Topics in Stereochemistry, Volume 8

TOPICS IN

STEREOCHEMISTRY

VOLUME 8

A WILEY-INTERSCIENCESERIES

ADVISORY BOARD

STEPHEN J. ANGYAL, Universityof New South Wales, Sydney,Australia JOHN C. BAILAR, Jr., University of Illinois, Urbana, Illinois OTTO BASTIANSEN, University of Oslo, Oslo, Norway GIANCARLO BERTI, University of Pisa, Pisa, Italy DAVID GINSBURG, Technion,Israel Institute of Technology,Haifa, Israel WILLIAM KLYNE, Westfield College, University of London, London, England KURT MISLOW, Princeton University, Princeton, New Jersey SAN-ICHIRO MIZUSHIMA, Japan Academy, Tokyo, Japan GUY OURISSON, University of Strasbourg, Strasbourg, France GERHARD QUINKERT, Johann WolfgangGoethe-Universifiit,Frankfurt am Main, Germany VLADO PRELOG, Eidgeniissische Technische Hochschule, Zurich, Switzerland HANS WYNBERG, University of Groningen, Groningen, The Netherlands

TOPICS IN

STEREOCHEMISTRY EDITORS

ERNEST L. ELIEL Professor of Chemistry University of North Carolina Chapel Hill, North Carolina

NORMAN L. ALLINGER Professor of Chemistry University of Georgia A thens, Georgia

VOLUME 8

g/i2 A N INTERSCIENCE @ PUBLICATION

JOHN WILEY & SONS

New York

London

Sydrrey

Toronto

An Interscience @ Publication Copyright @ 1974, by John Wiley & Sons, Inc. All rights reserved. Puhlished simultaneously in Canada. No part of this book may be reproduced by any means, nor trailsrnitted, nor translated into a machine language without the written permission of the publisher.

Library of Congress Catalog Card Number: 67-1 3943 ISBY 0-471-23755-8

Printed in the United States of America. 109 8 7 6 5 4 3 2 1

To the memory of Jacobus Hendricus van’t Hoff and Joseph Achille Le Be1 on the hundredth anniversary

of the conception of the tetrahedral carbon atom

INTRODUCTION TO THE SERIES

During the last decade several texts in the areas of stereochemistry and conformational analysis have been published, including Stereochemistry of Carbon Compounds (Eliel, McGraw-Hill, 1962) and Conformational Analysis (Eliel, Allinger, Angyal, and Morrison, Interscience, 1965). While the writing of these books was stimulated by the high level of research activity in the area of stereochemistry, it has, in turn, spurred further activity. As a result, many of the details found in these texts are already inadequate or out of date, although the student of stereochemistry and conformational analysis may still learn the basic concepts of the subject from them. For both human and economic reasons, standard textbooks can be revised only at infrequent intervals. Yet the spate of periodical publications in the field of stereochemistry is such that it is an almost hopeless task for anyone to update himself by reading all the original literature. The present series is designed to bridge the resulting gap. If that were its only purpose, this series would have been called “Advances (or “Recent Advances”) in Stereochemistry.” It must be remembered, however, that the above-mentioned texts were themselves not treatises and did not aim at an exhaustive treatment of the field. Thus the present series has a second purpose, namely to deal in greater detail with some of the topics summarized in the standard texts. It is for this reason that we have selected the title Topics in Stereochemistry. The series is intended for the advanced student, the teacher, and the active researcher. A background of the basic knowledge in the field of stereochemistry is assumed. Each chapter is written by an expert in the field and, hopefully, covers its subject in depth. We have tried to choose topics of fundamental inport aimed primarily at an audience of organic chemists but involved frequently with fundamental principles of physical chemistry and molecular physics, and dealing also with certain stereochemical aspects of inorganic chemistry and biochemistry. It is our intention to bring out future volumes at intervals of one to two years. The Editors will welcome suggestions as to suitable topics. We are fortunate in having been able to secure the help of an international board of Editorial Advisors who have been of great assistance by vii

viii

INTRODUCTION

suggesting topics and authors for several articles and by helping us avoid duplication of topics appearing in other, related monograph series. We are grateful to the Editorial Advisors for this assistance, but the Editors and Authors alone must assume the responsibility for any shortcomings of Topics in Stereochemistry. N . L. Allinger E. L. Eliel January 1967

PREFACE

Volume 8, like most previous volumes in the series, contains four chapters. Interest in stereochemical applications of nuclear magtietic resonance spectroscopy remains high. Volume 7 had a chapter on applications of the nuclear Overhauser effect; the first chapter in the present volume, by N . K. Wilson and J. B. Stothers, deals with stereochemical aspects of carbon-I3 NMR. Although two complete books on the topic of 13C NMR have recently appeared, the applications of the technique to stereochemical problems seemed extensive and significant enough to warrant separate treatment. We were fortunate in being able to persuade the author of one of the books to coauthor a self-contained chapter on this topic. The chapter is a gold mine of useful information. About two-thirds of it deals with the relation of 13Cchemical shifts to configurational and conformational parameters and similar, though less extensive, correlations involving *H-13C spin couplings. The remaining third of the chapter relates to dynamic phenomena: averaging of spectra in the rapid-exchange limit, barrier measurement by coalescence and line shape analysis, conformational population measurements in the slow-exchange limit, and-less familiar from proton NMR spectroscopy-the use of relaxation measurements in the determination of rotational barriers. The a priori determination of molecular geometry and molecular energy continues to be a subject of great interest. In the preceding volume there was a chapter on ab initio quantum-mechanical calculations pertaining to carbonium ions. Unfortunately, calculations of this type are confined to small molecules and are still somewhat controversial. For larger molecules, molecular mechanical calculations present the currently preferred approach, but they also (and we speak here from personal experience) are not without difficulties. Both methods have in common the requirement for sophisticated computers and substantial expenditure of computer time. R. Bucourt, in the second chapter, presents a lucid summary of the semiquantitative method he has developed for predicting conformation and relative stability of conformational and configurational isomers through consideration of torsional angles alone. Although not as accurate as computer methods, the torsion angle approach provides a basic understanding of the problem, is much easier and cheaper to use, requires much less iX

X

PREFACE

preparation, and is considerably superior to the mere inspection of Dreiding molecular models. One of the more interesting conformations of six-member rings is the boat-twist form. Although this form was recognized by Sachse in his classical (1890) paper on nonplanar six-membered rings, it was later believed to be of minor importance because of its lesser stability compared to the chair. In recent years, however, a number of molecules have been found that exist preferentially in the twist-boat form or in which, at least, that form contributes substantially to the overall molecular population. Unfortunately, this in turn has given rise to some confusion regarding boat versus twist forms and entropy criteria in the recognition of boat-twist conformations. G.M. Kellie and F. G.Riddell, in the third chapter, give a clear and well-organized description of this problem and, by pointing out the pitfalls into which past investigators have stumbled, set up a series of caveafs for future researchers. The last chapter, by R. M. Moriarty, provides a complete and exhaustive discussion of the configurational and conformational aspects of fourmembered rings. It may come as a surprise that this ring system, which is generally thought of as one of the less important ones, has given rise to a very long chapter in this volume; but there is, in fact, a great deal of recent information available in this system and our gratitude is due to the author of this chapter for collecting it all in one place. The chapter ranges from spectroscopic measurements of four-membered rings (which have uncovered much information on degree of puckering and on folding barriers) to four-membered rings in natural products and from simple carbocycles to fused heterocyclic systems. We think that the production of Volume 7 in “coldtype” has been successful and are continuing with this rather economical method of production. Since Volume 9 will probably not appear until 1975, we are dedicating Volume 8 to the memory of Jacobus Hendricus van’t Hoff and Joseph Achille Le Be1 on the occasion of the centennial of the conception of the tetrahedral carbon atom, 1874-1974. This series (among others) is proof of the immense fertility and impact of van’t Hof€‘s and Le Bel’s ingenious idea, one hundred years ago. ERNEST L. ELIEL NORMANL. ALLINGER May 1973

CONTENTS

STEREOCHEMICAL ASPECTS OF lSC NMR SPECTROSCOPY by Nancy K. Wilson, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, and J . B. Stothers, Department of Chemistry, University of Western Ontario, London, Canada.. ...............................

1

THE TORSION ANGLE CONCEPT IN CONFORMATIONAL ANALYSIS by Robert Bucourt, Centre de Recherches Roussel-Waf, Paris, France ............................................. 159 NONCHAIR CONFORMATIONS OF SIX-MEMBERED RINGS by G. M . Kellie and F. G. Riddell, Department of Chemistry 225 The University, Stirling, Scotland. ........................ STEREOCHEMISTRY OF CYCLOBUTANE AND HETEROCYCLIC ANALOGS by Robert M . Moriarty, Department of Chemistry, University of Illinois at Chicago Circle, Chicago, Illinois. ................ 271 Subject Index

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Cumulative Index, Volumes 1-8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

434

STEREOCHEMICAL ASPECTS OF NANCY K

3C NMR SPECTROSCOPY

. WILSON

National I n s t i t u t e o f Environmental Health Sciences Research Triangle Park. North Carolina J

. B . STOTHERS

Department o f Chemistry. University o f Western Ontario London. Canada

.................... 11 . 3~ S p e c t r a l Parameters .............. A . 1 3 C Shieldings . . . . . . . . . . . . . . . . . B . 1 3 C Coupling Constants . . . . . . . . . . . . . C . 1 3 C R e l a x a t i o n Times . . . . . . . . . . . . . . I 1 1 . C o n f i g u r a t i o n a l E f f e c t s on 1 3 C Parameters and Stereochemical Assignments . . . . . . . . . . . . . A . Alkanes and A1 k y l D e r i v a t i v e s . . . . . . . . . B. A l i c y c l i c Derivatives . . . . . . . . . . . . . C . Alkenes and D e r i v a t i v e s . . . . . . . . . . . . D . Saturated Heterocycles . . . . . . . . . . . . . 1 . 1. 3.Dioxanes . . . . . . . . . . . . . . . . I . Introduction

2.

3

.

4 . Monosaccharides and O l i g o s a c c h a r i d e s

3

3

7 10 15 15 25 48 54 54

.

56

...

61

P i p e r i d i n e s . P i p e r a z i n e s . and D e r i v a t i v e s C y c l i c S u l f o x i d e s and R e l a t e d Systems

2

....

63 1

Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

STEREOCHEMICAL ASPECTS OF

2

IV.

V.

3C NMR SPECTROSCOPY

5.

Phosphetane, Phospholene, and Phosphorinane Derivatives

6.

Nucleosides and N u c l e o t i d e s

................ ........

73

82

. . . . . . . . . . . . . . . . 85 F. Polymers and Peptides . . . . . . . . . . . . . 88 G. O r g a n o m e t a l l i c s . . . . . . . . . . . . . . . . 93 A p p l i c a t i o n s o f 1 3 C NMR t o Chemical Rate Processes . 96 A. Chemical E q u i l i b r i u m and Exchange . . . . . . . 96 B. S p i n - L a t t i c e R e l a x a t i o n S t u d i e s . . . . . . . . 129 E.

Aromatic Systems

C.

Proton-Enhanced Nuclear I n d u c t i o n Spectroscopy

,

144

. . . . . . . . . . . . . . . 144 . . . . . . . . . . . . . . . . . . . . . 146

Summary and Prognosis References

I.

INTRODUCTION

Applications of proton nmr spectroscopy to the elucidation of stereochemical features of molecules are well established and are routinely exploited, but for numerous systems the information available from 'H results is either limited or somewhat difficult to interpret unequivocally. In principle, stereochemical information for a wide variety of systems is provided by nmr parameters of several other nuclei. One of the most potent sources of such data is 13C nuclei. The tremendous strides taken in the advancement of 13C nmr techniques and instrumentation over the past two or three years have rendered 3C spectroscopy a routine chemical tool offering powerful new approaches to the solution of a wide range of problems. Although, at the present time, the number of published examples of stereochemical applications of 13C nmr is small, it suffices to confirm the expected utility. Perhaps more significantly, there are clear indications of potentially valuable new applications. The primary purpose of this cha ter is to survey the various stereochemical implications of 3C spectroscopy as a guide to the scope and limitations of this important new tool in the light of present developments. The coverage is not comprehensive but rather is intended to be illustrative. Some possible directions in which further research may lead to fruitful discovery are discussed, since

'

NANCY K. WILSON AND J. B. STOTHERS

3

there is little doubt that the number and variety of stereochemical applications of 13C nmr will mushroom in the next few years. Since several full discussions of the general theory and applications of nmr spectrosco are available (1) and since two detailed presentations of "C spectroscopy have recently appeared ( 2 ) , only those features of particular consequence for stereochemical investigations are briefly reviewed in this chapter and discussion of experimental methods or techniques is limited to a few recent developments. In the following section, the major stereochemical features of the spectral parameters: shieldings, coupling constants, and relaxation times, are discussed in a general fashion. The specific applications of trends in these parameters to stereochemical assignments are described for various families of compounds in the third section. The fourth section is devoted to the consideration of dynamic processes amenable to investigation by 3C spectroscopy and, in a broad interpretation of "stereochemical implications," includes the use of 13C data for the study of molecular motion. Finally, some probable future developments are discussed.

II.

3C SPECTRAL PARAMETERS A.

13C S h i e l d i n g s

In contrast to protons, carbon-13 nuclei absorb over a relatively wide range which for commonly encountered, neutral organic compounds is about 220 ppm. With signal positions referenced to tetramethylsilane (TMS) O), the common spectral range is 6, 0 to 220, with increasing positive values toward lower fields (higher frequencies) by analogy with the 6 scale for protons. The most highly shielded carbon in a diamagnetic environment yet reported is that of carbon tetraiodide (3), 6c -292, while charge-bearing carbons in alkyl carbocations absorb as low as 6c 334 (4). Since 13C spectra are routinely recorded with complete proton decoupling, they consist entirely of singlet signals (provided other magnetic nuclei are absent), and, usually, separate resolved signals are seen for each individual carbon in molecules of moderate complexity. For example, the spectra of steroids generally have few, if any, overlapping signals. Consequently, 13C spectra are potentially rich sources of shielding (chemical shift) information. Although a detailed discussion of 13C shieldings is beyond the scope of this chapter, some general trends are briefly noted as an indication of the magnitudes of such shieldings. In general, the trends are similar to those found for protons,

(6Fs

STEREOCHEMICAL ASPECTS OF

4

'3C NMR SPECTROSCOPY

with sp3-hybridized carbons absorbing at high fields and sp2carbons at low fields; for hydrocarbons, the approximate ranges for such carbons are 0 to 50 and 100 to 150 ppm, respectively. Except for the central carbon in allenic structures, which is strongly deshielded, 6c 198 to 213 (5), sp-hybridized carbons absorb at intermediate fields; for alkynes, the range is 6c 67 to 92. The effects of electronegative substituents follow the expected patterns with increasing shifts to lower fields caused by more polar groups. For example, the carbinyl carbons in aliphatic alcohols absorb at 50 to 75 and carbonyl carbons appear in the range 6c 160 to 220. One striking feature of 13C shielding data is the remarkable consistency of substituent effects in closely related systems, with the general finding that simple additivity relations correlate the shielding data within various families of compounds with good precision (2). An early example described by Grant and Paul (6) for acyclic hydrocarbons is

i

6, = B

i

+ f

A. n 3 ij

where 6c is the ith carbon shielding, A * is an additive shift parameter for the jth position, n i j is {he number of substituents in the jth position, and B is a constant. The A . and B values were determined by linear regression analysis gf the body of data. For linear hydrocarbons, only five parameters are required to define the shieldings and these factors -- labeled a , 8 , y , 6, E -- are the shifts produced along an alkyl chain by replacing a hydrogen atom with a methyl group, i.e., the methyl substituent effects at the a, 8 , y , 6, and E positions.* Similar factors can be deduced for other substituents by a comparison of the shieldings for RX with those for RH. The effects f o r a variety of substituents thus derived are listed in Table 1, from which it is apparent that appreciable effects are observed at carbons four and five bonds from the substituent. The y effects are of particular interest in the present context since these upfield shifts appear to arise primarily from steric interactions in gauche rotamers. Qualitative support for this notion is given by the results of a similar analysis of substituent effects in fixed cyclic systems for which y effects for both gauche and a n t i orientations of each substituent can be separately evaluated. A t present, generalized theoretical treatments of 3C shieldings have not been particularly successful except within

'

*With eq.[l], 15 parameters were required for branched systems, but by considering primary, secondary, tertiary, and quaternary carbons separately, relations with four parameters for each carbon type have been developed (7) which correlate the data for 59 paraffins.

NANCY K.

WILSON AND J . B. STOTHERS

5

Table 1. S u b s t i t u e n t E f f e c t s a i n Acyclic A l i p h a t i c Systems (2) ( i n ppm)

Substituent

CH3

c1

Br lo-I lo-OH 2O-OH 1°-NH2 COOH

a 9.1 31.2 20.0 -10.0b 48.3 40.8 28.9 20.9

8 9.4 10.5 10.6 11.3 10.2 7.7 11.4 2.5

Y -2.5 -4.6 -3.1 -1.0 -5.8 -3.7 -4.6 -2.2

6

E

0.3 0.1 0.1 0.2 0.3 0.3 0.7 1.0

0.1 0.5 0.5 1.0 0.1 0.3

--

aNegative and p o s i t i v e values denote u p f i e l d and downf i e l d s h i f t s , respectively. bMarker e t a l . (8) found t h e a e f f e c t s i n i s o p r o p y l i o d i d e and t - b u t y l i o d i d e t o be +1.4 and +13.7 ppm, r e s p e c t i v e l y . r e s t r i c t e d s e r i e s of compounds, and t h e t r e n d s i l l u s t r a t e d i n Table 1 a r e not y e t q u a n t i t a t i v e l y understood. Nevertheless, q u a l i t a t i v e , empirical i n t e r p r e t a t i o n s of t h e geometric dependence of t h e y e f f e c t have been u s e f u l . A s e m i t h e o r e t i c a l r a t i o n a l i z a t i o n of i t s o r i g i n has been presented by Grant and Cheney (9) i n terms of B model f o r nonbonded s t e r i c i n t e r a c t i o n s between c l o s e l y neighboring hydrogen atoms i n hydrocarbons. According t o t h e i r p r o p o s a l , t h e C-H bonds o f t h e i n t e r a c t i n g hydrogens s u f f e r s t e r i c p o l a r i z a t i o n such t h a t t h e e l e c t r o n d e n s i t y a t t h e carbons i s changed because o f t h e nonbonded r e p u l s i o n between hydrogens on y-carbons i n gauche (1) o r e c l i p s e d o r i e n t a t i o n s . The f o r c e a s s o c i a t e d with t h e nonbonded i n t e r a c t i o n energy h a s a component along t h e C-H bond a x i s which a f f e c t s t h e e l e c t r o n d e n s i t y a t t h e y-carbons. From c o n s i d e r a t i o n of t h e conformations of t h e methyl groups i n o-xylene, Grant and Cheney derived an e m p i r i c a l expression f o r t h e s t e r i c a l l y induced s h i f t i n terns of t h e geometry of t h e i n t e r a c t i n g hydrogens. From t h e i r r e l a t i o n , t h e value of - 4 . 8 ppm was c a l c u l a t e d f o r t h e s t e r i c s h i f t i n gauche-butane ( 1 0 ) . Since anti-butane i s favored i n f r e e energy by 0 . 3 kcal/mole over gauche-butane (11), butane e x i s t s a s a ca. 2 : l mixture of rotamers a t room temperature. I f it i s assumed t h a t t h e y-carbons a r e unaffected i n t h e a n t i rotamer, a s t e r i c s h i f t of -1.8 ppm i s p r e d i c t e d which compares favorably with t h e A . value of -2.5 ppm (Table 1 ) . The examination of 3 o t h e r systems ( S e c t . 111) r e v e a l s , however, t h a t t h e model is

STEREOCHEMICAL ASPECTS OF

6

1

3C NMR SPECTROSCOPY

2

only qualitatively valid. Nevertheless, consideration of y substituent effects is valuable for stereochemical elucidations. Similar y shifts occur in systems containing heteroatoms. For example, a comparison of the methyl carbon shieldings of the methylhydrazines reveals an effect of -5.3 ppm for ymethyls which is entirely consistent with the preferred conformation 2 having orthogonal lone-pair orbitals (12). It is well established that diastereotopic nuclei are intrinsically nonequivalent; they are said to be anisochronous (13). Examples abound in proton spectra, typical of which are

xq 3

R

z

3

R

I

2 4

R

zI 6

the methyl protons of isopropyl groups and methylene protons in systems such as 3-5 (R = HI. Although for appreciable nonequivalence it is usually considered necessary for the compound to have a preferred conformation or preferred conformations in which the yeminal protons occupy significantly different magnetic environments, this is not a requirement. The shielding difference due to nonequivalence, A6, may be enhanced if the system has a preferred conformation, but this is an additional factor. Thus, A6 = A + Aid where Acp depends on conCP former populations and Aid arises from the intrinsic diastereomerism. The relative magnitudes of Aid and Acp may be determined by variable-temperature studies (13). At high temperatures the populations of rotamers are equal, in the limit, so that Acp = 0 and the limiting value of A6 is Aid. At sufficiently low temperatures, the three (+)-rotamers are "frozen" out and the spectrum is the superposition of the spectra of the

NANCY K. WILSON AND J. B.

7

STOTHERS

i n d i v i d u a l rotamers. Cases have a l s o been s t u d i e d where Acp = 0 f o r s t r u c t u r a l reasons so t h a t Aid can be measured d i r e c t l y ( 1 3 a ) . I n g e n e r a l , A 6 v a l u e s f o r d i a s t e r e o t o p i c p r o t o n s are small and a r e n o t always observable; furthermore, q u a n t i t a t i v e p r e d i c t i o n s of t h e nonequivalence are e s s e n t i a l l y impossible. For n u c l e i , however, one may a n t i c i p a t e c o n s i d e r a b l y l a r g e r A 6 v a l u e s because of t h e g r e a t e r chemical s h i f t range and sens i t i v i t y t o s u b s t i t u e n t s . The few r e s u l t s c u r r e n t l y a v a i l a b l e confirm t h i s p r e d i c t i o n and i n d i c a t e t h e p o t e n t i a l u t i l i t y of 1 3 C s t u d i e s of v a r i o u s a l i p h a t i c systems; b u t no variable-temp e r a t u r e 13C r e s u l t s have been r e p o r t e d from which t h e r e l a t i v e magnitudes of Acp snd h i d can be deduced.

B.

13C

Coupling Constants

The body o f published d a t a on 13C s p i n - s p i n c o u p l i n g cons t a n t s i s probably l a r g e r t h a n t h a t f o r 13C s h i e l d i n g s a t t h e p r e s e n t t i m e , because t h e e f f e c t s of s p i n coupling a r e m a n i f e s t i n t h e s p e c t r a of o t h e r n u c l e i . For example, p r o t o n s p e c t r a of carbon-containing compounds a r e composites of t h e absorpt i o n p a t t e r n s f o r p r o t o n s on 1 2 C I t h e major spectrum, and t h e a b s o r p t i o n s of t h e p r o t o n s on 1 3 C , having i n t e n s i t i e s of 1.1%of t h e 12C-H a b s o r p t i o n s , termed t h e 13C s a t e l l i t e s . Since J CH v a l u e s a r e r e l a t i v e l y l a r g e , 100 t o 280 Hz, the I 3 C s a t e l l i t e s a r e w e l l removed from t h e major a b s o r p t i o n and, i n g e n e r a l , t h e 13C s a t e l l i t e s of p r o t o n s whose s i g n a l s a r e n o t c l o s e t o o t h e r proton s i g n a l s a r e r e a d i l y d e t e c t e d provided high conc e n t r a t i o n s and/or time-averagin t e c h n i q u e s are employed. Measurements o f 13C-lH and 13C-1'F c o u p l i n g c o n s t a n t s from 'H and 19F s p e c t r a have been p o p u l a r and t h e l i t e r a t u r e on such couplings i s voluminous (1, 2 ) . Most o f t h e a t t e n t i o n , howe v e r , has been d i r e c t e d toward understanding s p i n - s p i n i n t e r a c t i o n s through one bond; t h u s couplings through two, t h r e e , and f o u r bonds a r e n o t n e a r l y so w e l l d e f i n e d . The l a t t e r can be expected t o f u r n i s h s t e r e o c h e m i c a l information on t h e b a s i s of t h e well-known behavior o f proton-proton couplings s i n c e , i n t h e average energy approximation (14), i f t h e c o e f f i c i e n t s of t h e wave f u n c t i o n s a r e i d e n t i c a l , two coupling c o n s t a n t s , JCHand J,,, may be r e l a t e d a s

where # ( O ) i s t h e e l e c t r o n d e n s i t y a t n u c l e a r magnetogyric r a t i o , and AE i s energy. Recent INDO c a l c u l a t i o n s f o r propane (15) p r e d i c t a d i h e d r a l an l e s i m i l a r t o t h a t f o r JXCCH (X = H, "F,

t h e nucleus, 6 i s t h e t h e mean e x c i t a t i o n v i c i n a l couplings i n d e endence f o r JcccH 3pP) i n XCCH fragments.

8

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

S u f f i c i e n t d a t a f o r 3C couplings through two o r more bonds a r e a v a i l a b l e t o confirm e x p e c t a t i o n s regarding t h e i r u t i l i t y a s stereochemical probes, and it is on t h e s e c o n s t a n t s t h a t we have placed t h e emphasis i n t h e following s e c t i o n s . Since 13C-lH coupling c o n s t a n t s a r e dominated by t h e Fermi c o n t a c t term, a major f a c t o r c o n t r i b u t i n g t o t h e i r magn i t u d e i s t h e degree of 8 c h a r a c t e r of t h e bonding o r b i t a l s. Although o t h e r important c o n t r i b u t i n g f a c t o r s have o f t e n been neglected i n i n t e r p r e t a t i o n s of t h e observed t r e n d s , it is reasonable t o expect t h a t p e r t u r b a t i o n s a f f e c t i n g t h e o r b i t a l h y b r i d i z a t i o n may be r e f l e c t e d i n t h e J C H v a l u e s . Among such p e r t u r b a t i o n s , s t e r i c compression and s t r a i n may c o n t r i b u t e i n s p e c i f i c cases. An i n t e r e s t i n g comparison of t h e s e f a c t o r s i s provided by t h e o l e f i n i c J C H v a l u e s f o r t r i m e t h y l e t h y l e n e , 140.0 Hz; t r i - t - b u t y l e t h y l e n e , 143.3 HZ; and bicyol0[3.3.11non-1-ene (61, 156.2 HZ ( 1 5 ) . The l a t t e r v a l u e i s t h e same a s

6

those f o r cyclohexene and e t h y l e n e , although t h e double bond i n 6 i s undoubtedly s t r a i n e d . The marked decrease i n JcHf o r t h e t r i a l k y l e t h y l e n e s has been a t t r i b u t e d t o s t e r i c compress i o n of t h e o l e f i n i c hydrogen, which is n o t a f a c t o r f o r 6. A a r t from a few such examples, d i s c u s s i o n of t h e one-bond l%-X spin-spin i n t e r a c t i o n s i s excluded i n t h i s c h a p t e r . Although t h e r e s o l u t i o n i n t h e e a r l i e r techniques f o r d i r e c t observation of 3C s p e c t r a was i n s u f f i c i e n t t o permit measurements of 3C-X coupling c o n s t a n t s through more than one bond i n most systems, t h e p r e s e n t l y a v a i l a b l e i n s t r u m e n t a t i o n is q u i t e capable of providing t h e s e d a t a f o r longer range i n t e r a c t i o n s . In a d d i t i o n , a number of i n d i r e c t methods based on multiple-resonance techniques have been developed e s p e c i a l l y f o r such determinations ( 2 ) . Nevertheless, f o r p r a c t i c a l reasons, t h e number of workers p r i n c i p a l l y concerned with t h i s t o p i c has remained r e l a t i v e l y s m a l l , b u t more r e c e n t developments have e s t a b l i s h e d t h a t 3C-1H coupling information can be f a i r l y r e a d i l y obtained. Heretofore, t h e t i m e r e q u i r e d t o g e n e r a t e s p e c t r a with s u f f i c i e n t signal-to-noise (S/N) l e v e l s from n a t u r a l abundance m a t e r i a l s presented a major o b s t a c l e t o i n v e s t i g a t i o n s of t h e s e parameters. Generally, n a t u r a l abundance 3C s p e c t r a a r e recorded under conditions of complete proton decoupling f o r optimum s e n s i t i v i t y while reducing t h e sampling time req u i r e d t o o b t a i n s a t i s f a c t o r y S/N l e v e l s . Simultaneous s t r o n g

NANCY K.

WILSON AND J. B.

STOTHERS

9

i r r a d i a t i o n of t h e e n t i r e proton spectrum while recording t h e 3C absorption not only c o l l a p s e s t h e proton-induced multip l e t s t o s i n g l e l i n e s b u t a l s o produces a n u c l e a r Overhauser enhancement of t h e 13C s i g n a l s because s a t u r a t i o n of t h e prot o n s a l t e r s t h e equilibrium population of t h e 13C n u c l e a r energy l e v e l s t o more favorable v a l u e s ( 1 7 ) . The Overhauser e f f e c t can l e a d t o an i n c r e a s e i n i n t e g r a t e d i n t e n s i t y of a given s i g n a l of n e a r l y 300%. I n t h i s mode of o p e r a t i o n , however , t h e 3C-1H spin-spin coupling information is l o s t , although t h e coupling i n t e r a c t i o n s with any o t h e r magnetic nuc l e i a r e u n a f f e c t e d , rendering t h e s e d a t a r e a d i l y a v a i l a b l e . This i s e x p e c i a l l y valuable f o r organophosphorus compounds and has been e x p l o i t e d by s e v e r a l workers a s discussed l a t e r . S i m i l a r l y , a v a r i e t y of o t h e r I3C-X coupling c o n s t a n t s have been determined. Since JCH = (yH/yD)JCD, measurements of J C H values can be accomplished by i s o t o p i c s u b s t i t u t i o n of hydrogen by deuterium. Although of somewhat l i m i t e d g e n e r a l u t i l i t y , t h i s approach has proved u s e f u l f o r c e r t a i n systems. An i d e a l method i s undoubtedly one which provides a l l of t h e 13CI H coupling information without r e q u i r i n g a d d i t i o n a l chemical manipulations o r extremely long sampling times. Since decoupl i n g and Overhauser e f f e c t s have d i f f e r e n t time dependences, it i s p o s s i b l e t o observe e i t h e r s i n g l y . I f t h e proton-decoupling i r r a d i a t i n g power i s t e r m i n a t e d , t h e 3C- 'H coupling r e t u r n s immediately , b u t t h e Overhauser enhancement decays much more slowly because r e e q u i l i b r a t i o n of t h e nuclear energy l e v e l populations i s determined by r e l a x a tion t i m e s . The Fourier transform mode of 13C o b s e r v a t i o n i s i d e a l l y s u i t e d t o c a p i t a l i z e on t h i s timing d i f f e r e n c e s i n c e i n d i v i d u a l d a t a a c q u i s i t i o n p e r i o d s a r e of s h o r t d u r a t i o n (0.1-1 s e c , t y p i c a l l y ) r e l a t i v e t o t h e p u l s e r e p e t i t i o n r a t e used i n t h e s e experiments (5-15 s e c , t y p i c a l l y ) . Thus, i f t h e decoupling frequency is gated o f f during t h e t i m e t h e sample i s s u b j e c t e d t o t h e 13C observing p u l s e and gated on immedia t e l y a f t e r , t h e f r e e i n d u c t i o n decay p a t t e r n i s t h a t from a coupled spectrum enhanced by t h e Overhauser e f f e c t . A l l of t h e 13C-lH coupling information i s t h e r e f o r e a v a i l a b l e i n the F o u r i e r transformed spectrum. [This method i s n o t a p p l i c a b l e i f t h e y 1 v a l u e s a r e r e l a t i v e l y s h o r t (62 s e c ) . ] A few s t r i k i n g examples of t h e use of t h i s technique have been r e p o r t e d (18) and t h e success achieved c l e a r l y confirms t h e p o t e n t i a l of t h e method.* * I t may be noted t h a t g a t i n g t h e decoupler i n e x a c t l y t h e o p p o s i t e f a s h i o n , i . e . , on only while i r r a d i a t i n g and observing t h e 1 3 C spectrum, provides a completely decoupled spectrum without Overhauser enhancement (18a, 1 9 ) . This technique app e a r s promising f o r h i g h l y p r e c i s e i n t e g r a t i o n s and may elimina t e t h e need f o r " d e f e a t i n g " t h e Overhauser e f f e c t by t h e addi t i o n of paramagnetic m a t e r i a l ( 2 0 ) .

10

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

The p r i n c i p a l disadvantage of coupled 13C s p e c t r a is t h e extens i v e overlap of m u l t i p l e t s a r i s i n g from s i m i l a r l y s h i e l d e d carbons. This problem may be a l l e v i a t e d i n many systems by t h e simultaneous use of t h e i n c r e a s i n g l y popular l a n t h a n i d e s h i f t reagents. I n any e v e n t , t h e 13C-1tI coupling information i s now much more r e a d i l y a v a i l a b l e d i r e c t l y from 1 3 C s p e c t r a . A l l of t h e foregoing d i s c u s s i o n concerned t h e examination of compounds containing I 3 C i n n a t u r a l abundance. I s o t o p i c enrichment with 3C , of course , c o n s t i t u t e s an a l t e r n a t i v e r o u t e t o t h e determination of s p e c i f i c coupling c o n s t a n t s and has been employed i n s e v e r a l i n s t a n c e s , most of which, however, were c a r r i e d o u t before t h e development of t h e c u r r e n t l y a v a i l a b l e instrumentation.

C.

I3C

Relaxation Times

Although many s t r u c t u r a l c h a r a c t e r i s t i c s of molecules a r e c l e a r l y revealed by t h e chemical s h i f t s and coupling c o n s t a n t s , a d d i t i o n a l s t r u c t u r a l information a s w e l l a s i n s i g h t i n t o dynamic molecular processes can be gained from r e l a x a t i o n time measurements. The two c h a r a c t e r i s t i c times, T1 f o r s p i n - l a t t i c e r e l a x a t i o n , and T 2 f o r spin-spin r e l a x a t i o n , d e s c r i b e d i f f e r e n t time-dependent processes occurring i n t h e n u c l e a r spin system (21), both involving n o n r a d i a t i v e t r a n s i t i o n s . Spin-lattice interactions reestablish t h e equilibrium d i s t r i bution of s p i n s which e x i s t e d before t h e absorption of radiofrequency energy. The excess n u c l e a r s p i n energy i s t r a n s f e r r e d t o o t h e r degrees of freedom of t h e molecular system i n which t h e magnetic n u c l e i a r e embedded (the l a t t i c e ) with consequent thermal e q u i l i b r a t i o n of t h e s p i n system and t h e l a t t i c e . Any l o c a l f l u c t u a t i n g magnetic f i e l d s having frequency components a t t h e n u c l e a r Larmor frequency can induce t r a n s i t i o n s between n u c l e a r s p i n l e v e l s and t h u s c o n t r i b u t e t o TI. Since molecular motion produces such l o c a l f i e l d v a r i a t i o n s with t i m e , T i values r e f l e c t both t h e degree and t h e type of molecular motion. Spin-spin r e l a x a t i o n involves t r a n s i t i o n s between nuclear s p i n s t a t e s by mutual exchange of s p i n energy between neighboring n u c l e i . Energy i s conserved w i t h i n t h e nuclear s p i n system; t h u s t h i s r e l a x a t i o n process does not a f f e c t t h e thermal d i s t r i b u t i o n of s p i n s b u t does govern t h e l i f e t i m e of a given s p i n s t a t e and, t h e r e f o r e , can a f f e c t t h e shape of t h e observed s i g n a l s . The major f e a t u r e s governing T I and T2 values a r e considered i n t h e sequel. Mechanisms of s p i n - l a t t i c e r e l a x a t i o n have been discussed r e c e n t l y i n d e t a i l by Lyerla and Grant ( 2 2 ) . Contributions t o T1 a r e shown t o a r i s e from any of t h e following phenomena: dipole-dipole i n t e r a c t i o n s with nearby magnetic n u c l e i , e l e c t r i c quadrupolar i n t e r a c t i o n s , s p i n r o t a t i o n i n small o r very

NANCY K. WILSON AND J . B. STOTHERS

11

symmetric molecules, chemical s h i f t a n i s o t r o p y ( e s p e c i a l l y a t very high f i e l d s ) , s c a l a r coupling, and t h e presence of paramagnetic m a t e r i a l s . For most reasonably l a r g e and asymmetric molecules, t h e r e l a x a t i o n of p r o t o n a t e d carbons i s dominated by d i p o l a r i n t e r a c t i o n s with t h e d i r e c t l y bonded p r o t o n s and T 1 i s given ( 2 3 ) by

where N i s t h e number of d i r e c t 1 bonded p r o t o n s , yc and y H a r e t h e magnetogyric r a t i o s of "C and 'H, r i s t h e C-H i n t e r n u c l e a r d i s t a n c e , and T e f f i s t h e e f f e c t i v e c o r r e l a t i o n time f o r r o t a t i o n a l r e o r i e n t a t i o n . Equation [ 3 ] i s v a l i d i n t h e motional narrowing approximation, i n which 1 / T e f f i s much g r e a t e r than t h e resonance f r e q u e n c i e s of t h e 1 3 C and ' H nuc l e i . For medium-sized molecules i n nonviscous s o l v e n t s , T is to s e c , and t h i s c o n d i t i o n i s met. Because of t h e i r high magnetogyric r a t i o , p r o t o n s a r e e f f i c i e n t d i p o l a r r e l a x e r s , b u t f o r carbons l a c k i n g p r o t o n s t h e r-6 term i n eq. [ 3 1 r e n d e r s d i p o l a r r e l a x a t i o n by neighboring p r o t o n s essent i a l l y n e g l i g i b l e . Thus f o r carbons without a t t a c h e d p r o t o n s , o t h e r mechanisms may become important o r may, i n f a c t , domin a t e . Since T i also depends on T e f f , d i f f e r e n c e s i n motion from one p a r t of a molecule t o a n o t h e r , a n i s o t r o p i c r e o r i e n t a t i o n , can produce unequal v a l u e s of l/IVTl f o r d i f f e r e n t prot o n a t e d carbons. A measurable c o n t r i b u t i o n t o 1 / T 1 from i n t e r n a l r e o r i e n t a t i o n w i l l a r i s e i f t h e c o r r e l a t i o n times f o r i n t e r n a l motion a r e c l o s e t o o r s h o r t e r than t h e c o r r e l a t i o n t i m e s f o r o v e r a l l molecular r e o r i e n t a t i o n ( 2 3 ) . Furthermore, nonprotonated carbons having t h e same T e f f w i l l have much longer Ti v a l u e s , s i n c e t h e s e n u c l e i l a c k t h e e f f i c i e n t d i p o l a r r e l a x a t i o n of p r o t o n a t e d carbons. T o i l l u s t r a t e t h e e f f e c t s of i n t e r n a l motion on T I v a l u e s t h e d a t a f o r 1-decanol ( 2 4 ) a r e shown i n 7. The i n c r e a s e by 065=-0_84

H0-cHC , HC , HC , HC ,

H,CCH,C

11

16

22 31

H,CH,C

H,CH,

I

more than a f a c t o r of 4 along t h e chain c l e a r l y i n d i c a t e s a l a r g e degree of i n t e r n a l motion o f t h e methyl group r e l a t i v e t o t h e C H 2 0 H . The p r o g r e s s i v e decrease of T 1 from t h e former t o t h e l a t t e r shows t h a t i n t e r n a l motion becomes more r e s t r i c t ed toward t h e hydroxyl end of t h e molecule presumably because i n t e r m o l e c u l a r hydrogen bondi-ng e f f e c t i v e l y "anchors" t h a t end of t h e chain. In s m a l l e r systems, t h e "anchoring" i s much l e s s e f f e c t i v e a s evidenced by t h e T 1 d a t a ( 2 5 ) f o r 1-butanol

12

STEREOCHEMICAL ASPECTS OF 13C NMR SPECTROSCOPY

( 8 ) , i n d i c a t i n g t h a t o v e r a l l s i z e i s a l s o an important f a c t o r a f f e c t i n g r e l a t i v e molecular motions. 3 0 39 3 6 4 2

HO-CH,CH,CH,CH, 8

I n more complex systems, t h e u t i l i t y of t h e f a c t o r s a f f e c t i n g T1 f o r s t r u c t u r a l e l u c i d a t i o n o r f o r s t u d i e s of molec u l a r motion i s c l e a r l y i l l u s t r a t e d by t h e r e s u l t s (23) f o r c h o l e s t e r y l c h l o r i d e ( 9 ) . A l l protonated carbons of t h e r i n g

9

system have t h e same 1/NT1 v a l u e s , i n d i c a t i n g t h a t t h e o v e r a l l molecular r e o r i e n t a t i o n i s i s o t r o p i c . Methine carbons a r e r e a d i l y d i s t i n g u i s h e d from methylene carbons s i n c e t h e i r T I v a l u e s a r e twice a s l a r g e , whereas quaternary carbons e x h i b i t much l a r g e r T1 values because they l a c k d i r e c t l y bonded protons. The e f f e c t s of i n t e r n a l r e o r i e n t a t i o n a r e e v i d e n t from t h e long T1 values f o r t h e methyl carbons which, i f r e l a x e d only by d i p o l a r i n t e r a c t i o n s and only through p a r t i c i p a t i o n i n t h e o v e r a l l i s o t r o p i c motion of t h e molecule, would be expected t o have values near 0.5/3 = 0.17 s e c , r a t h e r than 1 . 5 t o 2 . 1 s e c . I n t e r n a l o r segmental motion of t h e s i d e chain is a l s o shown by t h e i n c r e a s e i n 91 toward t h e f r e e end of t h e chain. Typical 1 3 C T1 values i n l i q u i d s range from about 30 msec f o r carbons i n t h e s i d e chain of ribonuclease A (26) t o about 130 s e c f o r t h e i n t e r n a l a c e t y l e n i c carbon i n degassed phenyl-

NANCY K. WILSON AND J . B. STOTHERS

13

acetylene (27). Some r e p r e s e n t a t i v e d a t a a r e l i s t e d i n T a b l e 2 f o r a v a r i e t y of r e l a t i v e l y small molecules. C l e a r l y none of t h e s e e x h i b i t such s h o r t T 1 v a l u e s as t h e r i g i d s i d e c h a i n s of n a t i v e aqueous r i b o n u c l e a s e A o r t h e s m a l l T 1 noted above f o r C - 1 i n decanol, both of which are i n d i c a t i v e o f r e s t r i c t e d molecular motion. The v a l u e s f o r some of t h e s e examples, howe v e r , r e f l e c t t h e i n f l u e n c e of d i f f e r e n t r e l a x a t i o n mechanisms. For example, s c a l a r coupling t o bromine i s important i n methyl bromide and probably dominates i n bromoform (31). Spin-rotat i o n r e l a x a t i o n appears t o be dominant f o r carbon d i s u l f i d e a t 15 MHz although chemical s h i f t a n i s o t r o p y c o n t r i b u t e s a t low temperatures and high f i e l d s ( 3 0 ) . The r e l a t i v e l y long v a l u e s f o r cyclohexane and benzene r e f l e c t t h e f a s t tumbling of t h e s e molecules i n s o l u t i o n ; f o r each of t h e s e , t h e p r e s e n c e of d i s s o l v e d oxygen d e c r e a s e s T1 by about 5 sec (30) through an a d d i t i o n a l d i p o l a r r e l a x a t i o n c o n t r i b u t i o n ( w h i c h w i l l be even l a r g e r f o r longer T I v a l u e s ) . The long T1 v a l u e s f o r t h e q u a t e r n a r y carbons i n t h e v a r i o u s aromatic d e r i v a t i v e s are t y p i c a l of nonprotonated carbons which l a c k t h e e f f i c i e n t d i p o l a r r e l a x a t i o n of d i r e c t l y bonded p r o t o n s . Measurement of 13C s p i n - l a t t i c e r e l a x a t i o n t i m e s h a s become reasonably s t r a i g h t f o r w a r d w i t h t h e advent of high-resol u t i o n pulsed s p e c t r o m e t e r s employing f i e l d - f r e q u e n c y locks. D e t a i l e d d i s c u s s i o n s of t h e experimental t e c h n i q u e s r e q u i r e d a r e a v a i l a b l e elsewhere ( 2 2 , 3 3 34) and a r e n o t p r e s e n t e d ' measurements f o r s t e r e o here. S e v e r a l a p p l i c a t i o n s of 1 3 C 21 chemical e l u c i d a t i o n s and f o r a s s e s s i n g r e l a t i v e i n t e r n a l molecular motion are p r e s e n t e d i n Sect. IV. A s noted above, t h e e f f e c t s of spin-spin r e l a x a t i o n whereby neighboring n u c l e i exchange s p i n energy are m a n i f e s t i n t h e shape of t h e a b s o r p t i o n s i g n a l s . The s p i n - s p i n r e l a x a t i o n t i m e T I i s r e l a t e d t o t h e " n a t u r a l " width of a L o r e n t z i a n l i n e by T2 = l/nAu, where Au i s t h e f u l l l i n e width a t h a l f - h e i g h t . Since T2 i s an i n v e r s e measure of t h e broadening o f a s p e c t r a l l i n e , any f a c t o r which e f f e c t i v e l y v a r i e s t h e r e l a t i v e energ i e s of t h e s p i n l e v e l s and thereby i n c r e a s e s t h e s p r e a d of n u c l e a r p r e c e s s i o n f r e q u e n c i e s w i l l l e a d t o a p p a r e n t T, v a l u e s a p p r e c i a b l l s h o r t e r than t h o s e due t o t h e n a t u r a l l i n e width. F i e l d inhonogeneity broadening r e s u l t ? i n an observed l i n e width c n a r a c t e r i z e d by T t , with 1/TT = 1/7" + yAH0/2, where y i s t h e n u c l e a r magnetogyric r a c i o dnd a H 0 i s t h e magnetic f i e l d inhomogeneity, which i s g r e a t e r t h a n 0.05 Hz i n t h e b e s t a v a i l a b l e instruments. Low-frequency i n t e r a c t i o n s such a s chemical exchange and d i f f u s i o n w i l l c o n t r i b u t e t o T2, although they do n o t a f f e c t T1 v a l u e s , f o r which only high-frequency i n t e r a c t i o n s n e a r t h e Larmor frequency a r e e f f e c t i v e . Consequently, t h e i n v e s t i g a t i o n of chemical exchange by line-shape a n a l y s i s p e r m i t s t h e

-3, -4,

-5 -6

107 132 9.3

6lb

41 8 12

>50 15

29.3

27

27

29

28

27

Ref.

