, of which the charge compensation was found to be no larger than 85% [59]. Similar results were found for both the open and closed form. The titration experiments were used to calculate the binding constants of DET-4o and DET-4c, both of which are 2 × 105 . The CD measurements were complemented by UV–vis absorption measurements. The spectra of DET-4o and DET-4c show a hypochromic effect and a red shift. The strength of the binding could be controlled by adjusting the pH of the solution. As the pH was increased, the CD signal decayed, consistent with the hypothesis that the switch binds via electrostatic interactions between the ammonium groups of the switch and the negatively charged phosphate groups exposed at the outer surface of the DNA double helix. When the pH increases above 9.12, the CD signal corresponding to the switch is completely removed. The switches were also shown to bind to poly(dAdT)2 . Interestingly, the interaction showed enhanced chiroptical activity. As found for the poly(dGdC)2 , when poly(dAdT)2 is added to a solution of DET-4o or DET-4c the UV–vis absorption spectra undergo hypochromic effects and the CD spectra show ICDs corresponding to the isomer of the

307

SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

– – – (a)

(c)

– – – – (b)

(d)

Figure 8.19. Changes in both the CD (a) and absorption (c) spectra of the dithienylethene (DET-4)–poly (dGdC)2 complex due to cyclically performing photochemical ring-opening and ring-closure reactions. All spectra were taken at room temperature in aqueous buffer at a pH of 6.5. Photochemical ring closure was accomplished through the use of a UV lamp (λmax = 365 nm) and a 340-nm cutoff filter. Photochemical ring opening was performed with visible light, using a visible light-emitting lamp equipped with a fiber optic and a 520-nm cutoff filter. The CD spectrum of the open DET- 4o- poly (dGdC)2 complex shows a clear ICD corresponding to the open form of the switch. Irradiation with visible light results in the attenuation of the band corresponding to the open DET- 4o and the growth of a signal in the visible region corresponding to the closed DET- 4c. Several cycles of photochemical switching can be performed as indicated by the reversible changes in the CD signal (b) at 350 nm and the UV–vis signals (d) at 331 nm (DET4o) and 560 nm (DET- 4c) [58].

switch. The optimum ICD was obtained at a ratio of 1:1.7 switch:base pairs compared to a ratio of 1:1.3 for the poly(dGdC)2 complex. The ICD spectra for the poly(dAdT)2 appear more intense, especially when the bisignate signals for the closed form of the switch are compared. Also, because the signal for the DNA is slightly blue-shifted, a clear bisignate signal for the open form is visible. A more complicated relationship between the ratio of switch to DNA was observed. The intensity of the ICDs did not simply increase and plateau as DNA was added. Furthermore, for some ratios, unique ICD signals could be obtained, indicating that intermolecular interactions between the bound switches seem to play a role. The higher charge density associated with poly(dAdT)2 may allow for multiple orientations of the switch, the most stable of which depends on interactions between the bound switches. Regardless of the sequence used, both DET-4o and DET4c retain their photochemical switching abilities when complexed to the DNA. The chiroptical response can be modulated with photons as shown by the reversible changes in the CD spectra, allowing for a multitude of unique chiral states to be generated (Figure 8.19).

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8.4. CHEMICAL AND MECHANICAL SYSTEMS A porphyrin system displaying a dynamic memory in which supramolecular chirality can be reversibly stored and released provides an elegant example of a switchable molecular assembly that responds to chemical stimuli (Figure 8.20) [60]. Achiral porphyrins have been shown to form chiral aggregates in the presence of chiral noncovalent amino acid polymers. The use of cationic and anionic porphyrins permits hetero-aggregation to occur via electrostatic interactions of the oppositely charged porphyrins. The strength of the interactions allows the assembly of achiral molecules to maintain supramolecular chirality after removal of the asymmetric template. By utilizing porphyrins containing





SO3

O3S



N

N

NHHN

N–H H–N

N

N

O3S



H2TPPS anionic porphyrin

SO3

N

N

NH

+4H+

N

–4H+

N HH N

+H N

N H+ TpyP4+

H2TpyP neutral porphyrin

route a

+

HN

N

+

–H+

+

N

N

H6 cationic porphyrin

+H+

monomers nonchiral aggregate

route b

chiral aggregate

+H+

cationic porphyrins anionic porphyrins neutral porphyrins

monomers

chiral seeds chiral aggregate

Figure 8.20. On the top are shown the structures of, respectively: the anionic meso-tetrakis (4-sulfonatophenyl) porphyrin (H2 TPPS), the neutral meso-tetrakis (4-pyridyl) porphyrin (H2 TpyP), and its protonated form, the cationic (H6 TpyP)4+ . On the bottom the system is described schematically. Cationic and anionic porphyrins form a chiral aggregate in the presence of one enantiomer of the chiral template phenyl alanine (either L or D). After removal of the template, the aggregate maintains chirality. The aggregate can be disassembled by deprotonation. Two routes of disassembly can be hypothesized. In route a, the aggregate fully disassembles, leaving only monomers in solution. Reprotonation would result in an achiral aggregate. In route b, the aggregate disassembles; however, the disassembly is not complete due to the slow rate of deprotonation and leaves small chiral aggregates in solution. Upon reprotonation, the small chiral aggregates can be thought of as chiral ‘‘seeds’’ that direct the regrowth of the template in a chiral manner. (Reproduced by permission of the American Chemical Society [60].)

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SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

ionizable groups in the meso positions, a system for which it is possible to imprint, store, release, and restore chirality was developed. The porphyrins employed contain four protonated pyridine groups in the meso positions. Deprotonation results in the loss of the cationic charge and consequent disassembly of the chiral aggregate. The CD signal of the aggregate disappears upon increasing the pH (Figure 8.21). The deprotonation step is kinetically slow, allowing for chiral seeds to remain in solution, provided that 24 hours have not elapsed. The chiral seeds are very efficient templates for their own selfpropagation. Reprotonation therefore leads to the regrowth of the supramolecular chiral assembly, which displays a CD signal matching the signal of the initial chiral aggregate. The two states can be cyclically addressed even in the absence of the chiral template. When a template containing the opposite chirality is employed, the CD spectrum shows the mirror image. The above concept was extended to anionic porphyrin J-aggregates templated from  or -[Ru(phen)3 ]2+ [61]. It is known that H2 TPPS4 is zwitterionic at a pH lower than 3 and in the presence of a millimolar concentration of salt. Under these conditions H2 TPPS4 self-assembles to give both H- and J-aggregates, displaying absorption maxima at 422 and 490 nm, respectively. The authors showed that J-aggregates formed in the presence of one enantiomer of the title ruthenium complex can maintain memory of the chirality imprinted at pH 6 and can be switched on and off by simply modulating the pH. The chiroptical

15 a1,2,3

10 L

5

b1,2

0

0

–40

–5 D –10 –15 350

450 λ (nm)

a 0.0 370 390 410 430 450 λ (nm) (b)

–80

a1,2,3

400

b

0.8

40 Δε

CD (mdeg)

80

Abs (a.u.)

1.6

500

550

(a)

Figure 8.21. (a) CD spectroscopy is used to detect the disappearance and reappearance of the chiral porphyrin aggregate. The sign of the CD signal is dependent on the chirality of the template that is used to initially imprint the chirality. CD spectra of the erasure and restoration of the chiral aggregate upon changing the pH are shown. Aggregates were made using either L- or D-phenyl alanine templates at a pH of 2.3 and show CD spectra that are mirror images. Increasing the pH to 9 results in the disappearance of the CD signal (curve a1 becomes b1 for either the L- or Reducing the pH back to 2.3 restores the signal (a2 ). The cycle can be continued to

D-aggregate).

give b2 (no signal) and a3 (restored signal). At least 10 cycles can be performed. (b) The absorption spectra of the aggregate at pH 2.3 (a) and at pH 9 in which the aggregate disassembles to predominantly monomer (b). (Reproduced by permission of the American Chemical Society [60].)

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response could be controlled by cycling the pH between 2.5 and 6 of a solution containing chiral J-aggregates of H4 TPPS4 templated from -[Ru(phen)3 ]2+ in the presence of an excess of the -enantiomer of the complex. Upon raising the pH to approximately 6, the ICD of the J-aggregate disappears. Decreasing the pH back to 2.5 restores the CD signal with the same sign of the exciton couplet as that of the starting J-aggregate. As in the previous example, the propensity to reproduce the chiral conformation of the original aggregate during regrowth despite the introduction of a template that possesses the opposite chirality of the original is due to the remarkable inertness of these chiral aggregates and consequently to the presence of chiral seeds that have a stronger driving force to reconstruct the memorized supramolecular architecture compared to the ability of the template of opposite chirality to direct the converse structure. A thin film based on the layer-by-layer (LBL) assembly of DNA and poly(allylamine hydrochloride) (PAH) was shown to induce chirality in tetrakis(N -methylpyridinium-4yl)porphine upon its addition to the preexisting film (Figure 8.22) [62]. The induced chirality was evident by the appearance of a bisignate CD signal in the Soret band region with positive and negative Cotton effects at 423 and 445 nm, respectively, and a crossover at 432 nm. The authors attribute the Cotton effects to intercalation into the DNA and electrostatic binding [63]. A negative Cotton effect at 268 nm was assigned to DNA. Differences between the DNA CD band in the film compared to solution were attributed to polymer-salt-induced aggregation during assembly with PAH. The induced

Θ (mdeg)

12

(a)

0

–12

NH3 and H2O

HCI

–24 HCI Absorbance

(b) 0.6 As-prepared film (ICD)

A (no ICD)

B (ICD)

0.3 TMPyP 0.0 200

300

400 500 Wavelength (nm)

600

Protonated TMPyP

700

Figure 8.22. A chiral switch based on a layer-by-layer assembled DNA/poly (allylamine hydrochloride) film containing tetrakis (N-methylpyridinium-4-yl) porphine (TMPyP) additives is shown. The interaction between the dye and DNA is characterized by the appearance of an induced CD (ICD) signal corresponding to the main absorption band (Soret band) of the porphine. On the right is schematically presented the initial film (As-prepared film) that shows an ICD signal; the film after exposure to HCl gas (a), which breaks the interaction between the DNA and dye (TMPyP) and consequently cancels the ICD signal; the film after exposure to ammonium followed by H2 O (B), which restores the interaction and the ICD signal. On the left are shown the CD (a) and UV–vis (b) spectra of the films exposed to the same conditions described in the scheme on the right: signal of the film as prepared (dashed line); after exposure to HCl gas (dotted line); after subsequent exposure to NH3 gas (dashed–dotted line); and finally after exposure to water vapor (solid line). (Reproduced by permission of the American Chemical Society [62].)

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chirality could be switched off by exposure to HCl, which can protonate both the DNA and dye [62]. The loss of the CD signal was attributed to deintercalation of the dye due to possible electrostatic repulsions and changes in the structure of the DNA. Loss of the ICD was accompanied by a change in the color of the film from yellow to green. Exposure to ammonium gas restores the yellow color of the film; however, the ICD was not recovered until the film was subsequently exposed to water. A pH-switchable DNA complex was designed that utilizes an achiral naphthalene derivative (P) bearing a diaminopurine hydrogen bonding unit that can bind to an oligothymine template (Figure 8.23) [64]. Upon mixing a ssDNA template with the diaminopurine, the UV–vis spectrum underwent a blue shift and hypochromic effect. The CD spectrum of the complex showed a positive Cotton effect in the region where naphthalene absorbs, with a zero-point crossing at 338 nm. The authors deduced that the naphthalene guests are arranged in a right-handed helix [65]. When the pH is decreased from 9 to 2, the Cotton effect reverses, suggesting that a left-handed helix is formed. The Cotton effect begins to reverse at pH 5. A pH titration revealed that the pKa of P is 4.8, which is in the range of the value at which the helix inversion occurs, suggesting that protonation of the purine induces a rearrangement in the complex that results in an inversion of the helicity. P

Tn

H H N

O N

H N H

HO

O

O

O

N

OH

O OPO O

N N O

O

O

O

O n-1H

OH

O N N H O O

N O

O N

H

75 pH = 9

CD (mdeg)

50 25 0 –25 pH = 2

–50 –75 200

250

300

350

400

450

500

λ (nm)

Figure 8.23. A naphthalene–diaminopurine derivative, P (top left), forms a dynamic, helical hydrogen bonding assembly with an oligothymine template, Tn (top right), where n is the number of residues. At higher pH values a right-handed helix forms. At lower pH values a left-handed helix forms. CD spectra (bottom) of the complex ([P] = 2[T]T40 = 0.5 mM) at 268 K at various pH values show that the handedness of the complex can be controlled by pH. As the pH is changed from 9 to 2, the sign of the CD bands invert. (Reprinted by permission of John Wiley & Sons, Inc. [64].)

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Amphiphilic thin films composed of achiral molecules have shown supramolecular chirality, possibly resulting from mechanical or other effects during film preparation (Figure 8.24) [66]. Regardless of the mechanism, the induced chirality can be controlled by chemical stimuli. 5-Octadecyloxy-2-(2-thiazolylazo)phenol (TARC18) amphiphile forms a chiral film at the air–water interface that gives rise to a CD signal (Figure 8.25). The origin of the chirality is thought to arise from a spontaneous overcrowded packing of the functional groups into a helical sense during compression of the film. Two different types of chiral films could be formed; however, no control over the selection of the type of chiral film could be achieved. FT-IR analysis indicated that the films differed in their orientation to the plane of the film as well as their trans/gauche conformation. Interestingly, the chirality of the film could be erased and restored upon exposure to HCl gas and air. Several cycles could be repeated before the film began to peel from the substrate. An explanation for the observed behavior is that exposure to HCl gas protonates the nitrogen of the thiazolyl group, changing the conjugation of the molecule that is accompanied by a change in the packing of the film to a state where the chirality is lost. Exposure to air restores the conjugation and allows the film to reform the original chiral arrangement. Although the initial direction of the chirality is selected at random, switching only occurs between the initial direction of chirality and an achiral structure. The opposite chirality is not obtained upon exposing the film to air after loss of chirality through exposure to HCl. Films composed of tetrakis(4-sulfonatophenyl)-porphine or an amphiphilic benzthiazolyl derivative also showed supramolecular chirality; however, these films could not restore the chiral structure after its removal with HCl [67, 68]. Interest in the relationship between macroscopic spinning motion and chirality can be traced back to Louis Pasteur’s attempts at controlling optical activity by performing chemical reactions in a centrifuge or growing plants while rotating in a given direction [2]. Although no induction or inversion of chirality could be detected, more recently the relationship between vortices or macroscopic rotation and the chirality of supramolecular assemblies has shown interesting results that may lead to new insights regarding the origins of homochirality in nature [69–72]. Several reports have dealt with this

Interface

Interface

Compression

M-Chiral

Compression

Achiral

P-Chiral

Figure 8.24. A supramolecular chiroptical switch composed of achiral amphiphiles. Space-filling structures of achiral amphiphile (TARC18), which forms a Langmuir–Schaefer film at the air–water interface, and chiral supramolecular structures formed upon interface compression. (Reprinted by permission of John Wiley & Sons, Inc. [66].) (See insert for color representation of the figure.)

313

SWITCHING MOLECULAR AND SUPRAMOLECULAR CHIRALITY

0.6 b

OC18H37

12 a

a N

c

N

6 CD (mdeg)

Absorbance

OH

0.4

N S

0.2

c

0 –6

b

–12 0.0

300

400 500 Wavelength (nm)

600

(a)

300

400

500

600

Wavelength (nm) (b)

Figure 8.25. (a) Absorption and (b) CD spectra of 70 layer films on quartz or CaF2 substrates. The same spectra are obtained regardless of substrate used; however, the resulting films show one of two possible structures, both of which are formed by chance: (a) film I and (b) film II. The chirality can be removed by exposure to HCl gas: (c) film II after exposure to HCl gas. (Reprinted by permission of John Wiley & Sons, Inc. [66].)

challenging topic and include both static and dynamic systems. In the static systems the spinning sense of a solution results in the formation of one enantiomeric form of an assembly. For example, rotoevaporation of a solution of aggregating porphyrins showed a supramolecular chirality that was dependent on the direction of rotation of the spinning flask [73]. Similarly, spin-coated films of porphyrin–dendrimer wedges displayed a chirality dependent on the spinning direction of the substrate, while films prepared without spinning showed no chiral selection [69]. In dynamic systems the chirality of the system changes upon removal or reversal of the spinning perturbation. Stirring of noncovalent Jaggregates of protonated meso-tetrakis(4-sulfonatophenyl) porphyrin (H2 TPPS4) shows both static and dynamic induced asymmetry (Figure 8.26) [71]. The authors hypothesized that J-aggregates are inherently chiral and exist as racemic mixtures and their distribution can be influenced by chiral vortices. CD spectra taken of solutions stirred in a clockwise (CW) direction showed that  aggregates were preferentially formed. Reversing the direction of spinning to counterclockwise (CCW) showed a CD signal that indicates that the  aggregates are transformed to  aggregates. When the solutions are stirred for 24 h, a static induced chirality is realized. It was shown that in a mixture of J-aggregate enantiomers, the predominant supramolecular enantiomer deposits on the wall of the cuvette after stirring for 24 h. The monomers and minor enantiomer remain in solution. Applying a macroscopic vortex to a solution of J-aggregates results in the adhesion of one enantiomeric J-aggregate. Spinning in the opposite direction results in the deposition of the opposite enantiomer. The results indicate that stirring affects the distribution of enantiomers present in an initially racemic solution. Clockwise (CW) stirring prefers  aggregates, whereas counterclockwise (CCW) stirring prefers  aggregates. The effect of stirring in the presence of a chiral stimulus that favors the enantiomer that is opposite to that favored by the vortex was tested by the addition of a chiral ruthenium complex, [Ru(phen)3 ]2+ (vide supra), with a small enantiomeric excess of the -enantiomer. Stirring in a CW direction resulted in the deposition of -aggregates, despite the opposing driving force to form -aggregates. However, upon increasing the concentration of

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1000

600



E

Λ

Δ

(A) No Stirring

CD

400 CD (mdeg)



CCW CW

200

λ (nm)

λ (nm) JΛ JΔ

0



E

–200

CD

800

(B)

E

JΛ (C)

–400 CW

–600

CCW

–800 –1000 460

470

480 490 λ (nm)

500

510

Figure 8.26. The meso-tetrakis(4-sulfonatophenyl)porphyrin (H2 TPPS4) (10 μM) in aqueous solution at pH = 3 and [NaCl] = 0.3 M forms J-aggregates. On the left are shown CD spectra of the J-aggregates recorded at different stirring conditions: without stirring (continuous line), clockwise (CW) stirring (dashed–dotted line), and counterclockwise (CCW) stirring (dotted line). On the right, energy diagrams for the three mentioned conditions are shown: (a) In the absence of stirring, neither enantiomer is favored; (b) CW stirring favors the -enantiomer as shown by the negative CD couplet shown in the small inset; (c) CCW stirring favors the -enantiomer as shown by the positive CD couplet shown in the small inset. (Reprinted by permission of John Wiley & Sons, Inc. [71].)