3C Spin-Lattice

’

Tl

Some

a

CH3

Carbon d i s u l f i d e

A c e t i c acid, C-1

Chlorof o m

Bromof orm

32.4

1.65

8.8

21

T1

36

41.1 10.5

(TI, i n sec)

Methyl bromide

Cyclohexane

Compound

Relaxation T i m e s

%less otherwise i n d i c a t e d t h e t a b u l a t e d r e s u l t s were o b t a i n e d w i t h degassed samples. bNot degassed.

-CE EC H

Phenylacetylene, C - 1

Biphenyl, C - 1

CH3

C-2,

Mesitylene, C-1,

CH3

Toluene, C-1

Benzene

Compound

T a b l e 2.

30

31 32

31

31

31

30

Ref.

NANCY K. WILSON AND J. B. STOTHERS

15

determination of k i n e t i c d a t a f o r r e l a t i v e l y slow exchange processes which a r e d i f f i c u l t t o study by o t h e r methods; seve r a l examples employing 1 3 C techniques a r e discussed i n S e c t . Measurements of longer 1 3 C T2 values from p u l s e experiIV. ments a r e f a r less numerous than a r e T I determinations because of experimental d i f f i c u l t i e s and problems i n i n t e r p r e t a t i o n of t h e d a t a . For l i q u i d s of low v i s c o s i t y , it should be p o s s i b l e t o use t h e forced t r a n s i t o r y p r e c e s s i o n technique ( “ s p i n locki n g ” ) t o measure T2 values ( 3 3 ) . Since t h i s method r e q u i r e s only minor modifications of e x i s t i n g commercial spectrometers, it may prove valuable f o r t h e study of chemical r a t e p r o c e s s e s . In general T2 6 T I ,and f o r I 3 c n u c l e i T2 i s g e n e r a l l y s h o r t e r f o r those bonded t o quadrupolar n u c l e i such a s chlor i n e . For example, i n 0-dichlorobenzefle, t h e protonated carbons have T2 values of 7.7 and 6.4 s e c , which a r e e s s e n t i a l l y t h e same a s t h e TI v a l u e s , b u t f o r t h e chlorine-bearing c a r bons T2 i s 4 . 2 s e c compared t o t h e i r T I value of 66 s e c ( 3 5 ) . The much s h o r t e r T2 value f o r t h e l a t t e r a r i s e s from t h e lowfrequency-modulated s c a l a r i n t e r a c t i o n with c h l o r i n e . A simil a r r e l a t i o n s h i p i s found f o r chlorofoxm, f o r which T2 = 0.35 s e c and T I = 33 s e c ( 3 6 ) . F a s t r e l a x a t i o n of coupled protons can a l s o s i g n i f i c a n t l y shorten .T2 (37) such t h a t T2 << TI.

111. CONFIGURATIONAL EFFECTS ON 1 3 C PARAMETERS AND STEREOCHEMICAL ASSIGNMENTS

A.

A l k a n e s and A l k y l Derivatives

The i n f l u e n c e of a c h i r a l c e n t e r on t h e degree of nonequivalence of isopropyl methyl carbons has been determined f o r s e v e r a l a c y c l i c compounds (Table 3 ) . These d a t a show t h a t even i f t h e c h i r a l c e n t e r i s f o u r bonds from t h e d i a s t e r e o t o p i c methyl carbons, t h e i r s h i e l d i n g d i f f e r e n c e A 6 i s s i g n i f i c a n t , although, a s expected, A 6 d e c r e a s e s monotonically with i n c r e a s i n g s e p a r a t i o n . I t i s a l s o apparent t h a t A 6 depends markedly on t h e s t e r i c requirements of t h e s u b s t i t u e n t s a t t h e c h i r a l c e n t e r , i n d i c a t i n g , b u t not e s t a b l i s h i n g , t h a t d i f f e r ences i n conformer populations a r e p a r t i a l l y r e s p o n s i b l e f o r t h e observed nonequivalence. For t h o s e systems i n which t h e isopropyl group i s d i r e c t l y bonded t o t h e asymmetric carbon, i - P r C H ( X ) R ( f i r s t and t h i r d columns, Table 31, A 6 i n c r e a s e s , from 0.2 t o 7 . 2 ppm, a s R i s changed from Me t o t-Bu, c l e a r l y i l l u s t r a t i n g t h e e f f e c t of i n c r e a s i n g s t e r i c requirements of R. Coupled with t h i s observation i s t h e f a c t t h a t only one of t h e methyl carbons i s s h i f t e d markedly i n each s e r i e s , moving t o p r o g r e s s i v e l y lower f i e l d a s R i s changed from Me t o t-Bu. C o n s i s t e n t with t h i s t r e n d i s t h e observed d e c r e a s e of A6 from

t-Bu

3

7.2

3.3

2

1

n

2 2

2.2

A6

2.3 2.2 0.2

0.1

Et

A6 1.0 1.0

Et

R Et n-Pr

t-Bu

Et n-Pr i-Pr

R Me

6.9

2.7

1.5 1.4

0.2

A6

38,

R'

0.04 0.11

~0.03

0.14 0.08

A6

(in ppm)

t-Bu

39)

C3HSa Et Ph i-Prc Ph

R Me

Nonequivalence of Isopropyl Methyl Carbons in Aspmetric Systems (7,

C3H5 = cyclopropyl, for which A 6 = 0.64 ppm. %or these methyl carbons, AS = 1.6 ppm. ?For these methyl carbons, AS = 0.61 ppm.

a

R Et n-Pr n-Bu i-Bub i-Pr

Table 3.

NANCY K.

WILSON AND J. B. STGTHERS

17

3 . 3 t o 1.0 ppm f o r t h e change ( i - P r ) 2 C H C H 3 + ( i - P r ) 2 C H C H 2 C H 3 ( 7 ) . I n t h e s e r i e s of hydroxyethers, t h e cyclopropyl d e r i v a t i v e e x h i b i t s nonequivalence of t h e cyclopropyl methylene carbons while t h e corresponding i s o p r o p y l methyl carbons i n ROCH2C(OH) (Ph)i-Pr(R = M e , i - P r ) d i f f e r by 0.6 ppm ( 3 9 ) . The r e s u l t s f o r t h e e t h e r s l i s t e d i n Table 3 show t h a t A 6 i s app r e c i a b l e although t h e c h i r a l c e n t e r i s four bonds from t h e d i a s t e r e o t o p i c methyls. C l e a r l y , t h e nonequivalence produced by a c h i r a l c e n t e r tends t o be much l a r g e r f o r d i a s t e r e o t o p i c carbons than f o r protons and, t h e r e f o r e , w i l l be r e a d i l y obs e r v a b l e i n many more systems. The apparent downfieZd s h i f t e x h i b i t e d by one of t h e methyl carbons i n t h e series of i s o p r o p y l a l k y l c a r b i n o l s prompted Kroschwitz e t a l . ( 3 8 ) t o invoke a d e s h i e l d i n g 1 , 5 C H 3 * * * C H 3 i n t e r a c t i o n , a 6 e f f e c t . More r e c e n t l y support f o r t h i s i n t e r p r e t a t i o n has been found from t h e s p e c t r a of some c y c l i c d e r i v a t i v e s (see below). These workers suggested t h a t t h e l a r g e r d i f f e r e n c e s observed f o r t h e l a r g e r a l k y l groups could reasonably a r i s e from an increased population of rotamer 1 0 ; t h i s i s supported by t h e decreased v i c i n a l proton-proton

dti 10

coupling with R = t-Bu r e l a t i v e t o t h a t f o r R = H ( 3 8 ) . Undoubtedly t h e temperature dependence of A 6 f o r t h e s e d e r i v a t i v e s would be i n s t r u c t i v e . The temperature dependence o f t h e proton nonequivalence i n ROCH2C(OH) (PhIi-Pr (R = M e , i - P r ) has been determined and, s i n c e ASH changes i n t h e range 20 t o 110°C ( 3 9 1 , t h e values f o r t h e geminal carbons measured n e a r room temperature have c o n t r i b u t i o n s from both Acp and Aid. The analogous t e s t f o r t h e o t h e r hydroxyethers i s n o t p o s s i b l e because t h e A ~ Hvalues were n o t measurable. From t h e s e r e s u l t s , one may expect t h e 13C s p e c t r a of diastereomeric mixtures t o c o n t a i n many examples of d i a s t e r e o t o p i c nonequivalence; f o r example, f o r molecules c o n t a i n i n g two c h i r a l c e n t e r s , s e p a r a t e sets of s i g n a l s f o r t h e racemic and t h e meso forms may b e a n t i c i p a t e d . The observed s h i e l d i n g d i f f e r e n c e s f o r i n d i v i d u a l carbons i n t h r e e such m a t e r i a l s , 11 t o 1 3 , a r e shown below, b u t it was n o t p o s s i b l e t o a s s i g n s i g n a l s t o s p e c i f i c diastereomers ( 7 ) . The pure meso and

18

STEREOCHEMICAL ASPECTS OF

+ + 2;'

,2.0

<0.1

3C NMR SPECTROSCOPY

< 0.1

1.9

2.0

12

11

13

racemic diastereomers of 2,3-dichlorobutane and 2,4-dichloropentane, however, have been examined (40) and the pentane data are listed in Table 4. Proton studies (41) have indicated Table 4. Nonequivalence of Some Meso and Racemic Diastereomers ( 4 0 ) (in ppm)

A S (meso - racemic) Compound

Carbon

13c

2,3-Dichlorobutane

CH3 CHCl

1.99 1.09

2,4-Dichloropentane

CH3 CHCl CH2

-1.00 -1.13 -0.20

1H 0.04 -0.14

0.02 -0.19 0.04, 0.30

that meso-2,3-dichlorobutane, 14 to 16, exists preferentially as 14 while, for the racemic form, all three rotamers, 17 to 1 9 , have equal populations. On the average, therefore, it would appear that the methyl carbons in the racemic form ex-

NANCY K. WILSON

AND

19

J.B. STOTHERS

CI

CI

14

15

I

16

perience more gauche interactions than those in the meso diastereomer since in 1 4 , the major rotamer, each has one gauche interaction (with chlorine), whereas in 1 7 each has two (with chlorine and methyl). This is consistent with the higher

I

CI

17

H

CH,

in

19

shielding observed for the carbons in the racemic diastereomer. For 2,4-dichloropentaneI the major conformers for both racemic and meso forms are estimated to constitute 86% of the rotameric populations (42); they correspond to structures 20 and 21 (and its enantiomer), respectively. One of the methyl carbons in the meso form 2 1 is gauche with respect to the distal methine

20

21

carbon while all others are anti; consequently, the higher shieldings for the meso form seem consistent with expectations. With one exception, the A€iC values are nearly an order of maqIn addition, integration showed that nitude greater than A&,.

20

STEREOCHEMICAL ASPECTS OF

3C N M R SPECTROSCOPY

p r e c i s e q u a n t i t a t i v e d a t a f o r t h e composition of d i a s t e r e o meric mixtures a r e d i r e c t l y obtained; s i n c e dipole-dipole rel a x a t i o n is dominant f o r both forms (40) , s i g n a l a r e a s a r e d i r e c t l y p r o p o r t i o n a l t o population. These f i n d i n g s €or diastereomeric compounds i n d i c a t e t h a t I3C s p e c t r a should provide a valuable complement t o IH s p e c t r a f o r t h e determination of o p t i c a l p u r i t i e s by nmr. The a p p l i c a t i o n of proton s p e c t r a f o r t h i s purpose has been reviewed i n t h i s s e r i e s (43) and, more r e c e n t l y , an a d d i t i o n a l technique has been developed, namely, t h e use of c h i r a l s h i f t reagents ( 4 4 ) t o render e n a n t i o t o p i c n u c l e i nonequivalent. The l a t t e r method has t h e advantage of s i m p l i c i t y relative t o

T a b l e 5 . E f f e c t a of Chiral S h i f t Reagentsb on I3C S i g n a l s of Some Racemic Mixtures (46b)

Ef fecij, of R3Eu Compound PhCH ( M e ) OH

13c nucleus

Me

P S ~ ~8~

E€€ec$ of R3Pr PSa

2.1 6.7 0.9

<0.05 0.11 <0.05

-6.8 -13.5 -6.2

<0.05 0.28 0.17

CH C-1

2.9 9.2 6.5

0.18 0.34 <0.05

-6.8 -12.6 -3.8

<0.08 0.20 <0.05

PhCH-0-CH2

CH2 CH C-1

6.4 6.0 1.4

0.40 0.33 <0.05

-10.9 -10.5 -4.9

0.57 <0.08 0.16

trans-2-Methylcyclohexanol

Me

1.7 1.4 6.9

C0.05 <0.05 C0.05

-7.5 -15.6 -21.5

0.12 <0.05 0.38

CH C-1

PhCH (Me)NH2

n

Me

C-2 C-1

aFor 0.2 e q u i v a l e n t s of r e a g e n t , PS = average s h i f t (ppm)

of t h e i n d i c a t e d nucleus i n t h e two enantiomers, p o s i t i v e v a l u e s denote downfield s h i f t s ; A 8 = nonequivalence between enantiomers i n ppm induced by t h e c h i r a l r e a g e n t s , upper limi t s estimated from t h e l i n e widths compared with t h a t of TMS. bR = 3-hepta€luoropropylhydroxymethylene- (+) -camphorat0

.

WILSON A N D J. B.

NANCY K.

STOTHERS

21

o t h e r c u r r e n t methods (43, 45) , and, although examples of t h e use of l 3 C nmr f o r a s s e s s i n g o p t i c a l p u r i t y a r e l a c k i n g i n t h e l i t e r a t u r e , some preliminary r e s u l t s confirm i t s g e n e r a l u t i l i t y f o r t h i s purpose (461, a s i l l u s t r a t e d by some r e p r e s e n t a t i v e d a t a i n Table 5. Some y e a r s ago, Karabatsos e t a l . (47) noted t h e dependence of v i c i n a l 13C-lH coupling c o n s t a n t s ( J c c c ~on ) dihedral angle analogous t o t h e w e l l - e s t a b l i s h e d behavior o f protonproton s p i n i n t e r a c t i o n s ( 1 1 , b u t r e l a t i v e l y few a c y c l i c I3C examples a r e a v a i l a b l e . Measurement of t h e s e parameters f o r a l i p h a t i c s a t u r a t e d compounds seems u n l i k e l y t o become common f o r stereochemical e l u c i d a t i o n s because of t h e complexity of coupled s p e c t r a and because f r e e r o t a t i o n averages t h e coupl i n g s i n each rotamer. Nevertheless, systems can be envisaged f o r which such determinations could be v a l u a b l e , even though some cases may r e q u i r e s p e c i f i c 1 3 enrichment ~ t o permit an unequivocal a n a l y s i s , a s u t i l i z e d (47b) t o show t h e r e l a t i v e magnitudes of anti and gauche JCCCH i n propanal-3-13C ( 2 2 ) and

a

b 22

i t s oxime 0-methyl e t h e r ( 2 3 ) . For t h e s e compounds, AHo (22a -f = -800 cal/mole and AHo (23a + 2 3 b ) = 390 cal/mole; consequently, i f Pntz CCCH > a s expected from ' H r e s u l t s , a temperature i n c r e a s e should decrease JcccH i n 22 and i n c r e a s e JCCCH i n 23. Measurements over t h e range -35 t o +5OoC gave

2%)

GEEhe,

MeO-N

MeO-N

b

a 23

( 2 2 a ) , 0.7 ( 2 3 ~ x 1 ,3.5 ( 2 2 b ) , and 7.8 Hz ( 2 3 b ) . Since t h e f i r s t two a r e auche i n t e r a c t i o n s and t h e l a t t e r two a n t i , t h e s e v i c i n a l 93C-1H coupling c o n s t a n t s e x h i b i t t h e expected angular dependence. S i m i l a r l y , estimated v a l u e s f o r some simple a c e t a t e s were obtained ( 4 7 c ) . More r e c e n t l y , s e v e r a l v i c i n a l 3C-1H couplings, JCOCH, i n methyl e t h e r s , formates , 0.2

'

22

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

and a c e t a t e s have been determined u s i n g n a t u r a l abundance mater i a l s ( 4 8 ) . These d a t a e x h i b i t t h e expected geometric dependence although d e t a i l e d i n t e r p r e t a t i o n s and t h e e x t r a c t i o n of r e l i a b l e l i m i t i n g v a l u e s r e q u i r e more e x t e n s i v e s t u d y , e s p e c i a l l y with a view t o e s t a b l i s h i n g t h e importance of s u b s t i t u e n t e f f e c t s . Nevertheless, it i s a l r e a d y a p p a r e n t t h a t v i c i n a l I3C-’H i n t e r a c t i o n s are s t r o n g l y dependent on t h e r e l a t i v e o r i e n t a t i o n of t h e coupled n u c l e i . Recent s t u d i e s of c y c l i c systems confirm t h i s conclusion, as d i s c u s s e d l a t e r . Nonequivalence a r i s i n g from hindered r o t a t i o n about bonds having p a r t i a l double-bond c h a r a c t e r has been w e l l e s t a b l i s h e d by proton s t u d i e s of nitrogen-containing a l k y l d e r i v a t i v e s (1); t y p i c a l examples i n c l u d e amides ( 2 4 ) and nitrosamines f o r which, a t ambient temperatures, r o t a t i o n about one of t h e bonds t o n i t r o g e n is slow ( 4 9 ) . The s a l i e n t stereochemical f e a t u r e s ,

24

v i z . ( a ) t h e c o n f i g u r a t i o n and r e l a t i v e energy of i n d i v i d u a l rotamers i n unsymmetrical systems and (b) t h e thermodynamic parameters governing r o t a t i o n about t h e p a r t i a l double bond, a r e a c c e s s i b l e by nmr methods and I 3 C techniques may have wider scope i n t h e i r d e t e r m i n a t i o n because of t h e g r e a t e r s h i e l d i n g range. F u r t h e r , 3C r e l a x a t i o n time measurements can shed l i g h t on t h e r e l a t i v e n o b i l i t i e s of a l k y l groups on n i t r o g e n . Configurational e f f e c t s are considered below while a c t i v a t i o n b a r r i e r s and r e l a x a t i o n p r o c e s s e s a r e d i s c u s s e d i n S e c t . IV. 5Y n

0

anti

26

Of t h e s e systems, dimethylformamide (25) i s probably t h e s i n g l e mst s t u d i e d example (49). While i t s methyl p r o t o n s d i f f e r by 0.3 ppm a t room temperature, t h e methyl carbons d i f f e r by 5 p m (25, 50) , again i l l u s t r a t i n g t h e enhanced s e n s i t i v i t y of B 3 C n u c l e i t o t h e i r environment. The syn-placed n u c l e i i n 25 a r e t h e more s h i e l d e d i n nonaromatic s o l v e n t s .

NANCY K.

WILSON AND J . B. STOTHERS

23

The r e l a t i v e s h i e l d i n g s o f N-alkyl groups f o r some symmetrical amides and d e r i v a t i v e s a r e l i s t e d i n T a b l e 6 ; t h e nonequival e n c e of t h e N-ethyl carbons i n N,N-diethylpropionamide has T a b l e 6 . S h i e l d i n g D i f f e r e n c e s f o r Alkyl Carbons i n

Symmetrical Amides (25, 50) ( i n ppm) A6 (&anti

-

@yn)

hide

Cr-C

6-C

Y-C

6-C

( M e ) 2NCHO

5.1 5.2 3.1

1.4

0.5

0.1

3.3

1.2

0.2

0.03

(n-Bu) 2NCHO (Me)2NCOCH3 (n-Bu) 2NCOCH3 ( M e ) 2NCOC1

1.8

a l s o been examined b u t t h e d a t a were n o t r e p o r t e d ( 5 1 ) . The o r i g i n of t h e nonequivalence h a s been a t t r i b u t e d t o e l e c t r i c f i e l d e f f e c t s (50) and t o s t e r i c p e r t u r b a t i o n s ( 2 5 ) . The reduced A 6 v a l u e s f o r t h e acetamides, i n which b o t h a l k y l groups are e c l i p s e d by s u b s t i t u e n t s on t h e carbonyl carbon, s u p p o r t t h e s t e r i c i n t e r p r e t a t i o n . I n a d d i t i o n , t h e carbonyl carbons i n syn- and anti-N-methylformamide (26) d i f f e r by 3.3 ppm ( 2 a ) , w i t h t h a t of t h e syn isomer a t h i g h e r f i e l d ; t h i s i s c o n s i s t e n t w i t h y-gauche e f f e c t s i n o t h e r systems. The methyl carbons i n 26 d i f f e r by 3.4 ppm (25) and t h e r e l a t i v e i n t e n s i t i e s of t h e two s i g n a l s f o r each rotamer i n d i c a t e a 1 O : l (syn:anti) composition f o r t h e mixture, i n complete accord w i t h 'H d a t a ( 5 2 ) .

Comparable r e s u l t s may be a n t i c i p a t e d f o r oximes in which t h e hydroxyl oxygen would r e n d e r t h e syn and anti a l k y l carbons nonequivalent. For example, i n acetone oxime t h e methyl carbons d i f f e r by 6.8 ppm (25, 53) , w i t h t h e syn a t h i g h e r

24

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

f i e l d . A s with dimethylformamide, t h e nonequivalence of t h e methyl carbons i s somewhat s o l v e n t dependent ( 5 3 ) . The spectrum of butanone oxime ( 2 7 ) c o n t a i n s two groups of f o u r s i g n a l s i n t h e r a t i o 77:23. For t h e more i n t e n s e s e t t h e a-methyl carbon i s -6.0 ppm and t h e a-methylene carbon +5.9 ppm from the corresponding s i g n a l s i n t h e less i n t e n s e s e t , e s t a b l i s h i n g t h a t 27b i s t h e more abundant, again i n agreement with t h e

b

a

27

'H r e s u l t s ( 5 4 ) . I n t e r e s t i n g l y , t h e imino carbon i n 27b i s t h e more shielded (0.5 ppm) and, as expected from t h e amide d a t a , t h e C-4 methyl i n 27a i s s h i e l d e d by 1 . 2 ppm. Signific a n t l y d i f f e r e n t c o n f i g u r a t i o n a l e f f e c t s of t h e oxime hydroxyl group were revealed f o r Sp2-carbons i n t h e l o n e example of an a,B-unsaturated oximq ( 5 5 ) . For crotonaldehyde oxime, t h e 6ptzare -2.5 ( C = N ) , 5.0 (C-21, -2.0 (C-31, differences and 0.5 (C-41, while t h e r e l a t i v e i n t e n s i t i e s i n d i c a t e d t h e composition t o be 64% a n t i and 36% syn i n chloroform. In cont r a s t t o t h e s a t u r a t e d d e r i v a t i v e s t h e a- and y-carbons are deshieZded i n t h e syn form b u t a r a t i o n a l i z a t i o n of t h i s behavior i s not apparent and t h e examination of a d d i t i o n a l examples i s c l e a r l y warranted, Several nitrosamines have been examined by 13C n m (56) and t h e r e s u l t s € o r some s y m n e t r i c a l l y s u b s t i t u t e d cases a r e given i n Table 7. Although t h e A 6 values are markedly a t t e n u a t e d along t h e a l k y l c h a i n , s i g n i f i c a n t d i f f e r e n c e s a r e s t i l l found f o r t h e y-carbons. F u r t h e r m r e , t h e d i f f e r e n c e s are comparable t o those i n oximes b u t l a r g e r than those i n amides, a t r e n d which may crudely r e f l e c t t h e l e n g t h of t h e bond about which r o t a t i o n i s hindered, b u t t h e necessary s t r u c t u r a l d a t a t o t e s t t h i s n o t i o n are unavailable. The 1 3 C s p e c t r a of some N-alkyl-N-nitrosoanilines showed only a s i n g l e isomer f o r t h e N-Me, - E t , -n-Pr, -n-Bu, and -t-Bu d e r i v a t i v e s , while N-secbutyl-N-nitrosoaniline e x h i b i t e d two s e t s of a l k y l s i g n a l s with A 6 values of 9.7 (a-CH) , 1 . 5 (8-CH2) , 2.5 (8-CH3) I and 0.2 (Y-CH3); u n f o r t u n a t e l y , t h e r e l a t i v e i n t e n s i t i e s were n o t reported. Based on t h e s h i e l d i n g s f o r t h e o t h e r N-alkyl-Nn i t r o s o a n i l i n e s , t h e n - a l k y l d e r i v a t i v e s appear t o e x i s t as 28 and t h e t - b u t y l d e r i v a t i v e a s 2 9 .

6PYn -

NANCY K. WILSON AND J. B.

STOTHERS

25

Table 7. Shielding D i f f e r e n c e s f o r Alkyl Carbons i n Symmetrical Nitrosamines (56) ( i n ppm)

A6

NitroSamhe

Me2NNO Et2NNO

(n-Pr) 2NNO ( i - P r ) 2NNO (Z-BU)~NNO (i-Bu) 2NNO

(&anti - p Y n )

a-C

B-C

7.9 8.9 9.0 5.7 10.1 9.5

3.0 2.2 4.6 2.2 1.0

28

Y-C

6-C

0.5 0.6 0.4

-0

29

For a s e r i e s of simple sp3 systems, YCX3, t h e I3C s h i e l d i n g s have been c o r r e l a t e d with t h e YCX bond angle and with Z, t h e number of e l e c t r o n s surrounding t h e I3C nucleus (57) , b u t t h e general u t i l i t y of t h i s approach remains t o be e s t a b l i s h e d .

B.

Alicyclic D e r i v a t i v e s

For comparison with t h e s u b s t i t u e n t e f f e c t s i n a l i p h a t i c systems discussed e a r l i e r (see Table 1 1 , t h e corresponding r e s u l t s f o r s e v e r a l monosubstituted cyclohexanes (58) a r e l i s t e d i n Table 8. The v a l u e s given f o r s p e c i f i c r i n g carbons a r e t h e i r s h i e l d i n g s r e l a t i v e t o cyclohexane. The t r e n d s a r e s i m i l a r t o those f o r a c y c l i c systems with p o s i t i v e (deshieldi n g ) a and 6 e f f e c t s and negative ( s h i e l d i n g ) y e f f e c t s , b u t the 6 effects are also shielding, i n contrast t o t h e aliphatic results. Since t h e monosubstituted cyclohexanes e x i s t a s equilibrium mixtures of a x i a l and e q u a t o r i a l conformers, t h e r e l a t i v e amounts of a x i a l forms a r e given i n Table 8 f o r t h e

26

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

T a b l e 8. S u b s t i t u e n t E f f e c t s a i n Monosubstituted Cyclohexanes (58)

Substituent

CH3 COOH COOMe NH2 OH

c1 Br I

Y

B

c1

5.8 16.1 15.8 23.5 42.4 32.2 25.0 4.2

8.4 2.0 2.0 10.1 8.4 9.6 10.3 12.2

6

%

-0.6 -1.0 -1.2 -1.1 -1.2 -2.0 -2 .o -2.1

-0.5 -1.4 -1.6 -1.8 -2.6 -2.4 -1.5 -0.2

b axial 5 9 10 12 25c 33 35 33

aI n ppm. Negative and p o s i t i v e v a l u e s i n d i c a t e u p f i e l d and downfield s h i f t s , r e s p e c t i v e l y . h a l u e s obtained from t h e - A G O compilation of Hirsch ( 5 9 ) , unless otherwise noted. % - o m E l i e l and G i l b e r t ( 6 0 ) . purpose of b e t t e r understanding of t h e s p e c t r a l f i n d i n g s . The e f f e c t s l i s t e d f o r methylcyclohexane a r e e s s e n t i a l l y those f o r t h e e q u a t o r i a l conformer, b u t f o r t h e halocyclohexanes t h e a x i a l conformer makes a s u b s t a n t i a l c o n t r i b u t i o n . As a repr e s e n t a t i o n of t h e d i f f e r e n c e s between a x i a l and e q u a t o r i a l s u b s t i t u e n t s , t h e s h i e l d i n g s f o r c i s and trans-4-t-butylcyclohexyl d e r i v a t i v e s may be compared. Such comparisons (Table 9 ) Table 9. Comparison of Axial and E q u a t o r i a l S u b s t i t u e n t E f f e c t s a i n Cyclohexanes

A6 Substituent CH3 COOMe OH

c1

c-1

c- 2

c- 3

c-4

Ref.

-4 s 56 -4.5 -5.4 -0.3

-3.62 -1.5 -2.4 -3.6

-6.42 -2.8 -4.7 -6.5

0.16 0.6 0.9 1.0

61 62 63 62

NANCY K. WILSON AND J. B.

STOTHERS

27

show t h a t , i n g e n e r a l , an e q u a t o r i a l s u b s t i t u e n t d e s h i e l d s t h e and y-carbons r e l a t i v e t o t h e e f f e c t of an a x i a l group. These d a t a f o r t h e y-carbons r e l a t i v e t o t h e y e f f e c t s i n Table 8 e s t a b l i s h t h e mark$d geometric dependence of the y e f f e c t . A s noted i n Sect.11, s t e r i c p o l a r i z a t i o n a r i s i n q from nonbonded i n t e r a c t i o n s o f c l o s e l y neighboring atoms on t h e y-carbons q u a l i t a t i v e l y accounts f o r t h e u p f i e l d s h i f t which c h a r a c t e r i z e s t h e y e f f e c t . Methylcyclohexane has been examined a t a temperature s u f f i c i e n t l y low t h a t i n d i v i d u a l s p e c t r a of t h e a x i a l ( 3 0 ) and e q u a t o r i a l (31 ) conformers were observed (64) The C - 3 ( C - 5 ) a-, 6-,

.

30

31

and methyl carbons i n 30 absorb 6 ppm u p f i e l d from t h e i r c o u n t e r p a r t s i n 3 1 , although a l a r g e r d i f f e r e n c e might have been expected f o r t h e methyl carbon s i n c e it has two gauche i n t e r a c t i o n s , whereas C - 3 ( C - 5 ) has one. In c o n t r a s t , t h e methyl carbons i n 32 and 3 3 , t h e 9-methyldecalinsI d i f f e r by 1 2 . 4 ppm ( i n C D C 1 3 ) , with t h a t i n 33 a t higher f i e l d . This

d2 33

is q u a l i t a t i v e l y c o n s i s t e n t with methylcyclohexane because t h e methyl carbon i n 33 experiences two a d d i t i o n a l y-gauche i n t e r a c t i o n s which a r e absent i n 3 2 . Although 32 undergoes r a p i d

20

STEREOCHEMICAL ASPECTS OF l 3 C NMR SPECTROSCOPY

interconversion between e q u i v a l e n t forms, i t s methyl group i s a x i a l w i t h r e s p e c t to one r i n g and e q u a t o r i a l to the o t h e r i n both forms. Q u a n t i t a t i v e l y , however, t h e methyl s h i e l d i n g d i f f e r e n c e f o r 32 and 33 i s twice t h a t f o r 30 and 31. I n cont r a s t , t h e y e f f e c t s of t h e angular methyl a t C-2 and C-4 i n 33 are -5 ppm, by comparison with t r a n s - d e c a l i n , and a r e t h u s e n t i r e l y c o n s i s t e n t with t h e monocyclic and a c y c l i c r e s u l t s . A much more d e t a i l e d a n a l y s i s of t h e v a r i a t i o n of ygauche e f f e c t s i n hydrocarbons (61) revealed a range of 16 ppm, - 2 . 1 t o -17.0, with t h e s h i f t s i n c r e a s i n g with i n c r e a s e d s t e r i c crowding; i n g e n e r a l , i n c r e a s i n g r e s i s t a n c e t o d i s t o r t i o n , which could r e l i e v e s t e r i c i n t e r a c t i o n s , l e a d s t o l a r g e r u p f i e l d s h i f t s . Methyl carbons, f o r example, e x h i b i t s m a l l e r s h i f t s than methylene carbons, presumably as a consequence of g r e a t e r r i g i d i t y of s k e l e t a l l y bonded carbon. From considerat i o n of t h e number of p a i r s of c l o s e l y neighboring hydrogens i n v a r i o u s systems, D a l l i n g and Grant (61) e x t r a c t e d values f o r t h e y-gauche e f f e c t varying from -1.98 to -6.32 ppm p e r H * - * H i n t e r a c t i o n . C l e a r l y , t h e generation of a q u a n t i t a t i v e p r e s c r i p t i o n d e f i n i n g t h e y e f f e c t i s d i f f i c u l t , b u t even i n t h e absence of a s u i t a b l e r e l a t i o n , t h e geometric dependence of y e f f e c t s provides a powerful q u a l i t a t i v e t o o l € o r s t e r e o chemical assignments. I n e a r l y s t u d i e s of t h e e f f e c t s of s u b s t i t u e n t o r i e n t a t i o n , s e v e r a l oxygenated cyclohexyl d e r i v a t i v e s were examined (65) i n a d d i t i o n t o t h e polymethylcyclohexanes discussed above. Although the e a r l y s t u d i e s were r e s t r i c t e d to t h e c a r b i n y l carbon s h i e l d i n g s , t h e s e s h i e l d i n g s were found to r e f l e c t t h e o r i e n t a t i o n of t h e oxygen f u n c t i o n c l e a r l y . I n c i s - and trans-3- and -4-t-butylcyclohexane d e r i v a t i v e s , a x i a l hydroxyl, methoxyl, and acetoxyl groups s h i e l d t h e c a r b i n y l carbon by 5 ppm r e l a t i v e to t h e i r e q u a t o r i a l c o u n t e r p a r t s , t k e b y a f f o r d i n g a d i r e c t means of assignment f o r r e l a t e d systems. A l a t e r d e t a i l e d study of a l i c y c l i c a l c o h o l s (63) r e v e a l e d t h e y eff e c t s of a x i a l oxygen a t C-3(C-5) to be s i m i l a r to t h o s e of methyl groups. A s an example of the s e n s i t i v i t y of c a r b i n y l carbons to hydroxyl o r i e n t a t i o n , f o u r s e p a r a t e c a r b i n y l s i g n a l s were observed over a range of 4.6 ppm i n t h e spectrum of in a mixture of t h e f o u r 3,4-dimethylcyclohexanols 34-37; a d d i t i o n , 26 of t h e 28 p o s s i b l e remaining s i g n a l s were resolved, although assignments were not attempted ( 6 3 ) . The spectrum of t h e mixture of cis- and trans-3,4-dimethylcyclohexanones obtained by o x i d a t i o n showed t h e c i s isomer t o predominate. With t h i s f a c t , t h e assignment of t h e c a r b i n y l s i g n a l s t o 34, 36, 37, 35(low -+ h i g h f i e l d ) followed s i n c e the f i r s t p a i r l a c k the y-gauche i n t e r a c t i o n s of t h e second p a i r . Each of t h e foregoing examples e x i s t s e n t i r e l y i n t h e c h a i r conformation, b u t it i s o f i n t e r e s t t o c o n s i d e r t h e

NANCY K. WILSON AND J. B. STOTHERS

29

34

35

36

37

t r e n d s produced by c o n t r i b u t i o n s from t w i s t - b o a t forms. Howe v e r , r e s u l t s f o r o n l y a s i n g l e example are a v a i l a b l e ( 6 3 ) , namely c~s-1,4-di-t-butylcyclohexane (38) i n which C - 1 and C-2 a r e s h i e l d e d by 5.6 and 6 . 3 ppm, r e s p e c t i v e l y , r e l a t i v e t o t h e v a l u e s f o r t h e t r a n s isomer 39. The u p f i e l d s h i f t s i n t h e t w i s t - b o a t conformation, a l m o s t c e r t a i n l y f a v o r e d i n 38, a r e e n t i r e l y c o n s i s t e n t with increased s t e r i c congestion r e l a t i v e t o t h e c h a i r form.

38

39

The g e n e r a l b e h a v i o r of y e f f e c t s i n t h e cyclohexanes i n d i c a t e s t h a t c i s - and t r a n s - d i s u b s t i t u t e d cyclopropanes would be r e a d i l y d i s t i n g u i s h e d by 13C nmr, and a r e c e n t s t u d y o f s e v e r a l 1 - s u b s t i t u t e d 2-phenylcyclopropanes h a s e s t a b l i s h e d t h a t t h e r i n g carbons i n t h e c i s isomers a r e c o n s i s t e n t l y s h i e l d e d r e l a t i v e t o t h o s e i n t h e t r a n s compounds ( 6 6 ) . The corresponding 2,2-diphenyl- and m o n o s u b s t i t u t e d cyclopropanes were a l s o examined. The l a t t e r s e r i e s provided a s e t o f subs t i t u e n t e f f e c t s from which t h e s h i e l d i n g s i n t h e trans-2phenyl d e r i v a t i v e s could b e p r e d i c t e d w i t h good p r e c i s i o n , b u t

30

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

s u b s t a n t i a l d e v i a t i o n s from a d d i t i v i t y were found f o r t h e c i s isomers. An a d d i t i v e r e l a t i o n f o r t h e l a t t e r s e r i e s i s g i v e n , however, by t h e s u b s t i t u e n t e f f e c t s generated from t h e l-subs t i t u t e d 2,2-diphenyl d e r i v a t i v e s (which d u p l i c a t e t h e s t e r i c crowding of t h e cis-2-phenyl s e r i e s ) . A stereochemical dependence of t h e geminal 3C-1 H coupl i n g c o n s t a n t s between C - 1 and t h e methylene protons c i s and t r a n s t o t h e s u b s t i t u e n t i n a s e r i e s of monosubstituted cyclopropanes was revealed by a high-resolution study ( 6 7 ) . A l though t h e d i f f e r e n c e s a r e small (Table 10) compared t o t h e values f o r t h e corresponding couplings i n v i n y l d e r i v a t i v e s (see below), t h e t r e n d i s t h e same, w i t h t h e t r a n s proton exh i b i t i n g t h e m r e p o s i t i v e value; however, t h e geminal coupling Table 10. Long-Range 13C-lH Couplings i n Monosubstituted Cyclopropanes (67) ( i n Hz)

H I Br

c1

-2.55 -2.3 -1.55 -1.15

COCl NH2

-2.2 -1.0

-2.55 -5.5 -5.35 -5.05 -3.2 -4.0

-2.55 -1.1 -0.75 -0.55 -1.25 +0.65

-2.55 -2.75 -2.9 -3.05 -2.35 -2.9

-2.55 -2.85 -2.85 -2.75 -2.5 -2.7

between C-2(C-3) and t h e methylene protons does not follow the same p a t t e r n . Various c o r r e l a t i o n s f o r t h e C-H and H-H coupl i n g c o n s t a n t s i n t h e s e cyclopropanes were examined b u t addit i o n a l d a t a a r e required t o e s t a b l i s h t h e i r v a l i d i t y . A major d i f f i c u l t y i s t h e ambiguity i n t h e n a t u r e of t h e s e 13C-lH i n t e r a c t i o n s s i n c e they may be viewed as e i t h e r geminal o r v i c i n a l . I n o t h e r systems, s a t i s f a c t o r y c o r r e l a t i o n s have been found f o r C-H and H-H coupling c o n s t a n t s occurring through t h e same number of bonds ( 6 8 ) .

NANCY K. WILSON AND J. B. STOTHERS

31

Methyl s u b s t i t u e n t e f f e c t s i n cyclopentane and cyclohept a n e systems have been s t u d i e d by t h e examination of s e v e r a l d i - and t r i m e t h y l d e r i v a t i v e s a s w e l l a s t h e corresponding methyl-substituted a l c o h o l s , a c e t a t e s , and ketones ( 6 9 ) . For t h e cyclopentane d e r i v a t i v e s ( 6 9 a ) , t h e observed t r e n d s a r e c o n s i s t e n t with those found f o r t h e cyclohexanes i f due allowance i s made f o r t h e l e s s puckered n a t u r e of t h e five-membered r i n g . This d i f f e r e n c e i s manifest i n t h e reduced y e f f e c t s e x e r t e d by t h e methyl groups on t h e cyclopentyl r i n g carbons; f o r example, t h e e f f e c t s a r e s i m i l a r i n t h e cis- and t r a n s - l r 2 dimethyl d e r i v a t i v e s and i n t h e 1,3-dimethyl isomers. In f a c t , t h e only l a r g e d i f f e r e n c e i n y s h i f t f o r e i t h e r p a i r i s t h e - 2 . 6 ppm s h i f t of t h e methyl s i g n a l i n cis-1,2-dimethylcyclopentane r e l a t i v e t o t h a t of t h e t r a n s isomer. Although i n each p a i r one of t h e methyl carbons i s a x i a l a t a given ins t a n t , i t s i n t e r a c t i o n with t h e y r i n g carbon must be s i g n i f i c a n t l y l e s s than t h e corresponding i n t e r a c t i o n s i n methylcyclohexane ( s e e 4 0 and 4 1 ) . Three p a i r s o f cis- and trms-methylcyclopentanol isomers were a l s o examined and, although unequivo c a l assignments f o r s p e c i f i c isomers were n o t p o s s i b l e , two

40

41

sets of s i g n a l s of d i f f e r e n t i n t e n s i t i e s were r e s o l v e d , establ i s h i n g t h a t each mixture contained d i f f e r e n t c o n c e n t r a t i o n s of t h e isomers. In g e n e r a l , t h e s i g n a l s f o r corresponding carbons were not g r e a t l y s e p a r a t e d (<1ppm), although t h e methyl s i g n a l s f o r t h e 2-methylcyclopentanols d i f f e r e d by 4.6 ppm. The l a t t e r observation c l e a r l y d i s t i n g u i s h e d t h e isomers s i n c e t h e methyl carbon i n t h e cis isomer is expected a t s i g n i f i c a n t l y higher f i e l d owing t o i t s c l o s e r approach t o t h e hydroxyl group. This i s comparable t o t h e s h i f t found f o r cis- and trans-1,2dimethylcyclopentane, and Roberts e t a l . (63) have recognized t h e s i m i l a r i t y of OH and CH3 y e f f e c t s . The e f f e c t of europium tris(dipiva1omethane) , Eu(DPM13, on t h e s p e c t r a of t h e s e isomeric mixtures, however, provided a means f o r d i s t i n g u i s h i n g t h e s i g n a l s f o r t h e c i s and t r a n s isomers of 3-methy1cyclopentanol and 1,3-dimethylcyclopentanol; t h e d a t a a r e l i s t e d i n Table 11. For each p a i r , one s e t of s i g n a l s tends t o undergo l a r g e r downfield s h i f t s , with t h e g r e a t e s t d i f f e r e n c e e x h i b i t e d by t h e c a r b i n y l carbon. The

N

w

19.5 17.0

0.5 0.5

&s-l,3-Dimethyl tran.s-l,3-Dimethyl

aGiven i n ppm; measured i n CH2C12 s o l u t i o n s . bChelate/cyclopentanol.

22.6 24.0

C-1

0.4 0.4

Mole r a t i o b

rxs-3-Methyl trans- 3-Methyl

Substituent

3.6 3.6

4.1 5.2

6.4 6.9 6.5 5.8

c- 3

c- 2

3.6 3.6

4.8 4.6

c-4

A€i

6.6 5.8

6.8 6.8

c-5

8.4 8.1

1-Me

T a b l e 11. E f f e c t of Eu(DPM)3 on I3C S h i e l d i n g s a of I s o m e r i c Methylcyclopentanols (69)

2.3 1.7

2.7 2.5

3-Me

NANCY K. WILSON AND J . B. STOTHERS

33

l a r g e r s h i f t was a t t r i b u t e d t o i n t e r a c t i o n with an a x i a l hydroxyl group, behavior s i m i l a r t o t h a t found f o r t h e cis- and trms-4-t-butylcyclohexanols ( 6 9 ) . I t was noted t h a t t h e e f f e c t s a s s o c i a t e d with a x i a l hydroxyls must be l a r g e enough t o overcome t h e a t t e n u a t i o n of t h e s h i f t expected because of a decreased tendency f o r complex formation a r i s i n g from s t e r i c hindrance r e l a t i v e t o an unhindered e q u a t o r i a l hydroxyl. Thus it appears t h a t d i f f e r e n t i a l s h i f t s produced by complex f o r mation with t h e r a r e e a r t h s h i f t r e a g e n t s may be u s e f u l f o r a i d i n g stereochemical assignments. On t h e b a s i s of t h e c o n s i s t e n t t r e n d s a s s o c i a t e d with y i n t e r a c t i o n s and t h e i r g e n e r a l behavior i n cyclohexane systems C h r i s t 1 and Roberts (69b) have analyzed I3C s p e c t r a of some 40 cycloheptane d e r i v a t i v e s i n conformational terms. They found g e n e r a l l y good agreement with p r e d i c t i o n s based on t h e t w i s t c h a i r form which, according t o f o r c e - f i e l d c a l c u l a t i o n s , i s t h e most s t a b l e conformation. Unambiguous assignments f o r s e v e r a l c e n t e r s w e r e obtained through t h e use of d e u t e r a t e d d e r i v a t i v e s and t h e s h i f t s induced by added paramagnetic r e agents. C h a r a c t e r i s t i c d i f f e r e n c e s i n t h e s p e c t r a of c i s t r a n s isomeric p a i r s of methylcycloheptanols p e r m i t t e d t h e assignment of s p e c i f i c s i g n a l s t o i n d i v i d u a l isomers. Although t h e small 6 e f f e c t s of s u b s t i t u e n t s i n a c y c l i c systems a r e not r e a d i l y i n t e r p r e t a b l e , t h e s e e f f e c t s tend t o be l a r g e r i n c y c l i c systems and, i n some i n s t a n c e s , appear capable of providing stereochemical information. Lippmaa and h i s co-workers have r e c e n t l y reported t h e I3C s h i e l d i n g s f o r an extensive s e r i e s of monosubstituted cyclohexanes (58) and adamantanes ( 7 0 ) which shed l i g h t on t h e behavior of 6 e f f e c t s . In t h e former s e r i e s , t h e 6-carbon (C-4) i s c o n s i s t e n t l y s h i e l d e d , r e l a t i v e t o cyclohexane, f o r a wide v a r i e t y of subs t i t u e n t s , and t h e u p f i e l d s h i f t i s a s l a r g e a s 2 ppm (Table 8 ) . Although t h e monosubstituted cyclohexanes are e q u i l i b r i u m mixtures of two c h a i r conformations, t h e major s p e c i e s i s t h e e q u a t o r i a l conformer; consequently t h e s u b s t i t u e n t i s a t a maximum s e p a r a t i o n from t h e &-carbon much of t h e t i m e and it seems u n l i k e l y t h a t t h e s e 6 e f f e c t s have any s t e r i c component. Supporting evidence f o r t h i s i s given by t h e d a t a f o r 2-chloroand 2-hydroxyadamantane (701, each of which has two carbons i n t h e 6 p o s i t i o n , b u t each i s o r i e n t e d d i f f e r e n t l y with r e s p e c t t o t h e s u b s t i t u e n t (see 1 2 ) . The two o r i e n t a t i o n s a r e e x a c t l y analogous t o t h o s e of C-4 i n a x i a l and e q u a t o r i a l monosubstit u t e d cyclohexanes. I n each of t h e s e 2-adamantane d e r i v a t i v e s , t h e &-carbons have i d e n t i c a l s h i e l d i n g s , confirming t h e absence of a s i g n i f i c a n t s t e r i c c o n t r i b u t i o n . The s h i e l d i n g e f f e c t s a r i s i n g from a 1,3-syn-diaxial arrangement of s u b s t i t u e n t s may be expected t o l e a d t o s h i f t s d i f f e r e n t from those above s i n c e t h e t e r m i n a l groups a r e much

34

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

42

c l o s e r i n space. The r e l a t i v e l y few examples c u r r e n t l y a v a i l a b l e i n d i c a t e d t h a t 6 e f f e c t s between s y n - d i a x i a l groups a r e deshielding. For example, t h e methyl s h i e l d i n g s f o r cis- and trans-4-hydroxy-9-methyl-trans-decalin (43 and 4 4 , r e s p e c t i v e l y ) may be compared with t h a t f o r 3 3 ; i n t h e a l c o h o l s , t h e

43

44

hydroxyl group i s a x i a l and e q u a t o r i a l , r e s p e c t i v e l y . Thus, i n 4 3 , t h e methyl and hydroxyl groups a r e s y n - d i a x i a l while i n 44 t h e i r r e l a t i v e o r i e n t a t i o n i s comparable t o t h a t o f C-4 and t h e hydroxyl i n e q u a t o r i a l cyclohexanol. The methyl s h i e l d i n g s (62) a r e 19.1, 16.8, and 15.7 ppm i n 4 3 , 4 4 , and 3 3 , res p e c t i v e l y , showing t h a t t h e methyl carbon i s appreciably deshielded when s y n - d i a x i a l t o t h e hydroxyl. I t may a l s o be noted t h a t t h e 6 e f f e c t of t h e e q u a t o r i a l hydroxyl i n 44 i s +1.1ppm, i n c o n t r a s t t o t h e values of -1.2 and -1.5 ppm found f o r cyclohexanol and 1-adamantanol. While t h e geometry of t h e s e c e n t e r s of i n t e r e s t i s comparable, t h e f a c t t h a t a p r i mary carbon i s involved i n 44 and secondary carbons i n the o t h e r s may w e l l have an important bearing on t h e observed effects. Long-range s h i e l d i n g e f f e c t s a r i s i n g from t r a n s a n n u l a r i n t e r a c t i o n s i n medium r i n g s may be a n t i c i p a t e d b u t f e w d a t a a r e c u r r e n t l y a v a i l a b l e . One series, which h a s been b r i e f l y examined, shows t h a t endocyclic heteroatoms i n t h e 5-position of eight-membered r i n g ketones ( 4 5 , 4 6 ) markedly i n c r e a s e d t h e t h e carbonyl carbon s h i e l d i n g (71). These d a t a a r e given i n Table 1 2 . Since it is w e l l e s t a b l i s h e d t h a t carbonyl s h i e l d i n g s a r e s e n s i t i v e t o t h e p o l a r i z a t i o n of t h e 71 bond (2), the u p f i e l d s h i f t s apparently induced by t h e s e heteroatoms a r e c o n s i s t e n t with s u b s t a n t i a l e l e c t r o n donation t o t h e carbonyl group through a t r a n s a n n u l a r i n t e r a c t i o n such a s

NANCY K. WILSON AND J. B.

STOTHERS

35

and t h e magnitudes i n d i c a t e t h a t t h e r e l a t i v e s t r e n g t h s o f t h e i n t e r a c t i o n a r e N >> S > 0. I n f a c t , t h e 70 ppm s h i f t found

a X = CH,

b C

x: s

x =0

46

T a b l e 1 2 . Carbonyl S h i e l d i n g s of Cyclooctanone and Some Analogs (71)

In C6H12/CHC13

I n CgH12 A6b

Compound

4 5a 4 5b 45c 46

PPm

-

212.4 210.9 208.7 199.6

(1:g)

A6b 218.2 215.8 214.3 129.7

-1.5 -3.7 -12.8

-2.4 -3.9 -88.5

aConverted from t h e o r i g i n a l d a t a (71) u s i n g 6zgH12 27.7 'Shift

r e l a t i v e t o cyclooctanone

.

36

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

f o r 46 i n a p r o t i c and p r o t i c media s t r o n g l y s u g g e s t s t h a t bond formation between n i t r o g e n and t h e "carbonyl carbon" i s induced by hydrogen bonding a t oxygen, s i n c e t h e "carbon 1" s i g n a l i s s h i f t e d w e l l above t h e normal range. C l e a r l y IYC nmr provides a v a l u a b l e new approach t o t h e i n v e s t i g a t i o n of such interactions. The g e n e r a l t r e n d s e x h i b i t e d by t h e s u b s t i t u e n t e f f e c t s i n t h e cyclohexanes are a l s o observed i n t h e s p e c t r a of a s e r i e s of s t e r o i d s . From c o n s i d e r a t i o n of t h e r e s u l t s f o r t h e simpler systems t o g e t h e r with off-resonance decoupling and s e l e c t i v e d e u t e r a t i o n , Roberts and h i s co-workers (72) comp l e t e d t h e assignments f o r 28 s t e r o i d s having common oxygencontaining s u b s t i t u e n t s . These s p e c t r a a l s o provide a d d i t i o n a l evidence o f t h e e f f e c t s of molecular asymmetry s i n c e t h e t e r m i n a l methyl carbons i n t h e c h o l e s t a n e s i d e chain a r e cons i s t e n t l y nonequivalent by 0 . 1 t o 0.2 ppm. These carbons are f o u r bonds from t h e n e a r e s t c e n t e r of asymmetry. This i n i t i a l study w a s r e s t r i c t e d t o 5a and A' s t e r o i d s and t h e e f f e c t s of common s u b s t i t u e n t s t h e r e i n . More r e c e n t l y , some 58 s t e r o i d s have been examined t o i n v e s t i g a t e t h e e f f e c t of a change i n c o n f i g u r a t i o n a t t h e A/B r i n g j u n c t i o n on t h e observed s h i e l d ings ( 7 3 , 7 4 ) . A comparison of t h e 5ci and 58 s k e l e t o n s (47 and 4 8 , r e s p e c t i v e l y ) shows t h a t pronounced d i f f e r e n c e s may be

47

a n t i c i p a t e d f o r C-7, C-9,

and C-19 because of t h e i r d i f f e r e n t The assignments f o r C-9 and C-19 a r e e s p e c i a l l y easy s i n c e methine and methyl carbon s i g n a l s a r e r e a d i l y i d e n t i f i e d by off-resonance decoupling ( 2 1 , and furthermore, t h e s h i e l d i n g s of t h e carbons i n t h e C and D r i n g s as w e l l as those i n t h e s i d e chain a r e l i t t l e a f f e c t e d by t h e geometry of t h e A/B f u s i o n . The observed d i f -

y-gauche i n t e r a c t i o n s i n t h e two systems.

NANCY K.

WILSON AND J. B. STOTHERS

37

f e r e n c e s are s u f f i c i e n t l y l a r g e t h a t t h e t y p e o f A/B r i n g f u s i o n can be a s s i g n e d from t h e r e s u l t s f o r a s i n g l e isomer. I n 47, C-19 h a s two gauche i n t e r a c t i o n s which are a b s e n t i n 48, and i t s s h i e l d i n g d i f f e r e n c e f o r t h e two s y s t e m s i s 12 I n c o n t r a s t , C-9 exppm, w i t h t h e former a t h i g h e r f i e l d . h i b i t s t h e o p p o s i t e b e h a v i o r because of two gauche i n t e r a c t i o n s i n 48 which do n o t o c c u r i n 4 7 . An u p f i e l d s h i f t o f 5 ppm i s found f o r C-7 i n 48 r e l a t i v e t o 47 which i s c o n s i s t e n t f o r t h e gauche i n t e r a c t i o n w i t h C-4 i n t h e 58 s k e l e t o n . I n a d d i t i o n t o t h e s e s h i f t s , t h e C-2, C-3, and C-4 s i g n a l s f o r t h e 56 s y s T a b l e 13. E f f e c t of A/B C o n f i g u r a t i o n on 13C S h i e l d i n g s i n S t e r o i d s ( 7 4 ) ( i n ppm)

A6a Skeleton Androstane

Cholestane

c-2

c-4

-0.8 -1.0 -1.0 -6.0b +1.5' -5.13~ +1.5'

-2.0 -2.4 -2.3 -3.1b -0.7' -4.5b -0.8'

-5.3 -4.1 -4.0 -4.8 -5.7 -5.6 -5.5

-14.5 -12.8 -13.0 -14.5 -14.0 -14.2 -12.4

12.0 11.1 11.1 11.8 12.1 11.5 12.1

Nil

-0.8 -5.3b -1.1

-2.5 -3.5b -2.3

-5.0 -5.4 -5.1

-14.3 -14.6 -13.0

12.0 11.5 11.2

Nil

-0.9 +0.3 -1.0 -1.7 -0.1 -0.1 -5.6; -5.4

-2.1 -1.7 -2.2 -2.0 -2.0 -1.6 -3.1; -3.5

-5.1 -5.6 -5.0 -5.9 -5.0 -5.5 -5.2 -5.1

-14.2 -13.0 -12.9

12.0 12.0 11.2 11.3 11.8 12.3 11.8 11.6

Substituent

Nil 3,17-dione 3-0x0-178-01 36,178-diol 3a,176-diol 36-01-17-one 3a-ol-17-one

3 8-01 3-one

Pregnane

11-one 3 ,20-dione 3,11,20-trione lla-01 116-01 38,206-diol 3B-ol-20-one

-

c-7

c-9

-11.8

-13.1 -14.6 -14.6 -14.4

c-19

aAr5 = ( 6 z B 6;"). b U p f i e l d s h i f t a c c e n t u a t e d by t h e axial hvdroxyl i n t h e 56 isomer 'Observed s h i f t a t t e n u a t e d by t h e a x i a l nydroxyl i n t h e 5a isomer.

38

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

tems tend t o appear a t s l i g h t l y higher f i e l d s , b u t t h e assignments f o r i n d i v i d u a l methylene carbons r e q u i r e a d e t a i l e d analy s i s of t h e d a t a . Representative d a t a f o r s e v e r a l isomeric p a i r s a r e c o l l e c t e d i n Table 1 3 from which it i s apparent t h a t t h e s h i f t s induced by a change i n geometry a t t h e A/B r i n g j u n c t i o n ( t r a n s -+ c i s ) a r e remarkably c o n s i s t e n t . The deviat i o n s from "normal" v a l u e s f o r t h e 3-hydroxy d e r i v a t i v e s a r e r e a d i l y ascribed t o t h e e f f e c t s caused by changes i n t h e hydroxyl o r i e n t a t i o n . For example, t h e 36-hydroxyl i s e q u a t o r i a l i n 5a-andro~tan-36~17f3-diol (49) and a x i a l i n t h e 58 isomer 50; consequently i t s y-gauche i n t e r a c t i o n s with C-1 and C-5

49

H

U

60

i n 50 s h i f t t h e C-2 and C-4 s i g n a l s u p f i e l d r e l a t i v e t o t h e i r p o s i t i o n s i n 49 even i n t h e absence of any o t h e r f a c t o r . I n c o n t r a s t t h e opposite t r e n d i s expected f o r t h e 3a-hydroxy der i v a t i v e s and i s observed i n t h e two examples a v a i l a b l e . Comparable t r e n d s have r e c e n t l y been found f o r a s e r i e s of b i l e a c i d s and d e r i v a t i v e s (74). Several hydroxyl-substituted p o l y c y c l i c systems have been examined t o c h a r a c t e r i z e t h e long-range s h i e l d i n g e f f e c t s of t h e OH group; t h e methyl s h i e l d i n g s f o r some of t h e s e model systems a r e l i s t e d i n Table 1 4 t o g e t h e r with t h e s h i f t s r e l a t i v e t o t h e p a r e n t hydrocarbon. The expected geometric dependence of t h e y e f f e c t i s evident from t h e 9-methyl-1-decal01 r e s u l t s . Of t h e s e v e r a l examples of t h e 6 e f f e c t , t h o s e i n which t h e r e i s a s y n - d i a x i a l arrangement ( 5 2 ) e x h i b i t a cons i s t e n t downfiela methyl s h i f t , by 1.6 t o 3.4 ppm, and q u a l i t a t i v e l y a p a t t e r n emerges. The s h i f t is l a r g e s t f o r t h e more r i g i d c a s e s , such a s 9-methyl-trans-decal-4B-01 and pregnan116-01, while i n more f l e x i b l e systems t h e s h i f t s a r e s m a l l e r . The 6 e f f e c t s of e q u a t o r i a l hydroxyls a r e a l s o d e s h i e l d i n g ,

W

ul

b E f f e c t of t h e 48-OH group.

C

&ROH

16.8 19.1

4a-OH 4B-OH

Difference i n shielding,

a

14.7 15.7

3a-OH 38-OH +1.1 +3.4

-1.0 0.0

+0.9 +2.1

16.6 17.9

2Ci-OH 2B-OH

A6a

1B-OH

C

Me

-5.9 +0.4

N i l Ia-OH

9B-Methyl-trans-decalin

6 15.7 9.8 16.1

Substituent

P a r e n t system

Pregnane

lla-OH 118-OH

12.3 12.9 15.5

+1.6b

38-01-1-A~ 19.4 3 ~ , 4 8 - ( 0 ~ ) ~ - A21.0 ~ N i l

+2 0

17.4 19.4

3-0x0-A' 3-0x0-66-OH-A'

+1.1

+0.6 +3.2

-

+3.4

12.4 13.5 15.8 N i l

Cho lestane

Me

6c

6a-OH 6B-OH

Substituent

P a r e n t system

Table 14. Long-Range S h i e l d i n g E f f e c t s of t h e Hydroxyl Group on Methyl Carbons i n P o l y c y c l i c Systems (62) ( i n ppm)

40

STEmOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

b u t small, i n c o n t r a s t t o t h e t r e n d i n monocyclic systems (Tab l e 8 ) . The 3-decal01 d e r i v a t i v e s show t h a t while t h e E e f f e c t of t h e e q u a t o r i a l hydroxyl i s z e r o , t h e a x i a l hydroxyl causes a 1 ppm u p f i e l d s h i f t of t h e methyl s i g n a l even though t h e groups a r e w e l l separated ( s e e 5 2 ) . This s h i f t may ref l e c t a s l i g h t d i s t o r t i o n of t h e s k e l e t o n t o reduce H * * * * O H i n t e r a c t i o n s , which enhances t h e y i n t e r a c t i o n s of t h e methyl. Some santonin d e r i v a t i v e s e x h i b i t r e l a t i v e s h i f t s compara b l e t o those f o r s t e r o i d s which provide a simple method of assignment f o r t h e 6,7 f u s i o n o f t h e l a c t o n e r i n g and t h e conf i g u r a t i o n of t h e methyl a t C - 1 1 i n 53-56 ( 7 5 ) . I n a-santonin ( 5 3 ) the l a c t o n e r i n g is t r a n s fused with e q u a t o r i a l bonds and t h e d i h e d r a l angle between C-8 and C-13 i s approximately l O O ' ,

54

53

55

56

whereas t h i s angle i s much smaller (near 20') f o r 8-santonin ( 5 4 ) . Because of t h i s d i f f e r e n c e C-7, C-8, C - 1 1 , and C-13 may be expected t o be more s h i e l d e d i n 5 4 ; t h e p e r t i n e n t d a t a (Table 15) a r e e n t i r e l y c o n s i s t e n t with an i n c r e a s e d y i n t e r a c t i o n between C-8 and C-13 i n 5 4 . I n t h e e p i d e r i v a t i v e s 55 and 56 t h e l a c t o n e r i n g i s c i s fused with t h e C-0 bond a x i a l and, again, t h e d i h e d r a l angle r e l a t i n g C-8 and C-13 i s l a r g e f o r t h e a-methyl ( 5 5 ) and small f o r t h e 8-methyl ( 5 6 ) ; t h u s t r e n d s s i m i l a r t o those i n t h e u s e r i e s a r e observed, a s expected (Table 1 5 ) . The r e s u l t s f o r C-6 and C-15 show t h a t while t h e c a r b i n y l carbon (C-6) r e f l e c t s t h e o r i e n t a t i o n o f t h e oxygen atom i n t h e usual way ( u p f i e l d s h i f t f o r a x i a l c a s e s ) , t h e angular methyl C-15 i s i n s e n s i t i v e t o t h e o r i e n t a t i o n of t h e oxygen. The l a t t e r observation may i n d i c a t e app r e c i a b l e d i s t o r t i o n of t h e c e n t r a l r i n g such t h a t t h e d i s tance between t h e l a c t o n e oxygen and c-15 is s i g n i f i c a n t l y

NANCY K. WILSON AND J. B. STOTHERS

41

Table 15. I3C Shieldings in Some Santonin Derivatives (75) PPm

ACI

Compound

C-6

c-7

C-8

c-11

C-13

C-15

53

81.5

76.5 76.9

23.3 20.3 23.4 18.3

41.2 38.2 44.2 41.3

12.5

55 56

54.0 49.5 43.8 41.8

25.3 25.2 25.2 24.9

54

80.8

9.9

14.9 9.6

larger than that in a usual syn-diaxial arrangement. Other features associated with the stereochemistry of the lactone fusion include a 10 ppm downfield shift for C-4 in the epi series (55and 5 6 ) while C-9 and C-10 undergo -4 and -2 ppm shifts, respectively. The origins of these changes are not clear and more than one factor may contribute, but the observed trends are useful for studies of related systems as noted in the original paper (75). Similar intercomparisons of the shieldings for a series of diterpenes not only demonstrated the utility of I3C nmr for structural and configurational elucidations in such systems but also illustrated its value for conformational analysis (76). From the data for the Ae(r)-pimaradienes (571, Wenkert and Buckwalter (76) were able to determine the conformation of ring C, which is difficult to do by other methods.

67

a R=CH,.R'=

C2H3

b R=C,H,.R'=CH,

Several studies (77-81) of norbornyl derivatives have characterized substituent effects in this ring system in which

42

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

a v a r i e t y o f y e f f e c t s occur. For example, an exo-2 group s h i e l d s C-7 while i t s endo c o u n t e r p a r t s h i e l d s C-6 (see 58 and 5 9 ) ; similarly 7-substituents exert d i f f e r e n t e f f e c t s a t the

58

syn and a n t i carbons ( 6 0 ) .

The d a t a i n Table 16 i l l u s t r a t e t h e former t r e n d s , which a r e found t o be e s s e n t i a l l y consist e n t with those i n cyclohexanes, b u t a l l 2 - s u b s t i t u e n t s s h i f t the C-6 s i g n a l u p f i e l d from i t s p o s i t i o n for norbornane reg a r d l e s s of o r i e n t a t i o n , although t h e e f f e c t i s l a r g e r f o r

ae

endo groups.

60

This g e n e r a l behavior f o r ex0 groups l e d t o t h e suggestion (77) t h a t overlap of t h e " t a i l s " of t h e ex0 bonding o r b i t a l s a t C-2 and C-6 may be r e s p o n s i b l e f o r t h e ex0 y e f f e c t s i n a manner analogous t o t h a t envisaged t o account f o r long-range H-H couplings i n an extended W arrangement (1). While t h e o r i e n t a t i o n of t h e s e o r b i t a l s i s i d e a l € o r such an i n t e r a c t i o n , t h e o r i e n t a t i o n of t h e a p p r o p r i a t e o r b i t a l s a t C-2 and C-7 ( t h e endo and anti o r b i t a l s , r e s p e c t i v e l y ) i s n o t ; t h u s i t i s not s u r p r i s i n g t h a t 2-endo groups do n o t s h i e l d C-7 i n a s i m i l a r fashion. The s p e c t r a of s e v e r a l 2,3-disubstit u t e d norbornanes show t h a t t h e i n d i v i d u a l s u b s t i t u e n t e f f e c t s are a d d i t i v e f o r t r a n s isomers, b u t t h a t s i g n i f i c a n t deviat i o n s from a d d i t i v i t y occur i n t h e c i s c a s e s ( 8 2 ) . The l a t t e r , however, are c o n s i s t e n t i n t h a t t h e observed s h i e l d i n g s a r e u p f i e l d from those p r e d i c t e d , with t h e l a r g e s t d e v i a t i o n s € o r C-2 and C-3; t h i s i s a l s o c o n s i s t e n t with o t h e r r e s u l t s presumably a r i s i n g from s t e r i c i n t e r a c t i o n s of c i s s u b s t i t u e n t s . As expected, carbon-bearing s u b s t i t u e n t s i n t h e s e bicyc l i c systems e x h i b i t c o n f i g u r a t i o n a l l y dependent s h i e l d i n g s with endo groups more s h i e l d e d than t h e i r ex0 c o u n t e r p a r t s if

WILSON AND J . B. STOTHERS

NANCY K.

T a b l e 16.

43

S u b s t i t u e n t E f f e c t s a i n Some 2 - S u b s t i t u t e d Norbornyl Systems ( 7 7 , 82)

Y

8

a

6

Orientation

C-2

C-1

C-3

C-4

C-6

C-7

C-5

Me

exo endo

6.7 4.5

6.7 5.4

10.1 10.6

0.5 1.4

-0.9 -7.7

-3.7 0.2

0.2 0.5

CH20H

ex0 endo

15.1 12.8

1.8 1.7

4.4 4.0

-0.2 0.4

-0.7 -7.2

-3.3 1.4

0.2 0.2

COOH

ex0 endo

16.7 16.2

4.6 4.2

4.4 2.1

-0.2 0.9

-1.0 -4.8

-1.8 1.9

-0.3 -0.6

COOMe

exo endo

16.4 15.9

5.1 4.0

4.2 2.2

-0.4 0.7

-1.4 -5.0

-2.1 1.7

-1.1 -0.7

NH2

exo endo

25.3 23.3

8.9 6.8

12.4 10.5

-0.4 1.2

-3.1 -9.5

-4.4 0.3

-1.2 0.6

OH

ex0 endo

44.3 42.4

7.7 6.3

12.3 9.5

-1.0 0.9

-5.2 -9.7

-4.1 -0.9

-1.3 0.2

OMe

ex0 endo

54.2 51.9

3.4 2.9

9.6 7.4

-1.8 0.1

-5.3 -9.6

-3.2 -1.4

-1.1 0.1

CN

ex0 endo

1.0 0.1

5.5 3.4

6.3 5.5

-0.3 0.2

-1.6 -4.9

-1.3 0.0

-1.5 -0.7

Br

exo endo

23.5 23.7

10.1 7.5

14.2 11.8

0.7 0.6

-2.2 -5.2

-2.8 0.9

-1.6 -0.2

c1

ex0 endo

32.1 31.0

9.6 7.2

13.8 11.2

0.0 0.6

-3.1 -7.4

-3.3 -0.4

-1.6 -0.2

X

all6 =

C

-

".

t h e carbon i s bonded d i r e c t l y t o t h e r i n g . Shielding d i f f e r e n c e s f o r more remote c a r b o n s are much smaller and somewhat v a r i a b l e . T y p i c a l d a t a are g i v e n i n T a b l e 17. The d i f f e r e n c e i n o r i e n t a t i o n f o r a 2-exo-methyl r e l a t i v e t o C-7 and an endomethyl r e l a t i v e t o C-6 i s a p p r e c i a b l e and i s r e f l e c t e d i n t h e h i g h e r s h i e l d i n g of t h e l a t t e r . Supporting evidence t h a t t h e endo-methyl C-6 i n t e r a c t i o n i n v o l v e s t h e endo p r o t o n a t C-6 i s g i v e n by t h e reduced d i f f e r e n c e s f o r t h e c o r r e s p o n d i n g methyl I t i s i n t e r e s t i n g t h a t t h e nonequivac a r b o n s i n norbornene. l e n c e ( A & ) o f exo- and endo-+methyl c a r b o n s i n s u b s t i t u t e d

44

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

norcamphors (62) i s a l s o less than those i n t h e 2-methylnorbornanes, while t h e ex0 double bond i n camphene (62) does n o t a l t e r t h e A 6 value. F u r t h e r , t h e A6 v a l u e s f o r the monomethyl and gem-dimethyl d e r i v a t i v e s of norbornane are comparable b u t

& \

10

61

& ‘0

62

t h e corresponding values d i f f e r s u b s t a n t i a l l y i n t h e ketones.

An i n t e r p r e t a t i o n of t h e s e t r e n d s could invoke d i f f e r i n g de-

g r e e s of t w i s t of t h e b i c y c l i c s k e l e t o n as a f u n c t i o n of subs t i t u t i o n , and an i n v e s t i g a t i o n of t h i s p o s s i b i l i t y warrants c o n s i d e r a t i o n . Enhanced d i f f e r e n c e s f o r exo- and endo-methyl carbons were found f o r t h e 13.2.11 system 63 which could be a t t r i b u t e d t o an a d d i t i o n a l i n t e r a c t i o n with t h e endo-3 prot o n , b u t t h e C-3 s h i e l d i n g i n 63 and t h e t h r e e methyl deriva0.2 t i v e s (Table 17) remains e s s e n t i a l l y con’stant, 6c 19.1

*

(82); t h u s an explanation of t h e l a r g e r A6 v a l u e s f o r the 63 d e r i v a t i v e s i s lacking. Although t h e d i f f e r e n c e s between synand anti-7-methyl carbons i n the 2-0x0 d e r i v a t i v e s a r e s m a l l , t h e syn-methyl t e n d s toward lower f i e l d . I n c o n t r a s t t o an e a r l i e r r e p o r t (83) , t h e spectrum of camphor-3,9,9,9-d1+ ( 8 4 ) obtained by one of us (84a) shows t h a t t h e more s h i e l d e d o f t h e gem-dimethyl s i g n a l s e x h i b i t s t h e c h a r a c t e r i s t i c e f f e c t s of deuterium s u b s t i t u t i o n ( 8 5 ) . The few oxygen-containing s u b s t i t u e n t s examined e x h i b i t much smaller stereochemical dependencies. The marked geometrical dependence of t h e methyl carbon s h i e l d i n g s i n b i c y c l i c systems a f f o r d s a s i m p l e method f o r assignment of c o n f i g u r a t i o n , which h a s a l s o been e x p l o i t e d i n a v a r i e t y of mechanistic s t u d i e s t o monitor deuterium incorp o r a t i o n ( 8 2 , 8 6 ) . The s t e r e o s e l e c t i v i t y of deuterium exchange by homoenolization a t t h e gem-dimethyls i n 1,3,3-Me362 and 7,744e2-63 has been determined i n a s t r a i g h t f o r w a r d

Table 17. I3C Shieldings of Some Substituents in Bicyclic Systems

&c Parent Norbornane ( 5 8 , X = H)

Norbornene

Camphene (62)

Bicyclo[2.2.1]heptan2-one (62)

Bicyclo[2.2,1J hept5-en-2-one Bicyclo r3.2. lloctan6-one ( 6 3 ) Bicyclo[2.2.2]oct5-en-2-one

agendo

C bsyn

.

'anti.

Substituent

ex0

endo

2-Me 2,2-Me2 1,2-Me2 1,3-Me2 trans-2 I 3-Me2 2-Me-2-OH 2-CH2OH 2 ,2- (CH20H)2 2-COOMe 2-OMe

22.3 31.6 19.9 22.8 21.6 31.1 66.4 67.5 175.4 55.6

17.4 27.2 15.2 18.2 16.1 26.3 64.3 66.2 174.3 56.4

5-Me 21.7 20.4 trans-5,6-Me2 5-COOMe 175.6 5-OMe 56.5 28.5

A&a -4.9

Ref.