-[Ru(phen)3 ]2+ , the -aggregate was deposited when CW spinning was performed. The results show that the conformational fate of a supramolecular aggregate is dependent on a competition between macroscopic mechanical forces and molecular level chiral interactions.

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41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.

66. 67. 68. 69. 70. 71. 72. 73.

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9 ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS Cheng Yang and Yoshihisa Inoue

9.1. INTRODUCTION The last decade has witnessed rapid progress in supramolecular chirality research [1]. Chiral phenomena in supramolecular systems, such as chirality induction, chiral association, recognition, memory and amplification, which primarily originate or develop from molecular chirality, are often much more complicated and therefore more challenging than those at the molecular level. Besides the significantly larger number of incorporated building blocks (atoms and molecules), supramolecular chiral structures integrated by noncovalent interactions, such as electrostatic, hydrogen bonding, and van der Waals, π –π stacking interactions, are free from the strict geometrical restrictions of covalent bonds dominating the molecule chirality. Therefore, chiral supramolecular structures are usually more flexible, diverse, and adjustable in geometry, leading to novel chiral phenomena and architectures beyond the limitations of individual molecules. Furthermore, supramolecular chirality is not necessarily based on molecular chirality, but can also be generated upon aggregation of achiral molecules. Elucidating such unconventional higher-order chiral phenomena is crucial for understanding a wide variety of chiral architectures in the nature. Biomolecules by themselves are chiral supramolecular systems, and most of the physical and chemical events occurring in biosystems, including enzyme catalysis, molecular recognition, pharmacological action, and helix formation in DNA and proteins, are intrinsically chiral and supramolecular. Studies on supramolecular chirality provide insights into the biological superstructures and functions, and they may shed light on the origin of biomolecular homochirality. Supramolecular chirality is also important in chemical and materials science and technology, and it finds practical

Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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applications in asymmetric catalysis, chiral separation and sensing, data storage, optical devices, and liquid crystal displays. Electronic circular dichroism (ECD) is the most powerful and versatile tool among various spectroscopic techniques employed in the study of molecular and supramolecular chiral phenomena. ECD spectroscopy, relying on the differential absorption of rightand left-handed circularly polarized light, is indispensable in particular for the study of enantiomeric supramolecular systems and events that produce significant changes in chiroptical properties. Other spectroscopic methods, such as NMR, UV–vis, fluorescence, and IR spectroscopy, are achiral in nature and hence applied to the study of diastereomeric supramolecular systems. X-ray crystallography can directly provide the absolute structures of chiral molecules and molecular assemblies, but is applicable only to crystalline samples and not suitable for the observation of dynamic chiral behavior. In contrast, ECD is more widely applied not only to liquid samples but also to amorphous and crystalline samples and even to gaseous samples, and it can monitor the kinetic and dynamic chiral processes under a variety of conditions. Other chiroptical techniques that use circularly polarized light include optical rotatory dispersion (ORD) [2, 3], vibrational circular dichroism (VCD) [4], fluorescence-detected circular dichroism (FDCD) [5, 6], and circularly polarized luminescence (CPL) [7]. ECD is undoubtedly more widely applicable than these methods: ECD has obvious advantageous over ORD, especially for relatively weak transitions; VCD in the infrared region provides chiral information about the relevant covalent bonds but is less sensitive than ECD; FDCD and CPL are more sensitive than ECD but applicable only to fluorescent species. ECD plays an irreplaceable role in supramolecular chirality research as a highly sensitive tool for determining the chiral sense of the relative orientation of chromophores in a supramolecular system. Chiral chromophores are inherently CD-active and often exhibit significant changes in CD intensity upon aggregation or complexation with other molecules, enabling us to quantitatively investigate the kinetics, thermodynamics, and structural changes associated with such processes. Achiral chromophores incorporated in a chiral supramolecular environment may also show appreciable induced CD through extrachromophoric chiral perturbation upon noncovalent interactions with chiral entities in supramolecular system. ECD spectral studies can provide insights into the relative orientation of the relevant chromophore and chiral center and is therefore a highly efficient tool for analyzing complicated chiral supramolecular phenomena. The significance of ECD in supramolecular chirality research is underscored by the vast number of publications devoted to the application of ECD to supramolecular systems. In this chapter, we will review the ECD studies on chiral supramolecular systems mainly in solution phase, which are sorted by the chiral event or method in supramolecular system. Several important rules and interesting phenomena relevant to the ECD spectra of chiral supramolecular systems will also be introduced with examples.

9.2. CHIRALITY SENSING WITH ACHIRAL CHROMOPHORE Detecting the chiral sense of asymmetric molecule or molecular assembly with achiral chromophore through noncovalent interactions represents an important application of ECD in supramolecular chemistry [8, 9]. Achiral chromophore is CD-silent by itself but can function as a chirality sensor or reporter when situated in chiral environment. This strategy can be used for the determination of the absolute configuration of a chiral molecule or the enantiomeric excess (ee) of a chiral compound. The CD intensity induced

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to achiral chromophore is not very strong in general, but can be significantly amplified by introducing two chromophores to the chiral system to cause an exciton coupling interaction. Such amplification enables sensing of chiral molecules that are barely CDactive or limited in quantity. Possible overlap with the inherent CD signals at shorter wavelengths may also be avoided by choosing an appropriate chromophore that absorbs at longer wavelengths. An ideal chirality-sensing host should bear a strong binding site(s) highly selective to the target chiral molecule and intensely absorbing chromophore(s) near the binding site(s). Hydrogen-bond and coordination are the most frequently employed interactions in the design of a sensing host, primarily due to their strong binding and directing properties. Other weak interactions, such as π –π , hydrophobic, and electrostatic interactions, may play major or supplementary roles under certain conditions. The exciton chirality method, originally proposed by Harada and Nakanishi, is the most frequently used method for analyzing supramolecular chirality by ECD [10, 11]. Exciton-coupling interaction of two transition moments leads to a splitting of absorption band (Davydov splitting) in UV–vis and ECD spectra. The coupling of two transitions arranged in P (plus, right-handed)-helicity gives a “positive” couplet, displaying a positive Cotton effect peak at a longer wavelength and a negative one at a shorter wavelength, and vice versa for the M -helicity. The couplet amplitude produced, being a function of the distance and angle of the two coupling transitions, is usually very strong and enables chirality sensing of a very small amount of chiral sample.

9.2.1. Chirality Sensing Through Hydrogen-Bonding Interaction Molecular recognition of free-rotating achiral biphenyl-2,2 -diols 1a–c with chiral diamines 2a–c (Figure 9.1) through hydrogen-bonding interaction was investigated by using ECD [12, 13]. Complexation of stereolabile 1 with enantiopure 2 hinders the free rotation about the interaromatic bond in 1 to achieve the point-to-axial chirality transfer from 2 to 1. A negative CD couplet centered at 324 nm was induced to the major transition band of 1a, which is assignable to the 1 La band of phenol units, upon complexation with (1R, 2R)-2a in toluene at a 1a/2a ratio of 2, while antipodal (1S , 2S )-2a gave a mirror-imaged spectrum (Figure 9.2). The CD amplitude was a critical function of the binding strength and the steric interactions between 1 and 2, and therefore it was maximized for the most bulky diamine 2a in toluene. However, the use of polar solvents, such as acetone, acetonitrile, and ethanol, significantly reduced the CD signal due to the weakening of the hydrogen bonds. Interestingly, the nature of the interaction between 1 and 2 is altered from hydrogenbonding to electrostatic by lowering the temperature. The proton transfer from 1a to 2a was confirmed in toluene at −80◦ C by the appearance of a phenolate absorption band at

Figure 9.1. Chirality sensing of (1R, 2R)-diaminocyclohexane 2a–c with biphenyl derivatives 1a–c.

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Δε (M–1cm–1)

1.0 0.5 0.0 –0.5 –1.0 –1.5

(1R,2R)-2a 280

320

400 360 Wavelength (nm)

440

Figure 9.2. Circular dichroism spectra of the complexes of host 1a with guest (1R,2R)- and (1S,2S)2a in toluene at 25◦ C. [1a] = 6.83 × 10−5 M, [2a] = 1.37 × 10−4 M. (Reprinted with permission from reference 14. Copyright Royal Society of Chemistry.)

412 nm [14]. The phenolate band and the corresponding Cotton effect were observed only upon addition of an excess amount of 2a (1.2 equivalents or more). The stoichiometric study suggested that 1a and 2a form a 1:2 complex at low temperatures. The anisotropy factor for the 1:2 proton-transfer complex is one order of magnitude larger than that for the 1:1 hydrogen bonding complex, suggesting that the axial chirality is more effectively fixed in the 1:2 complex. Although a solution containing 1a and 2a in 1:1 ratio did not show any CD signal, addition of an equimolar amount of achiral diisopropylamine to this solution induced CD signals, intensity of which was half of that for a 1:2 complex of 1a with 2a. 1,8-Naphthyridine derivatives 3a,b (Figure 9.3), in which the naphthyridine moiety acts as a proton acceptor while the pyrrole or indole moiety as a proton donor, were prepared as sensors for detecting monosaccharides [15, 16]. Complexation of 3a,b with 4c–h in dichloromethane led to significant changes in UV–vis, CD and fluorescence

OH

HO O

O

HO HO

OC8H17 C8H17O

OH

OH OH

HO

4b

4a N

N 3a

NH

OH HO

OH

HN

O

HO HO

OH

4c

HO HO

O OC8H17

O-C8H17

4d

OH OH

NH

N 3b

HO

Me

O

O

N

OH

OC8H17

C8H17O

OH HO

4e

HN

HO HO

4f O

O OC8H17

OH

4g

OH

CH2OH

HO HO

OCH3 OH

4h

Figure 9.3. Chirality sensing of monosaccharides 4a–h with achiral naphthyridines 3a,b.

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spectra. The two pyrrole rings in 3 takes a dual inward conformation when bound to chair-form pyranoside. Complexation of 3b with octyl-β-d-glucopyranoside 4a induced a positive CD signal at 442 nm, a strong negative one at 344 nm, and a much weaker one at 317 nm, while antipodal octyl-β-l-glucopyranoside 4b gave the mirror-imaged CD. However, the conjugated chromophore in 3b, involving a naphthyridine and two indoles connected with ethynylene linkers, appears to hinder the unambiguous analysis of the observed CD signals due to the overlapped transitions. Nevertheless, these sensing hosts may be used as a tool for distinguishing the monosaccharide enantiomers.

9.2.2. Chirality Sensing through Coordination A large number of achiral porphyrin-based sensors have been developed, exploiting the strong coordination ability and the large extinction coefficients of the Soret band. Nakanishi and Berova employed achiral bis(zinc porphyrin)s linked with a flexible tether as chirality probes for enantiomeric diamines and aminoalcohols [17–24]. Figure 9.4 shows typical tweezer porphyrin 5, which binds a variety of chiral diamines and aminoalcohols, including 6a–n, to produce bisignate CD signals at the Soret band as a result of the exciton coupling interaction of the twisted porphyrin transitions. The sign of CD couplet is nicely correlated with the absolute configuration of guest 6a–h, except for l-lysinol 6f, which, however, gives a consistent result by acylating the hydroxyl to give 6g [17]. As shown in Figure 9.5, an extremely large amplitude of > 1000 cm−1 M−1 was observed upon complexation of 6l with 5, for which the 1:1 stoichiometry was confirmed by a Job plot [18]. The couplet intensity was related to the difference in size between the smallest and largest substituents at the stereogenic center. Recently, this methodology was theoretically investigated by computer simulation with the potential optimized for liquid simulation [22, 23]. These studies not only provide

Figure 9.4. Chiral diamines and aminoalcohols 6a–n examined by chirality sensor ZnZn-5.

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ACD = + 1078

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MCH

420 440 Wavelength (nm)

CD amplitude (mdeg)

(a)

(b)

12 8 4 0

0

0.2

0.4

0.6

0.8

1.0

Molar fraction of host 5

Figure 9.5. CD spectrum of tweezer complex of 6l (20 equiv.) with ZnZn-5 (1 μM) in methylcyclohexane; ACD denotes the amplitude of the CD exciton couplet. (b) Job plot of ACD as a function of the molar fraction of host 5; [5] + [6l] = 1 μM. (Reprinted with permission from reference 18. Copyright American Chemical Society.)

an important support for the tweezer approach but also offer crucial insights into the structural factors governing the complexation and the couplet amplitude. The computational method was found useful for predicting the absolute configuration of more complicated chiral compounds with multiple stereogenic centers, such as cis- and trans-3-hydroxyl4-aryl/alkyl-β-lactams 6m and 6n, indicating that the remote stereogenic center has only a secondary effect on the inter-porphyrin twist. Inoue, Borovkov, and co-workers [25–38] proposed the chirality sensing by achiral bis(metalloporphyrin) 7 (Figure 9.6), relying on the exciton chirality method. As illustrated in Figure 9.6, coordination of an enantiopure monodentate ligand (Figure 9.7) leads

Figure 9.6. Chirality sensing mechanism for bis(metalloporphyrin)s. (Reprinted with permission from reference 36. Copyright American Chemical Society.)

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Figure 9.7. Mono- and diamines 8 and 9 examined with chirality sensor ZnZn-7.

to the conformational switching of bis(zinc octaethylporphyrin) ZnZn-7 from stacked syn to twisted anti [39]. Due to the steric repulsion between the ligand’s substituents and the ethyl substituents on the adjacent porphyrin, the anti -form thus produced is not linear but twisted to afford strong bisignate CD signals (Figure 9.8) at the Soret band [25–27]. The sign of the couplet is uniquely correlated with the absolute configuration of chiral ligand—that is, positive couplets for monodentate (S )-ligands and negative ones for (R)-ligands. Solvent does not significantly affect the CD spectra of ZnZn-7 complexes with simple amines 8a–d. However, the CD spectral behavior of the complexes with amino acid esters 8e–g strongly depended on the solvent polarity, affording a negative couplet in nonpolar solvents, in good agreement with the results for 8a–d, but a positive couplet in polar media [34], for which the increased effective size of the ester moiety by solvation would be responsible (Figure 9.9). The ECD spectrum is significantly temperature-dependent in this chirality sensing system, showing a gradual increase of the couplet amplitude at lower temperatures, due to the increased affinity of chiral alcohol and amine ligands. Other factors, such as the central metal and the binding stoichiometry, are also crucial in determining the sign and intensity of the induced ECD [35, 40]. MgMg-7, rather than ZnZn-7, exhibits a higher affinity to chiral alcohols to display a strong CD couplet even at room temperature [41]. Bis-porphyrin ZnZn-7 forms a 1:1 tweezer complex with suitable bidentate ligands, such as trans-1,2-(1R, 2R)-diaminocyclohexane 9a, exhibiting a bisignate CD signal. The tweezer complex is transformed to a 1:2 host–ligand complex in the presence of an excess amount of the ligand. The CD amplitude (ε) of the tweezer complex amounts to 500 M−1 cm−1 as a result of the rigid and optimized geometry, while the corresponding

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20

0

Δε (cm–1 M–1)

10

ε (105cm–1 M–1)

–10

–20

2

0 300

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500 Wavelength (nm)

600

Figure 9.8. UV–vis and CD (inset) spectra of 7 in the absence (dotted lines) and presence of 8a (solid lines) and 8e (dashed lines) in CH2 Cl2 (black lines) and in cyclohexane. (Reprinted with permission from reference 34. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.).

1:2 complex still gives a huge, but significantly smaller, ε of 200 M−1 cm−1 , due to the more flexible and dynamic structure. Similar stoichiometry-dependent chiroptical behavior is seen upon chirality sensing by tweezer bis(Zn porphyrin)s 10a–c with longer linkers (Figure 9.10) [42, 43]. All of these tweezers show high affinities (>105 M−1 ) to trans-1,2-diaminocyclohexane (9a) upon 1:1 complexation to give strong bisignate CD signals. However, further addition of 9a led to a red shift of the Soret band and a dramatic decrease of CD intensity with sign inversion, indicating switching of the bis-porphyrin conformation from tweezer to open form upon 1:2 host–ligand complexation (Figure 9.11).