-4.6 -5.5 -4.8 -2.1 -1.3 -1.1 +1.2

77 77 78 78 78 78 77 77 82 82

23.9

-4.6

81

19.5 18.8 173.9 56.3

-4.4 -4.7

-2.2 -1.6 -1.7 -0.2

77 78 82 82

3-Me 3 ,3-Me2 1 I 3 ,3-Me3 7-Me 1,7-Me2 1,7,7-Me3 5-Me 6-Me 6,6-Me2

14.1 23.4 23.3 12.gb 10.9b 19.9b 22 .o 20.9 26.3

10.7 21.6 21.6 12.lC 10.5c 19.3' 17.2 18.8 25.7

-3.4 -1.8 -1.7 -0.8 -0.4 -0.6 -4.8 -2.1

-0.6

77 77 82 77 82 77 77 77 81

3-Me 3,3-Me2

15.7 24.4

16.5 26.8

+0.8 +2.4

82 82

7-Me 7 I 7-Me2

15.6 25.2

8.5 17.9

-7.1 -7.3

82 82

3-Me 3I +Me2

14.4 24.3

17.5 27.5

+3.1 +3.2

82 82

- tjexo. C 45

46

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

f a s h i o n , although t h i s a n a l y s i s i s d i f f i c u l t by o t h e r methods. I n a similar manner, t h e acid-catalyzed racemization of camphene (61 ) has been examined u t i l i z i n g 61 -l0-l3C a s t h e s t a r t ing m a t e r i a l and following t h e incorporation of t h e I 3 C t r a c e r a t t h e exo- and endo-methyl carbons (C-8, C-9) a s a f u n c t i o n of t i m e (87) t o determine t h e r e l a t i v e r a t e s of methyl migrat i o n and Wagner-Meerwein s h i f t s . A s noted e a r l i e r , v i c i n a l 13C-lH coupling c o n s t a n t s may be expected t o e x h i b i t a stereochemical dependency by analogy with t h e w e l l - e s t a b l i s h e d t r e n d s f o r H-H s p i n i n t e r a c t i o n s . Preliminary r e s u l t s (88) f o r some 5-endo - s u b s t i t u t e d hexachlorobicyclo[2.2.llheptenes ( 6 4 ) confirm t h i s notion s i n c e t h e couplings of C-7 with t h e endo and e m -3 p r o t o n s (A and B i n 64) are 9 and 0 H z , r e s p e c t i v e l y , and t h e d i h e d r a l angles rel a t i n g t h e s e n u c l e i a r e approximately 150 and 90°, r e s p e c t i v e l y . A v a r i e t y of geminal couplings have a l s o been measured i n t h e s e systems, some of which a r e given i n 65 t o i l l u s t r a t e t h e i r remarkable v a r i a t i o n .

-

OAc

ti4

66

In general it i s found t h a t J C C C > JCCH ~ ( 2 ) , and t h i s t r e n d may be u t i l i z e d t o gain information on t h e stereochemist r y of deuterium atoms i n l a b e l e d compounds. Since 13C-2H coupling is n o t a f f e c t e d by proton decoupling, t h e s e coupling constants a r e d i r e c t l y measurable i n r o u t i n e s p e c t r a b u t , s i n c e t h e v a l u e s a r e s m a l l e r t h a n t h e correspondJcD= (YD/YI;I)JcH, ing 1 3 c - 1 ~i n t e r a c t i o n s by a f a c t o r of 6.51. In p r a c t i c e , t h i s means t h a t i n r o u t i n e F o u r i e r transform o p e r a t i o n with r e l a t i v e l y wide sweep widths J values of less than 0.5 Hz a e unresolved while l a r g e r J values a r e observed. AS an example of t h e p r a c t i c a l value of t h i s , t h e s p e c t r a of some deuteriuml a b e l e d camphors have been described ( 8 5 ) . I n t h e spectrum of camphor-3-exo-d1 (661, t h e C-5 s i g n a l appears as a t r i p l e t while C-7 remains unaffected, whereas t h e l a t t e r s i g n a l becomes a t r i p l e t i n t h e spectrum of camphor-3,3-d2 ( 6 7 ) . The r e l a t i v e o r i e n t a t i o n s of t h e s e n u c l e i a r e given i n 68, from which it i s apparent t h a t t h e o b s e r v a t i o n s a r e e n t i r e l y cons i s t e n t with e x p e c t a t i o n s . An a d d i t i o n a l u s e f u l f e a t u r e in t h e s e s p e c t r a i s t h e f a c t t h a t t h e geminal C-4 s i g n a l e x h i b i t s a r e a d i l y resolved i s o t o p e s h i f t of 0 . 1 ppm while JCCD i s unresolved. Thus 13C s p e c t r a of d e u t e r a t e d m a t e r i a l s provide d i r e c t information not only f o r t h e carbon b e a r i n g t h e label

NANCY K. WILSON AND J.

€3.

47

STOTHERS

b u t a l s o f o r t h e geminal and v i c i n a l carbons; t h e s e f e a t u r e s have been employed f o r a v a r i e t y of mechanistic s t u d i e s as well a s f o r s i g n a l assignments and stereochemical e l u c i d a t i o n s (85, 86).

&5

b 66

67

The J C H v a l u e s f o r bicyclobutane ( 6 9 ) , obtained by complete a n a l y s i s of t h e 'H and 1 3 C s p e c t r a (89) , a l s o o f f e r evidence of marked stereochemical e f f e c t s . The v i c i n a l couplings f o r t h e ex0 and endo protons, 16.0 and 5.3 Hz, r e s p e c t i v e l y , d i s p l a y t h e expected t r e n d , and t h e geminal JCCH v a l u e s vary s i g n i f i c a n t l y a s shown i n 69. Furthermore, t h e one-bond coupl i n g c o n s t a n t s f o r t h e methylene p r o t o n s d i f f e r by 1 6 Hz with v a l u e s of 153 (exo-H) and 169 Hz. I t i s i n t e r e s t i n g t h a t t h e t r e n d f o r t h e methylene couplings i s o p p o s i t e t o t h a t expected on t h e grounds of s t e r i c compression discussed i n Sect. 11.

69

A v a r i e t y of JCFvalues have been measured f o r t h e norbornyl system ( 7 7 ) through t h e examination of t h e methyl-2,2difluoronorbornanes and exo-fluoronorbornane. For t h e l a t t e r compound t h e t h r e e v i c i n a l couplings , 3 J C F , d i f f e r markedly;

48

STEREOCHEMICAL ASPECTS OF

’

3C NMR SPECTROSCOPY

f o r C-6, J = 9.8 Hz, and f o r C-4, J = 2.3 Hz, while J 1 Hz f o r C-7. This t r e n d i s c o n s i s t e n t with a Karplus r e l a t i o n f o r t h e s e v i c i n a l i n t e r a c t i o n s , s i n c e t h e d i h e d r a l angles a r e approximately 1 7 0 , 120, and 90°, r e s p e c t i v e l y . Each of t h e d i f l u o r i d e s e x h i b i t s two doublets f o r each s k e l e t a l carbon, exc e p t C-5 and C-7, because of unequal coupling with t h e exoand endo-fluorines. Unfortunately, t h e ex0 and endo coupling c o n s t a n t s could n o t be unequivocally assigned, b u t t h e i r stereochemical dependence i s c l e a r . For t h e d i f l u o r i d e s t h e C-7 s i g n a l was a d o u b l e t , J = 4.3 t o 5.8 Hz, which must a r i s e from coupling with t h e endo-fluorine because of t h e r e s u l t f o r exo-fluoronorbornane. Carbons s e p a r a t e d by more than t h r e e bonds from the f l u o r i n e n u c l e i (C-5 and t h e methyl carbons) g e n e r a l l y appeared a s s i n g l e t s . The exceptions were t h e syn-7and endo-6-methyl carbons which l i e c l o s e t o t h e exo- and endof l u o r i n e s , r e s p e c t i v e l y . These gave r i s e t o d o u b l e t s , J = 4 . 5 and 7.0 Hz , r e s p e c t i v e l y . C l e a r l y , 3C-19F coupling i n t e r a c t i o n s a r e remarkably s e n s i t i v e t o geometry, and t h e v a r i a t i o n s can be h e l p f u l f o r both s i g n a l assignments and s t e r e o chemical e l u c i d a t i o n s .

C.

Alkenes and D e r i v a t i v e s

Although a considerable body of d a t a e x i s t s f o r alkenes ( 2 , g o ) , f u l l i n t e r p r e t a t i o n of t h e t r e n d s p r e s e n t s d i f f i c u l t i e s , e s p e c i a l l y i n d i s t i n g u i s h i n g between s t e r i c and e l e c t r o n i c c o n t r i b u t i o n s . Linear r e g r e s s i o n a n a l y s i s has afforded subs t i t u e n t parameters with which o l e f i n i c s h i e l d i n g s can be e s t i mated with good p r e c i s i o n ( 3 , 90, 9 1 ) . Each set c o n t a i n s parameters f o r c i s a l k y l groups, varying from -0.5 t o -1.8 ppm, i n d i c a t i n g t h a t t h e sp2-carbons absorb a t s l i g h t l y higher f i e l d s i n cis o l e f i n s . The d i f f e r e n c e s f o r p a i r s of c i s - t r a n s isomers a r e , however, highly v a r i a b l e , as some t y p i c a l d a t a i n Table 18 show. Thus t h e o l e f i n i c s h i e l d i n g s of alkenes a r e unrelia b l e i n d i c a t o r s of c o n f i g u r a t i o n . The l a r g e r d i f f e r e n c e s f o r t h e lower molecular weight 2-alkenes may i n d i c a t e t h a t t h e varying conformational and s t e r i c p r o p e r t i e s of t h e longer a l kyl chains produce s i g n i f i c a n t p e r t u r b a t i o n s a t t h e sp2-carbons. I n c o n t r a s t , t h e a-carbon s h i e l d i n g s a r e very s e n s i t i v e t o configuration (Table 18) ; i n v a r i a b l y t h e a-carbons a r e s h i e l d e d i n c?k-1,2-disub$tituted systems r e l a t i v e t o t h e t r a n s isomers. Comparison of t h e d a t a f o r alkenes w i t h t h o s e f o r t h e corresponding alkanes r e v e a l s t h a t c i s a-carbons a r e shielded while t r a n s a-carbons a r e deshielded. I n t r i s u b s t i t u t e d c a s e s , one of t h e a-carbons is c i s t o an a l k y l group i n both isomers whereas t h e remaining two a r e interchanged. On t h i s b a s i s , t h e d a t a f o r 3-methyl-2-hexene given i n Table 1 8 a r e r e a d i l y e x p l i c a b l e , although a t f i r s t glance t h e r e may appear t o be an anomaly. From an examination of an e x t e n s i v e

NANCY K.

WILSON AND J. B , STOTHERS

49

T a b l e 18. Geometric E f f e c t s a on O l e f i n i c and a-Carbon

S h i e l d i n g s i n A c y c l i c Alkenes (90, 92)

Olefinic

Olef i n 2-Butene 2-Hexene 2-Oc t e n e 3-Octene 4-Octene 2-Dodecene 4 - ~ o d ecene

c-2

c-3

1.4 1.1 1.1

1.4 0.9 0.9 1.0

1.9

1.0

-0.1

-0.7

Ci-C

0.2 0.6

5.5 5.1 5.2 5.2 5.5

0.3

6 . 5 ( C - 1 , c-4) 5 . 4 ((2-3) , 4 . 9 (C-6)

2.0

c- 5 5-Dodecene 6-Dodecene 3-Methyl-2-hexene

c-4

(C-11, (C-11, (C-11, (C-3)

5.9 5.9 5.5

(C-4) (C-4) ((2-5)

C-6

1.0

0.5

5 . 7 (C-4, c-7) 5 . 7 (C-5) 0.0 8.5 -7.9

(C-1) ((2-4) (3-Me)

- a ( & t r a n s - & c i s ) ; i t a l i c i z e d v a l u e s a r e 50.3 ppm w h i l e a l l C C o t h e r s a r e 20.1 ppm. Z 6,. bCH3CH=C(CH3)C,H,, g E

c

-

s e r i e s of o l e f i n s Roberts and co-workers (90) found the a v e r age d i f f e r e n c e s between c i s and t r a n s a-carbons i n 1,2-disubs t i t u t e d systems t o be 5.3 ppm (a-CH3) and 5.6 ppm (a-CH2) , and i n t r i s u b s t i t u t e d cases t o b e about 8 ppm f o r methyl and methylene carbons. Comparable v a l u e s f o r s e v e r a l a d d i t i o n a l i s o m e r i c p a i r s o f d i - and t r i s u b s t i t u t e d e t h y l e n e s have been r e p o r t e d ( 9 3 ) . Hence, w i t h b o t h isomers a v a i l a b l e , assignment of c o n f i g u r a t i o n by 13C nmr i s s t r a i g h t f o r w a r d . The c o n f i g u r a t i o n a l assignments f o r the 5-ethylidenenorbornenes (78) and two 3-ethylidene-2-methyl c y c l o b u t a n e d e r i v a t i v e s (94) a r e s p e c i f i c examples. From the d a t a f o r a s i n g l e i s o m e r , however, one can compare t h e r e s u l t s w i t h t h o s e for t h e c o r r e s p o n d i n g a l k a n e t o determine t h e c o n f i g u r a t i o n a t t h e double bond; even w i t h o u t t h e spectrum of t h e a l k a n e , s u f f i c i e n t l y p r e c i s e e s t i m a t e s of i t s s h i e l d i n g s are p o s s i b l e ( 2 , 7). From their a l k e n e d a t a , Roberts and co-workers (90) d e r i v e d p a r a m e t e r s d e f i n i n g t h e e f f e c t of t h e o l e f i n i c bond on t h e a-carbon s h i e l d i n g s r e l a t i v e t o t h e values f o r t h e p a r e n t alkane (Table 191.

STEREOCHEMICAL ASPECTS OF

50

3C NMR SPECTROSCOPY

Table 19. Shielding E f f e c t s a of t h e O l e f i n i c Bond on t h e a-Carbons (90) ( i n ppm) a-Carbon

O l e f i n type 1-Substituted 1, l - D i s u b s t i t u t e d cis-l,2-Disubstituted trans-l,2-Disubstituted Trisubstitutedb

CH3

A B

C

Tetrasubstituted

-0.3 t o -1.1 -1.5 ? 0.2 +3.8 t 0.3 +1.6 -+3.4 --4.6 -0.6

CH2

+1.8

-1.0 t o -2.4 -2.6 t 0.3 +3.0 t 0.2 +l.1 -+3.4 --5.2

a P o s i t i v e e f f e c t s denote downfield s h i f t s . b H

\ ,c=c

\

CA Several cc,p-unsaturated carbonyl d e r i v a t i v e s have been examined t o i n v e s t i g a t e t h e e f f e c t s of s u b s t i t u e n t o r i e n t a t i o n on o l e f i n i c s h i e l d i n g s (95, 9 6 ) . Again, l i n e a r r e g r e s s i o n a n a l y s i s yielded parameters which c o r r e l a t e t h e observed s h i e l d i n g s . The o v e r a l l f i t of t h e s e d a t a i n d i c a t e s t h a t reasonably good p r e d i c t i o n s f o r r e l a t e d systems a r e p o s s i b l e such t h a t stereochemical assignments could be made. This may be e s p e c i a l l y valuable €or tri- and t e t r a s u b s t i t u t e d systems which l a c k v i c i n a l proton couplings a c r o s s t h e double bond, While t h e carbonyl carbon i n t h e s e d e r i v a t i v e s is n o t p a r t i c u l a r l y s e n s i t i v e t o t h e geometry of p o l a r s u b s t i t u e n t s , a p a r t from t h e tendency f o r c i s halogens and t h e methoxyl group t o s h i e l d t h e carbonyl, o t h e r a-carbons e x h i b i t t r e n d s similar t o those found f o r o l e f i n s , thereby a f f o r d i n g a s t r a i g h t f o r w a r d means of c o n f i g u r a t i o n a l assignment. For example, a- and 6phosdrin (70) were r e a d i l y d i s t i n g u i s h e d by t h e 3.4 ppm g r e a t e r s h i e l d i n g of t h e a l l y l i c methyl carbon f o r t h e former ( 9 7 ) ; t h i s i s c o n s i s t e n t with e a r l i e r stereochemical assignments based on proton r e s u l t s ( 9 8 ) . S i m i l a r l y , i n c i s - and transc i t r a l (71 and 72) t h e a l l y l i c methyl carbons a t C-3 d i f f e r by 7.4 ppm and t h e C-4 n u c l e i by 8.0 ppm i n o p p o s i t e d i r e c t i o n s a s expected ( 9 9 ) . The t e r m i n a l methyl carbons d i f f e r by 7.9 ppm i n each isomer.

NANCY K.

51

WILSON AND J . B. STOTHERS

B

0

(MeO),POHH

(MeO)3bO_(:oOMe

H,C

COOMe

H,C

8

oc 70

71

72

From t h e behavior of a-carbons i n o l e f i n s it i s n o t surp r i s i n g t h a t t h e c a r b i n y l carbons i n a l l y 1 a l c o h o l s a r e markedl y dependent on s u b s t i t u e n t o r i e n t a t i o n a t t h e o l e f i n i c carbon. R e s u l t s f o r a s e r i e s of t h e s e a l c o h o l s (91) i n which c i s - t r a n s p a i r s were examined revealed t h e following u p f i e l d s h i f t s i n t h e c i s isomers: C H 3 , -6.3; C1, -3.7; B r , -2.6 ppm, whereas a c i s i o d i n e deshiezds t h e c a r b i n y l carbon by 1 . 0 ppm. With t h e exception of t h e l a t t e r , c o n f i g u r a t i o n a l assignments i n rel a t e d systems a r e r e a d i l y accomplished a s has been i l l u s t r a t e d by Bhalerao and Rapoport (100) i n t h e i r study of t h e s t e r e o chemical course of a l l y l i c o x i d a t i o n w i t h selenium d i o x i d e . A few d i e n e s have been examined (90, 93, 1 0 1 ) , and t h e s e d a t a i n d i c a t e t h a t t h e t r e n d s f o r sp3-carbons i n t h e s e systems a r e comparable t o those i n monoenes, r e g a r d l e s s of t h e proximi t y of t h e double bonds. S i m i l a r r e s u l t s were found f o r a few polyenes. A t p r e s e n t , t h e p a u c i t y of d a t a p r e c l u d e s d e t a i l e d a n a l y s i s of t h e o l e f i n i c s h i e l d i n g s i n conjugated dienes. The apparent a l t e r n a t i o n of s u b s t i t u e n t e f f e c t s along a conjugated chain, noted e a r l i e r (page 2 4 ) , has been examined i n some det a i l ( 1 0 2 ) f o r a s e r i e s of t r a n s - 1 - s u b s t i t u t e d 1,3-butadienesI b u t without t h e corresponding r e s u l t s f o r t h e c i s isomers, poss i b l e stereochemical c o n t r i b u t i o n s remain unknown. As noted e a r l i e r (page 30) , geminal 13C-lH s p i n couplings e x h i b i t stereochemical dependencies, b u t i f o p e r a t i n g through t h e TI bond i n o l e f i n s , 13C=C-H, a t r e n d i s not apparent i n a l l c a s e s without r e l a t i v e s i g n determinations. A s t h e d a t a i n Tab l e s 20 and 2 1 show, however, J C ~v aH lues a r e consistently more p o s i t i v e i f t h e proton i s c i s t o another proton (73) r a t h e r than c i s t o a s u b s t i t u e n t on t h e double bond ( 7 4 ) . This t r e n d i s comparable t o t h a t found f o r cyclopropane d e r i v a t i v e s . B analogy with v i c i n a l H-H couplings one may expect v i c i n a l " G I H i n t e r a c t i o n s through TI bonds t o depend on geometry, b u t

Table 20. O l e f i n i c 1 3 C - 1 ~Coupling C o n s t a n t s i n some Vinyl D e r i v a t i v e s , CH2=CHX ( i n Hz) O r i e n t a t i o n of H r e l a t i v e t o X

cis X

JCH

CN CHO

trans JCCH

163.2 156.6

S i c 13

-4.4 -3.4 -0.8 -7.9

159.9

OAc

c1

162.6

Br I

163.8 164.1

JCCH

Ref.

165,4 162.3

0.3

160.9

-2.5 7.6

103 104 105 105 105 106 107 108 106 105 109

JCH

1.8

160.9 -8.3 -8.5

159.6 159.2

-7.8 -6. 3a

1-C1-1-Ph

7.1 7.5 4.2 5.6a

a O r i e n t a t i o n taken r e l a t i v e t o c h l o r i n e .

T a b l e 21.

O l e f i n i c I3C=C-H Coupling C o n s t a n t s i n Some 1 , 2 - D i s u b s t i t u t e d Ethylenes ( i n Hz) O r i e n t a t i o n of s u b s t i t u e n t s

Substituent

c1 Br I COOEt

52

cis

trans

Ref.

15.4 14.7 11.0 3.1

<0.3 -0.4 -1.4 -2.8

107 107 110 105

NANCY K. WILSON AND J. B. STOTHERS

H

53

H

H X 73

74

few data are available. Nevertheless, stereochemical assignments for the E and Z isomers* of phosphoenol-a-ketobutyrate (75 and 76, respectively) were based on the vicinal 13C-lH coupling of the olefinic proton in samples 13C-enriched at the carbony1 position (97). The observed values of 9.5 and 2.9 Hz,

75

76

respectively, compare favorably with the data for phosphoenolpyruvate, which were determined to confirm the assignments for the methylene protons in the 'H spectrum (111). It seems clear that measurements of these interactions should provide a valuable method for stereochemical assignments for a wide variety of trisubstituted alkene derivatives. In the general discussion of 13C coupling constants (Sect. 11-B) , it was noted that one-bond 13C-lH couplings appear to decrease with increasing steric compression, but the results for the vinyl derivatives in Table 20 show no striking variation, although each value is greater than that for ethylene, 156.2 Hz (2). With bulky alkyl groups bonded to the olefinic carbons, however, the one-bond couplings decrease markedly; some representative data are listed in Table 22. For each of these al*The descriptors E and Z give the relative orientation of the two groups of highest priority, according to the Cahn-Ingold-Prelog sequence rules, which are bonded to each end of the olefinic bond. E denotes the configuration in which these groups lie on opposite sides of the double bond, while Z denotes the isomer in which the highest priority groups are on the same side; for 1,2-disubstituted ethylenes, these correspond to the trans and cis isomers, respectively.

54

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

Table 22. Some Olefinic, One-Bond I3C-lH Coupling Constantsa (in Hz) 1,l-Di-t-butylethylene cis-4,4-Dimethyl-2-pentene

Trimethylethylene 2,4,4-Trimethyl-2-pentene cis-Di-t-butylethylene trans-Di-t-butylethylene Tri-t-butylethylene

151.gb 152.2 (C-2) 150.0 (C-3) 149.4 (C-2) 147.4 (C-3) 148.4b 148.0 148.3 147.6 143. 3b

aReference 112 I unless otherwise indicated. bReference 16. kenes, the JCH values are significantly smaller than the ethylene value and there is a distinct decrease as the double bond is more heavily substituted. This is consistent with an interpretation based on steric compression, but the validity of this notion remains to be established and further refinements in the theory are required.

D.

Saturated Heterocycles 1.

1,3-Dioxanes

Two groups have examined rather extensive series of alkylated l13-dioxanes and compared their data with the trends found for the methylcyclohexanes (113,114). From these results it appears that substituent correlations can indeed by transferred from the carbocyclic systems to these heterocyclic analogs if due allowance is made for the effects of the ring oxygens. Since C-0 bonds are shorter than C-C bonds, C-2 of the 1,3-dioxane ring is closer to C-4 and C-6 and, consequently, syn-axia1 interactions between these positions are larger in the heterocyclic system; thus conformational energy differences ( A G O ) are larger for 2-, 4-, .and 6-substituents (115). The absence of axial bonds at the 1- and 3- positions reduces the AGOvalues for 5-substituents, and axial carbons at this position appear to be deshielded relative to their equatorial counterparts presumably because of the low compression of an axial group at C-5. It is well established that cis-2-methyl-5-t-butyl-l,3-dioxane exists almost exclusively in the conformation having the t-butyl group axial (115a, 116). The data for the alkyl substituents in the series of derivatives having either 2- or 5-t-butyl groups (113)

NANCY K. WILSON AND J. B. STOTHERS

55

provide clear indications of substituent position and orientation. Equatorial 2-methyl carbons absorb near 6c 21.3 and equatorial 2-t-butyl carbons near 35.0 (quaternary C) and 25.0 (CH3), whereas equatorial 4-methyl carbons in these systems appear near 22.0 ppm. The shielding difference for axial and equatorial groups at C-5 is sufficiently large to provide a ready distinction, even though the 5-methyl carbons absorb at inexplicably high fields relative to their counterparts in the methylcyclohexanes. An axial 5-methyl carbon is 3.5 ppm l e s s shielded than the equatorial, while the corresponding differences for 5-t-butyl groups are 2.1 ppm for both the quaternary and methyl carbons. This trend is opposite to that found for the methylcyclohexanes and presumably results from the lack of syn-axial nonbonded interactions with the 3,5-positions. From the data for the 2,2-dimethyl derivatives the normal trend is apparent, with the axial carbons and the 4,6-carbons shifted to higher field. This is the expected y-gauche effect. It is interesting that the methyl carbons of equatorial 5-t-butyl groups are significantly deshielded (2.6 ppm) relative to those in equatorial 2-t-butyl substituents, although the quaternary centers differ by 4.5 ppm in the opposite direction, because the quaternary carbon in the 2-t-butyl groups is 6 to the two oxygens. In any event, the stereochemistry of the substituents is readily apparent from their 13C shieldings, and the trends exhibited by the ring carbons are analogous to those found for the methylcyclohexanes, with the exception of the very small changes caused by axial substitution at C-5. A detailed study of the ring carbon shieldings in several 2-, 4-, and 6-methyl-substituted 1,3-dioxanes (114) gave additional strong evidence of the remarkably reproducible effects caused by alkyl substitution, provided the compounds lack synaxial methyl-methyl interactions. From the data for 25 derivatives, methyl substituent effects at the various ring positions were determined with which the C-2, C-4, and C-5 shieldings could be correlated with standard deviations of better than 0.4 ppm. Far greater deviations were invariably found, however, for all systems which would have syn-axial methyl groups in chair conformations, with somewhat larger deviations for those having 2,4-syn-axial interactions than for the 4,6-cases. These discrepancies were taken as evidence for the presence of significant amounts of nonchair conformations, and the differences for the 2,4- and 4,6-syn-axial interactions are consistent with this view, since steric crowding may be expected to be greater in the former cases. More recently, a detailed proton study of some of these compounds has provided definitive evidence of the presence of twist-boat conformations (117). The results for trans-2,4,4,6-tetramethyl-l,3-dioxane are illustrative. The deviations.between the observed and predicted ring carbon shieldings for conformation 7 7 were found to be 3.7 (C-21,

56

STEReCCHEMICAL ASPECTS OF

77

78

3C NMR SPECTROSCOPY

79

5.5 (c-4), 1.6 (C-5), and 3.6 ppm (C-61, with the observed signals at lower field than predicted, as is the general tendency. At 220 MHz, the spectrum of the C-5 and C-6 protons was readily analyzed to yield vicinal coupling constants of 11.8 and 4.4 Hz. The larger value requires a trans diaxial disposition, or nearly so, of the vicinal protons which does not occur in 77 but it is readily attained in 78, a twist-boat. Although the orientation of the ring protons in 79 satisfies the requirement, the much higher potential energy of such systems having axial 2-substituents renders 79 unlikely as a major contributor. On this basis, 78 must be a principal conformer in the overall conformational equilibrium,'andthe potential utility of the observed deviations of the ring carbon shieldings from the predicted values is clearly indicated. The instrument employed in this study lacked spin decoupling capability and, consequently, an analysis of the methyl region of the 13C spectra was not attempted. From the results for the other examples discussed above, however, it seems reasonable to expect that the methyl shieldings will also be helpful for stereochemical analysis.

2.

Piperidines, Piperazines, and Derivatives

A series of alkylpiperidines, principally the methylpiperidines, has been examined to test for the existence of substituent parameters with which to correlate the shielding data (118). The parameters derived from N-methyl-, 4-methyl-, and 2,6-dimethylpiperidine correlate the results for a variety of piperidines and piperazines reasonably well, with the exception of the example having syn-axial methyl roups, 2,2,6,6-tetramethylpiperidine. For this compound, the q3C signals were found at significantly lower field than predicted, by 10.0 (C-21, 5.8 (C-3), and 5.4 ppm (C-4) , presumably because of severe distortion from perfect chair conformations. Since the deviations are comparable to those found for the corresponding 1,3-disxanes, discussed above, this piperidine may exist in twist-boat conformations, but the available data are insufficient to judge the degree of distortion from the chair. The results for c i s and trans-3,5-dimethylpiperidine are qualitatively analogous to those for the 1,3-dimethylcyclohexanes, with all carbons in the trans isomer at higher fields than those in the cis form (119).

NANCY K. WILSON AND J. B.

STOTHERS

57

The s h i f t s a r e -2.0 (‘2-2) , -5.5 (C-3) , -4.2 (C-4) , and -0.8 ppm (CH3). Since t h e t r a n s isomer i s a r a p i d l y e q u i l i b r a t i n g mixt u r e of conformers, 80, through r i n g r e v e r s a l and n i t r o g e n i n v e r s i o n , averaged s h i e l d i n g s are observed f o r each carbon. Cons e q u e n t l y , t h e observed s h i f t s a r e less than t h e v a l u e s would

be i n a “ f i x e d ” system having an a x i a l methyl group. I t i s i n t e r e s t i n g t h a t t h e methyl s i g n a l f o r t h e t r a n s form i s u p f i e l d r e l a t i v e t o t h a t f o r t h e c i s isomer, i n c o n t r a s t t o t h e trend. f o r a x i a l 5-methyl carbons i n 1,3-dioxanes. Since t h e methyl s i g n a l i s an average of a x i a l and e q u a t o r i a l environments, one can e s t i m a t e t h a t t h e a x i a l i s s h i e l d e d by approximately 1.6 ppm, which i s about one-third of t h e s h i f t experienced by an In the piperidines, there a x i a l methyl i n t h e cyclohexanes. i s only a s l i g h t p r e f e r e n c e f o r t h e conformations having equat o r i a l N-H bonds; t h u s an a x i a l 3-methyl group e x p e r i e n c e s s y n - a x i a l i n t e r a c t i o n s w i t h b o t h , a n a x i a l N-H and t h e lone p a i r The decreased on n i t r o g e n a s w e l l a s w i t h t h e C-5 p o s i t i o n . s h i e l d i n g may i n d i c a t e t h a t an a x i a l lone p a i r t e n d s t o des h i e l d a s y n - a x i a l carbon, b u t t h e p o i n t remains t o be e s t a b l i s h e d . Undoubtedly t h e s t e r i c compression of an a x i a l 3methyl group i n t h e p i p e r i d i n e system i s l e s s t h a n t h a t i n t h e methylcyclohexanes because of t h e s h o r t e r N-H bond and t h e f a c t t h a t t h e r e i s a s i g n i f i c a n t population w i t h an a x i a l lone pair. I n a d d i t i o n , t h e r e may be some d i s t o r t i o n from a perf e c t c h a i r form such t h a t t h e s y n - a x i a l i n t e r a c t i o n with C-5 i s a l s o reduced. I t would be informative t o examine t h e Nmethyl d e r i v a t i v e s s i n c e t h e s e have a s t r o n g p r e f e r e n c e f o r conformations having an a x i a l lone p a i r on n i t r o g e n .

58

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

It has been suggested t h a t an a x i a l lone p a i r appreciably d e s h i e l d s a syn-axial methyl carbon, b u t t h e evidence i s n o t compelling. As model systems, t h e 13C s p e c t r a of a- and 8prodinol ( 8 2 ) were recorded and t h e downfield s h i f t of 4 ppm

81

observed f o r t h e 3-methyl carbon i n t h e isomer was a s c r i b e d t o a d e s h i e l d i n g e f f e c t of t h e lone p a i r (120). Unfortunately t h i s i n t e r p r e t a t i o n l e a v e s out of account the f a c t t h a t t h e 3methyl group i n B-81 i g anti t o t h e hydroxyl, whereas i n a-81 it i s gauche. In t h e l a t t e r isomer, t h e r e f o r e , t h e methyl carbon w i l l experience a s i g n i f i c a n t y-gauche e f f e c t which i s absent i n t h e former. The methyl s h i e l d i n g d i f f e r e n c e f o r t h e corresponding c o n f i g u r a t i o n a l change i n t h e 1-hydroxy derivat i v e s of trans-9-methyldecalin i s 6.3 ppm (Table 1 4 ) , i n d i c a t ing t h a t t h e e f f e c t of t h e a x i a l lone p a i r i n t h e p i p e r i d i n e s may n o t be deshielding. As noted above, t h e examination of some simpler p i p e r i d i n e s should be i n s t r u c t i v e . The t y p i c a l s h i f t s a r i s i n g from syn-axial i n t e r a c t i o n s of an a x i a l methyl i n a c h a i r conformation occur i n N-methylpip e r i d i n e hydrochlorides a s shown by p r o t o n a t i o n of 1 , 2 , 6 - t r i methylpiperidine, which g i v e s a mixture of two s t e r e o i s o m e r i c s a l t s d i f f e r i n g i n o r i e n t a t i o n of t h e N-methyl group( 1 2 1 1 , c i s and t r a n s with r e s p e c t t o t h e d i e q u a t o r i a l 2- and 6-methyls. In the minor isomer (30%), having a c i s a x i a l N-methyl group, C-3 and C-5 a r e s h i e l d e d by 7.4 ppm and t h e N-methyl i s 4 . 5 ppm u p f i e l d from i t s p o s i t i o n i n t h e t r a n s isomer,in which t h e N-methyl group i s e q u a t o r i a l . These changes are analogous t o t h e s h i f t s found f o r l-cis-2-c~s-3-trimethylcyclohexane r e l a t i v e t o l-trans-2-cis-3-trimethylcyclohexane, namely, 8.3 ppm f o r C-4 and C-6 (y-gauche t o t h e a x i a l 2-methyl i n the former) and 11.6 ppm f o r t h e 2-methyl carbon ( 6 1 ) . The domp a r a b l e s h i f t s f o r t h e y-gauche r i n g carbons i n t h e two systems i n d i c a t e t h a t t h e o r i e n t a t i o n of t h e s e c e n t e r s r e l a t i v e t o the a x i a l methyl i s s i m i l a r f o r both, while t h e s m a l l e r s h i f t f o r t h e l a t t e r c e n t e r i n the heterocycle may be due i n p a r t t o t h e charge on t h e n i t r o g e n . On t h e b a s i s of t h e r e s u l t s f o r t h e p r o d i n o l s (811, some 4-piperidonesI and s u b s t i t u e n t parameters d e r i v e d from t h e s e

NANCY

K. WILSON AND J. B. STOTHERS

59

and the p i p e r i d i n e d a t a ( 1 2 1 ) , 13C nmr has study (120) of the stereochemistry of some methyl-4-phenylpiperidin-4-01s (82) The t h e y isomer t o have e q u a t o r i a l phenyl and

.

been employed i n a isomeric 1 , 2 , 5 - t r i 3C d a t a i n d i c a t e methyl groups ( 8 3 )

82

and s i n c e t h e spectrum of t h e 6 isomer showed no appreciable u p f i e l d s h i f t s f o r C-3 and C-6, it was concluded t h a t it e x i s t s p r e f e r e n t i a l l y a s 8 4 . X-Ray s t u d i e s have shown t h a t t h e y and 6 isomers e x i s t a s 8 3 and 84 i n t h e s o l i d s t a t e ( 1 2 2 ) . The d a t a f o r t h e a isomer were less r e a d i l y i n t e r p r e t e d b u t seemed t o be b e s t accommodated by 8 5 w i t h a s t r o n g

83

84

preference f o r the skew boat 8 5 b . Upon p r o t o n a t i o n , t h e ahydrochloride apparently favors t h e c h a i r 8 5 a with an equat o r i a l N-Me bond. The y-hydrochloride corresponds t o 8 3 , while an epimeric mixture a r i s i n g from a x i a l and e q u a t o r i a l p r o t o n a t i o n of 84 i s formed from t h e 6 isomer. The propionyl o r a c e t y l e s t e r s of 8 2 , t h e promedols, were a l s o examined and p r e f e r r e d conformations f o r t h e esters and t h e i r hydrochlorides were deduced from t h e 13C d a t a (120b). The 13C d a t a f o r t h e preceding systems a s w e l l a s f o r q u i n u c l i d i n e and some i n d o l e s have l e d t o t h e assignment of s i g n a l s i n a v a r i e t y of a l k a l o i d s of moderate complexity ( 1 2 3 ) . One of t h e s e examples a l s o i n d i c a t e d t h a t 1 3 C nmr should be u s e f u l f o r stereochemical e l u c i d a t i o n s i n t h e s e systems, a l though most of t h e examples published h e r e t o f o r e a r e n o t illustrative. In t h e spectrum of 1,2,3,4,6,7,12,12b-octahydro-

60

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

indolo[2,3-a]quinolizine ( 8 6 ) , t h e c l e a r s e p a r a t i o n of t h e C-4, C-6, and C-12b s i g n a l s i n d i c a t e d t h a t t h e s e s i g n a l s may provide a means of stereochemical assignment f o r t h e q u i n o l i z i d i n e r i n g fusion i n r e l a t e d a l k a l o i d s ( 1 2 4 ) . The 2-t-butyl d e r i v a t i v e of 86 was r e p o r t e d (124) t o e x h i b i t t h e same p a t t e r n f o r t h e carbons j u s t mentioned; both compounds a r e known t o exist p r e f e r e n t i a l l y w i t h a t r a n s r i n g f u s i o n .

Another a s p e c t of t h e I3C s t u d i e s o f t h e simpler n i t r o g e n h e t e r o c y c l e s has been t h e measurement of c o n t a c t s h i f t s of some p i p e r i d i n e s , q u i n u c l i d i n e , and 1-azaadamantane caused by coordination with paramagnetic n i c k e l (11) a c e t y l a c e t o n a t e (125) For t h e N-methylpiperidines, t h e a- , B- , and y-carbons e x h i b i t a l t e r n a t i n g u p f i e l d and downfield s h i f t s , r e l a t i v e t o t h e p a r e n t compound, which a r e r a p i d l y a t t e n u a t e d with i n c r e a s i n g s e p a r a t i o n from the coordination c e n t e r . I n c o n t r a s t , f o r t h e N-H p i p e r i d i n e s t h e c o n t a c t s h i f t s a r e much l e s s r a p i d l y a t t e n u a t e d . The d i f f e r e n c e was a t t r i b u t e d t o t h e o r i e n t a t i o n of t h e lone p a i r on nitrogen which is almost e n t i r e l y a x i a l f o r the U-meth 1 d e r i v a t i v e s . This apparent conformational dependence of y3C c o n t a c t s h i f t s was reproduced by MO c a l c u l a t i o n s f o r a c a t i o n r a d i c a l formed by e l e c t r o n a b s t r a c t i o n from t h e ligand. It was proposed t h a t the d i s t r i b u t i o n of e l e c t r o n s p i n over the carbon s k e l e t o n depends s t r o n g l y on t h e o r i e n t a t i o n of the lone p a i r . From their r e s u l t s , Morishima e t a l . (125) suggested t h a t t h e marked s e n s i t i v i t y of I3C c o n t a c t s h i f t s t o lone-pair o r i e n t a t i o n should b e u s e f u l f o r s t u d i e s

.

NANCY K. WILSON

AND

J. B. STOTHERS

61

of molecular conformation associated with lone-pair electrons, features which are not readily accessible by other techniques. The relative orientation of a nitrogen lone pair and a vicinal C-H bond has been found to influence the magnitude of the 13C-lH coupling constant (126). The 'JCH values for the ring proton in a series of diastereomeric 2- and E-oxaziridines establish that there is a small but consistent difference of 4.5 to 7 Hz between the Z and E isomers (126a). The larger values for the Z isomers in which the lone pair is cis to the C-H bond indicate a positive contribution by the lone pair. Similar differences had been reported (126b,c) for some N-alkylaziridines and an imidazolidine, but the stereochemistry had not been rigorously established. Additional examples of the influence of neighboring lone pairs on some 13C couplings have been found for phosphorus heterocycles to be discussed later. 3.

Cyclic Sulfoxides and Related Systems

In a brief 13C examination of penicillin (87) and its sulfoxides (88) appreciable differences in the C-methyl shieldings were found (127). The 2B-methyl carbon is shielded by 6.6 and 11.3 ppm in the a- and 6-sulfoxides, respectively, relative to that in 87. It was suggested (127) that these

COOMe 87

62

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

shifts arise from an appreciable steric effect of the sulfoxide bond since the dihedral angles between the 6-Me-C and S C bonds are 85 and 60°, respectively. The shielding difference of 2.3 ppm between the 2a-methyl carbons in the sulfoxides was similarly rationalized, since in the i3 isomer the 2a-methyl carbon is anti with respect to the sulfoxide oxygen, while the more shielded 2a-methyl carbon in the a-sulfoxide is gauche. Some support for this interpretation is given by the data for the exo- and endo-sulfoxides of 2-thiabicyclo[2.2.1lheptane, for which C-6 is 2.2 ppm upfield in the endo isomer relative to the ex0 form and C-7 is shifted 0.9 ppm in the opposite fashion (128a). The shielding effects of an axial S W bond in some trimethylene sulfite derivatives have also been briefly examined (128b). In the meso-4,6-dimethyl isomers 89 and 90, the C-4, C-6 signals of 89 are 9.3 ppm upfield from those in

90

89

90, presumably because of the y-gauche effect of the axial S O in the former. It is also interesting that the axial methyl group in 91 shields the y-gauche methine carbon by 1.9 ppm, a considerably smaller effect than that observed for the nitrogen heterocycles and the methylcyclohexanes discussed previously. This may indicate distortion of the ring from a chair

91

conformation to reduce the syn-axial interaction of the axial methyl and the S+O bond. These preliminary results for the S+O bond in a variety of environments indicate that a detailed examination of such systems should be rewarding.

NANCY K. WILSON AND J. 4.

€4.

63

STOTHERS

Monosaccharides and OZigosaccharides

The marked orientational dependence of the shielding effects of the hydroxyl group on the ring carbons in substituted cyclohexane systems clearly indicates that 13C nmr should prove valuable for the characterization of isomeric polyhydroxyl derivatives (65, 72). This point has been amply demonstrated by the results for several monosaccharides and their glycosides (129), with the results for a series of inositols (hexahydroxycyclohexanes) serving as excellent models (130). From the inositol data, it became apparent that the expected qualitative trends are followed, although quantitatively the shifts are smaller than those found for the cyclohexanols. Not surprisingly, the shielding effects of an axial hydroxyl group on its neighboring carbinyl carbon depend on the orientation of the hydroxyl on the latter center. Dorman and co-workers (130) thus derived two sets of substituent parameters, for ring carbons bearing axial or equatorial hydroxyls, using scyzlo-inosito1 in which the six hydroxyls are equatorial as the base case. Methylation of an hydroxyl group shifts the carbinyl carbon appreciably downfield (an a effect) but the shifts of more remote carbons were found to be variable, with the exception of the B effect of -4.5 ppm produced by an axial methoxyl. More recently, Dorman and Roberts (131) have reexamined their results in terms of the contributing conformational isomers, to show that the more variable shifts caused by the methoxyl groups are indeed consistent with conformational populations. For example, the absence of a shift for the y-carbons (C-3,5) upon methylation of an axial hydroxyl is consistent with the expected low, probably negligible population of conformer 9 2 . Furthermore, since the methoxyl carbon is y-gauche with respect to C-2 in 93 (C-6 in 9 4 ) , the upfield 6 effect of an axial methoxyl is unexceptional. Regularities in the effects of methylation of equatorial hydroxyls were revealed by similar

92

93

94

considerations. For systems having two neighboring equatorial hydroxyls, conformations 9 5 to 97 are populated, with the smallest population expected for 95 because the methoxyl group

64

STEREOCHEMICAL ASPECTS OF

H

3C NMR SPECTROSCOPY

H H

96

H 95

97

is gauche to both 8-carbons, whereas in 96 and 97 it is gauche to only one. The observed methylation shift of -0.7 ppm is significantly smaller than that expected for 95 (about -5 ppm), indicating that the steric interactions of the 0-methyl with the equatorial hydroxyls in 96 and 97 are small. A similar shift was found for the 8-carbon bearing an equatorial hydroxyl in the systems represented by 98 to 100 indicating that 1 0 0 is more highly populated than 98. This conclusion is substantiated by the fact that the 8-carbon having the axial hydroxyl

OH

I

-cw OH

I

C

H

I

H

C”3

H

I

99

98

100

NANCY K. WILSON AND J. B .

STOTHERS

65

is shielded upon methylation of the central hydroxyl by -4.4 ppm. The latter observation suggests that the relative populations are 1 0 0 > 99 > 98 for these cases. Since these trends are readil interpreted in conformational terms, it would appear that '3C nmr offers a potentially powerful approach for detailed conformational analysis. The shieldings of the methoxyl carbons in the methylated inositols also appear to depend on their orientation, with equatorial methoxyls absorbing near 6c 60 if flanked by two equatorial hydroxyls but at 6c 58 if flanked by one axial and one equatorial hydroxyl group. The lone axial methoxyl in this series was at 6 c 62.5. The spectra of the monosaccharides were assigned by the methods employed for the inositols coupled with the knowledge that the anomeric carbons appear at lowest field because of the two bonded oxygens, and the hydroxymethyl carbons absorb at highest field; the latter are readily identified by off-resonance decoupling. In the aldopyranoses, the hydroxymethyl carbons are equivalent, or nearly so, in each anomeric pair. The earlier examinations of these simple sugars utilized steadystate (cw) operation and consequently the spectra were those of the equilibrium mixtures of anomers. Thus, for most cases, two sets of signals were obtained whose relative intensities gave a direct measure of the equilibrium composition. With Fourier transform operation, spectra can often be obtained rapidly enough to permit the observation of individual anomers before mutarotation. D-Glucose has received the most attention, with the spectra of its 3-d, 5,6,6,-d3, 3-0-methyl, and 2-deoxy derivatives as well as those of the methyl glucosides and 1,2,3,4,5,6-13C~enriched material having been reported (129). From the unequivocal assignments of the ring carbons in the a and $ anomers, it was clear that the y effect of the axial hydroxyl in the former differs at C-3 and C-5 (see 1 0 1 ) , amounting to -2.9 and -4.4 ppm, respectively. Presumably the y effect differs at the two positions because of the change in ring geometry caused by the ring oxygen, which could enhance steric interaction with the syn-axial hydrogen on C-5. The shift of the C-3 signal was essentially the same as that found for the inositols, -2.8 ppm. on

101

OH

102

66

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

Dorman and Roberts (130) tested the utility of their substituent parameters derived from the inositol spectra for the correlation of the hexopyranose results and found the standard deviation to be 1.2 ppm; in general the observed shieldings are greater than predicted. From the data for the methyl glycosides it was found that the axial methoxyl carbon is shielded by about -2 ppm relative to the equatorial in each anomeric pair (129, 132). This trend is opposite to that found for the methyl inositols and is presumably due to conformational differences arising from the replacement of a flanking hydroxymethylene group by oxygen. The methoxyl signals for the methyl D-xylopyranosides show the same behavior as those in the hexose pyranosides. It may be noted that the acetoxyl methyl shieldings of the polyacetate derivatives of these sugars appear to be insensitive to configuration (131, 132). A few pentose aldopyranoses were included in the initial studies; and it was clear from its 13C spectrum, that arabinopyranose exists predominantly in the 1C conformation; thus, in the B anomer the 1-hydroxyl group is axial (202). The methoxyl signal of methyl 8-D-arabinopyranoside is -1.65 ppm upfield from that of the a anomer (133), in agreement with this interpretation. Although D-ribose was included in some of the earlier studies (1291, the appearance of signals attributable to furanoside rings was noted in only one of these (134), but the two low-field signals observed were not assigned. Recently D-ribose has been examined with Fourier transform techniques and the observed signals assigned to each of the four cyclic forms, the pyranose ( 2 0 3 ) and furanose ( 1 0 4 ) anomers (135); in

103

104

the same study, the presence of the four forms of 2-deoxyribose was also revealed. By comparison of these spectra with those of methyl-B-D-ribopyranoside, methyl-6-D-ribofuranoside, 9-8D-ribopyranosyladenine, adenosine, and 2-deoxyadenosineI the assignments were completed (135). A similar examination of Dfructose had shown the presence of the expected four anomers, and integration of these spectra gave the equilibrium composition (136). The 13C results for the monosaccharides offer an excellent

NANCY K. WILSON

AND

J. B. STOTHERS

67

starting point for analysis of the spectra of oligosaccharides, and a few reports for the latter systems have appeared (131, 136, 137). In a preliminary note, the assignment of configuration for the glycosidic linkage in glucobioses was demonstr.ated since the central anomeric center is consistently shielded in the a-linked compounds relative to its absorption for the 6

OH

OH

105a R=OH; R = H

105b

R = H ; R'=OH

anomers (137a). In the initial detailed examination of disaccharides (131), the spectra of cellobiose ( 1 0 5 ~ lactose ~ ) ~ ( 2 0 5 b ) , maltose ( 2 0 6 ) , and sucrose (207) as well as some of their acetoxyl derivatives were analyzed. The assignment of the anomeric (C-l,l' c1 and 6) and hydroxymethyl signals (C-6,6' a and 6) was straightforward, as was the identification of C-4' (a and 6) bearing the glycoside bond because of the downfield shift caused by ether formation. For 1 0 5 , in which the monomers are 6-linked, the signals for C-lIl - 2 I l -3, - 4 , -5, and

106

107

I

OH

68

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

-6 are essentially unchanged from their positions for the monomers, indicating that steric perturbations at these positions are similar in the dimers. It was found that the C - 4 ' , C-6', and glycosyl carbon shieldings are independent of the configuration at C-1'. Thus the spectra contain fewer than the maximum 24 lines which could conceivably arise from each anomeric mixture; in fact, no more than 15 separate lines were resolved at best and only 12 appeared in the cellobiose spectrum. After identification of the signals noted, detailed comparison of the data permitted Dorman and Roberts (131) to assign most of the other signals with reasonable confidence, and their interpretations led to certain general conclusions. The effects produced by linking a pyranose moiety equatorially to glucose are comparable to those produced by forming the methyl glucoside, whereas the formation of disaccharides by an a linkage produces shifts indicative of either substantial conformational changes or major steric interactions. The maltose (106) and sucrose ( 1 0 7 ) results compared with those of their monomers revealed both up- and downfield shifts, suggesting that there are conformational changes since steric interactions generally produced upfield shifts only. Some indication of conformational changes as a function of pH was also found for methyl 8-maltoside and maltose while the spectra of glucose, the methyl glucosides, and sucrose in 1 N NaOH are little changed from those in neutral solutions. Dorman and Roberts (131) also demonstrated that 13C spectra of polysaccharides may be obtained by cw operation, although FT operation is undoubtedly the better approach. In fact, the disaccharides of the initial study (105-107) have been reexamined by the FT method more recently and the inherently higher resolution (because of the absence of passage broadening) has resolved a f e w of the closely neighboring signals (137b,c). In addition to sucrose, some disaccharides containing a furanose moiety have been examined by 3C nmr. For example, the equilibrium mixture of D-turanose, exhibiting 31 separately resolved signals, was found to contain three species, two of which were the expected glucopyranosylfructofuranoses (136). The spectrum of nystose (208) was found to resemble closely the sum of the spectra of 209 and 1 1 0 , 8-D-fructofuranose, while that of 109 closely resembles the sum of sucrose ( 1 0 7 ) and 110. These results (137d) indicate that homologation of D-fructofuranosyl residues does not cause major perturbations of the shielding interactions. From the spectra of disaccharide 111 and methyl a-Didopyranosiduronic acid, Perlin and co-workers (138) concluded that the biopolymer heparin consists of an alternating sequence of 1,4-linked residues of a-L-idopyranosyluronic acid 2-sulfate and 2-deoxy-2-sulfamino-e-D-glucopyranosyl 6-sulfate as shown

NANCY K . WILSON AND J. B .

69

STOTHERS

0

HocYoQ ~ H ~ O H

OH OH

CH20H

109

108

CH20H

110

in 1 1 2 . The close agreement between the shieldings of the three materials was taken as evidence that the idouronic acid residue in heparin is depicted most satisfactorily as the X ( L ) conformation. In the spectrum of the polymer, however, no lowintensity signals arising from the minor D- lucuronic acid moiety were detected, but nevertheless its q 3 C spectrum constitutes good roof of stereochemistry of the principal segment. Vicinal lgC-lH couplings have been measured for a variety of monosaccharide derivatives using 3C-enriched materials and proton spectroscopy at 100 and 220 MHz (139). The results reveal the marked dependence on dihedral angle which was expected and thereby confirm the utility of these parameters for stereochemical elucidations. A number of interactions were examined for which the dihedral angle is nominally 60°, and

70

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

","

-Ooc&

,C(OH);,

I

HO

I

OSOj 111

the JCCCH values were found to vary from less than 1 to 3.3 Hz. For three glucopyranoses 1 1 3 , 3Jc6,H4 = 2 to 3.3 Hz, while in the pentaacetyl derivative 114 the vicinal couplings between

osqI & o *-

5%' I 0-0

osq112

C-1 and the axial protons at C-5 and C-3 are 2.5 and less than 1 Hz, respectively. In 6-D-glucose itself ( 1 1 5 ) , the vicinal couplings of the axial anomeric proton with C-3 and C-5 are

113

114

both less than 1 Hz. These relatively small values are consistent with expectations and a general effect of a neighboring oxygen seems to emer e. Those systems having an oxygen anti with respect to the q3C nucleus as in 116 consistently exhibit

NANCY K. WILSON AND J. B. STOTHERS

71

115

the smaller values (<1 Hz) while the JCCCHvalues are near 3 Hz if the oxygen is gauche as in 117. The difference in JCCCH for the axial anomeric proton in 115 does not appear to be a function of the oxygen through which the coupling is transmitted,

"c

e0

H

'3c@ 0

H

116

117

because the corresponding JCCCH values for the equatorial anomeric proton in a-glucose are both 5 to 6 Hz; the larger values are expected since the dihedral angle is 180O. Some additional data were obtained from furanose derivatives, most of which bore a 1,2-0-isopropylidene group which was thought to impart a degree of rigidity to the otherwise more flexible five-membered ring. Evidence supporting this notion was provided by the absence of coupling between H-2 and H-3, indicating a 2 , 3 dihedral angle of approximately 90'. This interpretation suggests that the angle between C - 1 and H-3 is near 140' in 118a for which JCCCH is 5.5 Hz. The vicinal C-6, H-4 interaction in 118a is 2.4 Hz, which upon comparison with the corresponding coupling of less than 1 Hz in the diastereomer 118b and the fact that the H-4, H-5 couplings are 8 . 0 and.7.5 Hz, led to the conclusion (139) that the preferred 5,6 rotamers in these cases are 119a and 119b, respectively. Although the CCCH dihedral angle is 60' in both cases, the oxygen is a n t i in 119b and would be expected to reduce the J value as mentioned above. The vicinal couplings of carbonyl carbons in closely related compounds are significantly larger. For example, 3Jc-1,~-3

72

STEREOCHEMICAL ASPECTS OF 13C NMR SPECTROSCOPY

118

a

R=OH, R'=H

b R = H . R'=OH

in 120 is 8.9 Hz, while in 121a and 121b, 3J~-6,H-4 = 9 and 6.6 Hz, respectively; the latter data indicate an important contribution of the 5-OH. In these lactones, the dihedral angles

b

a

119

are 1 0'. Thus these 3J~-6,H-4va-ies indicate t at factors other than dihedral angle alone are significant. The vicinal interactions of these carbonyl carbons through oxygen, COCH, were found to be less than 1 Hz, as expected for dihedral angles near 100°, the estimated values. Some geminal CCH couplings were also measured in these derivatives and found to vary appreciably. For example, the geminal interaction of C - 1 with H-2 is 5.7 Hz in 8-glucose but for 121a is less than 1 Hz in a-glucose; similarly, 2Jc,1,H,5 4.1 Hz but less than 1 Hz in 121b. This behavior was compared to that of geminal CCH interactions in olefins and cyclopropanes, discussed earlier, and Schwarcz and Perlin (139) proposed that the magnitude of these geminal interactions may depend on the orientation of the proton relative to neighboring electronegative substituents. Unfortunately, no relative sign determinations for the present system have been reported. Such data would be interesting for comparison with other systems.

NANCY K. WILSON

AND

73

J. B. STOTHERS

P

121

120

5.

a

R=OH,R'= H

b

R = H , R' = OH

Phosphetane, Phospholene, and Phosphorinane Derivatives

An extensive series of four-membered ring phosphorus heterocycles, including phosphetanes, their oxides, sulfides, and salts, has been examined by 13C nmr (140). Since the compounds studied were unsymmetrically substituted with methyl groups, several cis-trans isomeric pairs were included and their s ectra provide clear evidence of the effects of geometry on the y3C parameters. Most of the compounds in these studies may be represented by the general formula 1 2 2 , and some representative shielding data are listed in Table 23. Not surprisingly, it appears that the largest differences between cis and trans isomers, namely those in which the X and Y substituents are interchanged, are observed for the phosphetanes. In the other series, the C-2 shieldings are relatively insensitive

4

b b

0

Ph S

Ph Me

S Ph

Me Ph

OMe

0

OMe

0

c1

0

c1

5.9,119.2 6.9,120.7

129.5 132.2

9.8 11.5

Me 0

0 Me

0

129.9 131.9

6.7 5.2

137.7 140.1

P-c

Ph 0

--

c1

--

Me

--

Ph

Y

51.4 51.1

26.4 28.6

51.1 48.7 53.5 50.4

41.4 42.1

37.1 27.7

42.8 46.2

42.6 46.9

44.9 48.0

46.6 45.8

44.4 44.2

57.4 57.1

45.4 44.1

46.7 46.5

51.6 48.0

54.0 49.7

30.2 34.5

31.7 35.1

c-3

c-2

20.6 20.2

22.5 21.7

18.1 18.3

18.3 20.7

17.3 19.8

18.9 20.4

25.4 24.9

25.5 26.1

23.8 24.5

26.1 24.5

24.7 24.7

24.0 24.8

9.7 8.1

9.6 8.2

6.9 8.2

7.4 9.4

7.3 9.7

7.3 8.7

8.7 8.9

25.0 32.5

25.1 19.2 25.5 30.0

9.3 8.7

26.5 32.7

26.2 20.9

22.0 19.5

10.0 8.1

equatorial

3-Me

axial

2-Me

Shieldings

(ortho-C) 135.0 (ortho-C) 133.8

131.4

133.3 (0rtho-C) 132.7

135.1 (0rtho-C) 129.5

Other

3C Shieldings of Various 2I 2I 3,4,4-Pentamethylphosphetane Derivatives 122 (140) (SC, ppm from TMS)

Ph

c1

--

Me

--

Ph

--

X

Substitution

Table 23.

NANCY K. WILSON AND J. B. STOTHERS

75

to the relative orientation of the groups on phosphorus, but the most remote carbon in these molecules, the pseudoequatorial methyl at C-3, exhibits significantly different shieldings in each pair of isomers. Much more striking stereochemical effects are revealed by the 13C-31Pcoupling constants for these derivatives, although the C-2 interactions are again relatively insensitive to geometry. Pertinent data for these systems as well as those for the series represented by the qeneral formula 123 are collected in Table 24; the shieldings for the examples of the latter series appear in Table 25. Several distinctive features in the trends revealed by these data indicate that 13C spectra should be useful for distinguishing between cis-trans isomers in phosphetanes. The strikingly different geminal 13C-31Pcouplings for the 2-methyl carbons indicate that these interactions are remarkably sensitive to the relative orientation of the lone pair on phosphorus. Examples of this behavior have been found in other phosphorus derivatives as well. It is interesting that the vicinal coupling of the 3-methyl carbon displays a significant geometric dependence even though its orientation with respect to the phosphorus atom is the same in both isomers. Another general trend is revealed by the one-bond couplings to the phosphorus-bonded exocyclic atoms; without exception the endo-carbon ( Y in 1 2 2 , 1 2 3 ) exhibits the larger interaction. The smaller values of these onebond J values relative to those for C-2(4) are of interest because of the usual assumed correlation of bond angle with carbon hybridization. Since the C2-P-C4 angles are considerably smaller than the tetrahedral angle, it follows that these bonding orbitals have considerable p character, which would be expected to lead to smaller one-bond couplings that those for less strained bonds. Gray and Cremer (140), in drawing attention to this trend, noted that the stereospecificity in the exocyclic ' J values is relatively insensitive to the size of the substituent or its electronic nature and they suggest that the difference arises from differences in the phosphorus bonding orbitals directed toward the substituents. On this basis the greater l J for the endo C-P interaction indicates larger s character for this bond than for the pseudoequatorial ex0 C-P bond. Similar stereospecificities have been reported for the 3C parameters of some phospholenes, the five-membered ring phosphorus heterocycles (141). The cis and trans isomers of 1,2dimethyl-A3-phospholene ( 1 2 4 ) give markedly different 3C spectra with the P-methyl and C-methyl carbons shifted 6.4 and 7.0 ppm, respectively, upfield in the cis isomer. This indicates that the methyl carbons are significantly further apart in the trans isomer relative to their orientation in the cis compound. In addition, 13C-31Pcou ling was only resolved for the C-meth= 32 H z , a value comparable to yl in the trans isomer,

?Jeep

m 4

--

47.9 47.3 45.2 45.3

Ph

s

Ph Me

Me Ph

S

Ph 10.2 10.5

5.4 6.9

10.9 10.4

74.2 73.5

0 OMe

OMe 0

0

c1

1.6 1.8

10.0

6.3

6.2 11.2

56.8 55.4

c1

31.1 (35.9)

Me

0 Me

0

59.4 59.4

0

0

58.7 58.4

Fh

2.1 7.8

3.3 2.9

-7.7 -6.5 -7.8 -11.1

2.7 5.9

c-3

-5.9 -2.6

c-2

0

--

c1

(40.9) 36.9

(-33.7) -37.9

--

Me

lJCP

Ph

c1

--

Me

(-41.3) -42.8

x (Y)

--

Ph

--

122

Ph

Y

X

C-Me

Substi t u t i o n

2.1 3.1

1.7 2.5

2.9 5.5

3.8 5.4

4.6 2.2

4.6 1.3

37.1 2.5

30.5 4.3

31.8 4.9

Axial

~

3.7 3.4

4.2 2.2

6.6 3.7

6.8 5.3

3.6 4.4

3.5 4.6

33.5

0.0

2.1 26.9

2.5 27.8

Equatorial

2-Me

2JccP

17.6 22.2

20.9 21.5

23.8 18.5

30.1 20.5

23.0 12.6

23.1 16.9

2.4 1.8

0.0 8.9

0.0

13.5

3-Me

JCCCP

Other

8.8

(0rtho-C)

20.2 ( 0 r t h o - C ) 13.1

Table 24. 31P-1 3C Coupling C o n s t a n t s i n S e v e r a l Phosphetane D e r i v a t i v e s (140)

4

4

Ph

Me

Me

Ph

-

0

OMe

c1

0

0

c1

"Jc-4 ,P

0

OMe

OMe

OMe

0

123 (R = M e ) O

0

Ph

Me

Ph

(R = H ) 0

123

Me

31:5 (64.7) (37.3) 58.4

57.6

(72.3)

29.1 (34.7)

53.0 (50.1) 53.1 (51.7) 60.5 (58.8) 60.0 (57.7)

35.6 34.0 40.7 35.5

a

a a 20.7

23.1

20.1

20.1

20.0

18.0

17.6

18.3

23.7

25.2

24.4

23.9

(0rtho-C)

(ortho-C)

20.5 7.1 (eq) (4-Me) 20.5 8.7

(ax)

20.6 7.3 (eq) (4-Me) 20.6 6.8

(ax)

10.7

37.3

3.9

1

15.9

10.7

3.7

1

17.1

21.2

12.1

2

6.1

18.3

27.8

2.6

18.3

7.4

2.6

16.0

9.7

3.2

4.4 16.5

18.1

4.5

3.7 9.7

2.5 28.3

11.9

11.2

a

63.3 (52. 5)" 63.1 a (52.3) 79.3 (65.8)" 79.3 a (65.8) 48.6 a (47.7) 48.5 a (46.1)

45.2

2,2,3,3,4-'V'e5

2,2,3Me3

C-Me

0

c1

0

0

40.7 35.5

58.8 57.7

50.1 51.7

24.9

38.7

44.9

35.6 34.0

25.4

40.5

45.5

60.5 60.0

Me

Ph

9.4 119.4 6.3 120.5

39.7 39.7

30.3 30.3

52.9 52.9

c1

Ph

Me

37.4 34.6

c-4

31.0 34.5

c-3

50.0 48.4

c-2

53.0 53.1

OXe 0

0 OMe

131.4 133.1

P-c

23.1 20.7

20.1 20.1

17.8

18.1

16.7 17.3

16.9 19.4

Axial

18.0 20.0

18.3 17.6

23.3

24.4 25.2

23.7 23.9

15.9

15.9

14.1 15.8

22.1 20.7 23.9

14.8 16.0

Equatorial

3-Me

23.7 23.5

Equatorial

2-Me

Shieldings

20.5 20.5

20.6 20.6

Axial

3C S h i e l d i n g s of Some Polymethylphospnetane Oxides and S a l t s 2 2 3 (140) (6, ppm from TMS)

OMe

0

0 OMe

Ph

Ph

Y

0

X

Substitution

T a b l e 25.

7.1 8.7

7.3 6.8

Equatorial

4 -Me

NANCY K. WILSON AND J. B. STOTHERS

79

CH3 124

that found for the pseudoaxial C-2 methyl carbons in the phosphetanes discussed above. Similar results were found for 1 2 5 with the C-methyl carbons of the trans form deshielded by 7.2 ppm and exhibiting 2Jccp= 30 Hz, while no coupling was resolved for these carbons in the cis isomer. A clear indication

CIS

125

trans

of the importance of the lone pair on phosphorus for these geminal interactions was given by the observation of nearly equal geminal 2 J ~ couplings ~ p for the oxides corresponding to 1 2 5 ; the cis oxide has 'Jeep = 5.0 HZ while for the trans oxide, 2 Jccp= 4 . 0 Hz. A variation in the one-bond coupling of the isomeric phospholenes 124 was also noted. For the P-methyl carbon, 'JCpis 21.5 and 1 7 . 5 Hz for the cis and trans isomers, respectively. The corresponding values for the oxides were found to be 63.0 and 61.5 Hz. The large increase for the oxides in these phospholenes stands in marked contrast to the values observed for the phosphetane series. From the results for the 2-methyl-5-t-butyl-l~3,2-dioxaphosphorinanes ( 1 2 6 ) some interesting conformational differences relative to the behavior of the closely related 1,3dioxanes became apparent (142). In the cis isomer, the t-butyl methyl carbons absorb within the very narrow range found for equatorial t-butyl groups in the dioxane series (113), and the

80

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

qH3

0.

7

127

126

2-methyl and 4,6-carbons a r e 5.3 and 3.4 pprn u p f i e l d f r a n t h e i r p o s i t i o n s f o r t h e t r a n s isomer. These d a t a are e n t i r e l y c o n s i s t e n t with conformation 1 2 7 f o r t h e c i s compound, i n cont r a s t t o t h e behavior of t h e corresponding dioxane which i s known t o have an a x i a l 5-t-butyl group. A s noted i n t h e o r i g i n a l r e p o r t ( 1 4 2 1 , t h e marked decrease i n t h e conformational f r e e energy of t h e 2-methyl group i n t h e two systems i s presumably produced by t h e smaller s y n - a x i a l i n t e r a c t i o n s i n t h e phosphorinane system because of t h e considerably longer P-0 bonds. I n a d d i t i o n , t h e competition i n 1 2 7 i s between methyl and an e l e c t r o n p a i r r a t h e r than methyl and hydrogen a s i n t h e 1,3-dioxanesI and i n t e r a c t i o n s between t h e lone p a i r on phosphorus and those on oxygen may be important. Since t h e t - b u t y l methyl carbons of t h e t r a n s form absorb only 0.7 ppm downfield from those of t h e c i s isomer of 1 2 6 , i t was concluded t h a t t h e former e x i s t s a s the equilibrium mixt u r e 128, although predominantly i n t h e d i e q u a t o r i a l form.

128

This conclusion was l a r g e l y based on t h e f a c t t h a t a x i a l t-but y l groups i n t h e lI3-dioxanes e x h i b i t methyl a b s o r p t i o n about 2 ppm d a r n f i e l d f,rom t h a t of t h e i r e q u a t o r i a l c o u n t e r p a r t s . Although no stereochemical conclusions were drawn from t h e observed 13C-31P coupling c o n s t a n t s , it was noted t h a t t h e '5 v a l u e s a r e 42.8 and 32.2 Hz f o r t h e c i s ( a x i a l ) and t r a n s (predominantly e q u a t o r i a l ) P-CH3 groups, r e s p e c t i v e l y . I n add i t i o n , t h e geminal and v i c i n a l couplings d i f f e r e d s u b s t a n t i a l l y : 2Jcisl 4.0; 2Jtransl 1.2; 3Jcisl 4.8; 3Jtransl7 . 0 Hz. Presumable t h e s e t r e n d s could be h e l p f u l f o r stereochemical s t u d i e s of r e l a t e d 1,3,2-dioxaphosphorinane d e r i v a t i v e s .

NANCY K.

WILSON AND J. B. STOTHERS

81

F u r t h e r i n s i g h t i n t o t h e g e o m e t r i c dependence o f 3C-31P c o u p l i n g i n t e r a c t i o n s i s p r o v i d e d by t h e r e s u l t s f o r some 1,3,2-dioxaphosphorinan-2-ones i n which a v a r i e t y o f v i c i n a l 3Jcccp c o u p l i n g s o c c u r ( 1 4 3 ) . The o b s e r v e d v a l u e s are l i s t e d i n Table 26. C l e a r l y the o r i e n t a t i o n o f t h e P=O bond i s i m p o r t a n t , t e n d i n g t o d e c r e a s e the v i c i n a l c o u p l i n g w i t h equator i a l methyl carbons a t C-4(C-6) b u t i n c r e a s i n g 3J f o r C-5. In T a b l e 26.

V i c i n a l 13C-31P

Couplings i n 1 2 9 and 1 3 0 (143) 3

Compound

JCCP

R

c-5

R'

Equatorial

Axial

1 2 9 , R = Me, R ' = H

8.9

6.1

130, R = M e , R' = H

4.8

9.9

1 2 9 , R = R' = M e

9.1

5.9

1.8

5.9

1 3 0 , R = R' = M e

6.0

4.5

<0.6

11.0

t h e s e systems t h e d i h e d r a l a n g u l a r r e l a t i o n o f phosphorus changes from a b o u t 180' f o r t h e e q u a t o r i a l m e t h y l s t o a b o u t 60' f o r C-5 and t h e a x i a l m e t h y l s . I t i s i n t e r e s t i n g , theref o r e , t h a t w h i l e t h e r e l a t i v e magnitudes o f 3Jcccpf o r t h e gem-dimethyls i n t h e t r i m e t h y l d e r i v a t i v e s are i n t h e e x p e c t e d o r d e r , the v i c i n a l c o u p l i n g s f o r C-5 and the i s o l a t e d methyl ( R ) are r e v e r s e d i n 1 2 9 . Perhaps t h e comparison o f e n d o c y c l i c and e x o c y c l i c carbons i s n o t s t r i c t l y v a l i d , s i n c e t h e coupl i n g between phosphorus and C-5 c a n o c c u r through two p a t h I t may b e n o t e d , however, t h a t i n 1 3 0 t h e r i n g carbon ways.

129

130

82

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

couplings a r e approximately twice t h e couplings with t h e equat o r i a l methyl groups, s t r o n g l y i n d i c a t i n g t h a t f a c t o r s i n add i t i o n t o geometry a r e o p e r a t i v e . The geminal 13C-31P coupl i n g s i n t h e s e systems a l s o depend on t h e o r i e n t a t i o n of t h e P=O bond, b u t t h e d i f f e r e n c e s a r e l e s s than 1 . 5 Hz. One add i t i o n a l example i n t h i s series, 5,5-dimethyl-1,3,2-dioxaphosphorinan-2-oneI showed t h a t t h e four-bond coupling between t h e methyl carbons and phosphorus depends on t h e i r r e l a t i v e o r i e n t a t i o n s i n c e only t h e e q u a t o r i a l methyl s i g n a l was resolved i n t o a d o u b l e t , J = 1.0 Hz. The l a c k of measurable coupling f o r t h e a x i a l methyl i s consonant with t h e g e n e r a l behavior f o r a v a r i e t y of o t h e r i n t e r a c t i o n s i n which a W arrangement tends t o give t h e l a r g e r 4J v a l u e s . 6.

Nucleosides and Nucleotides

The p o t e n t i a l of v i c i n a l 13C-lH coupling c o n s t a n t s as stereochemical probes f o r nucleoside conformations has been examined i n a study of u r i d i n e ( 1 3 1 ) and two d e r i v a t i v e s having t h e C-2 p o s i t i o n of t h e u r a c i l moiety enriched with I3C ( 1 4 4 ) .

HO

OH

131

F o r u r i d i n e , t h e v i c i n a l couplings of C-2 with H-6 and H-1' were found t o be 8.0 and 2.4 Hz, r e s p e c t i v e l y . The former

v a l u e , which may be taken as r e p r e s e n t a t i v e of a d i h e d r a l ang l e ( $ ) of 180°, i s t h e same a s t h a t of u r a c i l . To i n t e r p r e t t h e l a t t e r value t h e v i c i n a l couplings of cyclonucleosides 1 3 2 and 1 3 3 were obtained s i n c e t h e s e couplings s e r v e t o t e s t €or t h e e x i s t e n c e of a Karplus-type r e l a t i o n (1)because s e v e r a l d i h e d r a l angles can be estimated with reasonable confidence. The 3JCH values a r e l i s t e d i n Table 27 and a p l o t of t h e s e dat a showed ( 1 4 4 ) t h a t t h e expected v a r i a t i o n with Q i s indeed observed. From this f i n d i n g , JC2,H11 f o r 1 3 1 i n d i c a t e s t h a t $ 2 45 o r 120°, corresponding t o t h e a n t i and syn conformations, r e s p e c t i v e l y . Since t h e l a t t e r form seemed h i g h l y u n l i k e l y because of e c l i p s i n g i n t e r a c t i o n s of t h e u r a c i l r i n g , it was

NANCY K. WILSON AND J . B.

STOTHERS

HO

83

H 132

133

Table 27. V i c i n a l 3C-1H C o u p l i n g s i n Uridine-2-l 3C and D e r i v a t i v e s (144) ( i n Hz) Vicinal nuclei

C-2

I

H-1

I

Compound

3J

131

2.4

132

3.6

133

6.6

Vicinal nuclei

Compound

3J

C-2,

H-2'

132

2.0

120

125

C-2,

H-5'

133

6.7

158

170

C-2,

H-5"

133

2.0

30

aDihedral angle i n degrees. concluded t h a t 1 3 1 e x i s t s i n t h e a n t i c o n f o r m a t i o n w i t h 4 ~ 2 ~ ~ 1 1 n e a r 45'. The f a c t t h a t Jc2,~11changed o n l y 0 . 1 Hz o v e r t h e t e m p e r a t u r e r a n g e 26 t o 6 7 O i n d i c a t e d t h a t t h e r e i s l i t t l e variation i n Both o f t h e s e c o n c l u s i o n s a g r e e w i t h

(I.

84

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

t h e r e s u l t s of o t h e r s t u d i e s , and Lernieux and co-workers ( 1 4 4 ) i n f e r r e d t h a t v i c i n a l coupling c o n s t a n t s should be v a l u a b l e f o r conformational s t u d i e s of o t h e r n u c l e o s i d e s , p e p t i d e s , and related materials. From t h e general t r e n d s e x h i b i t e d by v i c i n a l couplings f o r v a r i o u s n u c l e i , it follows t h a t v i c i n a l 13C-31P i n t e r a c t i o n s i n n u c l e o t i d e s might be informative. I n an attempt t o c a l i b r a t e t h e d i h e d r a l angular dependence i n t h e s e s y s t e m , f i v e 3 ' , 5 ' c y c l i c n u c l e o t i d e s known t o e x i s t i n t h e r e l a t i v e l y r i g i d conformation 134 have been examined (145). For a series of f i v e examples, t h e anti v i c i n a l coupling of C-2' w i t h

134

t h e phosphorus nucleus w a s found t o be 8.0 2 0 . 3 H z , whereas 3Jcpf o r C-4' was 4.6 f 0.2 Hz. Since t h e l a t t e r i n t e r a c t i o n has two pathways , POC5 I CL, I and POC3 1 C4 1 , t h e gauche coupling was taken a s 2.3 Hz. I t was noted t h a t t h e geminal couplings, 2Jcop,were a l s o e s s e n t i a l l y c o n s t a n t f o r t h e s e r i e s , 4.2 f 0.5 (C-3') and 7.2 2 0.2 Hz ( C - 5 ' ) , t h e d i f f e r e n c e p o s s i b l y r e f l e c t i n a v a r i a t i o n i n t h e POC bond angles s i n c e t h e corresponding %COP values i n a c y c l i c n u c l e o t i d e s a r e 5.0 f 0.6 Hz (146). Vicinal couplings i n some 2',3' c y c l i c n u c l e o t i d e s were a l s o measured f o r a few examples and were found t o be much more v a r i a b l e , i n d i c a t i n g t h a t t h e s e compounds a r e much less r i g i d and e x i s t a s e u i l i b r i u m mixtures of conformers. A comp a r i s o n of t h e 13C-3qP couplings with 1H-31P r e s u l t s (145) i n d i c a t e d t h a t t h e l a t t e r a r e perhaps mre u s e f u l f o r conformat i o n a l purposes because o f t h e i r somewhat q r e a t e r s e n s i t i v i t y t o d i h e d r a l angle; on t h e o t h e r hand t h e 3C r e s u l t s may be more r e a d i l y obtained i n complex systems. N o doubt t h e b e s t approach would employ both sets of r e s u l t s wherever p o s s i b l e . From t h e values f o r anti and gauche couplings from t h e 3 ' , 5 ' c y c l i c n u c l e o t i d e s , Smith and co-workers ( 1 4 7 ) estimated t h e r e l a t i v e populations of t h e rotamers about t h e O,C-3' bond i n uridine-3I-phosphate ( 1 3 5 ) t o be 0.31 ( P I ) , 0.04 (P2), and 0.65 (P3) (see 136). They concluded t h a t 135 e x i s t s preferent i a l l y i n the rotamer having phosphorus gauche t o C-2' and anti Combining t h i s conclusion with e a r l i e r proton d a t a t o C-4'.

85

NANCY K. WILSON AND J. B. STOTHERS

racil

-

OH

OqP0

138

135

led these workers to construct a complete conformation for 1 3 5 in solution, thus illustrating the utility of 13C-31P coupling information for conformational analysis.

E.

A r o m a t i c Systems

In the first systematic study of a series of closely related compounds, Lauterbur (148) established that substituent effects on the aryl carbon shieldings in a wide variety of meta- and para-substituted benzene derivatives are additive. Thus by combining the substituent effects observed for several monosubstituted benzenes one can predict the shieldings for a host of di- and trisubstituted derivatives with precisions approaching 1 ppm, provided the substituents are not ortho. In each case having ortho substituents the predicted values deviate from the observed shieldings, strongly indicating that steric interactions between the substituents perturb their normal contributions to the aryl shieldings. Qualitatively the deviations increase with increasing bulk of the substituents, behavior which is consistent with greater steric interference. Since the original studies, several additional examples have been described ( 2 ) which confirm the initial interpretation. Unfortunately most of the published data were obtained using less precise techniques than those currently available and detailed analysis of the deviations was unwarranted. Reexamination of these trends might be valuable. As matters stand, the 1 3 C data for such systems can indicate the degree of steric hindrance qualitatively. A similar interpretation of the carbony1 shieldings in a variety of substituted aryl ketones followed directly from these initial observations since the carbonyl absorption is essentially unaffected by a variety of meta and para substituents but is shifted to lower field by ortho groups (149).

86

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

Furthermore, the magnitude of the shift was correlated with the substituent. Since the highly hindered systems exhibited carbonyl absorption at positions comparable to those found for aliphatic systems, the trend seemed to reflect the degree of steric inhibition of conjugative interaction between the carbonyl and aryl groups. On the premise that the degree of interference is related to the angle of twist from coplanarity (6), an empirical expression relating 8 to the observed carbonyl shielding was developed which gave reasonable 8 values (149).* Examination of methyl benzoates, styrenes, and anisoles (2) reveals similar trends for the carbons in these substituent groups, suggesting that their 13C data serve as a qualitative indicator of steric inhibition of resonance. Recently the longer range 3C-13C coupling constants have been measured for a variety of monosubstituted benzene derivatives (152) and some of the observed trends have been attributed to polar interactions between the substituent and the ring. It would be interesting to compare the results with those for some hindered systems since the 3C-13C couplings may be sensitive to steric hindrance. A related study wherein the 13C-lH couplings of the Me, OMe, and CHO groups in a series of orthosubstituted toluenes, anisoles, and benzaldehydes were measured (153) indicated that these parameters provide a probe for ortho effects. An interesting demonstration of the sterochemical dependence of long-range 13C-19F coupling in an aryl system was reported by Jerome and Servis (154). In 1,4,8-trimethyl-5-fluorophenanthrene ( 1 3 7 ~ the ) ~ 4-methyl.signa1 exhibits a 24.0 Hz coupling with fluorine which upon saturation of the 9,lO bond

’

’

137 a

R=CH=CH

b

R = CHOHCHOH

c

R = O=CC=O

-It may be noted that a similar interpretation may be invoked to account for the carbonyl shieldings of hindered a , 8 unsaturated ketones (150), and an estimate of the angle of twist in one such system is in good agreement with the value obtained by x-ray analysis (151).