9.2.3. Chirality Sensing through Other Noncovalent and Covalent Interactions Supramolecular complexation through electrostatic, hydrophobic, and van der Waals interactions also induces ECD signals to achiral chromophores. Water-soluble achiral calix[n]arenes 11n (Figure 9.12) form host–guest complexes with chiral ammonium ions through electrostatic and cation–π interactions. Addition of (R)-12 to 114 produced a strong negative CD couplet (Figure 9.13) [44], which was interpreted by a twisted array of the benzene rings in 114 induced primarily by the largest naphthylethyl substituent in the chiral guest.

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Figure 9.9. Effects of strongly and weakly interacting solvents on the mechanism of supramolecular chirality induction in 7. (Reprinted with permission from reference 34. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.).

Figure 9.10. Chirality sensing with tweezer bis(Zn porphyrin)s 10a–c.

Boronic acids bind to organic 1,2- and 1,3-diols with high affinities through the reversible boronate formation. As shown in Figure 9.14, the diboronic acid-bearing 13 gives 1:1 adducts with several monosaccharides, including glucose, mannose, galactose, and talose, through the synergic formation of two boronate esters [45, 46]. Most of the

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(a)

(b)

Figure 9.11. UV–vis (top) and CD (bottom) spectral changes of (a) 10a and (b) 10b in the Soret region upon titration with (1R, 2R)-9a (0, 1, 2, 10, 50, 100 equivalent). (Reprinted with permission from reference 42. Copyright Royal Society of Chemistry.).

Figure 9.12. Achiral calixarene 11 for chirality sensing of 12.

d-saccharides, except for d-galactose, give a negative CD couplet upon esterification with 13, while the l-form afforded a positive couplet. Rosini and co-workers [47] used 4-biphenylboronic acid 14 for sensing chiral 1-arylethane-1,2-diols via boronate ester formation. The conformationally rigid fivemembered boronate ring can fix the two aromatic groups in a well-defined orientation to produce a strong CD couplet. Upon esterification with 13, all of the examined (R)and (S )-1-arylethane-1,2-diols consistently exhibited negative and positive couplet, respectively.

9.3. CHIRAL CONFORMATION OF MACROMOLECULE Macromolecules are usually conformationally diverse in solution, and ECD is a crucial tool for elucidating the static properties and dynamic processes of macromolecules, in particular those with helical conformation. Intense ECD signals are often observed for macromolecules composed of chiral subunits. Macromolecules made from achiral monomers may also take chiral conformations upon interaction with external chiral effectors. Even if the target macromolecule has no UV–vis absorption, CD spectral techniques may be applied by covalently or noncovalently attaching a chromophore. ECD spectroscopy is an important tool for analyzing the structures of biopolymers, such as DNA and proteins. Readers should consult (a) the sections in Chapter 4 of the present volume

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10000

[θ] (deg cm2dmol–1)

5000 114 – (S) –12 0

–5000 114 – (R) –12

Figure 9.13. Induced CD spectra of 114 in the presence of (R)- and (S)-12 in pH 7 phosphate

–10000

200

300 λ (nm)

400

buffer at 25◦ C. (Reprinted with permission from reference 44. Copyright Royal Society of Chemistry.)

Figure 9.14. Chirality sensing through boronate ester formation with chiral 1,2- and 1,3-diols.

2 and (b) relevant literatures for comprehensive information regarding the application of ECD to various biomolecules [48]. In this section, we will focus on the application of ECD to synthetic macromolecules, such as polymers and dendrimers.

9.3.1. Inherently Chiral Macromolecule Chiral polymer is obtained by polymerizing monomers with chiral substituent(s) or by inducing chirality in the main chain upon polymerization of achiral monomers under the influence of chiral initiator, additive, and so on. Copolymers of chiral and achiral monomers also show optical activities; and two intriguing phenomena, leading to the

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O N Δ

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N

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(S)

O

O C

N

N

C Y

X H H3C

C

H 3C (R)

H

(S)

15 X

Y

O

49

51

×

56

44

Figure 9.15. CD spectra of polyisocyanate with chiral side chain of different enantiomeric ratio: R:S = 100 : 0 (triangle), 0:100 (square), 49:51 (circle), and 56:44 (cross). (Reprinted with permission from reference 49. Copyright American Chemical Society.)

“majority rule” and the “soldiers and sergeants principle,” have been discovered upon ECD measurement of mixed chiral or chiral–achiral copolymers. The majority rule was first experimentally demonstrated by Green et al. [49] in their study on the polymerization of isocyanates with chiral substituent. The polyisocyanates thus obtained formed helices in solution, handedness of which was controlled by the ee of the chiral side chain. They found that the CD intensity of chiral copolymer 15 (Figure 9.15) obtained from a mixture of (R)- and (S )-monomers in varying ratios is not proportional to the ee of the used monomer, but behaves nonlinearly against the ee.

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Figure 9.16. Chiral copolymers 16 that obey the 16

majority rule.

Thus, the CD spectrum of 2% (S )-rich copolymer (i.e., R/S ratio = 49 : 51) was identical in sign and shape to that of homopolymer of (S )-monomer, but the CD intensity was unexpectedly strong, amounting to one-third of the homopolymer (Figure 9.15). It was interpreted that the energy barrier for helix reversal is much higher than the chiral bias caused by the pendant group [50], and therefore the helical sense will be controlled by the configuration of the majority pendant configuration. Thus, the CD spectrum of 12% (R)-rich copolymer (i.e., R/S ratio = 56 : 44) became exactly the same as that of (R)-homopolymer, indicating that the helix reversal was completely suppressed at that ee. The “soldiers and sergeants” principle is another interesting phenomenon related to the chirality induction in copolymer of chiral and achiral monomers. According to the principle, a minute amount of chiral monomer incorporated in copolymer with achiral monomer can dominate the overall helical sense of the copolymer. This phenomenon was first observed by Green and Reidy in their study of the specific rotation and CD intensity of copolymer 16 (Figure 9.16) obtained from the copolymerization of chiral and achiral monomers in various ratios [51, 52] Copolymer 16 containing 4% chiral component (x = 0, y = 4, and z = 96) showed a specific rotation comparable to that of 100% chiral homopolymer (x = 0, y = 100, z = 0), while by incorporating 1% chiral unit (x = 1, y = 0, z = 99) 16 achieved half the specific rotation of homopolymer (x = 100, y = 0, z = 0). Strong CD signal was observed even at a chiral unit content as low as 0.12% (x = 0.12, y = 0, z = 99.88), demonstrating that a minute amount of the chiral unit embedded in a long sequence of achiral N -hexylisocyanate units can appreciably bias the equilibrium between the right- and left-handed helices. The chiroptical properties of the copolymer did not change even if the chiral unit content was reduced to 15%. These observations indicate that a very small number of chiral inductor units, acting as the sergeants, can command a much large number of achiral soldier units in the copolymer to align in one direction. Dendrimers are repeatedly branched, monodisperse, and usually highly symmetric spherical macromolecules. Its highly branched 3D structure features high surface functionality and versatility. Dendrimers often show good conformational cooperativity and can convey local structural or chiral information to the next hierarchical level of structural organization. Dendrons 17–19 (Figure 9.17) are moderately soluble in water and highly soluble in organic solvents [53]. An intense negative couplet was observed for dendron 17 in both THF and water (Figure 9.17), indicating an M -helical conformation of anthranilate components in the dendron. The second-generation dendron 18 showed a negative couplet in THF but a positive one in water, indicating an M -to-P helix transition

329

330

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Me O O

O

O NH CO2R

O

OMe CI

O

(a)

N

O O

NH O

OR

Me

CI

O

OR

17 O

P

N HN

O O

O

HN

NH

O

O

RO

O

Me O

O

OR

Me

Me 18

OR

RO RO

OR

Me

O

OR

O HN O

O

O

1 0 –1 –2

240 260 280 300 320 340 360 380 400 λ (nm)

O

O O

O

2.4

RO

O

O

N H

H N

O

O NH N

O HN O RO

N

N HN

O

O O

Me

NH O Me RO

O

O

N HN

CI

θ/(105deg cm2 mol–1)

HN

O

17 THF 17 H2O 18 THF 18 H2O

O

NH N

19

18 UV (THF) π π*

2

HN

N

H N

HN N

O

Me

O

NH

O

Me

O O

Me

Me

O

M

(b)

O

O

RO

N

RO

OR O

NH N Me

H2O

O O O HN N O OH

HN

NH

O

O

O

N

RO THF

N O O N H HO O N

θ/(105deg cm2 mol–1)

R:/

OR

O

NH

UV (THF) 1.6

π

π*

19 THF 19H2O

0.8 0 –0.8 –1.6

O O

Me

230 250 270 290 310 330 350 370 390

OR

λ (nm)

Figure 9.17. (a) Direction of the electronic transition moment of the π –π ∗ transition at 316 nm and the sign of the corresponding CD couplet. (b) CD spectra of dendrons 17-19 in H2 O and THF, normalized for the concentration and the number of chiral terminal groups. (Reprinted with permission from reference 53. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.).

in water. Similar M -to-P transition was observed with the third-generation dendron 19 upon going from THF to water. In good agreement, the experimental IR spectral studies and the computational simulations indicate an increase of the gauche C–C and anti C–O bonds of the poly(oxyethylene) chains on going from organic to aqueous solution. The solvent-induced ECD change reflects the conformational fluctuations of the terminal chains that are coupled with the dendron’s helical secondary structure through correlated dendron-chain motions.

9.3.2. Chirality Induction in Achiral Polymer Polymerization of achiral monomer may give polymers with helical segments, handedness of which is, however, randomly populated in the polymer chain to give no ECD signal on

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

Figure 9.18. Condensation polymerization of 21 with 22 in chiral liquid crystal 20.

Figure 9.19. Chirality induction in achiral polymer 24 by chiral alcohols 25 and 26.

the whole. Polymerization with chiral catalysts or in chiral environment can give chiral polymer efficiently [54–56]. Akagi and co-workers [57] reported copolymerization in chiral liquid crystal 20 of achiral monomers 21 and 22 (Figure 9.18). The nematic phase of 20 is stable over a wide temperature range and remains stable upon addition of 21 and 22. Copolymers 23 obtained by condensation in (+)-20 and (−)-20 showed CD spectra with positive and negative exciton couplet, respectively. However, the couplet of copolymer 23 seems to originate from the chiral aggregation rather than the helical structure of the main chain (axial chirality) [57]. Achiral polymer can adopt a chiral conformation upon noncovalent interaction with chiral molecules. Fujiki and co-workers [58] reported the induced CD for achiral polysilylene 24 upon complexation with chiral alcohols 25 and 26 (Figure 9.19). Notable negative or positive CD couplet was induced when 24 was mixed with (S )- or (R)-25, for which the hydrogen-bonding interaction between the hydroxyl group in 25 or 26 and the ether oxygen in 24 is responsible. Interestingly, the majority rule does not work in this system, because a good linear correlation was observed between the ee of 24 and the induced CD intensity, which, however, offers a possibility to quantitatively determine the optical purity of chiral alcohols. Sada and co-workers [59] investigated the aggregation of chiral bis(dioxazolylpyridinyl)porphyrin 27 with achiral poly(trimethylene iminium) 28 (Figure 9.20). The formation of double-stranded structure, in which bidentate ligand 27 bridges two polymer chains of 28, was revealed by AFM and UV titration, while the ECD spectra provided the information about the 3D structure and the handedness of the supramolecular chirality. In the absence of polymer 28, 27 exhibited an apparent positive CD couplet in the Soret region, which was attributed to the dipole coupling between the porphyrin and terminal dioxazolylpyridine transitions. Upon addition of 28 to 27, the positive couplet was inverted in sign and decreased in intensity. Such an inversion was not caused by adding monomeric 29. This confirms the formation of helical double-stranded structure, in which the porphyrin rings are twisted in order to avoid the steric hindrance between the isopropyl groups in 27.

331

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

Helical aggregate of porphyrins

O N N

Hydrogen-bonding

H N NH

O

Achiral synthetic polymer

Hydrogen-bond pair

Double-stranded helix

Figure 9.20. Double-helical chiral aggregation of achiral polyamine 28 with bidentate chiral inductor 27. (Reprinted with permission from reference 59. Copyright 1998 American Chemical Society.)

30

31

Figure 9.21. Helical tubular structure formation of polythiophene 31 with schizophyllan 30.

ECD was used for detecting the assembling of water-soluble achiral polythiophene 31 with chiral polysaccharide, schizophyllan 30 (Figure 9.21) [60]. Upon addition of 30 to an aqueous solution of 31, both UV–vis and fluorescence peaks of polythiophene showed significant bathochromic shifts, reflecting the increased effective conjugation length of the polythiophene backbone. Formation of a tubular structure, in which polythiophene is included in the helical schizophyllan tube, was proposed based on the UV–vis titration and AFM measurement. An intense positive CD couplet observed in the polythiothene’s π –π * transition region indicates a right-handed twist of the backbone of 31 in the tubular structure.

333

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

9.3.3. Chiral Memory in Polymer Supramolecular chirality of conjugated polymers often exhibits unique dynamic features. Yashima and co-workers [61–78] investigated the chiral properties of a series of conjugated polymers (Figure 9.22). Achiral conjugated polymer 32, originally a mixture of at least four conformers of cis-transoid, cis-cisoid, trans-transoid , and trans-cisoid , forms a single dynamic helical structure upon complexation with chiral amines, showing a characteristic CD couplet (Figure 9.23) [62]. The amplitude of the couplet is augmented with increasing bulkiness of the chiral amine and also with decreasing distance between the chiral center and the amino group, indicating the importance of steric effect in the chirality transfer. One of the most intriguing phenomena associated with this conjugated polymer–chiral amine system is the memory of macromolecular chirality, which is preserved even after replacing the chiral amine attached to 32 with an achiral amine. As shown in Figure 9.23, addition of (R)-naphthaleneethylamine 35 to a solution of polymer 32 induces a negative CD couplet [64, 70]. Further addition of chiral amino alcohol (S )-36 to this solution leads to an inversion of the couplet sign from negative to positive. Surprisingly, the original negative couplet of [32·(R)-35] complex is not affected by the addition of achiral amine 37 and the subsequent removal of (R)-35 from the solution by gel permeation chromatography, and even upon further addition of (S )-36 [64]. The CD

Figure 9.22. Achiral conjugated polymers 32–34, which give helical conformation upon complexation with chiral amines.

334

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

(b) (32-(R)-35 complex) + (S)-36

3

[θ] (104 degree cm2 dmol–1)

2 1 0 –1

Figure 9.23. CD spectra in DMSO of (a) [32·(R)-35] complex, (b) a mixture of [32·(R)-35] complex with (S)-36, (c) a mixture of [32·(R)-35] complex with 37,

(d) Fractionated 32

–2

and (d) 32 isolated by GPC with a DMSO eluent containing 37 (0.8 M); [32] = 3.0 mg/mL (20.4 mmol in monomer unit/mL) for traces a–c and 0.13 mg/mL

(c) (32-(R)-35 complex) + 37 –3

(a) (32-(R)-35 complex) 310

350

400

450

Wavelength (nm)

500

550

for trace d. (Reprinted with permission from Macmillan Publishers Ltd. [64], copyright 1999.)

signal lasts for a long period of time to show only a 5% decrease in intensity after 3 months. The memory efficiency of the macromolecular helicity of 32 preserved by amino alcohols is a critical function of the number of methylene groups in amino alcohol but almost independent of its affinity to the carboxyl group. Similarly, intense CD was induced to achiral polymer 33 by keeping its solution containing chiral aminoalcohol at 50◦ C for 29 days. Once the helical polymer structure was induced, the helicity was memorized even after removal of the chiral amine and only about 10% decrease in CD intensity was observed after 29 days without any assistance of achiral amine [70, 78, 79]. Polymer 34 with bulky aza-18-crown-6 pendants forms a single helical structure upon complexation with chiral amines 39–41 (Figure 9.22), displaying a characteristic split-type CD at the absorption band of the backbone of 34.[76] Achiral cyanine dye 38 is entrapped in polymer 34 to form J aggregates, which afford CD signals when L-39 is coincluded. Interestingly, the supramolecular chirality of the J-aggregates was maintained even after the chirality of the polymer backbone was inverted by adding D-39.

9.3.4. Chiral Molecular Recognition with Polymer Inouye and co-workers [80] studied the CD spectral detection of saccharides with achiral water-soluble polymer 42 (Figure 9.24) in aqueous protic media. Meta-ethynylpyridine polymers 42 form helical structures in protic media through intramolecular solvophobic interactions. Hydroxyl groups of saccharide form a hydrogen bond to the pyridine nitrogens of 42 even in MeOH–H2 O mixture. In contrast to the weak CD signal induced upon complexation with d-glucose, 42 exhibits much stronger induced CD for octylβ-d-glucopyranoside. As shown in Figure 9.25a, the CD signal is inverted in sign by changing the solvent composition from MeOH/H2 O = 5 : 1 to 10:1, due to the varied ratio of d- and l-glucose in solutions of different composition. Furthermore, the CD spectra of 42 obtained immediately after the addition of d- and l-glucose are opposite in sign but gradually reduced in intensity to eventually converge to a common spectrum

335

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

OR

complexation N

I

N

N

N

N

N

N

N

NOH

N OH

N mutarotation of glucose

N

N

42a: R = (C2H4O)8CH3 42b: R = n-C4H9

complexation

N

N

n

42

N

N

N

N

N OH

N N N

OH

left-handed helical complex

right-handed helical complex

Figure 9.24. Chiral self-aggregation of achiral polymer induced by a saccharide. (Reprinted with permission from reference 80. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.) (See insert for color representation of the figure.)