NANCY K. WILSON AND J. B. STOTHERS

87

(as in diol 137b) is reduced to 15.7 Hz. Oxidation of 137a to the corresponding 9,lO-quinone ( 1 3 7 ~ also ) produced a marked ~ ~ to 16.0 Hz. Presumably the variadecrease in the 5 J value tion reflects the deviation from coplanarity principally caused by nonbonded interactions between the 4-Me group and fluorine. Some support for this interpretation was given by the fact that the 4-methyl carbon is deshielded by 3.3 k 0.1 ppm in 137a relative to the othersl which is consistent with its closer approach to fluorine in 137a. The effects of ortho substituents on geminal 13C-31Pcouplings in arylphosphines have also been found to be appreciable (155) as the data in Table 28 show. Introduction of an ortho substituent in either the tri-3-thienyl- or triphenylphosphine

'

Table 28. Geminal 3C-31P Couplings in Some Aromatic Phosphines (155) (in Hz)

Parent Compound

PIC-2

PIC-4

139

H Me Br

Me

+23.1 0.3 -1.7

+17.5 +27.4 +35.1

140

H (R' = H) Me ( R ' = H) Me (R' = C1)

+19.7 +26.4 +27.9

+19.7

R

138

138

+33.9

139

140

+1.1 PIC-6 0.4

0.6

88

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

series markedly increases the geminal coupling of the substituted ortho carbon while decreasing that of the unsubstituted ortho carbon. These trends have been attributed to changes in orientation of the lone pair on phosphorus relative to the aryl ring plane in the hindered systems. Introduction of nonortho substituents was reported to have little effect, as shown by the single example in Table 28. These and some 'H31P coupling data have been interpreted U55) in terms of a preferred conformation for the ortho-substituted arylphosphines in which the substituent is directed toward the lone pair on phosphorus. The observed stereospecificity for these geminal couplings should be valuable for conformational analysis of related systems, especially in those cases in which the proton spectra are less amenable to analysis. As an approach to the assessment of aromaticity of phospholes the 13C spectra of the series 1 4 1 to 143 have been recorded (156). The geminal 13C-31Pcouplings of the ortho phenyl carbons lie in the range +18.5 to +19.1 Hz, whereas the P,C-3 interactions differ substantially: +8.2 ( 1 4 1 ) , +1.9 ( 1 4 2 ) , and +23.2 Hz ( 1 4 3 ) . From these data Bundgaard and Jakobsen (156) suggest that preferred conformations may be

141

142

143

predicted since these geminal couplings are expected to exhibit maximum and minimum values for dihedral angles of 0 and 180° for C-3 and the lone pair, respectively. They concluded that the increase in 3J in going from 1 4 2 to 1 4 1 probably corresponds to a decrease in the average dihedral angle because of a lower barrier to pyramidal inversion at phosphorus in phospholes.

F.

Polymers and Peptides

The results of several studies of natural and synthetic polymers have clearly established the utility of 13C nmr for detailed investigations of stereochemical features in these systems, and the pioneering work has been reviewed recent1 (2). In general, for high molecular weight materials the ' 3 C

NANCY K. WILSON AND J. B. STOTHERS

89

line widths are significantly narrower than those in 'H spectra which, combined with the much larger shielding range, renders the 1 3 C approach potentially more valuable. An additional advantage is realized for solid polymers since narrow 13C li.nes are observed if the temperature of the solid sample is above its glass-transition temperature; this is true for solid elastomers, rubbery polymers, and more rigid materials in solid gels. Since the steric effects on shieldings for simple molecules are fairly well understood, at least qualitatively, the shielding trends exhibited by polymeric materials can be interpreted in a similar fashion. For example, the 13C spectra of c i s - and trans-l,&polybutadienes and -polyisoprenes show precisely the expected differences, with the carbons experiencing eclipsing y interactions.absorbing at higher fields than those lacking such perturbations (157). 13C spectra for a variety of vinyl polymers have also been reported; this includes studies of polystyrene, polyacrylic acid, polymethyl methacrylate, polyvinyl chloride, and polyvinyl methyl ether (158). For these vinyl polymers each monomeric unit in the polymer chain contains a chiral center; thus the specific ordering of these centers along the chain, the tacticity of the polymer, gives rise to stereochemical differences. A l though a given polymer may be predominantly in one form (isotactic, syndiotactic, atactic, etc.) , the 13C spectrum is a composite of the local stereochemistry at each carbon, the microtacticity. For a specific carbon in the chain its immediate neighbors determine the gross spectral behavior, and the next nearest neighbors and those beyond produce fine structure within the main absorption band. Information on triad and pentad sequences has been extracted from 13C spectra of a variety of polymer samples (158). Since it has been established that the different triad and pentad signals arising from the same carbon in different stereochemical environments exhibit the same Overhauser effects, the relative intensities give a direct measure of the proportion of the various species. The marked advantages of Fourier transform operation for investigations of these complex systems have been clearly demonstrated (157b, 158c, 159) and this approach has the additional feature that relaxation time measurements are readily accomplished. The latter data provide additional information on the microstructure of polymers as discussed in Sect. IV. Biopolymers constitute a class of materials for which I3C nmr investigations seem admirably suitable. In contrast to 'H methods, which have not been particularly successful with these systems, the initial 13C results are highly promisins. Within this general classification, peptides have probably received the most attention and certain stereochemical features have been revealed which are difficult to examine by other methods. Although most of the detailed work has been

90

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

accomplished with oligopeptides, well-resolved spectra of a number of high polymers have been reported. As an outstanding example of the power of I3C nmr for studies of complex systems the recent detailed examination of ribonuclease A may be cited (26, 160). It seems certain that, as background information for the lower molecular weight materials is collected, more detailed interpretations of the subtle variations in the spectra of the complex systems will become possible. One of the first illustrations of the potential of 13C nmr for peptide studies was the report of the spectrum of the decapeptide, gramicidin S-A (1611, from which the symmetry of the molecule was immediately apparent since the five pairs of amino acid residues gave only five carbonyl, five a-carbon, and five B-carbon signals. By comparison of the shieldings of the individual amino acids as their N-acetyl methyl esters with the values observed for the peptide, it was shown (161) that the differences are relatively small. Consequently signal assignments for individual amino acid residues in more complex systems may be expected to be relatively straightforward. There was, however, a change in the nonequivalence of the terminal methyl carbons of valine in the free amino acid, its acetyl methyl ester, and in the peptide, which may be an indication of different average rotational conformations in the three cases. Another example of small variations which may have conformational significance was reported by Christ1 and Roberts (162) who found that protonation of zwitterionic dipeptides not only produces the significant shielding changes expected for the amino acid unit directly involved but also causes a downfield shift of the next nearest carbonyl carbon. They suggested that the latter change may arise as a result of either the formation of an intramolecular hydrogen bond upon carboxyl protonation as in 144 or the disruption of an associated zwitterionic species 1 4 5 . At the present stage, these possibilities cannot be confirmed or denied. In simple peptides containing proline it has been found that the 13C shieldings of the proline ring carbons reflect the conformation about the amide bond to its neighboring amino acid such that syn and a n t i forms,* 146 and 1 4 7 , respectively, are readily detected. For a number of dipeptides separately resolved signals are consistently observed for the @-carbons of the proline ring and, for most cases, the y- and &-carbons each give rise to two signals (163). The proportion of the two conformers was found to be approximately the same in each case with the equilibrium favoring the a n t i ( 1 4 7 ) form, 60:40. *In the references cited these forms are designated as cis and trans forms, but this nomenclature seems infelicitous.

91

NANCY K. WILSON AND J . B. STOTHERS

p - C

//"

,

HI

0

\c

/'dH

144

\

/CHR

0

1C-NH

R

\C/-p*cCc,R' 1'

\+.'

NH3

145

I n a study of t h e o l i g o p e p t i d e s r e l a t e d t o oxytocin (1641, two t r i p e p t i d e s were found t o e x h i b i t doubling of t h e a-, 8 - , and 6-carbon s i g n a l s , whereas t h e higher p e p t i d e s d i s p l a y e d a s i n g l e s e t of p r o l i n e s i g n a l s . The l a t t e r o b s e r v a t i o n was taken a s evidence o f t h e presence of a s i n g l e rotamer corresponding t o 1 4 7 ( 1 6 5 ) . Proton nmr r e s u l t s a t 2 2 0 MHz had been

146

147

s i m i l a r l y i n t e r p r e t e d . From t h e I 3 C r e s u l t s f o r oxytocin, i t s o l i g o p e p t i d e s , and some vassopressin d e r i v a t i v e s (164, 165), Smith and h i s co-workers i n f e r r e d t h a t t h e carbonyl and a-carbon s i g n a l s appear t o be s e n s i t i v e t o conformational v a r i a t i o n s , b u t i n t e r p r e t a t i o n s a r e not y e t p o s s i b l e . S i m i l a r conc l u s i o n s had been drawn from a I 3 C study of valinomycin and nonactin ( 1 6 6 ) , an i n t e r e s t i n g f e a t u r e of which was t h e examin a t i o n of t h e e f f e c t of complexation with potassium ion. Sign i f i c a n t s h i f t s occur, es.pecially f o r t h e carbonyl s i g n a l s , i n d i c a t i n g t h a t conformational rearrangements a r e c l e a r l y m a n i f e s t i n t h e 1 3 C s p e c t r a , b u t a d d i t i o n a l information on t h e behavior of simpler s y s t e m s ' i s r e q u i r e d b e f o r e t h e v a r i a t i o n s can be i n t e r p r e t e d with confidence. Recent s t u d i e s (167, 168) have shown t h a t t h e conforma-

92

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

t i o n a l t r a n s i t i o n from a h e l i c a l c o i l t o a random c o i l f o r a polypeptide chain i s r e a d i l y monitored by 3C nmr. S p e c t r a of poly-(y-benzyl L-glutamate) ( 1 4 8 ) show well-defined s i g n a l s f o r t h e a - , B-, y-, carbonyl, and benzyl methylene carbons, which were r e a d i l y a s s i g n e d by comparison w i t h t h e spectrum of poly-2-glutamic a c i d (167). S p e c t r a o b t a i n e d i n 3% t r i f l u o r a c e t i c acid-97% chloroform-cll and i n 29% TFA-71% CDC13 r e v e a l a p p r e c i a b l e s h i f t s f o r t h e a- ( - 3 . 1 ) , B- ( 1 . 2 ) , y- ( - O . l ) , Bz ( 1 . 7 ) , e s t e r CO (2.71, and amide CO (-2.0 ppm) carbons. These s h i f t s were a t t r i b u t e d t o t h e d i s r u p t i o n of the h e l i c a l conformation by t h e added a c i d and may be compared w i t h t h o s e observed by 'H s t u d i e s i n which t h e a-proton was found t o s h i f t 0.5 ppm. I t was a l s o noted t h a t t h e s i g n a l s f o r t h e h e l i c a l form are somewhat broader than t h o s e f o r t h e random c o i l , as expected, because o f t h e reduced m o b i l i t y of t h e ordered conformation. S i m i l a r v a r i a t i o n s were observed f o r poly-(@-benz y l L - a s p a r t a t e ) , although t h e a-carbon s h i e l d i n g d i f f e r e d by only 1.50 ppm i n t h e two conformations. These r e s u l t s i n d i c a t e t h a t t h e amide carbonyl and t h e a-carbon s i g n a l s a r e conf o r m a t i o n a l l y s e n s i t i v e whereas t h e e s t e r carbonyl and benzyl

-

CH2

\COOCH2# 148

149

methylene carbon s h i e l d i n g s a r e s o l v e n t dependent. A similar examination of poly-(@J-6-carbobenzoxy-&-ornithine) (149) revealed analogous v a r i a t i o n s upon t h e a d d i t i o n o f TFA t o CDC13 s o l u t i o n s of t h e polypeptide (168). Assignments f o r t h e i n d i vidual carbons followed from t h o s e f o r o r n i t h i n e and some c a r bobenzoxylate amino a c i d s . I n CDC13 s o l u t i o n s , t h e amide c a r bony1 and a-6 carbon s i g n a l s a r e a p p r e c i a b l y b r o a d e r t h a n t h o s e f o r s o l u t i o n s c o n t a i n i n g TFA; i n f a c t , t h e a-carbon I n 11%TFA-89% CDC13 s i g n a l i s n o t d e t e c t e d i n p u r e CDC13. t h e backbone s i g n a l s (NHCO and a-C) appeared approximately 3 ppm u p f i e l d from t h e i r o r i g i n a l p o s i t i o n s , w h i l e t h e u r e t h a n e s i g n a l s s h i f t e d about 2 ppm downfield. Following t h e s h i e l d -

NANCY K.

WILSON AND J. B.

STOTHERS

93

i n g changes a s a f u n c t i o n of a c i d c o n c e n t r a t i o n r e v e a l e d t h a t t h e l a t t e r s i g n a l s undergo a g r a d u a l e x p o n e n t i a l s h i f t t o lower f i e l d i n d i c a t i v e of a s o l v a t i o n e f f e c t , whereas t h e former s h i f t s h a r p l y n e a r 0% TFA. For comparison t h e s e a u t h o r s n o t e d t h a t o n l y t h e a-proton s i g n a l i s measurably a f f e c t e d . Thus 13C s p e c t r a p o t e n t i a l l y p r o v i d e a more d e t a i l e d p i c t u r e of b o t h conformational and s o l v a t i o n changes. Dynamic i n f o r m a t i o n may a l s o be p r o v i d e d by r e l a x a t i o n t i m e s t u d i e s as w e l l a s by c a r e f u l examination, under h i g h - r e s o l u t i o n c o n d i t i o n s , of t h e s i g n a l s i n t h e t r a n s i t i o n r e g i o n . The p o t e n t i a l of t h e l a t t e r approaches i s c o n s i d e r e d i n S e c t . I V .

G

.

Organometall i cs

13C s p e c t r o s c o p y h a s long been viewed a s an a t t r a c t i v e method f o r a s s e s s i n g t h e n a t u r e of t h e bonding of c a r b o n n u c l e i i n o r g a n o m e t a l l i c s p e c i e s through examination of s h i e l d i n g s and c o u p l i n g c o n s t a n t s . These p a r a m e t e r s s h o u l d a l s o s e r v e a s s t e r eochemical p r o b e s f o r a v a r i e t y of systems and, i n f a c t , one of t h e f i r s t 13C s t u d i e s w a s an a t t e m p t t o e x p l o i t t h i s f e a t u r e t o o b t a i n an unequivocal s t r u c t u r a l proof f o r i r o n pentacarbony l ( 1 6 9 ) . For t h e t r i g o n a l bipyramidal form, which was t h e g e n e r a l l y a c c e p t e d s t r u c t u r e although unequivocal p r o o f was l a c k i n g , t h e r e a r e two carbonyl environments f o r which d i f f e r e n t s h i e l d i n g s a r e expected. I n t h e i n i t i a l s t u d y , however, o n l y a s i n g l e peak w a s observed. Subsequently, s e v e r a l reexami n a t i o n s have confirmed t h e o r i g i n a l o b s e r v a t i o n ( 2 ) and a s i n g l e t p e r s i s t s even down t o -150' a t 63 MHz. T h i s c o u l d a r i s e from r a p i d i n t r a - o r i n t e r m o l e c u l a r c a r b o n y l exchange o r from a c c i d e n t a l e u i v a l e n c e of t h e two s i g n a l s . A r e c e n t obsenrat i o n of t h e q3C-57Fe coupling i n Fe(CO)5 (170) e x c l u d e s i n t e r molecular exchange. The f a c t t h a t a s i n g l e t i s a l s o observed f o r each member of t h e s e r i e s , [Fe (COIL, (PEhPh3-n) 1 , n = 1-3, s t r o n g l y i n d i c a t e s t h a t r a p i d i n t r a m o l e c u l a r exchange i s occuri n g s i n c e a c c i d e n t a l e q u i v a l e n c e f o r t h e f o u r complexes seems h i g h l y improbable. D i f f e r e n t carbonyl s h i e l d i n g s have been o b s e r v e d i n o t h e r m e t a l complexes, e s t a b l i s h i n g t h a t c i s and t r a n s c a r b o n y l s a r e r e a d i l y d i s t i n g u i s h a b l e ( T a b l e 2 9 ) . From t h e s e d a t a it i s app a r e n t t h a t t h e " t r a n s i n f l u e n c e " (171a) of l i g a n d s f o r a v a r i e t y of m e t a l complexes i s r e a d i l y examined by 13C nmr a s some p r e l i m i n a r y r e s u l t s f o r methylplatinum examples have demons t r a t e d ( 1 7 2 ) . I n t h e 13C spectrum of dipropenerhodium a c e t y l a c e t o n a t e , t w o p a i r s of s i g n a l s a p p e a r f o r one of t h e o l e f i n i c c a r b o n s , i n d i c a t i n g t h e p r e s e n c e of two g e o m e t r i c isomers CRh coup( 1 7 3 ) . Each g i v e s r i s e t o a d o u b l e t because of l i n g . I t was noted t h a t t h e s h i e l d i n g d i f f e r e n c e o f 1 . 2 ppm p r o v i d e s much c l e a r e r evidence f o r t h e isomers t h a n t h e d i f f e r ences found i n 60 and 220 MHz p r o t o n s p e c t r a .

94

STEREOCHEMICAL ASPECTS OF

'

3C NMR SPECTROSCOPY

Table 29. Carbonyl Carbon Shieldings i n Some Metal Carbonyls , (CO) 5MR (171) M

R

cis W

M

6C

trans

(Ph0)3P

194.5 196.1 (Ph) (YZ-BuO)pP 196.9 (Ph)p(YZ-BuO)P 197.5

197.0 198.8 200.0 199.0

(YZ-BuO) 3P

(Ph)3Sb (Ph) 3 A s (Ph) 3 B i

197.0 197.5 197.8

199.1 199.7 198.3

6C

R

(Ph)3P C6H1l N H 2 Mo ( P h ) 3 P W

(i-Pro) 3P

cis

trans

198.0 199.1

199.8 201.9

206.5 206.2

211.0 209.7

Cr

C(0Me)Me

217.6

223.6

Wa

a-CgH5, Mea

239.2

217.8

a(CO) 3 (a-CsH5)W M e .

Coupling c o n s t a n t s a r e a l s o expected t o e x h i b i t s t e r e o chemical dependencies and a few examples e s t a b l i s h t h i s f e a t u r e . The geminal 13C-'H couplings i n K3[HIr(CN)5] a r e 5.7 ( c i s ) and 37.2 Hz (trans) and i n H M n ( C O ) 5 , 14.0 ( c i s ) and 7.0 Hz ( t r a n s ) (174) Geminal 13C-31P i n t e r a c t i o n s i n cis-[PtMep (PMepPh)2 1 were found t o be 9 k 1 ( c i s ) and 104 ? 2 Hz ( t r a n s ) and t h e s i g n s of t h e s e coupling c o n s t a n t s a r e o p p o s i t e (175). The s p e c t r a of t h e l a t t e r compound and some t r a n s analogs a l s o r e vealed t h a t t h e r e l a t i v e o r i e n t a t i o n of t h e phosphine l i g a n d s i s r e a d i l y apparent from t h e m u l t i p l i c i t y of t h e phosphorusbound methyl s i g n a l s . With phosphine l i g a n d s of t h e type MepPPh, t h e methyl absorption i s a 1 : Z : l t r i p l e t f o r complexes having t r a n s phosphines and a 1:l doublet f o r c i s complexes, s i n c e t h e absorption p a t t e r n f o r t h e s e systems depends on t h e r e l a t i v e magnitudes of 2 ~ p - p l and 'Jp-Me 3Jp-MeI (176). For example I R h C l 3 (CO) (P ( ~ - B u )pPh) 2 ( 1 5 0 ) , ~ ~ [PdC12 8 (P (72E 3 u ) p t - B ~ ) 21 , and [RuC12 (CO) 2 ( P E t 3 ) 21 ( 2 5 2 ) g i v e rise t o t r i p l e t s i g n a l s f o r each of t h e a l k y l carbons, while i n t h e f i r s t of t h e s e examples t h e C-1, C-2(6), C-3(5) phenyl s i g n a l s a r e Both [ I r C 1 2 (COOMe) (CO) (AsMepPh)21 and a l s o t r i p l e t s (176) [IrC12 (CHpC (Me)=CHp)(CO) (AsMe2Ph)p ] had been assigned s t r u c t u r e 252a from i n f r a r e d and proton s p e c t r a l d a t a . Their 13C s p e c t r a contain nonequivalent a r s e n i c methyl s i g n a l s c o n s i s t e n t with t h e absence of a plane of symmetry along an I r - A s bond. Simil a r l y , [IrClIMe(CO) (AsR2Ph)p] with R = Me o r E t , e x h i b i t doub l i n g of t h e methyl and e t h y l s i g n a l s , r e s p e c t i v e l y , confirming t h e i r formulation a s 1 5 2 b (176).

.

I

I

-

.

,

-

NANCY K. WILSON AND J. B. STOTHERS

f

~ R . ~ c '

OC

95

R

I

0

oc +/CI

I

oc

i

CI

CI

150

151

152

a

X=CI

b

X = I

Successful I3C experiments with much more complex species have been reported and have clearly demonstrated significant advantages over proton spectra both in xelative simplicity of interpretation and as sources of structural information. As an example, the spectrum of the corrinoid, aquocyanocobyric acid,

163

B

R=CN,R'~H~O

b

R = H20,R'. C N

R = R ' = CN

STEREOCHEMICAL ASPECTS OF

96

3C NMR SPECTROSCOPY

clearly reveals the presence of two isomers, 153a and b (177). In contrast to the proton spectrum, which contains separate signals for the 10-H only (separation 0.05 ppm), several carbons in the two isomers are nonequivalent. The spectrum of dicyanocobyric acid ( 1 5 3 ~ )contained 38 resolved signals, while the isomeric mixture of 153a and b (C46H67CoN1109) had 60 resolved lines. Since even some of the side-chain carbons differ in the two isomers, it was suggested (177) that the shielding differences reflect both electronic variations as well as conformational changes of the corrin ring. Doddrell and Allerhand have also demonstrated that useful 13C spectra are obtainable from a variety of corrinoids including vitamin B12 and coenzyme B12 (178). Specific assignments for several individual carbon nuclei within these systems have been made using a variety of techniques. The success in these initial investigations implies the utility of 13C spectroscopy for detailed studies of these biologically important materials.

IV.

APPLICATIONS OF

A.

13C

NMR TO CHEMICAL RATE PROCESSES

Chemical E q u i l i b r i u m and Exchange

In Sect. 111, stereochemical features revealed by the determination of 13C shieldings and coupling constants were illustrated and discussed for a variety of systems. The 13C parameters in these illustrations are those observed for compounds existing either as single individual species or undergoing rapid equilibration between conformations such that averaged values are observed. It is to be expected that, for systems having several energetically favorable forms, the kinetic and thermodynamic parameters governing the interconversions between these forms may often be accessible by nmr methods. Rate processes which are amenable to study by 13C nmr include many of the same processes which have been extensively studied by proton techniques, such as chemical exchange, hindered rotation, ring inversion, inversion at nitrogen, and certain molecular rearrangements. 3C spectroscopy has certain inherent advantages over the more familiar 'H and 19F techniques because carbon is a fundamental component of the molecular skeleton of organic molecules, and as such, its nmr parameters often reflect more directly structural variations arising from conformational interconversion, preferential molecular motion, and other dynamic processes on the molecular level. Additional major advantages include the following: several sets of carbon nuclei in the same molecule may participate in site exchange, giving redundancy which can increase the precision of the rate measurements, and if different sets of carbons have

'

NANCY K. WILSON AND J. B. STOTHERS

97

different coalescence temperatures, the determination of thermodynamic parameters is facilitated. Moreover, the signals of nuclei which are not involved in site exchange can serve as line-width references; and since the carbon shielding differences are large, the rate range over which rate measurements can be made is extended, which should increase the accuracy of the thermodynamic parameters obtained as well as raise the temperature at which many rate processes having low energy barriers can be observed into the accessible temperature region. The need for extensive deuteration or specific deuterium labeling to simplify the spectra is also eliminated. Furthermore, the predominance of dipole-dipole spin-lattice relaxation for most 13C nuclei allows the extraction of considerable information about molecular motion from IT1 measurements. Dynamic molecular processes whose effects are evident in nmr spectra can be roughly divided into three types: equilibria in which the rates of the interconversion of the equilibrating species are slow on the nmr time scale; processes occurring at rates sufficiently fast that there is partial or complete averaging of the spectra of the interconverting forms; and much faster processes whose effects are most evident in the relaxation times. In the slow exchange limit, the nmr spectrum of a system in which there are two or more equilibrating species consists simply of a superposition of the spectra of the individual species. This situation obtains when the lifetime of a nucleus in a given site or magnetic environment is long enough to allow several precessions of a given nucleus at the frequency characteristic of that site before jumping to another site. This nucleus gives rise to a resonance characteristic of that particular site; likewise, nuclei in the alternative site or sites give rise to resonances characteristic of those sites. Since absorption intensities are directly proportional to the relative populations of the nuclei (with due regard for possible complications arising from relaxation phenomena), measurement of the integrated intensities allows determination of the populations of the various species present and hence determination of equilibrium constants and free energies. When exchange or interconversion of contributing species is rapid, the observed nmr shielding of a given set of carbons is the average of the shieldings of these carbons in the various environments, weighted according to their populations. This results from the fact that the rate of transfer of the nuclei between the various sites is much greater than the difference in resonance frequencies between the sites, so that a given nucleus experiences the average of the different magnetic environments during the period of one precession. The single signal thus observed has a shielding

98

STEREOCHEMICAL ASPECTS OF 6 = C

i

Gin;

3C NMR SPECTROSCOPY

I41

where 6 i is the shielding of carbons at site i, and ni is its fractional population. A dependence of shielding parameters on temperature greater than can be accounted for by the expected variations in the medium (such as density changes) often indicates that an equilibrium between several forms with this sort of averaging is occurring. As the temperature is changed, the relative populations of course change, and thus the observed shieldings change. To obtain reliable estimates of the relative amounts of the various contributing species, when an averaging process is involved, the shieldings of the individual species must be determined. Although the use of model compound data is possible and has been popular, this method has pitfalls and can lead to erroneous results, as has been amply demonstrated for protons by Jensen et al. (179). Wherever possible, it is much better to obtain spectra at temperatures sufficiently low that the rates of interconversion are slow, so that the signals from the individual contributing forms can be distinguished. At intermediate rates, the effects of chemical exchange processes on nmr spectra are more complicated. Although attention is confined here to the simpler cases, full treatments are available (1, 49a, 180). For the specific situation in which there is exchange of uncoupled nuclei between two magnetic environments characterized by the resonance frequencies vA and vB Hz, with lifetimes in those environments or sites TA and T B sec, equal populations, equal values of T 2 , and a mean lifetime of the system defined as T = TATB/(TA + Tg), the effect of changing the rate of exchange on the nmr spectrum is as follows. If T >7 l/(vB - vA) , the individual resonances at vA and Vg appear in the spectrum. As the rate of site interchange increases (T decreases), the lines, initially having widths Avo, determined by T2* (cf. page 131, broaden and then move together until they coalesce to a broad singlet. The mean lifetime corresponding to the point at which coalescence occurs is given by T =

fi/2IT(VB - VA)

t51

As T decreases further, this singlet becomes narrower until the limiting line width, determined by T2*, is attained. This corresponds to the fast exchange limit or the condition T << 1/ (vB - vA). Several approximate methods exist for extracting T values from spectra in the rate ranges above or below coalescence but not yet at the fast or slow exchange limits. Two are especially useful for I3C studies. For the region below coalescence in which the peaks are broadened but do not overlap,

NANCY K. WILSON AND J. B. STOTHERS 1 / ~= ZIT(AV - Avo)

99

[61

where Av is the line width of the broadened line. It may be noted that eq. [6] is also applicable for many-site exchange, provided overlap of the resonance lines is negligible, since the lifetime of a single site is involved. Line-width measurements may also be used in the rate range above coalescence. The appropriate relationship is [71 1 / ~= TI (v* - vA) 2/(A~ - Avo) Equations [61 and 171 cannot be used near coalescence, when T Rather, the lifetimes must be determined by &/ZTI (VB VA) total line-shape analysis, using the complete equations governing the line-shape (180). Likewise the complete equations must be employed if the line widths of the signals for slow exchange are not small compared to their separation. Values of AG$, the activation free energy for interconversion or exchange, can be determined from the rate at the coalescence temperature, k, from eq. [5], and the Eyring equation,

-

.

k T .-AG+/RT h

k = ~ -

where K is a transmission coefficient, usually between 0.5 and 1.0, k is the Boltzmann constant, T is the absolute temperature, h is Planck's constant, and R is the gas constant. The error in AG+ determined in this way is usually less than 0.2 kcal/mole. The errors in the rates at other temperatures, and hence the accuracy of the other activation parameters, enthalpy AH*, and entropy AS*, depend to a large extent on the degree to which the field homogeneity is maintained and the accuracy of the value of the shielding difference between the alternative sites, vB - vA. The field homogeneity can be monitored by using as a reference a line for a nucleus which is not involved in the exchange process. To determine the best values of vB vA, one approach is to measure the temperature dependence of the shieldings in the temperature range below the slow exchange limit and extrapolate into the exchange region. An advantage of total line-shape analysis is that the input values of vB V A can be optimized for each temperature below the coalescence temperature at the same time that the best parameters for the line-shape fit are determined (181). The presence of several equilibrating forms or of one energetically favored form can often be established by the nmr spectrum at the slow exchange limit. Thus 13C nmr has been used (182) to study tautomeric equilibria in l-phenylpyrazolin5-ones ( 1 5 4 ) . Three tautomers are possible: a CH ( 2 5 4 ~ an ) ~ NH ( 2 5 4 b ) , and an OH form ( 1 5 4 ~ ) . In the carbon spectrum, these can be clearly distinguished, since 154a contains a sat-

100

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

b

a

C

154

urated carbon which is not present in the other two forms and The pyrazolinones with R = H, CH3, and COOC2H5, were shown to exist as 154c, whereas the amino compound, R = NH2, is 154a. It may be noted that, although 154a and 154b are easily distinguished in the 'H spectrum, discrimination between 154b and 154c is complicated by the similarity of NH and OH proton resonances and the possibility of proton exchange between the oxygen and the nitrogen; thus the results demonstrate the potentially greater effectiveness of 13C m r in these applications. An interesting observation of tautomeric equilibria in some derivatives of the natural product perezone (155) has been

1 5 4 ~lacks a carbonyl carbon.

NANCY K. WILSON AND J. B. STOTHERS

101

reported (183). Although the I3C spectrum of 155 itself clearly indicates the presence of only one isomer, the spectrum of hydroxyperezone hydrate ( 1 5 6 ) shows that an exchan e process is occurring in this derivative. The low-field s& region has two sharp lines at 118.9 and 111.2 ppm, arising from C-2 and C-5, respectively, and a single broad signal at 168.5 ppm instead of the six single resonances of the ring carbons expected in this region. The four remaining ring carbons C-1, C-3, C-4, and C-6 must therefore be nearly equivalent. An interconverOH

166

sion of energetically equivalent tautomeric forms of quinone

1 5 7 , R = -CH (CH3)C H ~ C H ~ C H(OH) Z C (CH3)2 , accounts for the ob-

served spectrum. The near equivalence of C-1, C-3, C-4, and C-6 results from proton exchange causing interchange of the hydroxyl and carbonyl groups at a rate of -lo3 sec-l. Hydroxyperezone was found to exhibit similar tautomerism.

167

Somewhat more complex systems are involved in the anomeric equilibria of D-fructose and D-furanose in water (136). For these ketoses, the complexity of the 'H spectrum precluded unequivocal assignments of the resonances, so equilibrium information was not obtainable from the proton results. The presence of two anomeric forms of D-fructose had been previously established by conventional (cw) 13C nmr (129b). With the enhanced sensitivity of Fourier transform proton-decoupled 3C experiments, the carbon spectra were well resolved and considerably easier to analyze than the proton spectra. It was possible to

102

STEREGCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

obtain quantitative results, since even minor components of the equilibrium mixture were observed. D-Fructose was shown to consist of four components in the following amounts at equilibrium in aqueous solution: 57% 8-D-fructopyranose (158bS, 31% 8-D) ~ 3% a-Dfructofuranose ( 1 5 8 d ) , 9% a-D-fructofuranose ( 1 5 8 ~ and fructopyranose ( 1 5 8 ~ ) . Additionally, the results confirmed a pyranose-furanose interconversion rather than an a-f3 anomerization as the major means of mutarotation of aqueous fructose. Similarly, the equilibrium composition of aqueous D-turanose

s

R.2

o C n p H OH '"b OH CHPH 2

"'b

CHPH OH OH CHpH

cCl-pH '"d

OH

OH

C V H c C H P H OH "'d OH CHPH

R3

OH OH 4

* OH OH

+

*

was determined to be 41% 3-O-(a-D-glucopyranosyl)-f3-D-fructofuranose ( 1 5 9 d ) , 39% 3-O-(a-D-glucopyranosyl)-~-D-fructopyranose (159b), 20% 3-0- (a-D-glucopyranosyl)-a-D-fructofuranose ( 1 5 9 ~,) and less than 4% 3-O-(a-D-glucopyranosyl)-a-D-fructopyranose ( 1 5 9 ~ )for which no signals were observed. Interestingly, separate signals were observed for the glucopyranose C-1 in each of the three anomers contributing to the spectrum. In the fast exchange region model compound data can be used to estimate the shieldings of the individual participants in an equilibrium. For example, with both 'H and I3C nmr measurements, it has been shown (184) that ethyl 7-phenylcycloheptatriene-7carboxylate (160b) and dimethyl 7-phenylcycloheptatriene-7-phosphonate (161b) exist in valence-tautomeric equilibria with the corresponding norcaradiene forms 260a and 161a. The 13C reson-

NANCY K. WILSON AND J. B. STOTHERS

103

ance of C-1 and C-6 in 1 6 0 and 161 occur at significantly higher fields than the a-carbon resonances in cycloheptatriene itself, but at much lower fields than those in the analogous norcaradienes, pointing to a rapid equilibrium in which exchange

leads to averaging of the shieldings. In addition, the C-1 and C-6 signals showed a marked temperature dependence, with line broadening becoming evident at low temperatures, which also is indicative of an exchange process. Estimates of equilibrium constants and thermodynamic parameters were made, drawing on the proton spectra of model compounds. A third substance of a similar type, dimethyl 2,5-dichloro-7-phenylnorcaradiene-7-phosphonate ( 1 6 2 ) , was shown to be a norcaradiene on the basis of similarities of the 13C shieldings and the 1H-31P couplings to those in model compounds. CI

I

CI

Binding of

162

3C-enriched sugars to the protein concanavalin

A in the presence of various metal ions has been studied (185).

Variable-temperature work indicated rates in the slow-to-medium exchange region. The absence of any change in the 13C shieldings of the sugars indicated that no conformational change accompanies binding. Further, relaxation time measurements pointed to a metal ion site in the protein situated very close to the binding site of sugar. Complex equilibria in chlorophyll ( 1 6 3 ) solutions have been examined (186a). The central magnesium atom in chlorophyll is known to have a coordination number greater than 4 , with one or both axial positions on Mg occupied by an electron donor group. These donor groups may be solvent molecules, or may be other chlorophyll molecules, with formation of dimers and higher oligomers, in which case the 9-keto carbonyl acts as a donor (186b).

104

STEREOCHEMICAL ASPECTS OF

P

'3C NMR SPECTROSCOPY

I

183

The disaggregation of hydrofuran (THE'),

'3C-enriched chlorophyll dimers by tetra-

Chl2

+

2THFe2Chl'THF

was followed by observing the C-9 resonance as a function of THF concentration in a nondonor solvent. The large shielding changes for C-9, reflecting a difference of 2.42 ppm between Chl2 and Chl-THE', confirm that the keto carbonyl is responsible for chlorophyll complexation. Although the potential of 13C nmr for the study of fast chemical exchange processes is well recognized, applications to many promising areas are still few in number. The study by Gansow et al. (187) of hindered rotation in N,N-dimethyltrichloroacetamide ( 1 6 4 ) is one of the few complete 13C studies of hindered rotation about single bonds in the literature. This amide was chosen because the rotational barrier had previously been determined by both 'H line-shape analysis and by 'H spin-echo measurements; therefore it provided a good test case for deter-

CCI,-

fj -N /\

CHS

164

NANCY K. WILSON AND J. B. S T O T H E R S

105

mining the utility of 13C line-shape measurements. At low temperatures, in the slow exchange limit, the methyl carbons are nonequivalent, since the partial double-bond character of the carbonyl carbon-nitrogen bond restricts rotation, so that one methyl is syn and one a n t i to the oxygen. The changes in the experimental spectra and the computer simulations of the spectra obtained from the best fit of the data are shown in Figure 1. The resulting values of the Arrhenius activation energy Ea from I H and 13C line-shap fitting agree well, and the agreement with lH spin-echo results is also adequate, as can be seen from Table 30. Free energy of activation values determined from 'H and 13C coalescence temperatures and that from spin-echo are all in resonable agreement.

Fig. 1. Observed and computer-simulated I 3 C nmr spectra of the methyl signals of i64 as a function of temperature. Lineshape analysis furnished the T values indicated (187). (Reproduced from J . h e r . Chem. SOC. by permission of the American Chemical Society.)

line shapea line shape line shape spin-echoc

1H 1H

1H

13c

Method

Nucleus

aIn 30% 1,2-dibromotetrafluoroethane. bAt the coalescence temperature. "eat. dCalculated from the rate constant at 17OC.

60 90 22.6 26.9

Irradiating frequency, MHz 16.4 17.4 16.6 14.6 0.8 5 0.8 k 0.8 ? 0.6 k

kcal/mole

Ea 1

17.5 18.3 17.6 18.0d

kcal/mole

AG+~,

13 -21 15 -18.5

Coalescence temperature, OC

Table 30. Activation Energies for Hindered Internal Rotation in 164 (187)

NANCY K. WILSON AND J. B. STOTHERS

107

165

Hindered rotation about the C12CH-C bond in 1,3,5-trimethyl-2-dichloromethylbenzene ( 1 6 5 ) has been investigated (188), and the AG+ values from 'H and 13C coalescence temperatures compared (Table 31). The rotational barrier determined from the coalescence of the methyl carbon resonances is in excellent agreement with that obtained from the coalescence of the ring carbons C-4 and C-6. Similarly the proton results are entirely consistent with the 13C results. TABLE 31. Activation Free Energy for Hindered Rotation about the C12CH-C2 Bond in 165 (188) Resonances observed

Coalescence temperature,OC

C-4I C-6 l-CH3, 3-CH3

12 -7

4-H, 6-H 1-CH3, 3-CH3

-5 0

AG*, kcal/mole

13.8 f 0.3 13.8 ?I 0.3 13.8 f 0. 2 13.9 f 0.3

Applications of 13C nmr to dynamic processes, which are perhaps the most numerous in the literature, aside from relaxation measurements, are those in which spectral changes with temperature are utilized to gain information on conformational processes in ring systems. A great deal of work has been done on conformational equilibria of substituted cyclohexanes by other techniques (189). It is not surprising, therefore, that substituted cyclohexanes would be among the first systems to be studied by 13C nmr, particularly since in many cases proton studies are of little value due to extensive overlap of the resonances of the conformational isomers. Room temperature proton-decoupled 3C spectra were obtained for 15 methylcyclohex-

'

108

STEREOCHEMICAL ASPECTS OF

'3C NMR SPECTROSCOPY

anes by Dalling and Grant (61); these were discussed in Sect. 111-B in regard to conformational effects on the carbon shieldings. Confcrmational free energies were crudely estimated for some of the cyclohexanes by comparison of the experimental spectra with those predicted for various values of A E . However, the experimental errors were of the same order of magnitude as the calculated conformational energies. Another study at ambient temperatures involved the examination of the carbon shieldings of several cyclohexanol derivatives, again at the fast exchange limit (65). Equilibrium constants were estimated by the use of shieldings of model compounds, and values of the conformational free energy for interconversion AG* were thus derived. The results agreed well with values obtained by other methods but this may be somewhat fortuitous in the light of the dangers associated with the use of model compounds. By decreasing the temperature significantly, the conformational interconversion can be slowed enough for signals from both conformers to be observed, and thus the equilibrium populations can be determined more accurately. For methylcyclohexane, low-temperature proton nmr was inadequate for the determination of the relative amounts of axial and equatorial forms as a result of the large value of the equilibrium constant and the similarity of the 'H shieldings of the two forms. At -llO°C, the 63.1 MHz 13C spectrum was predominantly that of the equatorial form 1 6 6 0 ; however, weak high-field signals due to C-3 and C-5 of the axial form 166b were also observed.

a

166

b

I

As the temperature was raised, these signals merged with those due to 166a until at -75OC, they could no longer be observed in the spectrum. The equilibrium constant obtained was approximately 100, much larger than those easily measured previously by proton nmr, clearly establishing the usefulness of 13C nmr for probing such systems (64). Low-temperature 3C magnetic resonance also made possible identification of the energetically unequal conformers of c i s 4-methylcyclohexanol ( 1 6 7 ) . From the relative intensities of the methyl signals the equilibrium amount of the axial methyl conformer 167a was found to be 7.7%, and the calculated free energy difference AG = -1.1 kcal/mole, favoring the equatorial conformer 167b (190). Similarly, cyclohexyltrimethylsilyl

NANCY K. WILSON AND J. B. STOTHERS

109

OH

a

b

167

ether (168) has been shown to consist of 10.1% of the axial conformer 368a at -103°C, giving a conformational free energy change of -0.7 kcal/mole for conversion of 168a to 168b, which agrees with that estimated from 'H spectra at room temperature and model compound data, but is undoubtedly more accurate (191).

a 168

b

Averaging of coupling constants may also occur when conformational inversion is rapid. Thus to measure the I3C-l9F couplings in 1,l-difluorocyclohexane ( 1 6 9 1 , the carbon spectrum was examined at -9OOC to slow the chair-chair interconversion. Coupling of C-3 with fluorine occurs only with the equatorial fluorine; at -90°C, 3 J c ~= 9.5 Hz, whereas at room temperature,

F 169

3JCF = 4.7 Hz because of averaging of the coupling to the axial (3Jc~ = 0 ) and equatorial (3JCF = 9.5 HZ) fluorines (192).

Similar averaging has been observed in norbornyl cations (4,193)I which are discussed later. Conformational inversion rates have been measured (194) for 1,l-dimethylcyclohexane (170), cis-1,2-dimethylcyclohexane (171), trans-1,3-dimethylcyclohexane (172), and cis-lI4-dimethylcyclohexane (173), as well as for cis-decalin ( 1 7 4 ) and cis-

6 - q 170

171

172

173

174

175

110

111

NANCY K. WILSON AND J. B. STCTHERS

176

-9-methyldecalin ( 1 7 5 ) . The rate constants for inversion were determined from the carbon spectra by use of the approximate equations [ 5 ] through [71 in the appropriate rate ranges. Note that k, the rate constant for conformational interchange, is equivalent to 1 / 2 ~ ,since it describes the rate of change at the individual sites, at each of which the lifetime is assumed to be the same; that is, T A = TB. The values of the barriers to interconversion obtained by this method agree well in most cases with those previously determined by other techniques for similar systems. Independent measurements on 171 and 1 7 3 , in a different solvent, produced AG% values which were also in essential agreement (190). Activation parameters for several substituted cyclohexanes and decalins are given in Table 32. Thermodynamic parameters for chair-chair interconversion of 1,1,3,3-tetramethylcyclohexane ( 1 7 6 ) have been determined, using iterative line-shape fitting of the methyl 3C resonance , and compared with those for 2,2,6,6-tetramethyl-l,l-difluorocyclohexane ( 1 7 7 ) and 3,3,5,5-tetrarnethyl-l,l-difluorocyclohexane ( 1 7 8 ) determined from total line-shape analysis of the 19F spectra (196). Although these parameters seem reasonable for 177 and 1 7 8 , the value of AS* for 1 7 6 , -13.2 eu, seems surprisingly large.

F

177

F

178

Ring inversion in 1,l-dibenzylcyclohexane ( 1 7 9 ) and its 4,4-dimethyl derivative 1 8 0 has been studied by both 'H and 13C nmr (197, 199), and the inversion barrier for chair-chair interconversion has been found to be similar to those in other cyclohexane derivatives; for 1 8 0 the barrier is 11.8 kcal/mole.

-13.2 f 1.0 -1.0 f 0.5 -9.0 f 1.0

6.4 f 0.2 9.8 f 0.1 5.8 f 0.2

176 177 178

9.9 f 0.6 13.6 2 0.7 12.4 2 0.7

a k , line-shape analysis;

175

180 181 174

173

--

4.5 2 3 4.1 f 3

172

5

*

?

--

2.5 3 3

LW, line width;

-0.7

3.5

-7.7

2.8 3.7 f 3 -3.5 f 3

10.8 11.3 f 0.7 9.3 t 0.7 12 5 1 11.1 f 0.7 11.0 f 0.7

Cyclohexane-dl1 170 171

eu

G*,

Mfl

Compound

kcal/mole

DR, double resonance.

12.6 12.6

--

10.3 10.2 10.3 9.9 9.8 9.8 9.3 9.0 f 0.1 10.1 f 0.1 7.4 f 0.1 11.8

AG +, kcal/mole

13c LS 13c LW 13c LW

195 194 'H LS,LW,DR 13c LW 13c LW 13c LW 13c LW 13c LW 13c LW 13c LS 19F LS 19F LS 'H LW

196 196 199 198 194 194

194 190 196

190 194

194

Ref.

Methoda

Table 32. Activation Parameters for Ring Inversion in Some Cyclohexanes and 3ecalins

113

NANCY K. WILSON AND J. B. STOTHERS

179

180

Yet another cyclohexane derivative for which 13C nmr has been used to obtain activation parameters (198) is y-1,2,3,4,5,6-hexachlorocyclohexane ( 1 8 1 ) . Total line-shape fitting was used. The resultant activation enthalpy and entropy are AH* = 9.9 ? 0.6 kcal/mole and AS* = -7.7 If. 2.5 eu for conformational conversion.

CI

Cl

181

Anet and co-workers have examined several larger ring systems with variable-temperature 3C and 'H magnetic resonance (200-202). By the use of high fields (resonance frequencies of 63.1 MHz for 13C and 251 M H z for 'H) which give much greater shielding differences, distinction of the signals due to individual conformers was possible. The cyclononane proton spectrum, a single line at room temperature, changes to two broad overlapping bands at -15OoC, but detailed analysis could not be carried out. The changes in the 13C spectrum as the temperature is decreased, however, are simpler. At -65", a single resonance is observed, which broadens at lower temperatures and at -162' is well resolved into two signals separated by 9 ppm, with relative areas of 2:l. A potential barrier of about 6 kcal/mole is consistent with the behavior of the proton spec-

114

STEREOCHEMICAL ASPECTS OF

b

3C NMR SPECTROSCOPY

C

182

trum. The 13C data support an equilibrium in which interconversion of twist-boat-chair conformations 182a,c occurs through a boat-chair intermediate 182b. A n alternative possible conformation, the twist-chair 1 8 3 , would give five different carbon signals in the slow exchange limit, and a barrier low enough to effect dynamic averaging at -162OC (<4 kcal/mole) appears unlikely. Further support for 182 as the favored form is gained from the spectra of 1,l-dimethylcyclononane (1841, which should show no dynamic nmr effects in the 13C spectrum, and dynamic effects in the 'H spectrum only for the ring protons, if it exists in the twist-boat-chair conformation. Such is the case, and the 'H temperature dependence indicates a barrier for 184 of about 9 kcal/mole (200).

183

Cyclodecane ( 1 8 5 ) , cyclododecane ( 1 8 6 ) , and cyclotetradecans ( 1 8 7 ) have been studied by the same methods (201). Although the proton spectra could not be completely analyzed because of their complexity, their temperature dependence indicated a conformational free energy barrier of approximately 6 kcal/mole for 185 and 7 kcal/mole for 1 8 6 and 1 8 7 . The 13C spectrum of 186 at -131OC consists of two resonances in a 2:l intensity ratio, which fits nicely with the square conformation 1 8 8 predicted by strain energy calculations and found by x-ray crystallography. The barrier determined from the 3C spectrum for the transformation of 188 to its mirror image is 7 . 3 kcal/ mole. Similarly, the 13C spectrum of 187 at -132OC supports the diamond lattice conformation 189.

NANCY K. WILSON AND J. B. STOTHERS

115

188

The question of whether oxacyclooctan-5-one (5-oxocanone,

1 9 0 ) exists predominantly in the boat-boat conformation 191 or the boat-chair conformation 192 was rather neatly answered by

the combination of 251 MHz proton nmr and 63.1 MHz carbon nmr (202). The 'H spectrum at room temperature contains three differently shielded sets of protons; the band due to the CH20CH2 protons, a singlet at room temperature, separated into two bands at intermediate temperature (--96OC), and at -104' and below four proton resonances were apparent. In addition to the carbonyl signal, the I3C spectrum exhibited four peaks at -45OC, each of which split into equal-intensity doublets at low temperatures while the carbonyl peak was unchanged. These results are inconsistent with conformation 191 which, because of its symmetry, should give rise to no more than one signal for the CH20 carbons and two for the CH20 protons. However, if the oxygens do not lie on the plane of symmetry, 192 could give the spectra observed. The process apparent in the 'H spectrum at the intermediate temperatures must involve an interchange of two protons on the same carbon (since no changes were observed in the carbon spectrum at these temperatures) and, therefore, is essentially a ring inversion with AG* = 9.0 kcal/mole at -88OC. The process evidenced by the 13C spectrum has to involve symmetry averaging, probably about a plane of symmetry

116

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

191

192

passing only through the carbonyl and ether functions, and can be considered to be a conformational racemization of a chiral conformation. For this process AG* = 7.8 kcal/mole at -1OO'C. The [lO]annulenes have eight possible isomers, differing in the arrangement of the five cis and/or trans double bonds in the 10-membered ring. Two of these isomers, prepared by photolysis, have been analyzed by variable-temperature 3C and l H nmr ( 2 0 3 ) . One gave singlet absorptions in both the proton and the carbon spectra, which were temperature invariant and pointed to either the planar form 193 for this substance or, alternatively, an averaging process between several nonplanar forms such as 194 with a very low energy barrier to interconversion (less than 5 kcal/mole) to account for the observed equivalence of both hydrogen and carbon nuclei. In conjunction with uv and proton nmr data on similar systems of known structure, the nmr results support the latter undergoing an averaging process similar to the interconversion of twist-boat cyclohexane conformers. The second [lo]annulene isomer had temperature-dependent roton and carbon spectra between -40 and -1OO'C. At -40'. the 1)3C spectrum was a broad singlet, which was resolved into five peaks at -100'. Presumably at low temperature the isomer is frozen into a single form, the stable puckered conformation

'

NANCY K. WILSON AND J. B. STOTHERS

117

193

1

194

195a. The data were interpreted as indicative of a process in which a trans double bond is able to migrate around the ring (as in 195) and thereby allow the automerization to take place. Computer simulations of the spectra expected for this mechanism agree well with the experimental 13C spectra (see Fig. 2 ) and lend credence to this interpretation of the data. It is interesting that conformational interconversions of this type must mean that these compounds are nonaromatic. One study of inversion at nitrogen employing variable-temperature 13C magnetic resonance has so far appeared in the literature ( 2 0 4 ) . In an ethylenimine having a nitrogen substituent containing an asymmetric center, slow inversion at the nitrogen will result in magnetic nonequivalence of both the vicinal protons and the 13C nuclei of the ethylenimine ring, as can be seen in 196. For the ethylenimine 197,two resonances due to the ring carbons, separated by about 5 ppm, were observed at 54'C, attesting to their nonequivalence. AS the temperature was increased, these resonances coalesced to a sharp singlet at 14OoC. Although no activation parameters were re-

118

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

195

ported, t h e d a t a i n d i c a t e t h a t 13C s t u d i e s would be u s e f u l i n determining i n v e r s i o n a l b a r r i e r s of t h i s type.

lee

197

Confirmation of bridged-nonbridged s t r u c t u r a l interconvers i o n s i n c e r t a i n metal carbonyls has been obtained from 13C s t u d i e s . Molecules such a s [ (h5-C5Hg)Fe (CO) 21 i* (198) had been "The symbol h5-C5H5 r e f e r s t o a n - l i g a t e d cyclopentadiene l i g a n d , whereas h1-C5H5 r e f e r s t o t h e o - l i g a t e d s p e c i e s .

NANCY K.

WILSON AND J. B.

STOTHERS

119

3C nmr s p e c t r a Fig. 2 . Observed and computer-simulated of 195 a t v a r i o u s temperatures. ( S p e c t r a k i n d l y provided by Professor S . Masamune and reproduced by permission of t h e Ameri c a n Chemical S o c i e t y . )

shown from p r o t o n s p e c t r a ( 2 0 5 ) t o p a r t i c i p a t e i n r a p i d b r i d g e nonbridge interchange a s i l l u s t r a t e d i n 199. X-Ray s t u d i e s of 198 i n t h e s o l i d s t a t e ( 2 0 6 ) c h a r a c t e r i z e d c i s and t r a n s isomeric bridged forms, 200 and 201. An a d d i t i o n a l nonbridged

li

199

120

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

200

form 202 had been postulated to exist in solution (207), but unequivocal evidence was lacking. The variable-temperature 3C nmr spectra of 198 revealed both cis-trans and intramolecular bridge-terminal carbonyl interconversions ( 2 0 8 ) . At ambient

\ co 201

202

temperatures, one broad resonance is observed *or the carbonyl (6, 2 4 3 . 0 ) and one for the cyclopentadiene fragment ( & c 86.1), each of which sharpens at higher temperatures. As the sample is cooled, several signals are resolved, whose temperature dependencies point to two processes occurring above about -35OC which lead to averaging of both the CO and C5H5 signals. The carbonyl spectra are shown in Figure 3 . Interconversion is slow at -85OC, but the close similarity of the shieldings precluded resolution (f0.6 ppm) of the separate signals belonging to the cis and trans forms, although the bridging ( 6 c 2 7 5 . 1 ) and terminal (6, 210.9) carbonyl resonances were easily distinguished. As the temperature is increased the energetically less favorable trans form undergoes intramolecular interconversion, leading to averaging of its CO signals and thus the appearance of a new signal at 6c 2 4 3 . 0 . Above -35OC, the cis form may also experience carbonyl interchange, or alternatively, the additional averaging process may result from participa-

NANCY K. WILSON AND J. B. STOTHERS

-73"

I

I

121

-12" -25"

-85"

I

I

-35"

Fig. 3 . I 3 C carbonyl absorption of 198 as a function of temperature. (Spectra kindly provided by Professor 0. A. Gansow and reproduced by permission of the American Chemical Society. ) tion in a cis-trans equilibration. N o evidence was obtained for the nonbridged form 202. Rapid intramolecular scrambling of carbonyl groups in tetrarhodiumdodecacarbonyl has also been investigated (209). The possible structures proposed were the bridged ( 2 0 3 ) and the nonbridged ( 2 0 4 ) forms, with the preponderance of evidence favoring 203. However, Cotton had suggested earlier (210) that this compound belongs to the general class of fluxional molecules, with isomerization between bridged and nonbridged forms through rapid bridge-terminal interconversions of carbonyl groups. The 3C spectrum demonstrated unequivocally the exis7

122

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

& ===-

co

‘co

‘co

CO

203

tence of four different types of carbonyl sites, as in 2 0 3 , since the broad unstructured resonance at room temperature became a quintet at the fast exchange limit (about 5OoC), with

204

relative intensities of 1:4:6:4:1 and a splitting of 17.1 Hz arising from the lo3Rh-13Ccoupling. Since 1JRh-c in [Rh(C0)2C1]2 is 68.8 Hz, the observed value for 203 is consistent with an averaging of the coupling with four rhodium nuclei with J 2 0 Hz for those to which the carbon is not directly bonded. The mechanism must‘be intramolecular because intermolecular exchange would eliminate the coupling. Thus 203 participates in rapid permutational isomerization reactions (fluxionality) by carbonyl bridge-terminal interconversions. It is believed that this scrambling probably proceeds by a sequence of rapid 203 = 2 0 4 isomerizations. Fluxionality is also characteristic of (h5-C5H5)(CO)2Fe(h1-C5H5) (205), which was the first substance of this genre to be studied by ‘H nmr. The proton results indicated that degenerate rearrangements in this system proceed by a series of

NANCY K. WILSON AND J. B. STOTHERS

123

206

1,2 shifts of the Fe (CO)2 (h5-C5H5). -88 to +5SoC also temperature three

Fe-C u bond as illustrated in 206, MR = The 1 3 C spectra over the temperature range support this mechanism (211). At ambient resonances were observed, a sharp signal for MR

206

the r-bonded ring, a broad one for the o-bonded ring, and a single resonance for the two carbonyls. The broad signal is resolved into three peaks, in a 2:2:1 intensity ratio, at -78' C; further, the signal due to C-1,4 sharpens more slowly with decreasing temperature than that due to C-2,3. From -70 to -88"C, the C-1,4 signal begins to broaden again as a result of hindered rotation about the Fe,C-5 bond leading to nonequivalence of C-1 and C-4 and also to nonequivalence of C-2 and C-3. For a 1,2 shift mechanism, the fluxionality can be described as a three-site exchange process (1,4; 2,3; 5; with 2:2:1 population ratios). Calculated spectra support this interpretation. Additionally, by line-shape analysis of the variable-temperature spectra, an Arrhenius activation energy for the exchange of 10.7 & 0.5 kcal/mole was obtained. A number of metal a-cyclopentadienyls have been examined (212). The 13C spectrum of CgHgSi(CH3)3 GO71 at -2OOC corresponds to the fluxional 5-isomer 2 0 7 a , having four signals in the ratio 2:2:1:3 (low to high field). In addition the presence of a weak high-field signal may be due to a vinylic isomer such as 207b, present to the extent of approximately 10% as judged from 'H spectra. At higher temperatures, broadening of the olefinic signals occurs, indicating interconversion of 207a and 207b; however, dimerization of these silyl compounds,

124

STEREOCHEMICAL ASPECTS OF 13C NMR SPECTROSCOPY

a

207

which takes place at elevated temperatures, precludes observations over the entire range in which spectral changes can be expected. C5H5Si(CH3)2Cl ( 2 0 8 ) and C H Si(CH3)C12 (209) show 5.5 similar behavior. Thus structures having nonequivalent ring carbons are characteristic of 207, 208, and 209 as well as CgHgGe (CH3)3 ( 2 1 0 ) and CgHgSn (CH3)3 ( 2 1 1 ) . The cyclopentadienyl derivatives of heavier elements seem to be either the 5-isomersI which undergo fast metallotropic rearrangement as in 206, or TI complexes. If the rate of rearrangement is so rapid that only a single averaged signal is observed for the ring carbons, as in C5HgHgCH3 ( 2 1 2 ) , a decision regarding the process responsible for the averaging is less certain. From line-width measurements, using eqs. [51 through [ 7 1 , and Arrhenius plots, activation energies were obtained for some of these migratory processes. Their values are listed in Table 3 3 . A n interesting aspect of the results for 211 is the use of 13C data to extend rate measurements into the relatively fast exchange region, in which 'H results gave a significant deviation from linearity in the Arrhenius plot because of spin-spin coupling. Both 'H and 13C gave essentially the same activation parameters. The mechanism of the intramolecular metallotropic rearrangement of trimethylstannylindene ( 2 1 3 ) has also been investigated by 13C nmr (213). The alternative means of fluxional behavior are either a 1,3 shift or two successive 1,2 shifts. For a 1,2 shift mechanism, the indenyl compound 213 must go

NANCY K. WILSON AND J. B. STOTHERS

125

Table 33. Activation Energies for Metallotropic Rearrangement in Some Organometallic Compounds from I3C Data kcal/mole

Ea I

AG a, kcal/mole

Ref.

205

10.7 1 0.5

--

210

10.7 1 0.9

211

Compound

211

213

13.4

6.4 1 1.0 6.8 1 0.7b 13.8 1 0.8

7.2 7.1

0.9

--

1.0 0.7b

212

212 212 213

aAt 300'K. brom combined I 3 C and 'H data; all other values from I3C data alone.

213

through an intermediate 214, which is less stable than 213 by about 9 kcal/mole. This would make A& much higher for 213 than for the analogous cyclopentadienyl compound 2 1 1 , if both migrations involve the 1,2 shift mechanism. If, however, both proceed by 1,3 shifts, the AG* values for 211 and 213 should be approximately the same (214). The activat,ion energy for 213, E, = 13.8 ? 0.8 kcal/mole, obtained from the temperature dependence of the C-8,9 and C-4,7 resonance by line-width

214

126

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

techniques, i s indeed s i g n i f i c a n t l y g r e a t e r than t h a t f o r 211 (Table 331, i n d i c a t i n g t h a t s u c c e s s i v e 1 , 2 s h i f t s occur. Low-temperature proton mr measurements on mixtures of magnesium cyclopentadienide and e i t h e r magnesium c h l o r i d e o r magnesium bromide i n d i c a t e t h a t t h e magnesium cyclopentadienyl h a l i d e s e x i s t a s equilibrium mixtures, (CgH5)zMg + M g X z e 2CgHgMgX, with CsH5MgX predominant. Q u a l i t a t i v e low-temperature carbon s p e c t r a obtained f o r commercial C5HgMgC1 i n t e t r a h y d r o furan a t -67OC e x h i b i t e d two peaks, with r e l a t i v e a r e a s of 4 : 1 , t h e l a r g e r presumably a r i s i n g from C5H5MgC1, and t h e s m a l l e r from an alkoxide impurity. The (CgHg)2Mg peak was n o t observed because of i t s low i n t e n s i t y . A t higher temperatures averaging occurred, i n d i c a t i n g exchange, a s was a l s o manifest i n t h e proton s p e c t r a . Other commercial cyclopentadienyl Grignard r e a g e n t s showed similar exchange e f f e c t s i n t h e i r 13C s p e c t r a t215). Olah and h i s co-workers have examined t h e u t i l i t y of 13C nmr f o r d i s t i n g u i s h i n g between bridged and r a p i d l y e q u i l i b r a t i n g s p e c i e s f o r a v a r i e t y of s t a b l e c a r b o c a t i o n i c systems (2b, 4 , 193, 216-221). I n s e v e r a l c a s e s , r a p i d degenerate r e a r rangements o c c u r , even a t low temperatures, and r e s u l t i n averaging t h e s h i e l d i n g s and coupling c o n s t a n t s . The dimethylisopropyl carbonium ion 215 i s i l l u s t r a t i v e ( 4 ) . The c e n t r a l c a r bons absorb a t tic 198.0 with lJCH = 65 Hz. These v a l u e s agree

CH,

%H, a

216

b

reasonably w e l l w i t h t h o s e expected f o r t h e e q u i l i b r i u m 215a a s estimated i n t h e following manner. The observed s h i e l d i n g s f o r t h e methyl and c e n t r a l carbons of t h e t - b u t y l c a t i o n a r e 48.3 and 330.0 ppm, r e s p e c t i v e l y . R e l a t i v e t o t h e former, t h e methine carbon i n e i t h e r 215a o r 215b would be expected t o experience t h e d e s h i e l d i n g e f f e c t s of t h e a d d i t i o n a l methyls ( - 1 4 ppm) and t h e neighboring c a t i o n i c c e n t e r (-20 ppm) and t h u s should absorb near 6, 82. The mean of t h e estimated s h i e l d i n g s f o r t h e c e n t r a l carbons i n 215 i s t h e r e f o r e (330 + 8 2 ) / 2 , o r 206 ppm. S i m i l a r l y , t h e mean of t h e geminal and d i r e c t couplings i n t h e t-bu,tyl c a t i o n i s 64 Hz. Both v a l u e s a r e c l o s e t o t h o s e observed f o r 215, t h e r e b y supporting t h i s d e s c r i p t i o n of t h e dimethylisopropyl carbonium ion.

==215b,

NANCY K. WILSON AND J. B. STOTHERS

127

In an analogous manner, 6c and J values may be estimated from models for the ethylenebromonium ion as an equilibrium mixture 2 1 6 ; these estimates are 6c -175, 'JCH -130 Hz. The observed values, 6c 75.6 and ' J C H = 185 Hz, are significantly different from those estimated for 2 1 6 , but are reasonably close to those anticipated for the bridged form 2 1 7 . H H-C-C

I I

&

+/H

2 7

H '

216

P

JCTH

H\+

On the basis of like comparisons, the data for the dimethylt-butyl and the methylethyl carbonium ions, as well as the

217

cyclopentyl cation 2 1 8 , indicate these to be equilibrium mixtures of degenerate ions, whereas the ethylene-p-anisonium ion

218

and the norbornyl cation 219 appear to be bridged (216). Although several related systems have been examined (2), only one additional example will be discussed, the 1,2-dimethylnorbornyl cation 220 (193). Several possible structures can be envisaged for this ion, including the static classical species 2 2 1 , an equilibrating system of degenerate classical ca-

128

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

218

tions 2 2 2 , a static, partially delocalized ion 2 2 3 , an equilibrating system of such delocalized ions 2 2 4 , and a symmetric

291

nonclassical cation 2 2 5 . Interest was focused on whether 220 exists as 2 2 3 , a structure analogous to that of the 2-methyl-

222

norbornyl cation, or whether it resembles the parent norbornyl cation 2 1 9 , and thus has structure 2 2 5 . The 'H spectra appear-

NANCY K. WILSON AND J. B. STOTHERS

129

ed to be compatible with 223 undergoing a rapid Wagner-Meerwein shift and thus indicated that 224 is the best representation. Comparison of the C-1 and C-2 shieldings with those observed for model systems led to the same conclusion, namely, that the best description is as a partially a-delocalized, rapidly equilibrating system of degenerate species, 2 2 4 . Raman spectra offered additional support for this interpretation.

224

226

B.

Spin-Lattice Relaxation Studies

Many 3C spin-lattice relaxation studies have been carried out in the past few years (22, 222) and a rapidly increasing number of applications of Ti measurements can be expected with increasing awareness of their potential for eliciting information about molecular geometry, interactions, and motions which is often unavailable from other sources. The advent of reliable and versatile instrumentation, which enables determination of T1 values by minor variations of normal pulsed Fourier transform techniques, places spin-lattice relaxation parameters in the same class with other nmr parameters such as shieldings and coupling constants which are routinely determined in structural and motional studies. Their utility is enhanced by the fact that under conditions of complete proton decoupling, the recovery of 13C magnetization is described by the single exponential time constant, Ti; thus the ease of interpretation

130

STEFEOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

of the results is increased (223, 224). The major features of relaxation processes were discussed in Sect. 11. Several examples of stereochemical applications of T1 measurements are discussed in the following paragraphs. In small, symmetric molecules, molecular tumbling is rapid and several mechanisms may compete with 'H-I3C dipole-dipole relaxation, which becomes less efficient as the correlation time for reorientation of the C-H internuclear vectors decreases. The T1 values obtained for small molecules are long, typically 10 to 20 sec for protonated carbons, and much longer, often greater than 100 sect for carbons without directly bonded protons. Several of these values are listed in Table 2 and were discussed briefly in Sect. 11. The following features characterize spin-lattice relaxation in such small molecules (31, 36). Carbon nuclei which are bonded directly to one or more protons are relaxed primarily by dipole-dipole interaction with those protons. Spin rotation can contribute to the relaxation, with this contribution greater at high temperatures and dominant for methyl groups, due to the rapid internal rotation about the CH3-R bond. Chemical shift anisotropy does not usually contribute significantly to the relaxation, and scalar relaxation appears to be important only if 13C is bonded to a quadrupolar nucleus of similar magnetogyric ratio, such as bromine. From measurements of the nuclear Overhauser enhancement, it is possible to extract the contribution of the dipole-dipole mechanism to the overall spin-lattice relaxation, since the fractional increase in intensity of the 13C resonance upon proton decoupling is TI

= 1.988(Tl/fl)

[gl

where is the dipolar contribution to TI. Thus for CHC13 at 30°C, q = 1.79 and T1 = 32.4 sec, indicating a dipolar contribution of 90%, with spin rotation accounting for most of the remainder (31, 36). The rotational diffusion constant can sometimes be determined from T1 data (36). Likewise, because the rotational correlation time -cc varies exponentially with temperature,

-cC

= -c:

e- E / M

9,

an activation energy E for rotational reorientation can be obif isotropic motained from the temperature dependence of tion is assumed. The correlation time ' I ~can be estimated from the relation

NANCY K.

WILSON AND J. B.

131

STOTHERS

which i s analogous t o eq. [3] f o r d i p o l a r r e l a x a t i o n under cond i t i o n s of motional narrowing. F o r CHC13, t h i s a c t i v a t i o n ene r g y i s 1.63 t 0.07 kcal/mole ( 3 6 ) . I n benzene, s p i n - l a t t i c e r e l a x a t i o n i s dominated by d i p o l e d i p o l e i n t e r a c t i o n , a l t h o u g h o t h e r mechanisms c o n t r i b u t e s i g n i f i c a n t l y ( 2 7 , 2 2 5 ) . Rapid r o t a t i o n a b o u t t h e s i x f o l d symmetry a x i s can l e a d t o s p i n - r o t a t i o n c o n t r i b u t i o n s t o t h e r e l a x a t i o n . I n monosubstituted benzenes, a l l T1 v a l u e s f o r p r o t o n a t e d c a r bons a r e s h o r t e r t h a n t h a t f o r benzene i t s e l f , a s shown i n T a b l e 34; d i p o l a r i n t e r a c t i o n s a r e dominant f o r t h e s e c a r b o n s , therefore t h e s h o r t e r T I values r e f l e c t a longer r o t a t i o n a l T a b l e 34. S p i n - L a t t i c e R e l a x a t i o n T i m e s f o r Some S u b s t i t u t e d Benzenesa

Ti, sec

Compound

c-1 b Benzene

c-2

c-3

Ref. c-4

CH3

23 29.3

C

27 27

58 89

20 23.6

21 24.5

15 17.3

N i trobenzenee

56

6.9

6.9

4.8

27

Phenol f

21.5 18.4

4.4 2.8

3.9 2.8

2.4 1.9

27 27

61 54

5.9 5.2

5.9 5.4

3.2 3.4

27 19d

10.3

10.3

5.8

Tolueneb

c Id

b Biphenyle

t-Bu tylbenzeneb

16.3

27 225

225

a A t 25.2 MHz and ambient t e m p e r a t u r e ; samples n o t degassed unless indicated. bNeat CDegassed. d05% i n acetone-dg. e 2 ~ %i n acetone-dg. fApproximately 17 mole % i n carbon t e t r a c h l o r i d e .

.

c o r r e l a t i o n t i m e due t o t h e l a r g e r s i z e and lower symmetry of t h e s e molecules. Although t h e T1 v a l u e s f o r t h e monosubstit u t e d benzenes l i s t e d i n Table 34 c a n n o t be p r e c i s e l y compared, s i n c e t h e y were o b t a i n e d i n d i f f e r e n t s o l v e n t s and some samples were n o t d e g a s s e d , i t i s a p p a r e n t t h a t carbons p a r a t o t h e subs t i t u e n t r e l a x f a s t e r t h a n t h o s e i n o r t h o and meta p o s i t i o n s .

132

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

Preferred rotation about the axis bisecting the substituent and the ring, the C2 molecular symmetry axis ( 2 2 6 ) , does not short~ for ~ the~ para , carbons. en the effective correlation time, T Rather, it leads to relaxation for the ortho and meta carbons

226

because the orientation of these C-H bonds with respect to the static magnetic field changes more rapidly than that of the para C-H bond. The maximum increase in T1 for the ortho and meta carbons, for very fast rotation about C2 compared to that about the other axes, is by a factor of [1/2(3 cos20 - 1)]-2 over that for the para carbon, which is equal to 64 for C-H bond angles of 60 and 120' with the rotational axis, as in the monosubstituted benzenes (23b). The motional anisotropy represented by the ratio of tumbling about the C2 axis to that about the other two axes can be estimated from the observed 51 values. Thus the ratio T1°'m/TIP in t-butylbenzene is 1.8, which corresponds to tumbling approximately 3.5 times faster about the long axis (225). Similar estimates have been made for a number of other monosubstituted benzenes (222, 225). Spin-lattice relaxation in mesitylene, 0-xylene, and pseudocumene (lI2,4-trimethylbenzene) has been carefully studied, and the factors.affecting the relaxation times have been discussed in considerable detail (29) For polysubstituted benzenes, comparable effects are noted and the shorter T1 values for carbons para to substituents are often useful for assigning signals to specific carbons. The spin-lattice relaxation times (in seconds) for 3-nitrobiphenyl are shown in 227 (225). The 4- and 4'-carbons have the shortest T I values since

.

these lie on the preferred rotation axis. The T1 values for C-2, C-5, and C-6 are smaller than those for the corresponding carbons in the other ring (C-2' , C-3' 1, because of the slower internal rotation of the ring having the nitro substituent.

NANCY K.

WILSON AND J. B. STOTHERS

133

The T I f o r C-6, p a r a t o t h e n i t r o group, i s t h e s h o r t e s t of t h e s e values f o r carbons n o t l o c a t e d on t h e long a x i s of t h e molecule, i n d i c a t i n g some p r e f e r e n t i a l o v e r a l l r o t a t i o n about an a x i s through C-6 and t h e n i t r o group. Phenyl benzoate T v a l u e s (228) r e v e a l s i m i l a r r e l a t i o n s h i p s . The r a t i o Tl0 1 /TIP . i s g r e a t e r f o r t h e phenoxy r i n g than

m

This s u g g e s t s t h a t f o r t h e benzoyl group, 2.5 compared t o 2 . 1 . t h e r o t a t i o n a l b a r r i e r about t h e C6H5-0 bond is lower than t h a t about t h e CgHg-CO bond (225).

I n s e v e r a l heteroatomatic compounds, analogous 41 d i f f e r ences a r e e v i d e n t a s a r e s u l t of a n i s o t r o p i c tumbling. The compounds 2- and 3-methylthiophene (229 and 230) have t h e s p i n - l a t t i c e r e l a x a t i o n times shown, which imply t h a t carbons a c r o s s t h e r i n g from t h e s u b s t i t u e n t may experience reduced motion, although no C-H bonds l i e on t h e p r e f e r r e d r o t a t i o n a l a x i s along t h e s u b s t i t u e n t - r i n g bond. The Ti v a l u e s f o r t h e a-, B-, and y-carbons of p y r i d i n e ( 2 3 1 ) a r e 19.1, 18.2, and 17.0 s e c , r e s p e c t i v e l y , which may i n d i c a t e p r e f e r r e d r o t a t i o n about t h e

1b

18

20

229

230

231

c2 a x i s ( 2 2 5 ) . However, t h e y-Ck.H bond i s known t o be s h o r t e r than t h e o t h e r C-H bonds i n t h i s molecule. Because of t h e P - 6 dependence of d i p o l a r r e l a x a t i o n , a small d i f f e r e n c e i n bond l e n g t h can have a l a r g e e f f e c t on TI. Thus i n t h e s e c a s e s , i n t e r p r e t a t i o n s s o l e l y i n terms of a n i s o t r o p i c molecular motion must be made c a u t i o u s l y , p a r t i c u l a r l y i f t h e observed v a r i a t i o n s i n T I a r e small.

134

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

Several f e a t u r e s of molecular motion i n mescaline, 3 , 4 , 5 trimethoxyphenethylamine hydrochloride, a r e r e v e a l e d by 51 measurements (225). The r e l a x a t i o n times f o r t h i s compound a r e given i n 232. I f t h e motion of t h i s molecule were e n t i r e l y i s o t r o p i c , a s a r i g i d body, t h e s u b s t i t u e n t methyl and methylene carbons would e x h i b i t T1 v a l u e s of about 0.10 and 0.15 s e c ,

r e s p e c t i v e l y , s i n c e t h e s e would have t h e same 1/NT1 a s t h e r i n g carbons. [This was i l l u s t r a t e d e a r l i e r f o r c h o l e s t e r y l chlor i d e ( 9 ) , f o r which the same v a l u e of l/NT1 w a s obtained f o r a l l s k e l e t a l carbons.] However, t h e v a l u e s f o r t h e methylene carbons of 232 a r e somewhat longer t h a n expected f o r r i g i d tumbling, r e f l e c t i n g g r e a t e r motional freedom f o r t h e s e carbons than t h e r i n g carbons. The o u t e r methoxyl groups, a t t h e 3 and 5 p o s i t i o n s , a r e l e s s mobile than t h e 4-methoxyl, although a l l t h r e e methoxyl carbons have much g r e a t e r m o b i l i t y than t h e r i n g and methylene carbons. This i s similar t o t h e s i t u a t i o n i n p o l y s u b s t i t u t e d benzenes, such as i s o d u r e n e , which a r e d i s c u s s ed below. Molecules of t h i s s i z e r e l a x almost e n t i r e l y by t h e d i p o l a r mechanism, a s i s e v i d e n t from t h e e s s e n t i a l l y m a x i m u m Overhauser enhancements ( - 2 . 0 ) found f o r a l l r i n g carbons, both protonated and nonprotonated ( 2 2 5 ) , i n 232. Often hindrance t o r o t a t i o n i s m a n i f e s t i n t h e r e l a t i v e Ti v a l u e s f o r a molecule. Thus, i n dimethyldiphenylmethane (233) t h e methyl carbons have a very s h o r t T1 of 0.9 s e c , which contrasts markedly with t y p i c a l v a l u e s f o r f r e e l y r o t a t i n g methyl carbons of 16.3 s e c ( t o l u e n e ) and 9.3 and 9.8 s e c ( i s o o c t a n e ) ( 2 a ) . The r o t a t i o n of t h e methyl groups i n 233 must be r e l a -

233

135

NANCY K. WILSON AND J. B . STOTHERS

t i v e l y slow, s i n c e khe methyl T1 v a l u e i s s h o r t r e l a t i v e t o khe o t h e r v a l u e s f o r protonated carbons. I t i s p o s s i b l e t o calcul a t e energy b a r r i e r s f o r r o t a t i o n around s i n g l e bonds i n some c a s e s (29, 226). Relaxation o f t h e methyl carbons i n 0-xylene i s dominated by t h e d i p o l a r mechanism due t o t h e r o t a t i o n a l b a r r i e r of a b o u t 2 kcal/mole ( 2 9 ) . Hemimellitene ( l r 2 , 3 - t r i methylbenzene, 234) and isodurene (1,2,3,5-tetramethylbenzene, 2 3 5 ) have an a d d i t i o n a l s t r u c t u r a l f e a t u r e which a f f e c t s t h e r o t a t i o n r a t e s of t h e methyl a t t h e 2-position. Two e q u i v a l e n t

11s

CHI

M 1.P 11.5

234

235

low-energy conformers f o r t h e 2-methyl groups, 236a and 2 3 6 b , g i v e r i s e t o a s i x f o l d r o t a t i o n a l b a r r i e r . I n 2 3 6 a , t h e 3methyl i s i n a minimum energy conformation r e l a t i v e t o t h e 2methyl, a s i s t h e 1-methyl i n 236b; t h u s t h e s e have t h r e e f o l d b a r r i e r s o f about 1.5 t o 2 kcal/mole. The 1-methyl i n 236a and t h e 3-methyl i n 236b a l s o have t h r e e f o l d b a r r i e r s , b u t t h e s e b a r r i e r s should be considerably h i g h e r due t o t h e p r e f e r r e d o r i e n t a t i o n of t h e 2-methyl. The 2-methyl w i l l have t h e same

k

b 236

s i x f o l d b a r r i e r i n b o t h 236a and 23621, which w i l l b e low, a s i s c h a r a c t e r i s t i c f o r a s i x f o l d b a r r i e r , so s p i n n i n g of t h i s methyl w i l l be r e l a t i v e l y f r e e . The T I v a l u e s a t 25.1 MHz shown i n 234 and 235 confirm t h i s a n a l y s i s : from t h e s e v a l u e s , combined w i t h T1 measurements a t 15.1 MHz and n u c l e a r Overhauser enhancement d e t e r m i n a t i o n s , t h e r o t a t i o n a l b a r r i e r s were

136

STEREOCHEMICAL ASPECTS OF 13C NMR SPECTROSCOPY

calculated to be 1.45 kcal/mole for 234 and 1.55 kcal/mole for 235 (226). Calculation of barriers from T1 data for methyl group rotation in some additional systems in which the internal reorientation of the methyl is restricted--acetone, dimethylsulfoxide, methyl acetate, t-butyl chloride, and l,l,l-trichloroethane--has recently been effected (227). Relating T1 values to specific steric interactions is usually difficult, and often the data can be more readily related to the presence of conformational energy minima. Thus for 1-methylnaphthalene, T1 is -6 sec for the ring carbons and 5.8 sec for the methyl carbon. Here the peri proton hinders rapid rotation of the methyl group, so that the energetically favored conformer 237 is in a relatively deep potential well. In contrast, 9-methylanthracene ( 2 3 8 ) , with two peri protons to hinder rotation of the methyl group, has a ring carbon 91 of about 4 sec while for the methyl carbon, Ti = 14.0 sec. In this case the peri interactions cause strong ground-state compression, so that the barrier to rotation becomes relatively lower (22).