3 MeOH / water

CD/(mdeg)

CD/(mdeg)

2

1

0

–1 300

8

5:1 6:1 7:1

8:1 9:1 10:1 310

320

330

340

350

360

6 β-glucose +7 +2.4 mdeg 4 (337 nm) 2

time 0h 1h 3h 8h 15 h 24, 48 h 15, 24, 48 h 8h

0

5h 3h α-glucose –2 –3 1h +2.4 mdeg 0h (337 nm) –4 300 310 320 330 340 350 360

λ (nm)

λ (nm)

(a)

(b)

Figure 9.25. (a) Induced CD spectra of a mixture of 42a (1 mM in monomer unit) and D-glucose (0.3 M) in 5:1–10:1 MeOH/H2 O at 25◦ C. (b) Time-dependent CD spectra of a mixture of 42a (1 mM in monomer unit) and α- or β-D-glucose (0.3 M) in 5:1 MeOH/H2 O at 25◦ C. (Reprinted with permission from reference 80. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.) (See insert for color representation of the figure.)

after standing the solution at 25◦ C for 24 h (Figure 9.25b). These phenomena were rationalized in terms of the anomerization of d-glucose between the α- and β-forms in the protic solvent.

9.4. SUPRAMOLECULAR COMPLEXATION WITH CHIRAL MOLECULAR HOST ECD is a powerful tool for studying the supramolecular complexation behavior of inherently chiral host molecules, because achiral chromophoric guests often become CD-active when bound to a chiral host. The CD signals thus induced provide crucial information about the spatial arrangement of the chromophoric guest(s) included. On the other hand, the guest inclusion may also cause a change in host conformation, which can be reflected in the CD spectrum. Hence, ECD spectral study enables us not only to qualitatively detect the supramolecular complexation and guest orientation but also to quantitatively determine the binding stoichiometry and affinity.

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

9.4.1. Binding with Cyclodextrin Cyclodextrins, a family of cyclic oligosaccharides typically composed of 6–8 glucose units linked by α-(1 → 4) glycosidic bonds, are water-soluble truncated cone-shaped macrocyclic hosts with a hydrophobic cavity that can include a wide range of organic guests through hydrophobic interactions. Cyclodextrin is inherently chiral, and the complexation of chromophoric guest in its cavity induces appreciable CD signals in the guest’s absorption region. By using the ECD response as a tool for detecting supramolecular interaction, Tokura and co-workers [81] investigated the complexation behavior of benzoylbenzoates with cyclodextrins in mid-1970. Mason [82] predicted that the anisotropy (g) factor induced to an achiral chromophore that is oriented randomly to a chiral molecule will be much smaller (10−5 –10−6 ) than the one in fixed orientation (10−2 –10−3 ). Harata and Uedaira [83, 84] attempted to calculate the sign of ECD induced to a chromophoric guest complexed with cyclodextrin by using Kirkwood’s [85] oscillator theory. Later, Kajtar et al. [86] proposed empirical “sector rule” to correlate the sign of induced CD signal with the orientation of transition moment of a chromophoric guest complexed with cyclodextrin. According to the sector rule (Figure 9.26), a positive CD signal is induced when the transition moment of a chromophore is located in the conical sector along the cavity axis, while a negative one to a more slanted transition located outside the cone. Kodaka and others further discussed the correlation of induced CD with the location and orientation of a chromophore complexed by various cyclodextrins [87–91]. Thus, the “Kodaka rule” says that when a chromophoric guest is accommodated inside the cavity, a transition parallel to the cavity axis induces positive CD and a perpendicular transition causes negative CD, but exactly the opposite is true for a chromophore located outside the cavity. These rules have been well-confirmed by the experimental results and therefore used as a standard tool for analyzing or interpreting the orientation of chromophoric guest in and around the cyclodextrin cavity [92–98]. For instance, methyl orange 43 with an azobenzene chromophore (Figure 9.27) exhibits a positive CD upon inclusion by β-cyclodextrin with its π –π * transition being aligned along the cavity axis, whereas the azobenzene moiety in compound 44, being laterally positioned above the cyclodextrin portal, affords a positive CD for the π –π * transition [99]. Brinker and co-worker [94]

Figure 9.26. Sector rule for predicting the sign of induced CD upon complexation in cyclodextrin cavity.

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

Figure 9.27. Methyl orange 43 azobenzene-bridged 43

cyclodextrin 44.

Δε (M–1cm–1)

44

λ (nm)

Figure 9.28. Induced CD and orientation of azi-adamantane 45 upon complexation with β- (top) and γ -cyclodextrin (bottom). (Reprinted with permission from reference 94. Copyright 1998 American Chemical Society.)

investigated the orientation of azi-adamantane 45 (Figure 9.28) included in the cavity of α-, β-, and γ -cyclodextrin by ECD. Complexation of 45 with β-cyclodextrin induced positive CD, while γ -cyclodextrin complex only afforded a much weaker negative CD (Figure 9.28). By taking into account the size and shape of 45, the azo chromophore is deduced to be located near the portal of β-cyclodextrin or inside the γ -cyclodextrin cavity, as illustrated in Figure 9.28, which induces the positive or negative CD, respectively, according to the sector rule applied to the π –π * transition which is perpendicular to the N=N bond. The weaker CD intensity observed with γ -cyclodextrin is ascribed to the higher guest mobility in the γ -cyclodextrin cavity. CD spectral titrations with 45 gave the association constants of 6150 and 2740 M−1 for β- and γ -cyclodextrin, respectively.

337

338

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

4

HO

θ/(mdeg)

2

O

OH O OH HO

O HO O OH

0

O OH O HO

HO

–4

O

–6

HO

O

46

OH O OH

–2

OH OOH

O O

OH O OH MeO OH OH O O

OH

O

200

220 240 260 280 Wavelength (nm)

HO

Figure 9.29. CD spectral changes of m-methoxybenzyl-β-cyclodextrin (0.1 mM) upon addition of cyclooctene.

θ/(mdeg)

By appending a chromophore, cyclodextrin becomes CD-active. In aqueous solution, the chromophore appended to cyclodextrin is often included in its own cavity, but can be driven out of the cavity by adding an appropriate guest as a competitor. The CD spectral changes thus induced can be used as a measure of guest inclusion. As illustrated in Figure 9.29, 6-O-m-methylbenzoyl-β-cyclodextrin shows a negative CD at the 1 Lb band and a weak positive CD at the 1 La band, indicating shallow penetration of the benzoate moiety into the cavity. Addition of cyclooctene leads to a gradual increase of CD intensity at both the 1 Lb and 1 La bands, suggesting the change of orientation of the methylbenzoyl moiety caused by the guest inclusion. A quantitative CD spectral titration gives the association constant of 11,120 M−1 [100, 101]. γ -Cyclodextrin, possessing a cavity larger than its lower homologues, can accommodate two planar aromatic guests, which are usually stacked in a chiral fashion to produce a split ECD. Inoue and co-workers [97, 102–110] investigated the 1:2 host–guest complexation of anthracenecarboxylic acid (AC) with γ -cyclodextrin derivatives, before examining the asymmetric photocyclodimerization of AC. The intimate stacking of ACs in the cavity caused significant changes in UV–vis, NMR, fluorescence, and CD spectra. As shown in Figure 9.30, the complexation of AC with monoaltro-γ -cyclodextrin 47 led

Wavelength (nm)

Figure 9.30. CD spectral change upon addition of AC (0–0.3 mM) to the solution of monoaltroγ -cyclodextrin 47 (2 mM) in pH 9.0 aqueous buffer.

339

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

to a strong positive couplet at the 1 Bb band, indicating the P -helical arrangement of two ACs in the cavity.

9.4.2. Binding with Biomolecule DNA forms three types of duplexes with different helical structures (i.e., A-, B-, and Z-DNA) through multiple hydrogen-bonding and stacking interactions of A–T and G–C ˚ width × 8-A ˚ depth nucleobase pairs. B-DNA has the major and minor grooves of ∼13-A ˚ ˚ and 4.5-A width × 6-A depth, respectively. The major groove comprises more nucleobase substituents and phosphodiesters, while the minor groove is walled by the hydrophobic part of sugar. A guest molecule may be bound to the major or minor groove or intercalate in between two base pairs. The CD intensity induced to a groove-bound chromophore is thought to be one or two orders of magnitude greater than that of an intercalated one [111]. Because of the existence of multiple binding sites, the complexation behavior with DNA is sometimes complicated and a critical function of the guest concentration and the ionic strength [112, 113]. For example, acridine orange intercalates to DNA to give negative CD at low concentrations, but much stronger positive CD at higher concentrations due to groove binding. Furthermore, the intercalating and groove-binding ligands couple to each other to give a split CD. The CD signal induced to a chromophore upon interaction with DNA crucially depends on the DNA structure. As shown in Figure 9.31, addition of sulfonated Ni porphyrin 48 to right-handed B-DNA of poly(dG-dC)2 induces no appreciable CD signal at the Soret band (∼400 nm) of 48 [114]. However, once the B-DNA is converted to left-handed Z-form by adding spermine, an intense negative couplet emerges at the Soret band, enabling selective sensing of Z-DNA. The electrostatic interaction of negatively charged 48 with the protonated spermine bound to Z-DNA is the main driving force for the ternary complexation of 48 with a Z-DNA–spermine complex, in which the exciton

20 15

– O3S

48 + Z-DNA 48 + B-DNA

SO3



N N Ni

10

N

CD/(mdeg)

N

5

– O3S

– SO3

48

0 –5 –10 –15

250

300

350

400

450

500

550

Wavelength (nm)

Figure 9.31. CD spectrum of NiTPPS 48 (4 μM) in the presence of poly(dGdC)2 (50 μM) in righthanded B-form (gray) and in left-handed Z-form induced by adding spermine (black). (Reprinted with permission from reference 114. Copyright 2009 American Chemical Society.)

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C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

(M)-49

(P)-49

Figure 9.32. (M)- and (P)-helicene 49.

coupling arises from the through-space interaction of bound porphyrins. The induced CD of a ternary DNA–spermine-48 complex disappears by raising the pH to 8.2, but is recovered by lowering the pH back to 6.9, suggesting that the induced CD can be modulated reversibly by pH. Enantioselective complexation with DNA is expected to occur for chiral species, and ECD is a powerful probe for investigating the chiral recognition upon complexation with DNA [115–117]. Sugiyama and co-workers studied the complexation behavior of (P )and (M )-helicene 49 with the B- and Z-form DNA of d(CGCm8 GCG)2 (Figure 9.32). The CD intensity of (P )-49 was reduced by 70% upon complexation with Z-DNA, but no appreciable change was induced by B-DNA. In contrast, antipodal (M )-49 did not show any chiral discrimination upon interaction with Z-DNA, for which the five-fold smaller affinity for (M )-49 would be responsible. Complexation with protein is a crucial issue in various biological phenomena, such as enzyme catalysis, antibody–antigen interaction, and drug delivery. Folding of polypeptide chain often produce crevices or cavities that function as binding sites for organic guest molecules. These binding sites are usually hydrophobic in nature and surrounded by a set of amino acid side chains that are arranged to optimize the noncovalent interactions with specific ligands. Commonly, more than one binding site will be created near the surface of a protein, and therefore the complexation of a guest with protein is elaborate in general. The binding affinity and stoichiometry of a guest in different binding sites rely on the size, shape, and functional group of the guest and the noncovalent interaction operating. In view of the intrinsically chiral nature of protein, ECD is one of the most crucial and widely employed tools for studying the interaction of organic guests with proteins. Inoue and co-workers [118–120] have studied the binding of AC to bovine (BSA) and human serum albumin (HSA) by means of ECD. As illustrated in Figure 9.33, complexation of AC with BSA induced well-structured CD at 330–400 nm. The intensity of positive CD induced was almost proportional to the AC concentration to reach a maximum at AC/BSA = 1 and then decreased gradually to eventually give negative CD upon further addition of AC. Detailed Job plot and titration experiments using CD, UV–vis, and fluorescence spectroscopy revealed the presence of four independent binding sites for AC in BSA, which respectively accommodate 1, 3, 2, and 3 AC molecules in the following order of affinity: K = 5.3 × 107 , 1.3 × 105 , 1.4 × 104 , and 3.0 × 103 M−1 . Similarly, a CD spectral titration with HSA showed four inflection points at AC/HSA = 1, 2, 5 and 10, indicating the presence of five binding sites that accommodate 1, 1, 3, 5, and >10 AC molecules in the order of decreasing affinity [120].

9.4.3. Binding with Synthetic Chiral Host Shinkai and co-workers [121–123] investigated the binding of achiral guests 50 and 51 by per-(S )-2-methylbutylated calixarenes of different ring sizes, 52[n] (Figure 9.34). In

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ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

AC/BSA 1

(a)

10

5

q (mdeg)

10

(c)

0

0

5 (b) 1

5

q391 (mdeg)

10

0

0 –5 –5 10 –10

–10 300

350

400

0

2

Wavelength (nm)

4

6

8

10

AC/BSA

Figure 9.33. CD spectral change upon addition of AC to a phosphate buffer solution (pH 7) of BSA (0.08 mM) at 25◦ C; (a) [AC] = 0–0.08 mM (from bottom to top); (b) [AC] = 0.08–0.8 mM (from top to bottom); (c) CD intensity at 391 nm as a function of AC/BSA ratio. (Reprinted with permission from [118]. Copyright 2003 American Chemical Society.)

50

51

52[n]

Figure 9.34. Chiral calixarenes 52[n] and achiral azobenzene guests 50 and 51.

the absence of guest, positive CD is observed for 52[4], but split CD for 52[6] and 52[8]. Addition of aliphatic alcohols did not appreciably change the CD spectrum of 52[4], but considerably reduced the CD intensities of 52[6] and 52[8]. 4-Cyano-4 -(diethylamino) azobenzene 51 showed a negative CD couplet upon complexation with 52[6]. However, a positive couplet was observed with 52[8], suggesting that the CD-active species are not monomeric but are instead aggregates of 51, which are arranged counterclockwise with 52[6] and clockwise with 52[8]. Synthetic chiral host 53 shows a dramatic CD change upon complexation with sulfate anion [124]. In the absence of sulfate, chiral guanidium host 53 exhibits a simple positive Cotton effect. Addition of sulfate leads to the formation of 2:1 complex (Figure 9.35),

342

C O M P R E H E N S I V E C H I R O P T I C A L S P E C T R O S C O P Y, V O L U M E 2

N N

N O N H O

N O

N H

OTBDPS

SO42– O

OTBDPS

N H O

N H O S

53 TBDPSO

O H N

O H N

O O

N

N

Figure 9.35. 1:2 Complexation of sulfonate anion with chiral guanidine host 53.

inducing a bisignate Cotton effect. Further addition of sulfate switches the complex stoichiometry from 2:1 to 1:1 with accompanying CD spectral change from bisignate to simple negative one.

9.5. CHIRAL MOLECULAR ASSEMBLY Chiral chromophoric compounds often form aggregates with accompanying CD spectral changes. Thus, CD spectral study provides not only the evidence for aggregation but also the structural information of the supramolecular assembly [125]. Achiral chromophore included in well-defined chiral aggregates, such as liquid crystal, may also display induced CD signals, from which the chiral supramolecular structure can be deduced [126–129].

9.5.1. Chiral Homo-aggregate Cyclodextrins modified with a long rigid chromophore of appropriate size are prone to thread together to give linear self-aggregates or supramolecular polymers, in which the chromophore group penetrates into the cavity of other cyclodextrin. Harada and coworkers [130] revealed that β-cyclodextrin 4-aminocinnamate 54 (Figure 9.36) forms a tail-to-tail dimeric aggregate in aqueous solution, while 4-(trinitroanilino)cinnamate 55, possessing a bulkier terminal group, forms head-to-tail aggregates to give a gel. The induced CD signals at 220–350 nm (Figure 9.37) are attributed to the inclusion of the chromophore in the β-cyclodextrin cavity. Interestingly, addition of urea (2 M), which is known to break the hydrogen bond, does not alter the CD spectrum, but the supramolecular polymer is disassembled by adding a better guest, adamantanecarboxylic acid, to give much weaker CD.

9.5.2. Chiral Hetero-aggregate The sergeants and soldiers principle and the majority rule originally found for conventional copolymers are also applied to supramolecular polymers [131–149]. Meijer and co-workers [145] studied the chiral supramolecular aggregation driven by hydrogenbonding and π –π stacking interactions. C3 -symmetric 56 (Figure 9.38), possessing nine identical chiral lipophilic chains at the periphery, forms a columnar structure through intermolecular hydrogen-bonding and stacking interactions. The anisotropy (g) factor of a solution of 56 is not proportional to the ee of 56 but obeys the majority rule (Figure 9.39). The free energy penalty for helix inversion is eight-fold larger than that

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OR

R:

54

55

Figure 9.36. Chromophore-appended β-cyclodextrins 54 and 55.

(a)

30

AdCA 25 20 (b) θ (mdeg)

15 Urea 10 5 0 –5 –10 250

300 λ (nm)

350

400

Figure 9.37. Circular dichroism spectra of 1 mM 55 (black line), in the presence of 2 M urea (gray line) and in the presence of an excess of adamantanecarboxylic acid (AdCA) (dashed line). The inset shows the gel-to-sol transition upon addition of (a) 40 mM AdCA and (b) 2 M urea to a 20 mM solution of 55. (Reprinted with permission from reference 130. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.)

for incorporating an antipodal monomer with keeping the original helicity, which is the origin of the majority-ruled behavior of this system. The self-assembling mechanism of structurally resembling chiral (R)-57 and achiral 58 (Figure 9.40) was also investigated by ECD spectroscopy [136, 147]. A positive CD couplet was observed for (R)-57 aggregates, indicating the formation of right-handed

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N

Figure 9.38. C3 -symmetrical disk-shaped dendrimer (R)- and (S)-56.

helical columnar structure. Temperature-dependence behavior of the CD intensity of (R)57 revealed two distinct regimes of nucleation and elongation [150]. Above the critical elongation temperature, (R)-57 exists in the nonhelical nucleation state and gives almost no CD, and the chiral aggregates start to elongate only below that temperature. A mixture of (R)-57 and 58 obeys the sergeants and soldiers principle, because all supramolecular columns are in the same handedness upon addition of only 4% (R)-57 to 58,

9.5.3. Chirality Memory in Supramolecular Assembly Chiral supramolecular assembly originally constructed from chiral subunits may preserve its chiral character even after the chiral component is removed or replaced by an achiral substitute, provided that the kinetic and dynamic requirements are met. Reinhoudt and co-workers [151, 152] discovered an interesting chirality memory phenomenon in the hydrogen-bonded aggregation of calix[4]arene dimelamines 59 (Figure 9.41) with chiral cyanurates. Calix[4]arene dimelamine 59 and (R)-barbiturate ((R)-BAR) forms M -helical complex (M )-[593 ·(R)-BAR6 ] in benzene through multiple hydrogen-bonding interactions, while the assembly of 59 with (S )-BAR affords antipodal (P )-[593 ·(S )BAR6 ]. The chiral barbiturate components of (M )-[593 ·(R)-BAR6 ] can be substituted for achiral cyanurates. Thus, addition of achiral butylcyanurate (BuCYA) to a solution of (M )-[593 ·(R)-BAR6 ] leads to the displacement of (R)-BAR by BuCYA with only accompanying a slight CD change, indicating preservation of the helical structure and sense. The rate-determining step of the racemization involves the dissociation of 59 from an intact assembly, followed by a quick disk-rotation and reassembling to the antipodal assembly.

ELECTRONIC CIRCULAR DICHROISM OF SUPRAMOLECULAR SYSTEMS

345

100 80

Δε (L/mol.cm)

60 40 20 0 –20 –40 –60 –80 –100 200

250

300

350

400

450

500

λ (nm) (a)

0.002

g

0.001

0.000

–0.001

Figure 9.39. (a) CD spectra of octane solutions of dendrimer (S)-56 (open circles) and (R)-56 (closed circles); c = 2.49 × 10−5 M. (b) Anisotropy (g) factor as a function of the enantiomeric excess of

–0.002 –100

–50

0

50

100

Enantiomeric excess [%] (b)

56 at 20◦ C (closed circles) and 50◦ C (open circles). (Reprinted with permission from reference 145. Copyright 2005 American Chemical Society.).

9.6. SPONTANEOUS SYMMETRY BREAKING IN SUPRAMOLECULAR SYSTEM Controlling microscopic chiral event through macroscopic operation provides an important and intriguing tool for readily manipulating molecular and supramolecular chirality. Several recent studies based on ECD spectral analysis have drawn much attention to this possibility. Sodium chlorate crystallizes in l- and d-chiral forms in statistically equal numbers when crystallized from an aqueous solution without stirring. Interestingly, the crystals formed from a stirred solution are exclusively l- or d-chiral, although the handedness is not controlled [153]. It is believed that the autocatalytic secondary nucleation—that is, the formation of new crystal nuclei in the vicinity of an existing parent crystal—is responsible for this chiral symmetry-breaking processes. Chiral

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R HN

O

O

H N R

NH O

R

57: R =

Figure 9.40. Self-assembling chiral 58: R =

benzenetricarbamides (R)-57 and achiral 58.

N HN R

2

NH2

H2N

N

N

N NH

1

R

N NH

N

HN

R

R

2

1

(R)-BAR O

BuCYA

O O O

59: R1 = NO2; R2 = (CH2)3CH3 O HN O

X: NH

X

N

C CH3

O BuCYA (R)-BAR (S)-BAR

Figure 9.41. Chirality memory in a hydrogen-bonded assembly.

autocatalysis was also observed with the random generation of large ee in the crystallization of 1,1 -binaphthyl melt [154]. Ribo and co-workers [155, 156] investigated the spontaneous chiral symmetry breaking in the vortex motion-induced chiral J-aggregation of 5,10,15-tris(4-sulfonatophenyl)20-phenylporphyrin 60 during rotary evaporation, with accompanying strong exciton coupling ECD signals at the Soret band. Thus, the clockwise/counterclockwise rotation affords negative/positive CD couplet, respectively, at high 85% probabilities, while unstirred aggregation leads to no chirality dominance. It was concluded that the motion of oligomeric blocks formed during the aggregation of 60 is diastereotopic, when a particular vortex direction is externally prescribed, and such a preferential asymmetric accretion is imprinted into the aggregated material as the newly arriving blocks weld at definite arrangements.

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Me O

Me O

Me

Me O

Me O

Me O

Me O

O Me

O

O

O

Me

O

O

Me O

O

H O

O

O O

N

O

Zn N

Me O

O

O Me

O N

O Me

O

O

O

O O

O H

O O Me

O

O Me

O Me O

O

O Me

O

O

O

O

O Me

O Me

O

O

N

O

Me O

O Me

O

Me O

O

Me O O

O Me O O

Me O

O Me

O Me

O Me

O O

Me

O Me O Me

O Me

61

200 CCW

CD (mdeg)

100 0 OFF –100 CW –200 350

400

450

500 λ (nm)

550

600

650

Figure 9.42. CD spectra emerged upon rotary stirring in clockwise (CW) and counterclockwise (CCW) directions and without stirring (OFF). (Reprinted with permission from reference 157. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.)

Aida and co-workers [157] reported the induction of negative/positive CD couplet at the Soret band upon clockwise/counterclockwise rotary stirring of a solution containing dendric zinc porphyrin 61 (Figure 9.42). This stirring-induced exciton coupling was attributed to the macroscopic chiral alignment of the nanofibers formed by J-aggregation of 60 upon rotary stirring.

9.7. SUMMARY Supramolecular chirality is a highly intriguing, rapidly growing area of chemistry and biology. Investigations of supramolecular chirality not only provide valuable insights into the chiral phenomena occurring in natural and artificial supramolecular systems, but also

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offer guiding principles for designing advanced supramolecular materials and for better understanding and mimicking the biological and pharmacological processes. This is also a challenging interdisciplinary subject that requires theoretical and experimental knowledge and techniques in quantum chemistry, synthetic chemistry, stereochemistry, supramolecular chemistry, and analytical chemistry. ECD spectroscopy is a powerful indispensable analytical tool for investigating chiral supramolecular phenomena, owing to the development of theoretical and instrumental CD spectral tools applicable to supramolecular systems. Nakanishi and Harada’s exciton chirality theory is the most widely applied approach that allows the determination of chiral spatial arrangement of chromophores as well as the design and construction of chiral supramolecular architectures. Other principles, such as the sector rule for cyclodextrin complexation, are also crucial for elucidating the detailed supramolecular orientation and conformation in certain systems. ECD is applicable to most of the chiral supramolecular phenomena, including the complexation of chiral/achiral hosts with achiral/chiral guests and the aggregation of molecules with chiral elements. Chromophores with high extinction coefficients are normally favored in ECD measurement, and chiral/achiral chromophores are commonly introduced to such supramolecular systems that lack absorption at appropriate wavelengths. Quantitative interpretation and prediction of supramolecular ECD are still a significant challenge at the moment. There are reasons to believe that broader implementation in the near future of the fast advancing quantum mechanical methodologies for predicting the chiroptical properties will bring considerable success to the field.

ACKNOWLEDGMENTS The authors are grateful to the supports of this work by PRESTO, JST (CY) and JSPS (YI).

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10 THE ONLINE STEREOCHEMICAL ANALYSIS OF CHIRAL COMPOUNDS BY HPLC-ECD COUPLING IN COMBINATION WITH QUANTUM-CHEMICAL CALCULATIONS ¨ Gerhard Bringmann, Daniel Gotz, and Torsten Bruhn

10.1. INTRODUCTION The combination of HPLC with analytical methods, like NMR, MSn , and CD is one of the most powerful analytical tools for the structural elucidation of chiral compounds, especially in natural product chemistry, where one often has to deal with complex mixtures, small product quantities, and/or chemically or stereochemically unstable substances [1]. In 1980 Mason and co-workers [2] reported the first hyphenation of HPLC with a CD dichrograph. By this combination it became possible to measure absorptions and optical activities simultaneously, in the on-flow mode. Salvadori et al. [3] were the first to describe the determination of absolute configurations of simple and known chiral compounds by recording their CD signals at a suited single wavelength and interpreting the obtained CD effect by empirical or nonempirical rules like, for example, the octant rule or the exciton chirality method. A huge step forward was provided by Mannschreck and co-workers [4, 5] in 1992: They succeeded for the first time in the online measurement of full CD spectra by HPLC in the stopped-flow mode. The main advantage of the technique is that stereoisomers no longer need to be separated in a time-consuming semipreparative way for offline CD measurements. In an analogous way, the HPLC-NMR technique was refined in the 1980s and 1990s and in 1998 Bringmann et al. were the first to report on HPLC-ROESY-NMR measurements in the online structural analysis of natural products [6]. Together with the HPLC-MSn technique the concept of the “analytical triad” LC-MSn -NMR-CD was born [7], permitting the elucidation of full absolute stereostructures directly from the peak in crude mixtures, thus saving the often laborious, time- and money-consuming isolation procedures. In the following years, several convincing examples that evidenced Comprehensive Chiroptical Spectroscopy, Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, First Edition. Edited by N. Berova, P. L. Polavarapu, K. Nakanishi, and R. W. Woody. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

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the efficiency of this method were reported, such as the online structural elucidation of the configurationally semi-stable biaryl alkaloid dioncophylline E [8] and the dimeric metabolite ancistrogriffithine A, which possesses two stereocenters and two chiral axes [9]. Another interesting application of the analytical triad is the direct monitoring of biotransformations of metabolites in plant cell cultures and their structural analysis as described by Iwasa et al. [10–12]. HPLC-CD has also become a valuable analytical method in the pharmaceutical industry for drug screening and quality management [13, 14]. Thus, the scope of this chapter is, to demonstrate the huge potential of HPLC-CD coupling in modern analytical chemistry.

10.2. HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY Between 1960 and 1970, high-performance liquid chromatography (HPLC) was developed as a new and efficient analytical tool. Today, chiral resolution by HPLC is the most widely practiced analytical method for determination of optical purity, being applicable even to samples that include many impurities [15]. In addition, liquid chromatography is the only technique that permits the separation and identification down to femtomolar components in complex matrices, but also allows for the isolation and purification of synthetic industrial products in ton quantities [13, 16]. With the high safety standards, optical-purity analysis of pharmaceutical agents and agrochemicals is nowadays strictly required, since the presence of “undesired” stereoisomers, even in small quantities, may sometimes lead to harmful side effects [17, 18]. In this context, HPLC-CD coupling—that is, the hyphenation of a CD dichrograph to an HPLC device—offers a unique potential for the stereochemical investigations on chiral analytes, even if occurring in trace concentrations and accompanied by further byproducts. Important information that can be obtained from an HPLC-CD experiment are the determination of the enantiomeric (or diastereomeric) excesses [19], the study of isomerization processes of stereochemically unstable analytes [5, 20], the determination of the elution order of stereoisomers, and the measurement of full CD spectra of even minor compounds from crude extracts or reaction mixtures. The current chapter focuses on the latter three issues.

10.3. THE HPLC-CD DEVICE In general the setup of common HPLC-CD interfaces as schematically depicted in Figure 10.1 has essentially remained unchanged since its first introduction in 1980 by Mason et al.: The outlet of a standard HPLC system is connected to a flow cell installed within a “normal” CD detector. In the early days of HPLC-CD coupling, only individually constructed instruments were used by a small number of experts in the field. But meanwhile the technique has become broadly available to nonspecialized end-users and some companies offer benchtop solutions for HPLC-CD applications at affordable costs. Usually an optical detector and a chiroptical one are connected in series to record UV and CD spectra simultaneously. Similar to usual UV detection in chromatography, a phase-sensitive CD trace can be obtained by monitoring the differential absorption of left- and right-circularly polarized light (A = AL − AR ) at a fixed wavelength λ, and the resulting output is thus a plot of A against time. The hyphenation of the chromatographic system to the spectrometer can be achieved by using a motor valve, permitting to stop the solvent flow through the measurement

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Standard HPLC device Motor valve

Column UV detector

CD detector

Recorder output Waste UV signal A ‘On-flow ’ chromatograms at a fixed wavelength λ

A

ΔA

CD signal at λ1 t

UV

A

UV

Recorder ΔA

CD

λ

λ1

Full online spectra recorded in the λ “stopped-flow” mode

CD

λ1

λ λ

Figure 10.1. General schematic representation of a standard HPLC-CD device.

cell—for example, by redirecting the eluent from the HPLC pump directly into a waste flask. Consequently, full CD and UV spectra can be recorded in the stopped-flow mode with commercially available ECD detectors usually covering the spectral range from 200 to 850 nm. In addition, some HPLC pumps offer the possibility to keep the current eluent composition constant during the stopped-flow measurement thus permitting to subsequently proceed with the analysis of further substances within the same run. The huge potential and wide application range of HPLC-CD hyphenation is based on the simple experimental setup and, in particular, on the fact that CD itself is a quite sensitive method that can detect trace amounts of chiral compounds as long as they contain sufficiently UV-absorbing chromophores [21, 22]. In order to further improve the sensitivity of CD measurements also more specialized CD detection devices applying laser-beam sources [23, 24] or using phase-sensitive FDCD (fluorescence detection circular dichroism) [25–27] have been developed. Of these, however, only the laser-based CD detectors have so far been used in HPLC-CD hyphenation [23]. Beyond the outstanding potential of HPLC-CD alone, the additional hyphenation of high-performance liquid chromatography with further spectroscopic methods—that is, with tandem mass spectrometry (HPLC-MS/MS) and NMR spectroscopy (HPLCNMR)—has led to the “analytical triad” LC-MS/MS-NMR-CD [7]. This combined methodology has, during the past years, been applied to the full structural elucidation of—even complex—natural products right from crude extracts, as part of the strategy of a spectroscopy-guided search for structurally novel metabolites (Figure 10.2).

10.4. CHOICE OF THE CHROMATOGRAPHIC SYSTEM Mixtures of diastereomers can, in principle, be separated by HPLC on achiral phases. The chromatographic resolution of racemic mixtures, by contrast, requires a chiral auxiliary. It can be achieved by various approaches [13, 28], for example by the conversion of

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HPLC

HPLC

NMR

MS Fragmentation patterns by MS/MS or exact mass from HRMS - molecular formula - constitution HPLC Polarizer

Resolution of crude extracts or reaction mixtures by HPLC

CD

1D and 2D experiments (1H, 13C, TOCSY, COSY, NOESY, HMQC, ROESY)

NMR - constitution - relative configuration

'On-flow' monitoring of chiral analytes and recording of full CD spectra in the 'stopped-flow' mode - enantiomeric excesses (ee) Detector - absolute configuration - ...

CD Quantum-chemical calculations NMR and CD calculations absolute configuration

Full absolute stereostructures right from the peak of the chromatogram of a crude mixture!

Figure 10.2. The fruitful interplay of HPLC-MS/MS, HPLC-NMR, and HPLC-CD within the ‘‘analytical triad’’ combined with quantum-chemical calculations.

the enantiomers into diastereomeric derivatives using chiral reagents and subsequent separation on an achiral column, by using a chiral mobile phase, or by complex formation with chiral additives (like, for example, cyclodextrins [29]). The derivatization, however, requires an additional synthetic step prior to chromatography and can be hampered by different reaction rates of the enantiomers (leading to a kinetic racemic resolution). The use of chiral solvents or additives usually causes substantial disadvantages, especially in hyphenated HPLC-CD applications, since (depending on the detection wavelength) the chiral auxiliary itself may give its own CD response and may, thus, falsify the overall signal. This can imply even more serious drawbacks if a solvent gradient is applied—that is, with a varying composition of the mobile phase. Consequently, HPLC on a chiral stationary phase (CSP) is the most common and broadly applicable method for online HPLC-CD analysis. To date, a plethora of both normal- and reversed-phase CSPs have been developed, of which more than 100 are commercially available [30]. The chiral resolution is based on diastereomeric interactions of enantiomers with the CSP, namely their differential adsorption, resulting in different retention times for the two enantiomers. For a given resolution problem the separating capacity and recognition ability of a CSP can be evaluated qualitatively and quantitatively by two main characteristic values: The separation (or selectivity) factor α and the resolution factor R (t1 and t2 are the retention times of the faster and the more slowly eluting enantiomers, respectively; t0 is the retention time of a nonretained compound, that is, the dead time; k1 and k2 are the retention factors; w1 and w2 are the peak widths at their bases) [31,

T H E O N L I N E S T E R E O C H E M I C A L A N A LY S I S O F C H I R A L C O M P O U N D S

32]: α=

k2 (t2 − t0 ) = , (t1 − t0 ) k1

R=

2(t2 − t1 ) , w1 + w2

k1 =

(t1 − t0 ) , t0

(t2 − t0 ) . t0

k2 =

The separation factor α reflects the selectivity of the CSP, namely, the affinity of the selected column for the individual enantiomers. The column performance is expressed by the plate number N ; thus the more efficient the column, the smaller will be the peak width w at a given retention time t for a component: 

t N = 16 w

2 .

The fundamental equation for optimizing HPLC separation conditions relates the resolution R to the number of theoretical plates N , the selectivity factor α, and the retention factor k2 : √   k2 N α−1 R= . α 1 + k2 4 Thus, R is a basic measure of the efficacy of the chromatographic system in separating two components in a mixture and in order to provide a good resolution, the three terms have to be maximized [32, 33]. Optimization of the experiment usually involves manipulation of column and mobile-phase parameters to alter the relative migration rates of the components in the mixture and to reduce peak broadening. While baseline separation between two peaks usually requires an R value >1.5, a resolution around R = 1.0 may sometimes be sufficient for HPLC-CD measurements. The reason for this seemingly higher resolution of LC-CD compared to LC-UV lies in the fact that CD spectra contain one (half) dimension more than UV spectra, in having positive and negative signals. Since enantiomers exhibit opposite Cotton effects, the CD signals of overlapping enantiomeric peaks partially compensate each other. Thus, in contrast to UV detection, two residual—opposite—signals may still remain at the edges of the seemingly unresolved peak in the UV chromatogram. Already during optimization of the chromatographic system the CD trace may provide a first hint at partial success, long before the resolution of the two peaks becomes visible by UV detection [34, 35]. Increasing N by lengthening the column leads to a longer retention time and augmented peak broadening, which may not be desirable. Alternatively, the number of theoretical plates can effectively be increased by reducing the size of the stationary-phase particles. In addition, separations may be improved by controlling the retention factor k . The retention factors should normally lie between 2 and 5, but for complex mixtures a larger range may be required to resolve all components. The value of the retention factor for a given compound depends on its chemical properties and the following experimental variables: 1. Flow rate 2. Composition of the mobile phase (including pH value)

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3. Column temperature 4. Stationary phase In many cases, the quality of the resolution is most efficiently improved by manipulating the selectivity factor α. If α is close to 1.0, optimization of k and increase of N may not be sufficient to achieve good separations with reasonable retention times. In these cases, k is optimized first and then α is increased, again by changing the mobilephase composition or the column temperature or by switching to a different stationary phase. Detailed procedures for optimizing the chromatographic system for an individual application have intensely been reviewed in various papers and book contributions [30, 36–38].

10.5. CHOICE OF APPROPRIATE DETECTION WAVELENGTHS The choice of a suitable detection wavelength is of utmost importance for HPLC-CD measurements, since it determines the response factor of the detector, which, in turn, affects both its sensitivity and selectivity. Concerning the selectivity, one may choose one of the following two “adjustment modes,” depending on the desired information: A nonselective detector will monitor the majority of different components of a mixture, while the optimization of the detection wavelength to a selected compound might preferentially record a response arising from one single species in a crude extract. Detection wavelengths below 250 nm are generally more suitable to reflect a plethora of different chiral substances in complex mixtures, since a large number of chromophores exhibit significant absorptions in this wavelength region. On the other hand, this also means that UV and CD detection are often hampered by interfering contributions of the solvents used as the mobile phase, especially if they are not completely devoid of absorbing contaminants. While the mobile phase has of course to be chosen primarily according to an optimum solubility of the analytes and the efficacy of the separation, a fine-tuning of the solvent composition may be advantageous or can even become necessary, especially for the measurement of full online CD spectra by HPLC-CD coupling: Then it may be advisable to substitute the eluent by a solvent with a similar polarity but different UV properties. Sometimes it also may be important to substitute a hydrogen-bond donating solvent like MeOH by a nonprotic one, to achieve spectra more similar to the gas-phase spectra and to the results of quantum-chemical predictions. For example, acetonitrile can often be used instead of methanol to minimize undesired absorptions by the solvent in the region around 200 nm. Table 10.1 lists approximate cutoff wavelengths below which the eluent absorbance may become unacceptable. Below the wavelength λ0 , the absorption of the solvent exceeds 0.05 absorbance units (relative to water) with a pathlength of 10 mm (i.e., A1cm > 0.05), while the absorption of the solvent is even 20 times higher at λ1 (A1cm > 1.0). Online CD measurements can be performed without problems down to λ0 , while CD curves should be interpreted with caution in the region between λ0 and λ1 , especially if the UV curve of the eluent rises steeply and/or if the observed/expected Cotton effects are small. Below λ1 CD measurements may yield ambiguous and sometimes badly reproducible results due to the strongly interfering UV absorption of the eluent. If at all possible, the detection of CD curves below λ1 should thus be avoided. In conclusion, the detection wavelength has to be adjusted carefully and sometimes a change of the mobile phase (if applicable) can offer an alternative to obtain CD spectra of highest possible quality.

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TAB L E 10.1. Solvent Cutoff Wavelengths of Some Commonly Used HPLC Eluents [39] Eluent Dichloromethane Methanol or 2-propanol n-Hexane Acetonitrile Water

λ0 (nm)

λ1 (nm)

245 240 225 200 190

230 205 195 190 185

On the other hand, the sensitivity of the HPLC device is associated with the detection limit (LOD), which is strongly dependent on the spectroscopic properties of the analyte, but also on the stationary phase and the applied eluent. Since CD spectroscopy monitors the difference between the absorption of left- and right-circularly polarized light, the best signal-to-noise ratio (S/N) is usually obtained if ε is large and, at the same time, ε is comparatively small. Consequently, the most intense absorption may sometimes not provide the wavelength of choice for the detector setting. In general, CD detection affords the optimum S/N if the anisotropy factor g (see Section 10.6) is maximized. This is, however, possible only if the UV and CD properties of the compounds to be analyzed are known or can be estimated reasonably well. Frequently, the detection wavelength is more easily adjusted if the CD signal is known to arise from a specific transition like, for example, in the case of n → π * transitions in saturated ketones (around 300 nm). Furthermore, if the CD signal is expected to result from an exciton coupling—that is, the dipole–dipole interaction of locally excited states in adjacent, (ideally) identical chromophores—the CD detector is usually set to a wavelength that is red-shifted by about 10 nm as compared to the maximum absorption of the racemate. Since, by definition, the CD effect tends to zero at the UV maximum, this arbitrary shift of the CD detection wavelength usually fits the lowenergy extreme value of the respective couplet quite well. It is noteworthy that the CD response will switch sign if the detection wavelength is blue-shifted as compared to the corresponding UV absorption (for details see the chapter about the exciton chirality method). If two separate instruments are used for UV and CD detection, these can be adjusted to different wavelengths (as long as the g factor is not necessarily required). This might be advantageous since both sensitivity and selectivity can to some degree be tuned independently by the choice of the respective detection wavelengths of the UV (sensitivity) and CD (selectivity) detectors.

10.6. QUANTITATIVE ANALYSIS AND EE DETERMINATION USING HPLC-CD DETECTION: THE ANISOTROPY FACTOR G A common drawback in chromatography arises from the fact that the absolute quantity of a compound is hard to determine, especially at a single point of the chromatogram. However, with simultaneous UV and CD detection the so-called anisotropy or dissymmetry factor g can be derived from the ratio of the dichroic signal and absorbance [2, 34, 40, 41]: A . g= A

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The g factor does not depend on the sample concentration and is linearly related to the enantiomeric excess (ee), provided that the pathlength is the same for the UV and the CD measurement: ee . g = g max × 100 Thus, if the anisotropy factor g of the pure enantiomer (g max ) is known, the enantiomeric composition of the eluates can easily be determined at every single point of the chromatogram directly during the HPLC analysis: ee =

g g max

× 100

The direct measurement of the enantiomeric excess in a scalemic mixture is fundamental, for example, for the optimization of fraction collection in preparative liquid chromatography if two enantiomers can be resolved only partially on a given chiral stationary phase: The g factor of a pure enantiomer has a well-defined, constant value (g max ), which decreases when the first eluted peak in a partially resolved racemate becomes contaminated by the more slowly eluting peak—that is, by the oppositely configured analyte. Thus, monitoring of the anisotropy factor g permits to collect the largest-possible fractions of optically pure material from a partially resolved racemic or scalemic mixture [40].

10.7. GENERAL INTERPRETATION OF CD SPECTRA There are several strategies for the stereochemical analysis of experimental CD spectra, from merely empirical methods to quantum-chemical calculations. The most common (and merely experimental) approach to determine the absolute configuration of a novel chiral substance is the comparison of its CD spectrum with that of a structurally closely related, configurationally known compound. As simple and straightforward as this seems at first glance, the method implies hidden—and thus dangerous!—traps, since it is often difficult to judge whether the chosen reference structure is really ‘comparable’ or not. Of course the compared substances have to possess identical chromophores, with a similar stereo-orientation to each other. The pivotal effect of the conformation of the chromophores (e.g., of a phenyl substituent) on the overall CD can be seen in rocaglamide AE (1) versus its close, but cyclic, analogue cyclorocaglamide (rocaglamide AN, 2) [7, 42, 43], which shows a nearly opposite CD spectrum, despite the identity of the absolute configuration at all five stereocenters! The bridging in 2 stabilizes one particular conformational array, which is also present—but less populated—in 1, where chiroptically opposite conformers prevail. Furthermore, it is indispensable to know the influence of the different substituents of the chromophores on the CD spectrum. In most cases, simple substituents such as OH, OMe, or Me groups usually have no significant impact on a CD curve (Figure 10.3)—as long as their effects are overlayed by more dominant chromophores such as the naphthyl ring in dioncopeltine A (3) and habropetaline A (4) and if they do not have an effect to the conformation. By contrast, more strongly electron-withdrawing or -donating groups can effect a significant influence on the spectrum by altering the electronic structure and polarity of the subunits, thus changing the electron distribution in the chromophores, and the assignment of absolute configurations by a mere comparison of the CD spectra may become doubtful in such cases [44].

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40 Cyclorocaglamide (2)

OMe OH OH

O

O HO

S R R R S

C

NMe2 O

Ph

CD [mdeg]

O

OMe

O OO

0 –20

MeO

O

20

–40 200

C

NMe2 O

Ph MeO

Rocaglamide AE (1)

OMe

OMe Rocaglamide AE (1)

OH

SRR RS

Cyclorocaglamide (2) 300

250

350

wavelength λ [nm] (a)

Me HO M MeO HO

R R

NH

OH Me 5'

CD [mdeg]

50 Dioncopeltine A (3)

25

Me HO M

0 Habropetaline A (4) –25

MeO MeO

Dioncopeltine A (3)

R

NH OH Me R

5'

Habropetaline A (4) –50 200

250

300

350

wavelength λ [nm] (b)

Figure 10.3. (a) Comparison of the CD spectra of rocaglamide AE (1) and cyclorocaglamide (2). Although they are constitutionally very closely related and possess the same absolute configuration, the CD spectra are nearly mirror-image like! (b) Dioncopeltine A (3) and habropetaline A (4). Changing the substituent at C5 from OH to MeO does not have any significant effect on the spectrum.

The use of semiempirical approaches (like the octant rule for saturated ketones) or of the nonempirical exciton chirality method may be a good alternative to derive absolute configurations from experimental CD curves. The octant rule and the exciton chirality approach are described in detail in other chapters of this volume. However, these methods are again limited to specific structures or to a detailed knowledge of transitions in the chromophores. The octant rule can only be applied to cyclic saturated ketones (or aldehydes) with known, rigid conformation and is not valid in the presence of an additional stronger chromophore, while the exciton chirality method has a broader range of application. In any case, however, the knowledge about the mutual orientation of the dipole moments of the chromophores is essential: Without knowing the exact and energetically relevant conformation(s) of the investigated structure, it is not possible to unambiguously assign absolute configurations. Thus, conformational analyses using, for example, DFT methods, are usually applied to give information about the different possible conformations of a new structure and then the exciton chirality method may become applicable [45].

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Chiral product of natural or synthetic origin

Experimental UV spectrum

+

Experimental CD spectrum 8

Comparison

exp.

0 8

–8

0

–16

Single UV spectra Starting geometry

Conformational analysis

Overall UV spectrum

Boltzmann weighting Single CD spectra

–24 200

calcd.

–8 250 16 24200 250 300 350

Absolute stereostructure

Comparison UV correction

Overall CD spectrum

Corrected overall CD spectrum

Figure 10.4. Flowchart of a general approach to calculate UV and CD spectra and of the determination of the absolute configuration by the comparison of experimental and computational results.

When completely new compounds with unknown chromophores are analyzed, or when there is a doubt in the applicability of certain helicity rules, the use of quantumchemical calculations is often the only way to determine the absolute stereostructure. This is achieved by comparing the experimental spectra with the ones quantum-chemically predicted for the respective stereoisomers (usually enantiomers). Which of the semiempirical, ab initio, or DFT methods will be the most appropriate has to be carefully decided and will be discussed in other chapters so that only some key facts of the basic, general approach (Figure 10.4) will be mentioned here: The first—and mandatory—step in any calculation of CD spectra has to be a solid conformational analysis with suited methods that yield reliable energies for the investigated class of compounds. CD spectra are very sensitive to even slightest conformational changes of the chiral molecule, and it can happen that two conformations with the same absolute configuration give rise to nearly mirror-image like CD curves. For example, the dihedral angle at the biaryl axis of a (P )-1,1 -binaphthyl has a drastic influence on the CD spectrum of the compound. With an angle between 50◦ and 100◦ a positive exciton couplet in the CD spectrum is produced, whereas an angle above 120◦ will give a negative one, although the absolute configuration of the chiral axis remains the same [45]. The observed experimental CD spectrum is the macroscopic result of the CD spectra originating from all individual molecules in a population—that is, the energy-weighted summation of the single CD spectra of all possible conformations of the measured structure according to their percental occurrence in the equilibrium mixture. The contribution of a single conformer to the overall CD (or UV) spectrum can be calculated based on a Boltzmann statistical weighting of the energies of the conformers found during the conformational analysis. In general, every conformation within an energy range of ∼12 kJ/mol above the global minimum may contribute to a significant degree, and so all conformations with an energy above this value can usually be disregarded for the subsequent calculation of the CD and UV spectra [46]. These CD computations will not give rise to full curves, but only to bar spectra (one single value for the energy of each of the excited states). To achieve a result that is optically comparable with the experiment, the single values have to be overlaid with

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Gaussian-shape functions (sometimes Lorentz curves will be used instead) [47]. All of the single spectra thus obtained will then be summed up, taking into account the Boltzmann statistics of the conformational analysis, finally providing the full predicted CD and UV curves. In principle, it would be preferable to use the highest-level method available for the computation of the excited states of the chiral molecule. In practice, however, this is not feasible and one has to find a compromise between accuracy and computational costs.

10.8. APPLICATION OF THE ‘‘UV SHIFT’’ A simple empirical approximation, the so-called UV shift [46, 48], can sometimes help to keep the calculation time low. It is based on the following considerations: The most common software packages for quantum-chemical calculations will always compute rotational and oscillator strength values at certain excitations in one run. For both values the same method is used to obtain the energy of the excited state and thus the wavelength of the excitation. This means that any systematic error with respect to the wavelength determination will be the same for both spectra. Identification of the extent of this error is much easier for the UV than for the CD curve. By comparing the experimental UV spectrum with the calculated one, it is possible to determine the difference between the lambda values of the experimental and the calculated maxima—that is, the “UV shift” This empirical factor can then be applied to the CD spectrum, thus providing a better match between the experimental and the calculated data. If this match is not evident, the chosen calculation method is either unsuited or the absolute stereostructure (maybe even the constitution) for which the computation was done does not correspond to the analyzed compound. The use of the UV shift is, however, only recommended if the UV spectrum is already of sufficient quality, which, in simple words, means that the number of maxima, their relative intensities, and the energy differences between them should be the same in the experimental spectrum as in the computed one. Application of the UV shift often permits to tolerate larger systematic errors—for example, by using smaller basis sets, which can allow for significantly reduced computational time.

10.9. HPLC-CD IN PRAXIS In the following, the still underestimated potential of HPLC-CD analysis and its possible application areas will be demonstrated by a detailed description of two representative configurational assignments of chiral natural products, in particular the determination of the absolute configuration by a combination of HPLC-NMR, HPLC-CD, and quantumchemical calculations. Through these examples the reader will get an idea of how to perform a full configurational elucidation of chiral substrates by HPLC hyphenation techniques and will gain a feeling about possible difficulties encountered during the structural analysis and receive useful advice to overcome them. This provides a general guideline of how to proceed for the full stereochemical assignment of novel-type chiral compounds even from crude mixtures.

10.9.1. Ancistrocladium B—A Configurationally Semi-Stable, Axially Chiral Biaryl Ancistrocladinium B (5) is a novel-type metabolite isolated from an as yet not fully identified, possibly new Ancistrocladus species from the rainforest in the Democratic

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Republic of Congo [49]. It is one of the first of the recently discovered N , C -coupled representatives of the naphthylisoquinoline alkaloids. Its typical occurrence as a double peak in the HPLC chromatogram in combination with the observation that all isolation attempts always led to the same 45:55 mixture according to NMR and analytic HPLC indicated the presence of two diastereomers slowly interconverting at room temperature (Figure 10.5). That these were the respective atropo-diastereomers—that is, with different configurations at the (apparently configurationally semi-stable) novel N , C axis—became evident from the fact that both had the same configuration at the stereocenter at C3, S , as determined by oxidative degradation [50]. Due to the semi-stable configuration at the N , C axis, all offline spectra (NMR, CD) always recorded the diastereomeric mixtures, hampering an unambiguous elucidation of the absolute stereostructures with common methods, making ancistrocladinium B an excellent example of how to apply the so-called “analytical triad”, that is, the combination of HPLC-NMR, HPLC-MS, and HPLC-CD. 10.9.1.1. Optimizing the HPLC Separation Conditions. As for all HPLC hyphenation techniques, the first and most important step to the unequivocal elucidation of the constitution and the stereostructure of ancistrocladinium B (5) was the elaboration of a reliable method for the full resolution of this compound by HPLC. To get baseline-separated peaks, several columns (normal phase, RP-C18 and -C8 ) and solvents (acetonitrile, methanol, water) were tested. In addition, the pH value of the mobile phase and the temperature of the column had to be optimized to provide a good separation of the two presumed atropo-diastereomers, preferably with short retention times. After intense efforts, the best separation was achieved by using a Symmetry-C18 column (Waters, 4.6 × 250 mm; 5 μm) at 10◦ C with an isocratic solvent system of methanol and water (60:40, acidified with 0.05% TFA, flow rate: 0.8 mL/min). These conditions yielded a clear baseline separation with short retention times (Figure 10.5), giving one peak at about 17 minutes (Peak A) and a second one at about 19 minutes (Peak B). Still, a preparative separation of the two peaks to give fully pure diastereomers was not possible due to their slow interconversion at room temperature.

LC-UV 231 nm Peak A Peak B

MeO

*

Me OH

OMe

t [min]

N * OMe Me

17

19 LC-CD 235 nm

Me

Ancistrocladinium B (5) * stereogenic elements of initially unknown absolute configuration

Figure 10.5. HPLC-UV and HPLC-CD t [min] 17

19

(on-flow) chromatograms of ancistrocladinium B (5).

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MeO

Me H S OH OMe N 6′

MeO

3

P

OMe Me H

Me H H N M 7′

3 S

Figure 10.6. Online-ROESY NMR

6′ 7′

MeO (P,3S)-5 (Peak A)

correlations diagnostically indicative for the relative configuration of the

OMe Me HO Me (M,3S)-5 (Peak B)

Me

atropo-diastereomers of ancistrocladinium B.

10.9.1.2. Information Obtained by HPLC-MS and HPLC-NMR Measurements. This interconversion was, however, slow enough to permit a complete stereochemical analysis online, right from the peak in the chromatogram, by applying the analytical triad for further structural investigations, using the optimized separation conditions described above. By HPLC-MS, each of the two peaks gave a mass of m/z = 406. HPLC-HRMS(ESI) experiments showed that both compounds were cationic, having the same molecular formula, C25 H28 NO4 + . This again confirmed that ancistrocladinium B was indeed a mixture of two isomers, probably atropo-diastereomers. For both peaks, 1 H, 13 C, COSY, ROESY, HMBC, and HMQC spectra were recorded by online HPLC-NMR measurements, using a Bruker Cryoprobe for higher 13 C sensitivity and a flow insert (CryoFit, Bruker) for HPLC-NMR hyphenation. The two compounds showed nearly identical NMR spectra, except for the fact that some of the signals displayed slightly different chemical shifts. The results corroborated the anticipated constitution of ancistrocladinium B (Figure 10.6); in addition, based on the online-ROESY correlations, even the relative configurations of the compounds were unambiguously assigned: The faster eluting Peak A displayed a diagnostically significant interaction between H7 and the proton at the stereocenter C3, showing these two protons to be both on the same side of the molecule—that is, both up (as drawn in Figure 10.6, left) or both down. The more slowly eluting Peak B, by contrast, had a strong correlation between H7 and the protons of Me3, hinting at the opposite relative configuration axis versus center (Figure 10.6, right). Therefore, the faster eluting atropo-diastereomer of ancistrocladinium B had to be (P , S )- or (M , R)-configured, while the more slowly eluting one had the (P , R)- or the (M , S )-configuration. Together with the (S )-configuration at C3 as already known from the degradation experiment, the two (3R)-configured stereoisomers were excluded. 10.9.1.3. HPLC-CD and Quantum-Chemical CD Calculations. To get an independent and unambiguous proof for the above assignments HPLC-CD measurements in combination with quantum-chemical calculations were performed. The full CD spectra of the two peaks were recorded online in the stopped-flow mode (Figure 10.7), and these spectra were nearly mirror-image like. It is known that the chiral axis in biaryls often dominates the CD spectrum and that additional stereocenters usually do have a negligible effect only (for exceptions due to the strong chromophores close to the stereogenic center, see reference 51). Thus, the CD spectra alone would already have provided a clear hint that the two peaks in ancistrocladinium B correspond to atropo-diastereomeric compounds. Assuming that the exciton chirality method (see Chapter 4 in this volume) was valid for ancistrocladinium B, the positive couplet around 350 nm would have predicted the (P )-configuration for Peak A and, vice versa, the (M )-configuration for Peak B with its negative couplet at 350 nm. However, without knowing the exact conformations of

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6

6 exp. Peak A

3 CD [mdeg]

CD [mdeg]

3

0 calcd. for (P,S)

–3

exp. Peak B

0

–3 calcd. for (M,S)

–6 200

–6 250 300 350 wavelength λ [nm]

MeO S

400

250 300 350 wavelength λ [nm]

200

Me + OH OMe N 6′

Me

MeO S

P

MeO

MeO Me

M

6′

MeO

Me Me

(P,3R)-5

Me

6 exp. Peak A

calcd. for (P,R)

exp. Peak B

3 CD [mdeg]

CD [mdeg]

+ OH OMe N 6′ P

MeO

6

3

Me

Me R

Me HO

(M,3R)-5

MeO

MeO

Me R

N+

6′

Me HO

(M,3S)-5

MeO

MeO

N+ M

Me

(P,3 S)-5

400

0

–3

0

–3 calcd. for (M,R) –6

–6 200

250 300 350 wavelength λ [nm]

400

200

250 300 350 wavelength λ [nm]

400

Figure 10.7. Assignment of the absolute configuration to the two—configurationally semistable—atropo-diastereomers of ancistrocladinium B (5) by comparison of the experimental LC-CD spectra (stopped-flow) of Peak A (left) and Peak B (right) with the spectra calculated for (P, 3S)-5, (M, 3R)-5, (P, 3R)-5, and (M, 3S)-5 by using TDDFT with subsequent UV-shift correction.

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369

the diastereomers and the orientation of the dipole moments of the two chromophores, this was not a reliable assignment and thus computational calculations were done. To elucidate the absolute configuration of the diastereomers of 5 independently, the CD spectra of all possible configurations, (P , 3S )-5, (M , 3R)-5, (P , 3R)-5, and (M , 3S )5, were calculated and compared with the experimental results [46]. A conformational analysis was performed using B3LYP/6-31G* [52–55] yielding four relevant conformers for each diastereomer. For the subsequent TDAB3LYP/SVP [56, 57] calculations, solvent effects were taken into consideration by using the COSMO [58] approach, using an epsilon value of 56.52 and a refraction index of 1.33. By comparison of the calculated UV spectra with the experimental curves, a UV shift of 24 nm was determined and applied to the calculated CD curves. The CD spectrum computed for (P , 3S )-5 did fit quite well to the experimental one of Peak A, while the spectrum calculated for the (M , 3R)-enantiomer did not match the measured one, proving that Peak A was (P , 3S )configured. In the case of Peak B the comparison of the calculated spectrum of (M , 3S )-5 with the experiment showed a good agreement, while the curve calculated for (P , 3R)-5 again did not fit, corroborating the (M , 3S )-configuration of Peak B. 10.9.1.4. Further Investigations: Estimation of the Rotational Barrier. As already mentioned above, the iminium-aryl axis of ancistrocladinium B is configurationally semi-stable at room temperature. For an estimation of the barrier of rotation around the chiral axis, again HPLC experiments were carried out. For each of the two atropo-diastereomers the isomerization process was monitored by HPLC-UV measurements. The decrease of the diastereomeric excess of freshly purified fractions enriched in the respective (P )- or (M )-atropisomer was measured at three different temperatures

Peak B Peak A

t [min] 17

19

Isolation of Peak A

Isolation of Peak B

t = 330 min t

Figure 10.8. Determination of the axial isomerization

t = 180 min

t

rates of (P, S)-5 and (M, S)-5 by their chromatographic

t [min]

resolution and subsequent thermal equilibration over time (here exemplarily shown at 65◦ C), monitored by HPLC-UV on an achiral C18 phase.

t = 0 min 17

19 t [min]

17

19

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(55◦ C, 65◦ C, and 85◦ C, Figure 10.8), permitting determination of the respective rate constants of the isomerization process. By applying the Eyring equation, the Gibbs free energies of activation at room temperature (25◦ C) were calculated. The experimental values thus obtained were Grot = 105.8 kJ mol−1 for the isomerization from P to M and Grot = 105.7 kJ mol−1 for the conversion of M to P .1 In summary, the structure elucidation of ancistrocladinium B (5) impressively demonstrates the value of HPLC hyphenation techniques in modern natural products chemistry. Besides the establishment of the full constitution and relative configuration by HPLCNMR and HPLC-MS, also the absolute configurations of the two naturally occurring atropo-diastereomers of 5 were determined. Online HPLC-CD measurements were performed with trace quantities of crude material. Due to the unprecedented structure of the N , C -coupled chiral aryliminium cation, the CD spectra thus obtained could not be interpreted by empirical comparison with other compounds, but inevitably required quantum-chemical CD calculations. This finally permitted the unambiguous assignment of the full absolute stereostructures of the two diastereomers. Now knowing their elution order, HPLC techniques also served to determine the atropisomerization barriers by monitoring the decrease of the diastereomeric excess of freshly prepared samples enriched in one of the two rotational isomers. The absolute stereostructures of the two atropo-diastereomers of ancistrocladinium B (5) have meanwhile been confirmed by total synthesis [59].

10.9.2. The Absolute Axial Configuration of Knipholone and Knipholone Anthrone Knipholone (6) and knipholone anthrone (7) are well-known representatives of the class of naturally occurring phenylanthraquinones [60]. They are interesting biosynthetically (origin from eight plus four acetate units), pharmacologically (anti-infective and anti-tumoral properties), and, in particular, stereochemically, due to their rotationally hindered and thus configurationally stable biaryl axis (Figure 10.9) [60]. They have been initially discovered by Steglich, Dagne, and Yenesew in 1984 (knipholone) [61] and 1993 (knipholone anthrone) [62], but the elucidation of their correct absolute configurations succeeded in 2007 only [63]. Previous assignments using semiempirical calculations had deduced absolute configurations at the biaryl axis, which were in contrast to those expected from the results of a later stereoselective total synthesis using the lactone method [64, 65]. In nature, knipholone mostly occurs as a scalemic mixture (i.e., enantiomerically enriched, not enantiopure). In this chapter only, the stereostructure of the main enantiomer, (+)knipholone, will be discussed. In 2007 the correct absolute configuration was determined unambiguously and independently by renewed experimental work in combination with quantum-chemical calculations using higher-level methods [63]. The individual challenges arising in the course of these investigations will be described in the following paragraph, again demonstrating the value of the fruitful interplay of HPLC-CD measurements with computational work. 10.9.2.1. Remeasuring the CD Spectra of Knipholone and Knipholone Anthrone. As mentioned above, the initial assignment of the absolute configuration of knipholone (6) and knipholone anthrone (7) was in contrast to the results of the total Note that the two Grot values are not identical, although concerning the same transition state, due to the different energies of the two interconverting atropisomers, which in this case are diastereomers. This is also reflected by their experimentally determined isomeric ratio of 45:55 of M : P . 1

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HO

O

HO

OH

O

OH

Me

Me X HO

M

X HO

OH

P OH

Me

Me MeO O (M)-6 X = O (M)-7 X = H2

O OMe (P)-6 X = O (P )-7 X = H2

Figure 10.9. Structures of knipholone (6) and knipholone anthrone (7).

(+)–6

4 Δε [cm2/mol]

Δε [cm2/mol]

5

0

–5

8

from B. capitata

(+)–7 from synthesis from K. foliosa

0 –4

from B. frutescens

–8 200

300 400 wavelength λ [nm]

500

200

300 400 wavelength λ [nm]

500

Figure 10.10. Experimental CD spectra of (+)-knipholone (6, left) and (+)-knipholone anthrone (7, right) from different origins (measured in methanol).

synthesis by applying the lactone concept [64].2 Several independent approaches were followed to clarify the origin of this discrepancy. First of all, the CD spectra of 6 and 7 isolated from different natural sources were remeasured to provide new and reliable experimental data (Figure 10.10). In addition, the influence of different solvents and solvent mixtures (n-hexane, methanol, acetonitrile:water 60:40) was investigated, since these may have a significant effect on a CD spectrum, due to the polarity and the hydrogen-donor or -acceptor properties of the solvent but also due to possible aggregation of the analyte in solution. In the case of knipholone, however, the spectra did not show any significant differences, regardless of whether the compounds were isolated from varying natural sources or measured in different solvents (Figure 10.11).

2

Note that in this experimental work the use of an S -configured catalyst in the lactone-cleavage reaction unexpectedly seemed to give the P -configuration (as erroneously deduced from the initially wrongly attributed absolute (P )-configuration of (+)-knipholone). This seeming contradiction was solved by the new—and correct—assignment of the absolute configuration of (+)-knipholone as being M -configured in 2007 [64].

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8

(+)–6

(+)–7

in n-hexane in n-hexane Δε [cm2/mol]

Δε [cm2/mol]

5

0

–5

in acetonitrile:water (60:40)

0

–8

300 400 wavelength λ [nm]

in methanol

–4

in methanol 200

4

200

500

in acetonitrile:water (60:40) 300 400 wavelength λ [nm]

500

Figure 10.11. Experimental CD spectra of (+)-knipholone (6, left) and (+)-knipholone anthrone (7, right) in various solvent systems.

8

8

(+) –7

(+) –7 Δε [cm2/mol]

Δε [cm2/mol]

fresh sample 4 0

4 0 –4

–4 partially decomposed

(+)–6 –8

–8 200

300

400

wavelength λ [nm]

500

200

300

400

500

wavelength λ [nm]

Figure 10.12. Experimental CD spectra of freshly prepared (+)-knipholone anthrone (7) and of a partially decomposed sample (left) and comparison of the CD spectra of (+)-knipholone and (+)-knipholone anthrone (right).

The newly recorded CD spectrum of knipholone anthrone (7), by contrast, obviously differed significantly from the spectra measured earlier (Figure 10.12): The freshly prepared sample of 7 showed a quite intense CD couplet at about 300 nm with a positive first Cotton effect, while this couplet was almost completely absent in the spectrum measured previously [65]. The question why this intense couplet had not been observed during the initial investigations was answered by the following experiment: Keeping the freshly purified 7 for 2 h in methanol at room temperature under ambient light led to a drastic change in the measured CD spectrum due to an intensity loss of the couplet around 300 nm. This clearly hinted at a partial decomposition of the compound to give a new chiral—and likewise chiroptically active—product, because the whole CD spectrum would just have decreased in intensity if simply racemization had occurred. The loss of only one couplet might be explained by the oxidation of knipholone anthrone to knipholone: While both compounds show a similar negative Cotton effect (CE) around 210 nm, their CEs around 300 nm are opposite. Consequently, these couplets will largely

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1000 O

HO

OH

O

OH

HH HO

P

HO

800 Me O HO

600

Me

P OH

Me

Me 6

400

OH

O OMe

O OMe

7 *

unknown decomposition products

* 200 *

*

* *

0 3

4

5

6

32

7

8

9

10 t [min]

0h

CD [mdeg]

16 6h

24 h

Figure 10.13. HPLC-UV chromatogram of

0

a partially decomposed sample of knipholone anthrone (7) after 2 h at rt and ambient light (top) and full online HPLC-CD spectra of knipholone anthrone

−16 −32 200

300

400

wavelength λ [nm]

500

(7) after 0, 6, and 24 h in the flow cell (Chromolith column, solvent gradient of acetonitrile/water, both with 0.05% TFA).

compensate each other in a mixture of knipholone and knipholone anthrone resulting in a selective decrease of the intensity of the couplet at 300 nm. The above investigations exemplify that a detailed knowledge of the chemical stability of a given compound can be highly important for the measurements and interpretation of CD spectra: One may not only observe a decrease of the intensity of the entire CD curve, as in the case of a (partial) racemization, but also new signals may appear or genuine ones may disappear if new chiral compounds are formed in situ, thus changing the overall measured CD spectrum, which may easily lead to ambiguous or even wrong interpretations. Such falsifications of CD spectra by new (or existing) chiroptically active impurities can often be overcome by HPLC-CD: As an example Figure 10.13 shows the HPLC-UV chromatogram of partially decomposed knipholone anthrone (7) and full online CD spectra of 7. By HPLC-CD in the stopped-flow mode, the peak corresponding to knipholone anthrone was kept in the flow cell for several hours and the full CD curve was recorded after 0, 6, and 24 h. Since the sample was not exposed to light in the flow cell and air oxygen was largely excluded, no significant change of the CD spectrum was observed (Figure 10.13) even after 24 h, in contrast to the earlier presented offline measurement (cf. Figure 10.12), where decomposition may have significantly decreased the couplet at 300 nm already within a time span of 2 h.

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8 exp. for (+)–6

DFT/MRCI calcd. for (P)–7

4 Δε [cm2/mol]

Δε [cm2/mol]

5

0

0 –4

–5

exp. for (+)–7

DFT/MRCI calcd. for (P)–6 –8 200

300 400 wavelength λ [nm]

500

200

300 400 wavelength λ [nm]

500

Figure 10.14. Determination of the absolute configurations of (+)-knipholone (6) and (+)knipholone anthrone (7) by comparison of the experimental CD spectra with the CD curves calculated by DFT/MRCI.

10.9.2.2. Elucidation of the Absolute Configuration by QuantumMechanical Calculations. According to the exciton chirality method, the “newly found” couplet now also hinted at a (P )-configured biaryl axis of compound 7, again in contrast to the initial assignment of the absolute configuration as M [65]. Thus, in parallel to the renewed experiments, the computational investigations were rechecked leading to the conclusion that the previous semiempirical approaches had by far not been sufficient to unequivocally determine the absolute configuration 6 and 7. In the case of knipholone anthrone even TDDFT calculations led to ambiguous results and thus the DFT/MRCI approach developed by Grimme [66] was chosen for these phenylanthraquinones. Finally, the absolute configurations of the two compounds had to be revised: (+)-Knipholone (6) and (+)-knipholone anthrone (7) clearly do have the (P )-configuration (Figure 10.14), which is now in full accordance with the results of the total synthesis by using the lactone concept, and—in the case of 7—also with the attribution of the absolute configuration based on the exciton chirality method applied to the newly measured CD spectrum. 10.9.2.3. Stereochemical Correlation of 2 and 3 by Coelution Experiments. Additional support for the new assignment of the absolute configuration of the two compounds was expected from their stereochemically unambiguous interconversion by reduction of (P )-6 to give—if correctly assigned—(P )-7, and, vice versa, the oxidation of (P )-7 to deliver (P )-6, to be analyzed by chromatography on a chiral phase with online CD coupling (LC-CD). These investigations were, however, hampered by the partial racemization of the compounds under the applied conditions. Still, the enantiomers of the two compounds were easily resolved on a chiral OD-H column. Interestingly, they showed inverted elution orders: Thus, the (P )-enantiomer of knipholone (6) corresponded to the faster eluting peak of the two enantiomers, while for knipholone anthrone (7) the M -configured enantiomer had the shorter retention time (Figure 10.15). The described results highlight that elution orders of similar, but not identical, compounds do not necessarily provide a hint at their absolute configurations, because even two so closely related compounds—like 6 and 7—can show opposite elution orders of their identically configured enantiomers.

T H E O N L I N E S T E R E O C H E M I C A L A N A LY S I S O F C H I R A L C O M P O U N D S

HO

OH

O

O

HO

Me

Me P

O HO

OH

OH

SnCl2, HOAc Me

Me 7

OH

KOH, air

P

HH HO

375

6

O OMe

O OMe

(b)

(a)

P

P

M LC-UV

LC-UV KOH, air

LC-CD

LC-CD

t [min]

t [min] 25 35 0:100

30 40 69:31 (c)

(d) M

P

P M

LC-UV

LC-UV

Figure 10.15. Proof of the stereochemical

SnCl2, HOAc

identity of (+)-knipholone as P (b), since it was obtained by oxidation of enantiomerically pure

LC-CD

LC-CD

t [min]

t [min] 25 35 48:52

30 40 75:25

knipholone anthrone (100:0 P to M) (a), and, vice versa, enantiomeric resolution of—mainly (P)-configured—knipholone anthrone (7) (d) obtained by reduction of authentic knipholone (75:25P to M) (c).

An authentic sample of enantiomerically highly pure synthetic (+)-knipholone anthrone (Figure 10.15a) was oxidized to knipholone showing only a ratio of 69:31P (rapid) to M (slow). And, vice versa, an authentic sample of knipholone (6) isolated from B. capitata, which had a ratio of 75:25P to M , was reduced to knipholone anthrone (7), whose now more slowly eluting main peak coeluted with the peak of the pure (P )-enantiomer of 7. The interconversion showed that the more rapidly eluting peak of knipholone anthrone (7) was (M )-configured, while in the case of knipholone (6) the faster eluting one was P . These results are in agreement with the fact that at the chosen wavelength of 290 nm (P )-configured 6 shows a positive Cotton effect, while the (P )-enantiomer of 7 displays a negative one! The example reveals that even seemingly marginal structural changes can be accompanied by an inversion of the CD response, at least at a given wavelength λ. Due to the near-racemic character of the knipholone anthrone sample obtained by reduction of (P )-knipholone (Figure 10.15d), additional evidence of the identity of the

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P

P

M

P

t [min]

t [min]

t [min] 30 40

30 40

Near-racemate 45:55

Pure + ‘racemate’

30 40 Pure Knipholone anthrone

LC-UV

M

Figure 10.16. Spiking LC-CD t [min]

t [min] 30 40

t [min] 30 40

30 40

experiments to prove the identity of peaks, exemplarily for knipholone anthrone (7) of different enantiomeric ratios from different sources.

respective peaks, and thus of the reversed HPLC behavior of 7 in comparison to 6, was acquired by a spiking experiment by adding enantiomerically pure knipholone anthrone to that near-racemic sample of 7 with subsequent chromatographical analysis by using HPLC-UV and HPLC-CD (Figure 10.16). This experiment showed that after addition of pure (P )-configured knipholone anthrone to the racemate, the second-eluting peak increased in intensity. This clearly confirmed, once again, that the elution order for the diastereomers of 7 is inversed as compared to the chromatographic behavior of compound 6. 10.9.2.4. Knipholone and Knipholone Anthrone: Instructive Examples of the Manifold Aspects of HPLC-CD. The investigations on knipholone (6) and knipholone anthrone (7) exemplify several advanced aspects of HPLC-CD hyphenation: A general disadvantage might be that the solvent used for the HPLC-CD measurement may influence the experimental CD curves significantly, although such effects were shown to be negligible in the case of 6 and 7. In offline CD measurements, such aggregation phenomena can be evaluated by simply using different solvents. In online CD investigations, by contrast, hints at possible spectral changes originating from aggregated species can be obtained from a dilution series. Such a “dilution experiment” can sometimes be achieved by simply measuring the CD spectrum of the investigated compound at different positions of its peak in the UV-monitored chromatogram (e.g., left versus right slope). Another useful lesson one can learn from the racemate resolution and the online CD analysis of knipholone (6) and knipholone anthrone (7) is that even slight structural changes may lead to an inversion of the elution order of the respective enantiomers. Thus, the absolute configuration of structurally related analogues, and, in particular, of unknown compounds can usually not be determined for sure by simple comparison of relative retention times. Beyond the elucidation of the full absolute configuration by LC-CD in combination with empirical and nonempirical methods or quantum-chemical calculations, spiking (= coelution) experiments can help to establish the elution order of stereoisomers of known substances if stereochemically pure or enriched authentic

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material (e.g., from a total synthesis) is available. The chemical stability of the analyte has to be considered when performing CD investigations since chiral decomposition products can largely contribute to the overall CD response, thus possibly leading to an ambiguous or even wrong assignment of absolute configurations. Again online HPLC-CD measurements in the stopped-flow mode can be helpful to overcome such problems by selectively measuring only the correct, still structurally intact analyte (even in a mixture of a plethora of other CD-active products) and, in addition, by minimizing reactions of the analyte by exclusion of light and air oxygen within the HPLC-CD flow cell.

10.10. FURTHER EXAMPLES The value of the method is emphasized by a broad variety of further stereochemically intriguing examples from most different classes of compounds, with stereogenic centers or elements of axial or planar chirality, whose absolute configurations were established by HPLC-CD in combination with quantum-chemical CD calculations and/or by applying empirical or nonempirical rules. A few selected examples are shown in Figure 10.17, among them the 3,8 -linked biflavonoid 14 from Gnidia involucrate [67], whose absolute configuration was determined using Gaffield’s isochroman helicity rule [68, 69], and flavanthrin (8), a 9,10-dihydrophenanthrene dimer isolated from Pholidota chinensis [70], which was structurally elucidated by HPLC-CD in combination with quantum-mechanical

Me

SMe CN

R

NH OH Me Phylline (9) R

OMe HO

OH M

OH Flavanthrin (8)

HO

A synthetic quateraryl, 10

MeO calcd. S NH N H CCl3 (S)-TaClo (11)

OH

calcd.

O R S

t

Ph

Ph

HO Ph

N

N

N

Ph

Ph

β,β '-Coupled bisporphyrins, 12

N

Zn

N N

Ph

R

P

P

M

R

H

R

R

Ph

P

H

H OH O O

N Zn

OMe

exp.

exp.

N

Me OMe

M

HO R

Ph R = CH2OH

OH R

O

OH

OH A biflavonoid, 14

A configurationally semi-stable bi[10]paracyclophane, 13

Figure 10.17. Selection of structurally most diverse compounds with one or more stereogenic centers, axes, and/or elements of planar chirality from different research groups, stereochemically investigated by HPLC-CD hyphenation techniques.

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CD calculations. Further configurational assignments succeeded with synthetic quateraryls like 10 [71], the neurotoxin TaClo (11) [72], and the anti-malarial drug artemisinin [73], and all were investigated through the hyphenation of HPLC and CD. Some additional selected applications of HPLC-CD hyphenation will be highlighted in the following pages, involving online CD investigations on axially chiral bisporphyrins like 12, likewise synthetic paracyclophanes of type 13, and the natural alkaloid phylline (9) as illustrative examples.

10.10.1. The Stereostructure of Intrinsically Axially Chiral β,β  -Bisporphyrins The utility of the online CD analysis in combination with quantum-chemical CD calculations for the fast configurational assignment of chiral compounds has also been succesfully applied to unnatural, merely synthetic compounds possessing unprecedented stereostructures—for example, to the stereochemical characterization of the first intrinsically axially chiral bisporphyrins with a rotationally hindered direct β,β  -linkage [74, 75]. Among a whole series of β,β  -linked porphyrin dimers of type 12, several racemic free-base representatives could not be resolved, although a variety of different chiral HPLC phases were tried under various conditions [75]. By contrast, a couple of fully metalated dimeric porphyrins like, for example, rac-12a, rac-12b, and rac-12c (Figure 10.14) gave a clear baseline separation of the respective atropo-enantiomers at room temperature after extensive optimization of the separation conditions (Chirex-3010 column, n-hexane/CH2 Cl2 60/40). Note that for the online LC-CD measurements the CD detection wavelength was set to 435 nm, that is, red-shifted by about 10 nm as compared to the UV maximum of the racemate (as outlined above), since the CD spectrum was expected to arise from an exciton coupling of the two adjacent identical chromophores. The full online CD spectra were perfectly mirror-imaged and showed a positive first Cotton effect around 450 nm for the faster enantiomer (Peak A) and a negative one for the more slowly (Peak B) eluting atropisomer (Figure 10.18). The absolute configurations at the biaryl axis of the enantiomers (P )-12a and (M )-12a were established by HPLCCD experiments in the stopped-flow mode in combination with quantum-chemical CD calculations (ZINDO/S-CI//BLYP-D/SVP), revealing the (P )-atropo-enantiomer to be the faster eluting one. As expected, the CD spectra of 12b and 12c (differing from 12a in the metalation pattern and/or the meso-substituents) were strongly related to those of 12a, permitting, in this case, configurational assignment by comparison of these curves with the ones calculated for the enantiomers of the parent dimer 12a, (P )-12a, and (M )-12a. This clearly evidenced that the chromatographically faster atropo-enantiomers of both, 12b and 12c, were (P )-configured and that, consequently, the slower ones had the M configuration at the porphyrin–porphyrin axis, here proving that the substitution pattern and, in this case, also the type of the central metals may have only minor effects on the overall CD spectrum. On the other hand, the fact that the palladium(II) and copper(II) derivatives of rac12a (structures not shown) revealed an inverse elution order (with the M -enantiomer being the faster eluting one), as compared to that of rac-12a, rac-12b, and rac-12c, again shows that even small structural differences can, within the same class of compounds, lead to substantial changes of the chromatographical behavior, highlighting that a configuration assignment cannot be based on elution orders alone, but must be assisted by, for example, online CD investigations.

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LC-UV 425 nm

Resolution on a chiral HPLC phase (Chirex-3010®, rac-12a, CH Cl /n-hexane) 2 2 rac-12b, or rac-12c

Peak A Peak B

6

LC-CD t [min] 435 nm A

300

B

exp. for 12a 12b 12c

calcd. for (P)-12a

400

500

Online-CD (stopped flow)

6

CD [mdeg]

CD [mdeg]

Online-CD (stopped flow) 40 20 0 –20 –40 –60 –80

8 t [min]

8 t [min]

80 60 40 20 0 –20 –40

exp. for 12a 12b 12c calcd. for M-12a

600

300

wavelength λ [nm] A

Ar1 N

Ar1 N

Ar1

N

M1

Ar1 N

P

Ar2 Ar1 (P )-12a-c

Ar1

Ar2 N 2 N M N N

Ar2

400

500

600

wavelength λ [nm]

Ar2

N

N M1 N

B

N

Ar1 Ar2

Ar2

N 2N M N N

M Ar1

Ar2

Ar2

(M )-12a-c

Figure 10.18. Stereochemical characterization of the axially chiral β,β  -bisporphyrins 12a–c by online HPLC-CD measurements on a chiral phase and comparison of the experimental spectra with those obtained by quantum-chemical CD calculations [rac-12a (M1 = M2 = Zn, Ar1 = Ar2 = phenyl), rac-12b (M1 = Zn, M2 = Ni, Ar1 = Ar2 = Phenyl), rac-12c (M1 = M2 = Zn, Ar1 = Ar2 = 4methoxyphenyl)].

10.10.2. BI [10] Paracyclophane: An Axially Chiral, Yet Configurationally Semi-Stable Biphenyl Meso-compounds are constitutionally symmetric molecules that do possess pairs of stereogenic elements, but of opposite configurations each. They are, thus, achiral—at least on the time average: Even if possessing chiral conformations (maybe even exclusively), these may rapidly interconvert in flexible systems, so that the molecule will, macroscopically, appear as achiral above a certain temperature [76–78]. The bi[10]paracyclophane 13 (Figure 10.17) was synthesized by Tochtermann and co-workers [79, 80] since it was expected to constitute an unprecedented borderline case between an achiral meso-compound and an axially and planar chiral compound. It has two elements of planar chirality, whose absolute configurations were known to be opposite to each other from its synthesis so that one-half of the molecule was (pP )- and the other one (pM )-configured. In this remarkable molecule, rotation at the central axis will, despite the presence of the two planar-chiral elements, lead to enantiomers, (pM , aM , pP ) versus (pM , aP , pP ), not diastereomers. Different from the situation with similar, more hindered

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HPLC-UV at 210 nm

HPLC-CD at 210 nm

t [min] 8 10 12 14

HPLC-CD of Peak A

HPLC-CD of Peak B 10

12

calcd. for (pP,aM,pM)-13

6

Δε [cm2/mol]

8

exp. Peak B

4

2 0 –2

0 –4 –8

exp. Peak A –6

–12 200

250

300

wavelength λ [nm]

350

–10 200

calcd. for (pP,aP,pM)-13 250

300

350

wavelength λ [nm]

Figure 10.19. Resolution of an enantiomeric mixture of 13 by HPLC and determination of the absolute configuration by comparison of online CD spectra with the calculated CD curves.

(and thus C1 symmetric) analogues investigated earlier [80], the axis connecting these two moieties was configurationally semi-stable and, as a consequence, 13 should be a genuine meso-compound at higher and a “simple” C1 -symmetric compound at lower temperature. Due to the observed atropisomeric interconversion at room temperature, LC-CD was the method of choice for the investigation of the stereochemical properties of 13. Apparently due to the low rotational barrier at the central axis, the resolution was most unsatisfactory at ambient temperature, making it necessary to perform the separation at lower temperature: The best results were obtained using a Chiralcel ODRH column (Daicel) at 5◦ C and with acetonitrile/water (68:32) as the mobile phase. That the two peaks thus observed (Figure 10.19) indeed corresponded to the expected atropo-enantiomers of 13 was evidenced by their online CD analysis, which resulted in almost opposite CD spectra. It is noteworthy that although the two peaks of the enantiomeric mixture were not baseline separated, it was possible to obtain CD spectra of good quality. One reason is that, different from CD spectra of diastereomers, those of enantiomers are fully opposite and retain their qualitative appearance even if the sample is not enantiomerically pure (see also Section 10.4). Therefore, even enantiomers with nearly identical retention times, which thus give only one—seemingly unresolved—LCUV peak, may sometimes give full CD spectra by using the HPLC-CD method [34, 35].

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The chromatographic separation of the two enantiomers of 13 and their online CD measurement permitted assignment of their absolute configurations by quantum-chemical CD calculations (CNDO-S-CI//AM1 method) and comparison of the computed CD spectra with the experimental curves. As can be seen in Figure 10.19, the experimental CD curve of the more rapidly eluting Peak A showed a good agreement with the spectrum calculated for the (pP , aM , pM )-enantiomer of 13, while that of the slower Peak B matched well with the CD spectrum predicted for (pP ,aP ,pM ), thus permitting an unambiguous assignment of the two peaks, A and B, to the corresponding enantiomers. As another powerful application of the LC-CD hyphenation, the decrease of the CD curve of Peak A was monitored directly after resolution for the determination of the half-life (t1/2 ) of the racemization process at the biaryl axis of 13. Because of the relatively unstable axial configuration and, therefore, fast vanishing of the CD effect, the time for scanning the CD spectrum had to be reduced dramatically. This was achieved by minimizing the spectral width from 200–230 nm down to 30 nm. On the basis of these experiments, a t1/2 of about 70 s at room temperature was roughly estimated, which fitted quite well with the value obtained from previous NMR experiments [79].

10.10.3. Phylline, Structure Elucidation Directly from the Crude Extract Phylline (9) is a nice example of the application of the analytical triad LC-MS/MS-NMRCD. The HPLC-UV chromatogram of an extract of the rare tropical