237

238

3C spin-lattice relaxation times have been measured for several substituted ferrocenes ( 2 3 9 ) and interpreted in terms of internal motions ( 2 2 8 ) . In these compounds, the two rings may spin independently of each other and of the overall isotropic tumbling. A substituent X will slow the rotation of the substituted ring (A), while allowing essentially free rotation of the unsubstituted ring (B). The relaxation times of ring B

239

NANCY K. WILSON AND J. B. STOTHERS

137

carbons should be approximately four times those of the protonated carbons in ring A if the spinning of ring B is infinitely fast. Tlratios of 2 for X = acetyl and 2.4 for X = n-butyl have been observed. These correspond to spinning ratios, for the unsubstituted ring relative to the substituted ring, of about 4 for acetylferrocene and about 7 for n-butylferrocene. In Table 34, spin-lattice relaxation times are listed for phenol both as a neat liquid and as an approximately 17 mole % solution in carbon tetrachloride. It is apparent that T1 values are much shorter in the neat liquid, which suggests that the relaxation times directly reflect the effects of molecular association, in this case primarily hydrogen bonding. The relaxation behavior of phenol and of aniline as a function of concentration in several solvents has been studied (225). Some of these data are listed in Table 35. Intermolecular association is evidenced by the relatively small magnitude of TI at Table 35. Spin-Lattice Relaxation Times of Some Aminesa Amine

Aniline

n-Butylamine

Solution

T I , sec

c-4

c-1

c-2

c-3

--

5.3 11.7 3.55 3.47 1.07

2.85 3.13 0.26

15.0 3.12 2.13

12.1 3.98 3.46

Neat 20% v/v in CCl4 20% v/v in DMSO-d6 10% v/v in D M S O - ~ ~ 20% v/v in CF3COOH

---

5.2 11.5 3.5 3.5 1.21

Neat 15.4% w/w in CF3COOH 28.2% w/w in CF3COOH

13.4 1.54 0.97

13.4 2.30 1.50

---

4.4

8.8

aFrom refs. 222 and 225. T1 values at 3 8 0 C I 25.2 MHz, measured on undergassed samples. high concentrations, as aggregation reduces the rate of molecuThe increased viscosity lar tumbling and thus increases Teff. of the concentrated solutions may also shorten T i . Upon dilution, a trend toward longer T1 is apparent. Anisotropic molecular motion as indicated by the T l o i r n / T l p ratio is especially pronounced for the anilinium ion, presumably as a result of restriction of movement by ion pairing and electrostatic interactions. This behavior is similar to that found for n-butyl-

138

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

amine (240), which upon protonation to the n-butylammonium ion exhibits a decrease in the size of T1 by a factor of approximately 13 for the a-carbon and approximately 3 for the &-carbon (the terminal methyl) (229). Additionally, in the ion,T1 increases along the chain from the a-carbon to the &-carbon, resulting from the motional restriction of the NH3' end of the chain by interaction with the solvent and ion pairing. In contrast, 240 exhibits instead a small decrease in T1 along the chain from C-1 to C-4, 13.4 to 12.1 sec; thus there is little segmental motion (or localized motion along the aliphatic chain). This is comparable to n-butanol (81, as noted in Sect. 11-C, although the overall molecular reorientation is somewhat faster in 240 than in 8, as is evident from its longer T1 values. Although 8 undergoes little segmental motion, the longer chain of 1-decanol (7) does, as shown by the increase of more than a factor of 7 in Teff from the CH20H to the CH3 carbon (page 11). A large degree of internal motion for the methyl group with progressively increased restriction of movement towardthehydroxyl end of the molecule is indicated. Since such large variations in 91 are not characteristic of straight-chain aliphatic hydrocarbons, it is apparent that these effects require some restriction of the overall motion of the molecule; that is, the measureable effect of segmental motion is greater when the overall molecular reorientation is slower (24). Aliphatic amides and oximes have been studied (25) to probe the internal motions of the different aliphatic groups. N,N-Di-n-butylformamide (241) has T1 values of 3.1, 2.3, 1.6, and 1.1 sec for C-4, C-3, C-2, and C-1, respectively. Although the total change from one end of the chain to the other is small, some degree of segmental motion is implied. Methyl ethyl ketoxime (242) exhibits differences in relaxation times for

241

the two configurations with the hydroxyl syn to the methyl, 242a, and anti, 242b. As noted earlier (page 24) , the 13C spectrum shows that these isomers are present in a 7 7 ~ 2 3ratio, with 242a favored. The Ti values clearly indicate a much greater spinning rate for the imino methyl in 242a than in 242b. In 242b, the imino methyl has available a minimum energy conformation, which reduces its tendency to rotate. However, the

NANCY K. WILSON AND J. B. STOTHERS

139

Ck,

in

b

a 242

imino methyl i n 242n has opposing s t e r i c i n t e r a c t i o n s , with t h e hydroxyl and with t h e methylene; t h u s no p a r t i c u l a r conformation of t h i s methyl is e n e r g e t i c a l l y favored, and methyl r o t a t i o n i n 242a i s more r a p i d . This i s similar t o t h e beh a v i o r of t h e methyl carbon i n 9-methylanthracene ( 2 3 8 ) d i s cussed p r e v i o u s l y . I n t e r n a l motions i n some polymeric substances have a l s o been i n v e s t i g a t e d . I n h i g h and low molecular weight polystyr e n e s , i t has been shown t h a t d i p o l e - d i p o l e i n t e r a c t i o n s are t h e predominant means o f r e l a x a t i o n , even f o r t h e q u a t e r n a r y phenyl carbons. Neither t h e Ti v a l u e s nor t h e n u c l e a r Overhauser enhancements depend on t h e t a c t i c i t y of t h e polymer (159a). For mnl.ecular weights above 1 0 , 0 0 0 , t h e measured TI v a l u e s f o r CH carbons a r e independent o f molecular weight, showing t h a t t h e e f f e c t i v e r o t a t i o n a l c o r r e l a t i o n t i m e i s determined p r i m a r i l y by segmental motion r a t h e r than o v e r a l l molecular r e o r i e n t a t i o n ( 2 3 0 ) . Although d i p o l a r i n t e r a c t i o n normally l e a d s t o e x t e n s i v e l i n e broadening i n nmr s p e c t r a of s o l i d s , h i g h - r e s o l u t i o n 3C s p e c t r a have been o b t a i n e d from some g e l s of high molecular weight polymers. I t i s suggested t h a t t h e segmental motion i n t h e s e polymer g e l s l e a d s t o a v e r a g i n g of t h e d i p o l a r i n t e r a c t i o n s u f f i c i e n t t o reduce carbon l i n e broadening s i g n i f i c a n t l y ( 1 5 8 ~ ) 3C s p i n - l a t t i c e r e l a x a t i o n t i m e s have a l s o been determined f o r a number of b i o l o g i c a l l y important molecules and macromolecules, w i t h t h e r e s u l t a n t p r o v i s i o n of d e t a i l e d informat i o n on t h e i r s t r u c t u r e and molecular motion. C h o l e s t e r y l c h l o r i d e ( 9 ) , which e x h i b i t s segmental motion a l o n g i t s s i d e c h a i n , has a l r e a d y been d i s c u s s e d (page 12 ) . Proton-decoupl e d F o u r i e r transform s p e c t r a o f s u c r o s e (207) and adenosine 5'-monophosphate ( 2 4 3 ) have a l s o been r e p o r t e d (23b); t h e r e l a x a t i o n t i m e s of 243 a r e shown i n t h e accompanying diagram. The o v e r a l l motion of s u c r o s e i n aqueous s o l u t i o n i s i s o t r o p i c ; although t h e accuracy of t h e Ti measurements i n t h i s case was i n s u f f i c i e n t t o allow d e t a 4 l e d i n t e r p r e t a t i o n i n terms of mole-

.

140

STEREOCHEMICAL ASPECTS OF

3C NMR SPECTROSCOPY

243

cular motion, the TI values indicate internal motion of the hydroxymethyl groups. For the protonated carbons in 243 the relaxation times show that the rotational correlation times differ for the sugar and base rings. Carbons of the sugar ring have longer T1 values than the protonated carbons of the base. The shorter Ti, and thus longer Teffr values for the base carbons suggest somewhat greater motional restriction for the base, possibly because of intermolecular base stacking (23b). The carbon spectra of some amino acids bound to cationic exchange resins have been obtained (231). Detection of the signals from 13C nuclei not directly bonded to protons was facilitated by the reductions in TI resulting from binding to the resin. High-resolution spectra were observed for these liquid-solid systems, which points out another distinct advantage of 1 3 over ~ 1~ mz. Several peptide hormones and their constituent peptides have been studied (Sect. 111-F), and T1 measurements have been made for some of these (232). The helix-coil transition in poly-L-lysine was studied as a function of pH. A precipitous drop in TI, from 1.15 to 0.15 sec, was found for the carbonyl carbon upon helix formation, while T1 for the €-carbon changed from 0.58 to 0.2 sec. Other carbons exhibited smaller changes. This is in agreement with the expected decrease in conformational mobility, and thus increased Teff values with helix formation. The typical shielding changes accompanying the helix-coil transition, which were discussed earlier (page 921, were also observed for both poly-L-lysine and dodecalysine, (Llys)l2. The Ti values for the latter, however, showed no significant dependence on pH, thus indicating that no helical structure of (L-lys)lz is formed. This finding clearly demonstrates that shielding changes of oligopeptides induced by pH variations

NANCY K. WILSON AND J. B. STOTHERS

141

must be interpreted cautiously. The helix-coil transition of poly-(y-benzyl-L-glutmate) (248) was investigated (167) by 13C nmr and the T1 values determined for the helix form. Changes in carbon shieldings associated with this transition have been discussed previously (page 92). For the a-, $-, and y-carbons of 148, T1 is 0.03 sec; for the benzylic carbon, 0.10; the aromatic C-2,-6, 0.81; aromatic c-1, 3.3; the ester C=O, 1.93; and the amide C=O, 0.9 sec at a concentration of 30% w/v in 3% trifluoroacetic acid in CDC13. Thus it is clear that there is considerable motional restriction, which is especially pronounced for the a - , f33, and y-carbons, and is somewhat smaller for the benzylic and aromatic carbons. The relaxation times of histidine residues of the a subunit of tryptophan synthetase, specifically enriched in 3C and deuterated at C-2, have been measured and correlated with motional reorientation of the C-2 carbons. The results indicated that the imidazole side chains of the polypeptide are highly immobilized (233). Segmental motion and the conformation of native (244) and denatured (245) ribonuclease A have been examined by Allerhand et al. (26). Some T I values for the protonated carbons and rotational correlation times are given in Table 36. The a-carbon correlation time of 244 is characteristic of carbons on the

'

Table 36. Some 3C Spin-Lattice Relaxation and Rotational Correlation Timesa in Aqueous Ribonuclease A (26) Type of Carbon

24qb 7'1,

Carbonyls a-Carbons $-Carbons, Thr Rigid side chainsd E-Carbons, Lys

msec

416 42 -40 -30 330

245'

T ~ nsec ,

Ti, msec

--

539 120

30

- 30-0.070

TR,

nsec

--

99

--

0.40 0.48

306

0.076

--

aObtained for 0.019 M protein at 45' and 15.08 MHz. The Ti values have an estimated maximum error of +30%. $H 6.51. CpH 1.64. dBecause of the broad signal component in the region 6, 8-45, Ti is an estimate of the average value.

and

T

142

STEREOCHEMICAL ASPECTS OF

3C NMR

SPECTROSCOPY

protein backbone. Segmental motion of the side chains occurs to some extent, as shown by the T1 of -30 msec for the carbons of the threonine residues and the rigid side chains. Other carbons have much greater mobility; the relatively long T1 of the E-carbons in the lysine residues is an example. In 245 the Ti values for the a-carbons are much longer than in 244, indicating greater segmental motion of the backbone of the denatured protein. The lysine E-carbons do not appear to be significantly affected by denaturation. Proton-aecoupled 3~ spectra of aqueous unfractionated yeast transfer-RNA were observed in the presence of Mg2+ ions over the temperature range 27 to 82OC (234). At 82OC, tRNA is in the thermally denatured unfolded conformation, and its 1 3 C spectrum exhibits numerous sharp resonances, which were assigned to specific types of carbon atoms by comparison of the 13C shieldings with those of the mononucleotides of the four common bases (146a). The shieldings of folded tRNA, at 52OC, are very similar to those of the unfolded form, with the exception of the 4'-carbons, which are shifted upfield by 1.5 ppm, and the 2'- and 3'-carbons, which give only a single resonance at 8OoC in the unfolded form but are partly resolved at 5 2 O C . These changes apparently are associated with the conformational change on folding, but detailed interpretations are not yet possible. Many resonances of folded tRNA are broader than those of the unfolded species, and, as the temperature is decreased from 52 to 27'C, these signals become broader still, with loss of some of the fine structure of the spectrum. Dilution tends to reduce the broadening, which suggests that it is due to chemical shift nonequivalence produced by aggregation. The fact that the broadening is gradual over the entire temperature range rather than relatively abrupt as unfolding occurs at about 70 to 82OC indicates that the conformational change is not primarily responsible for the variations in line widths. The spin-lattice relaxation times for protonated carbons in this system were also determined as a function of temperature. At each temperature, carbons of the ribose rings have the same Ti, while T1 for the methylene carbon, C - 5 ' , is approximately half that of the methines. Thus all carbons in the ribose rings have the same Teff. Below 60°C, the T1 values are independent of temperature and are consistent with an effective rotational correlation time of 3 x 10-8 sec for the backbone of folded tRNA which does not undergo segmental motion. The T1 changes with temperature reflect the expected denaturation behavior, and at 81OC give Teff = 2.5 x 10-l' sec far the ribose carbons, indicating rapid segmental motion of the molecular backbone. Conformational changes in normal human and rabbit hemoglobins have been examined (235). The apparent differences between the various forms of hemoglobin have been interpreted on

NANCY K. WILSON AND J. B. STOTHERS

143

the basis of nearly identical quaternary conformations for the tetramer, and variable tertiary structures for the ci and $ subunits. In solution, rabbit hemoglobins appear to be more mobile than human hemoglobins. Metcalfe and co-workers have reported several studies of 3C spin-lattice relaxation in lecithin vesicles (236-238) Preliminary measurements on dipalmitoyllecithin ( 2 4 6 ) in aqueous suspension showed that motion of the lipid chains increases “262

.

toward the terminal methyl group. A longer T l ( 0 . 5 7 sec) for the N(CI-I3)3 carbons in the bilayer structure in water indicates relatively free motion, whereas in CDC13, micelle formation restricts this motion and results in a shorter 7’1 (0.19 sec) (236). The 7‘1 values given for 246 were measured for lecithin bilayers above the thermal transition temperature. Molecular motion increases toward both the terminal methyl of the side chain and toward the polar -N+(CH3)3 head group, and the lecithin is least mobile at the glycerol carbons. The temperature dependence of T1 showed a well-defined inflection at the phase transition. Similar T1 trends were observed for several other 13C Ti values predicted for a number of physlecithins ( 2 3 7 ) . ically reasonable models for the motion of the lecithin hydrocarbon chains were compared with the experimental data ( 2 3 8 ) . Three types of motion were considered: tumbling of the molecule about its long axis, isotropic tumbling of the vesicle as a whole, and motion about individual carbon-carbon bonds in the fatty acid side chains. The first two types of motion by themselves d o not explain the inequality of T I values along the chains. With motion about C-C bonds, the effects of the other types of motion become unimportant except for the first carbon in the chain, if their correlation times are greater than lo-’ sec. The correlation times derived (less than or equal to 10-l’ sec) indicate that the motion involved is oscillatory, rather than a rotational motion involving conformational change. Calculated values and the experimental data agree well for a model in which t.here is little decrease in correlation time in the first part of the chain, with a sharp decrease toward the terminal methyl.

STEFEOCHFMICAL ASPECTS OF

144

C.

3C NMR SPECTROSCOPY

Proton-Enhanced Nuclear I n d u c t i o n Spectroscopy

Waugh and his co-workers have developed an impressive technique (239) for enhancement of the resonances of rare nuclei in solids which can afford insight into some aspects of molecular motion. This technique, proton-enhanced nuclear induction spectroscopy, has been employed for the determination of 13C shielding anisotropies in a large number of simple organic solids (240). The shapes of the spectra obtained by this technique are sensitive to molecular motion, since each portion of the spectrum corresponds to molecules with a particular orientation. Motions about different symmetry axes of a molecule such as hexamethylbenzene can be clearly distinguished by their effects on the spectra. By this means anisotropic 13C spin-lattice relaxation in benzene, expected because of preferred rotation about the Cg axis, has been observed (241). It is to be noted that the relaxation is dominated by intramolecular interactions; thus the results relate to the orientation of a single molecule. Although there have been few applications of this method so far, its use will undoubtedly expand in the future, both because of its relative simplicity, and because it allows extraction of information about molecular properties which is inaccessible by other methods.

V.

SUMMARY AND PROGNOSIS

Throughout this chapter we have attempted to illustrate the potential of 13C nmr as a stereochemical tool. Although, compared with the commonplace usage of 'H techniques for solving questions of stereochemistry, the 3C approach has been underexploited, the principal obstacle has been eliminated with the development of better instrumentation. Further improvements can be anticipated, for example, in the data processing hardware and software, but current spectrometers are capable of generating a wealth of information from a wide variety of systems. There still remain many families of compounds which have yet to be examined in any detail but, on the basis of the available results, one can safely assume that their 13C spectra will be informative and useful. Understandably, the majority of the available data has been obtained for relatively small molecules and the trends exhibited by both the shieldings and coupling constants are understood only in an empirical fashion. It is to be hoped that theoretical interpretations can be improved to the point that meaningful predictions become possible. At present, the effects produced in a hydrocarbon skeleton by the introduction of a substituent appear to follow a well-defined pattern for the closely neighboring a-, 8-, and y-carbons, but the origin of

NANCY K. WILSON AND J. B. STOTHERS

145

these shifts has not been satisfactorily explained. Nevertheless, the y effects will continue to be valuable stereochemical probes. Much more recently it has been recognized that variations in 6 effects also reflect molecular geometry but relatively few data for well-defined model systems are available. Presumably this void may receive more attention. Although it has been established that 3C shieldings exhibit significant solvent effects, very few detailed studies of solute-solvent associations have been reported. It is abundantly clear that 13C shieldings and coupling constants are remarkably sensitive to molecular geometry and, therefore, to the specific conformation(s) of a given system. An improved understanding of the origins of the smaller variations in 13C parameters will undoubtedly lead to more sophisticated applications. For example, the number of well-resolved 13C spectra of highly complex compounds has established these as potentially rich sources of structural information. The very real advantages of 13C techniques over 'H examinations of high molecular weight systems, delineated previously, render 3C studies particularly attractive for materials of biological interest. As noted several times in the earlier discussion, full interpretations of these complex spectra require a much better understanding of the factors governing 3C shieldings. Significant variations, however, have been found for a number of large molecules which apparently arise from conformational alterations. These observations presumably will spur concerted activity with model systems in efforts to account for the changes. From the remarkable success of proton techniques for the collection of kinetic data in a host of systems it is easy to predict that analogous 13C studies will be valuable. There seem to be several advantages for 13C techniques. The inherently simpler 13C spectra are, in principle, more readily analyzed since in the vast majority of cases the first-order spectra require only careful line-width measurements. The relatively large shielding range also provides data over a wide temperature range, and, in fact, the range may be different from that over which the 'H spectrum undergoes its characteristic variation with exchange rate. Perhaps the most important single feature, however, is the fact that, in general, measurements will be possible for several exchanging centers in the same molecule. For protons, one is often limited to measurements of the absorption pattern of a single nucleus or group of equivalent nuclei. Furthermore, since the various centers undergoing exchange in the 13C spectra will tend to have different degrees of nonequivalence there may be several individual coalescence temperatures for different nuclei in the same molecule. In such cases, the temperature dependence of

146

STEREOCHEMICAL ASPECTS OF

'3C

NMR SPECTROSCOPY

the rate constant is very easily determined with reasonable precision. In any event techniques have extended the scope of kinetic studies by nmr to several systems which are not readily examined by other methods, as was illustrated for some medium and large ring cycloalkanes in Sect. IV. Undoubtedly, there will be considerable activity in this area of 13C nmr. Their relative simplicity renders spectra particularly suitable for relaxation time measurements, and pulse techniques provide a straightforward means for T1 determinations. The relatively recent, but intensive work on this parameter as a probe for assessing molecular motion has clearly established the utility of Ti values as a structural tool, thereby significantly expanding the total information provided by 3C studies. Knowledge of the relative motions of various portions of a given structure can shed light on the preferred conformation of the system. Relaxation time data can also be utilized to aid an assessment of specific intermolecular associations or complexation, thus providing a more detailed view of solvation phenomena. By any standards, the future of 13C nmr as a powerful structural tool seems assured. For stereochemical problems, it has the potential not only of providing unequivocal means for distinguishing s ecific configurations but there are clear indications that lPC parameters will permit detailed conformationa1 analysis of relatively complex systems. Ho efully, the foregoing discussions of the major areas in which p3C techniques have been established will spur activity in some of the unexplored and heretofore neglected areas as well as encourage efforts to improve our understanding of current observations through the examination of suitable model systems.

'

ACKNOWLEDGMENTS We wish to thank Professors F. A. L. Anet, A . J. Jones, G. Kotowycz, S. Masamune, A. S. Perlin, and J. D. Roberts, and Drs. G. A. Gray, G. C. Levy, and I. C. P. Smith for kindly providing manuscripts before publication. We acknowledge support, by the National Research Council of Canada, of the research cited herein which was carried out at the University of Western Ontario. We are grateful to Mrs. Sheila Collard for her careful preparation of the manuscript.

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NANCY K. WILSON AND J. B. STOTHERS

147

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STEREOCHEMICAL ASPECTS OF 13C NMR SPECTROSCOPY

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40. 41. 42. 43.

44.

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150 59.

60. 61. 62. 63. 64. 65.

66. 67. 68.

69.

70. 71. 72. 73.

74. 75. 76, 77. 78. 79. 80.

--

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111. 112. 113. 114. 115.

116.

117. 118.

119. 120.

121. 122. 123.

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3C NMR SPECTROSCOPY

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,

,

,

,

,

,

c.

,

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E. Wenkert, C.-J. Chang, D. W. Cochran, and R. Pellicciari,

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.

154 140. 141. 142. 143. 144.

145. 146.

147.

148.

149. 150. 151. 152. 153. 154. 155. 156. 157. 158.

STEREOCHEMICAL ASPECTS OF

3 C NMR SPECTROSCOPY

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171a. 172. 173. 174. 175. 176. 177. 178. 179.

155

(a) J. Schaefer and D. F. S. Natusch, Macromolecules, 5, 416 (1972); (b) D. M. White and G. C. Levy, i b i d . , 5, 526 (1972). V. Glushko, P. J. Lawson, and F. R. N. Gurd, J . BioZ. Chem. , 2 4 7 , 3176 (1972). W. A. Gibbons, J. A. Sogn, A. Stern, L. C. Craig, and L. F. Johnson, Nature, 2 2 7 , 840 (1970). M. Christ1 and J. D. Roberts, J . Arner. Chern. SOC. , 9 4 , 4565 (1972). W. A. Thomas and M. K. Williams, J . C. S . Chem. C o m n . , 1972 , 994. R. Deslauriers, R. Walter, and I. C. P. Smith, Biochern. Biophys. Res. C o m n . , 4 8 , 854 (1972). I. C. P. Smith, R. Deslauriers, and R. Walter, in Cherni s t r y and Biology of Peptides, J. Meienhofer, Ed., Ann Arbor Sci., Michigan, in press (1972). M. Ohnishi, M. C. Fedarko, J. D. Baldeschwieler, and L. F. Johnson, Biochern. Biophys. Res. Comun. , 4 6 , 312 (1972). L. Paolillo, T. Tancredi, P. A. Temussi, E. Trivellone, E. M. Bradbury, and C. Crane-Robinson, J . C. S. Chern. C o m n . , 1 9 7 2 , 335. G. Boccalon, A. S. Verdini, and G. Giacometti, J . Arner. Chern. SOC. , 9 4 , 3639 (1972). F. A. Cotton, A . Danti, J. S. Waugh, and R. W. Fessenden, J . Chern. Phys. , 2 9 , 1427 (1958). B. E. Mann, Chem. C o m n . , 1 9 7 1 , 1173. 0 . A. Gansow and B. Y. Kirnura, Chern. Commun. , 1 9 7 0 , 1621; L. F. Farnell, E. W. Randall, and E. Rosenberg, i b i d . , 1 9 7 1 , 1078; 0 . A. Gansow, B. Y. Kimura, G. R. Dobson, and R. A. Brown, J . h e r . Chem. soc. , 9 3 , 5922 (1971). Cf. A. Pidcock, R. E. Richards, and L. M. Venazi, J . Chern. SOC. ( A ) , 1 9 6 6 , 1707; T. G . Appleton, H. C. Clark, and L. E. Manzer, Coord. Chem. Rev. , 1 0 , 335 (1973). M. H. Chisholm, H. C. Clark, L. E. Manzer, and J. B. Stothers, Chem. C o m n . , 1 9 7 1 , 1627. K. R. Aris, V. Aris, and J. M. Brown, J . Organomet. Chem. , 4 2 , C67 (1972). G. M. Whitesides and G. Maglio, J . Amer. Chem. s o c . , 9 1 , 4980 (1969). A. J. Cheney, B. E. Mann, and B. L. Shaw, Chem. C o m n . , 1971 , 431. B. E. Mann, B. L. Shaw, and R. E. Stainbank, J . c. s. Chem. C o m n . , 1 9 7 2 , 151. D. Doddrell and A. Allerhand, Chem Commun., 1 9 7 1 , 728. D. Doddrell and A. Allerhand, Proc. Natl. Acad. sci. u. s. , 68, 1083 (1971). F. R. Jensen, C. H. Bushweller, and B. H. Beck, J . Amer. Chern. SO C., 91 , 344 (1969).

156 180. 181. 182. 183. 184. 185. 186.

187. 188. 189. 190.

191. 192. 193. 194. 195. 196. 197. 198. 199. 200.

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3C NMR SPECTROSCOPY

C. S. Johnson, Jr., Advan. Magn. Resomnce, 1 , 33 (1965). See also ref. 49a. T. Drakenberg, K.-I. Dahlqvist, and S. Forsen, Acta Chem, Scand. , 2 4 , 694 (1970). J. Feeney, G. A. Newman, and P. J. S. Pauwels, J. Chem. SOC. ( C ) , 1 9 7 0 , 1842. P. Joseph-Nathan, M. P. Gonzalez, L. F. Johnson, and J. N. Shzolery, Org. Magn. Resomnce, 3 , 23 (1971). H. Gunther, B. D. Tunggal, M. Regitz, H. Scherer, and T. Keller, Angew. Chem. I n t . E d . , 1 0 , 563 (1971). C. F. Brewer, H. Sternlicht, D. M. Marcus, and A . P. Grollman, Proc. NatZ. Acad. Sci. U.S., 7 0 , 1007 (1973). (a) J. J. Katz, T. R. Janson, A. G. Kostka, R. A. Uphaus, and G. L. Closs, J . Amer. Chern. Soc. , 9 4 , 2883 (1972); (b) K. Ballschmiter, K. Truesdell, and J. J. Katz, Biochem. Biophys. A ct a, 1 8 4 , 604 (1969). 0 . A. Gansow, J. Killough, and A. R. Burke, J . Amer. Chem. SGC. , 9 3 , 4297 (1971). R. Price, G. Schilling, L. Ernst, and A . Mannschreck, Tetrahedron L e t t . , 1 9 7 2 , 1689. E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, ConformationaZ A n al y s i s , Interscience, New York, 1965. H.-J. Schneider, R. Price, and T. Keller, Angew. Chem. , I n t . Ed. , 1 0 , 730 (1971). H . 4 . Schneider, J . Amer. Chem. SGC. , 9 4 , 3636 (1972). D. Doddrell, C. Charrier, and J. D. Roberts, &oc. NatZ. Acad. S c i . U. S . , 6 7 , 1649 (1970). G. A. Olah, J. R. DeMember, C. Y. Lui, and R. D. Porter, J. Amer. Chern. SGC. , 9 3 , 1442 (1971). D. K. Dalling, D. M. Grant, and L. F. Johnson, J . h e r . Chem. SOC. , 9 3 , 3678 (1971). F. A. L. Anet and A. J. R. Bourn, J . Am@. Chern. SOC. , 8 9 , 760 (1967). D. Doddrell, C. Charrier, B. L. Hawkins, W. 0. Crain. J r . , L. Harris, and J. D. Roberts, Proc. N a t l . Acad. Sci. U. S. , 6 7 , 1588 (1970). W. €3. Farnham, J . h e r . Chern. SOC., 9 4 , 6857 (1972). 0 . Yamamoto, M. Yanagisawa, K. Hayamizu, and G. Kotowycz, J . Map. Res. , 9 , 216 (1973). R. H. Levin, J. D. Roberts, H. Kwart, and F. Walls, J . Amer. Chern. SOC. , 9 4 , 6856 (1972). F. A. L. Anet and J. J. Wagner, J . Amer. Chern. Soc. , 9 3 , 5266 (1971). F. A. L. Anet, A. K. Cheng, and J. J. Wagner, J . Amer. Chern. SOC. , 9 4 , 9250 (1972). F. A. L. Anet and P. J. Degen, Tetrahedron L e t t . , 1 9 7 2 , 3613.

NANCY K.

203. 204. 205.

206.

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3C NMR SPECTROSCOPY

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3213 (1972). 228. G. C. Levy, Tetrahedron L e t t . , 1 9 7 2 , 3709. 229. G. C. Levy, J . C. S. Chem C o m n , , 1 9 7 2 , 768. 230. A. Allerhand and R. K. Hailstone, J . C b m . Phys. , 5 6 , 3718 (1972). 231. H. Sternlicht, G. L. Kenyon, E. L. Packer, and J. Sinclair, J . h e r . Chem. SOC. , 9 3 , 199 (1971). 232. I. C. P. Smith, R. Deslauriers, R. W. Walter, C. GarrigouLagrange, H. McGregor, and D. Sarantakis, International Conference on ESR and NMR in Biology and Medicine, New York, N. Y., December 1972. 233. D. T. Browne, G. L. Kenyon, E. L. Packer, H. Sternlicht, and D. M. Wilson, J . h e r . Chem. SOC., 9 5 , 1316 (1973); D. T. Browne, G. L. Kenyon, E. L. Packer, D. M. Wilson, and H. Sternlicht, Biochem. Biophys. Res. C o m n . , 5 0 , 42 (1973). 234. R. A. Komoroski and A. Allerhand, €?roc. NatZ. Acad. S c i . u. s. , 6 9 , 1804 (1972). 235. R. B. Moon and J. H. Richards, €?roc. NatZ. Acad. Sci. U. S. I 6 9 , 2193 (1972). 236. J. C. Metcalfe, N. J. M. Birdsall, J. Feeney, A. G. Lee, Y. K. Levine, and P. Partington, Nature, 2 3 3 , 199 (1971). 237. Y. K. Levine, N. J. M. Biidsall, A. G. Lee, and J. C. Metcalfe, Biochemistry, 11 , 1416 (1972). 238. Y. K. Levine, P. Partington, G. C. K. Roberts, N. J. M. Birdshall, A. G. Lee, and J. C. Metealfe, FEBS L e t t . , 23, 203 (1972). 239. A. Pines, M. G. Gibby, and J. S. Waugh, J . Chem. Phys. , 5 6 , 1776 (1972). 240. A. Pines, M. G. Gibby, and J. S. Waugh, Chem. Phy6. L e t t . , 2 5 , 373 (1972). 241. M. G. Gibby, A. Pines, and J. S. Waugh, Chem. Phys. L e t t . , 1 6 , 296 (1972).

THE TORSION ANGLE CONCEPT I N CONFORMATIONAL ANALYSIS ROBERT BUCOURT

Centre de Recherches Roussel-UcZaf

Paris. France

.

.................... 160 I 1. The T o r s i o n Angle Concept . . . . . . . . . . . . . 161 A . D e f i n i t i o n . . . . . . . . . . . . . . . . . . . 161 B . D e s c r i p t i o n o f Ring Geometry . . . . . . . . . . 162 I11. Monocyclic Molecules . . . . . . . . . . . . . . . . 165 A . Cyclohexane and Cyclohexanone . . . . . . . . . . 165 1 . C h a i r Form and I t s Deformations . . . . . . 165 2 . F1e x i b l e Form . . . . . . . . . . . . . . . 173 3 . I n v e r s i o n . . . . . . . . . . . . . . . . . 176 B . Cycl ohexene . . . . . . . . . . . . . . . . . . 183 C . Small Rings . . . . . . . . . . . . . . . . . . 187 D . Medium Rings . . . . . . . . . . . . . . . . . . 189 I V . Pol ycyc 1 ic Mol ecu 1es . . . . . . . . . . . . . . . . 192 A . S t e r i c R e l a t i o n s h i p s a t a Ring J u n c t i o n . . . . 192 1 . t r a n s Fusion . . . . . . . . . . . . . . . . 192 2 . c i s Fusion . . . . . . . . . . . . . . . . . 194 3 . Q u a s i - t r a n s and Q u a s i - c i s Fusions . . . . . 195 B . Conformation o f P o l y c y c l i c Molecules . . . . . . 198 I

Introduction

159

Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

160

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

.............

1.

Steroid Structures

2.

Application t o Structure-Activity Relationship

................ V . Conf orma t iona 1 Tra nsm is s ion . . . . . . . . . . . . A. Octahydronaphthal ene Compounds . . . . . . . . . 1 . t r a n s Fusion . . . . . . . . . . . . . . . . 2. c i s Fusion . . . . . . . . . . . . . . . . . B. Hexahydronaphthalene Compounds . . . . . . . . . C. Hydrindane Compounds . . . . . . . . . . . . . . VI. C o n t r i b u t i o n s f r o m X-Ray A n a l y s i s . . . . . . . . . VII. Conclusion . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . I.

198 203 205 205 205 207 209 21 2 215 218 21 9

INTRODUCTION

The t o r s i o n angle concept was f i r s t introduced t o organic chemistry i n 1960 by Klyne and Prelog (1) t o supply a p r e c i s e d e s c r i p t i o n of s t e r i c r e l a t i o n s h i p s a c r o s s s i n g l e bonds and t o provide a p a r t i c u l a r l y convenient t o o l f o r d e f i n i n g r i n g geomet r y . This chapter e x p l a i n s how t h e a p p l i c a t i o n of t h i s concept t o conformational a n a l y s i s has l e d t o t h e formulation of severa l r u l e s concerning: ( a ) r i n g conformations and deformations and t h e i r e f f e c t upon i n t e r a c t i o n s , and ( b ) geometry a t a r i n g j u n c t i o n and transmission of deformations. These r u l e s cons t i t u t e a convenient method f o r t h e study of t h e stereochemist r y of c y c l i c and p o l y c y c l i c molecules s i n c e a l l t h e conformat i o n s a molecule might adopt can be determined i n a very l o g i c a l way and e a s i l y t r a n s c r i b e d onto paper. Typical examples of t h e i r a p p l i c a t i o n a r e found i n : an improved, f a c i l e study of r i n g i n v e r s i o n ( 2 ) ; a c l e a r l y defined a n a l y s i s of t h e geometry of p o l y c y c l i c molecules, p a r t i c u l a r l y i n t h e complex case of a c i s f u s i o n ( 3 ) ; and t h e e l u c i d a t i o n of t h e phenomenon of conformational transmission ( 4 , 5 ) .

161

ROBERT BUCOURT

11.

THE TORSION ANGLE CONCEPT A.

Definition

Although a l r e a d y d i s c u s s e d by E l i e l , A l l i n g e r , Angyal, and Morrison ( 6 ) , and more r e c e n t l y i n Volume 4 of t h i s s e r i e s ( 7 ) , t h e t o r s i o n a n g l e concept i s analyzed i n some d e t a i l as i t i s e s s e n t i a l t o t h e understanding of t h i s c h a p t e r . Torsion a n g l e and d i h e d r a l a n g l e a r e two synonymous terms commonly used t o denote t h e a n g l e which c h a r a c t e r i z e s t h e s t e r i c r e l a t i o n s h i p between two v i c i n a l bonds i n a molecule. A system of t h r e e consecutive bonds a , b, C (see p e r s p e c t i v e view i n Fig. 1) d e f i n e s two h a l f - p l a n e s a, b and b, C i n t e r s e c t i n g along t h e c e n t r a l bond b. They form a f i g u r e known i n geometry a s a dihedron, from which i s o b t a i n e d t h e e x p r e s s i o n " d i h e d r a l angle" employed i n chemistry. The v a l u e of t h i s a n g l e g i v e s an a c c u r a t e e v a l u a t i o n of t h e r e l a t i v e p o s i t i o n s of t h e v i c i n a l bonds U and C.

el---o r torson ongle PerSDectlve

c V,ew from

V,ew from c side

D side

10r610"

"New

onp1.I

Newrnon projection

Fig. 1.

Dihedral o r t o r s i o n angle.

A r e p r e s e n t a t i o n of t h r e e c o n s e c u t i v e bonds more f a m i l i a r t o t h e o r g a n i c chemist i s g i v e n by t h e Neman p r o j e c t i o n (Fig. l), which i s obtained i n a p l a n e p e r p e n d i c u l a r t o t h e c e n t r a l bond b . The a n g l e made by t h e p r o j e c t i o n s o f t h e v i c i n a l bonds i n t h i s p l a n e i s t h e d i h e d r a l a n g l e , o r , more

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

162

a p p r o p r i a t e l y , " t o r s i o n angle." Despite t h e f a c t t h a t t h e two expressions a r e o f t e n used interchangeably, t h e term " t o r s i o n angle" i s considered p r e f e r a b l e a s being more p r e c i s e . I t r e f e r s s p e c i f i c a l l y t o t h e d i h e d r a l angle made by three cons e c u t i v e bonds, whereas t h e r e a r e many o t h e r types of d i h e d r a l angles which can be considered i n a molecule, such a s , f o r example, between " b e s t " p l a n e s encountered i n c r y s t a l l o g r a p h i c studies ( 8 ) . A s shown i n t h e Newman p r o j e c t i o n of Figure 1, t h e angle i s p o s i t i v e i f t h e d i r e c t i o n of r o t a t i o n which superimposes t h e f r o n t bond on t h e r e a r bond i s clockwise, and negative i f a n t i clockwise. The same s i g n i s obtained from whichever s i d e t h e system of t h r e e bonds i s viewed (a s i d e or c s i d e i n t h e f i g u r e ) . The smaller of t h e two p o s s i b l e t o r s i o n a n g l e s defined by t h e system i s u s u a l l y chosen. The atoms l i n k e d by t h e cent r a l bond b can be 8 p 3 or sp2 hybridized carbon atoms a s w e l l a s heteroatoms.

B.

Description o f Ring Geometry

The t o r s i o n angles of a c y c l e a r e those determined by each group of t h r e e consecutive bonds forming t h e c y c l e a s , f o r example, t h e bonds a , b , and C i n t h e cyclohexane molecule of Figure 2a. To d e s i g n a t e a t o r s i o n angle we can name, i n succ e s s i o n , t h e t h r e e bonds o r t h e four connected atoms and w r i t e When t h e r e i s no ambiguity, only t h e posi0a,b,c Or ' x , y , Z , u . t i o n of t h e c e n t r a l bond need be i n d i c a t e d : ab o r 0 This means Ob i s t h e t o r s i o n angle r e l a t e d t o t h e bond b.

Fig. 2.

Y,Z'

It is

Designation of t o r s i o n angles.

o f t e n u s e f u l t o know t h e p o s i t i o n of one t o r s i o n angle w i t h r e s p e c t t o another i n t h e r i n g , independently of t h e e x i s t i n g numbering given by nomenclature. The r e l a t i v e p o s i t i o n s of t h e c e n t r a l bonds of t h e two t o r s i o n angles a r e then denoted by two numbers, j u s t a s f o r t h e r e c i p r o c a l arrangement of two double bonds i n an unsaturated carbon chain. For example, t h e

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t o r s i o n a n g l e s Ob and Od of Figure 2b a r e i n t h e 1,3 p o s i t i o n , t h e d i r e c t i o n of numbering being chosen so a s t o minimize t h e value of t h e second number. A s w i l l be seen i n t h e following paragraphs, t h e e x a c t d e s c r i p t i o n of t h e geometry of a r i n g i s given by t h e sequence of t h e a l g e b r a i c v a l u e s of i t s t o r s i o n angles. On t h e p l a n a r r e p r e s e n t a t i o n , t h e s e v a l u e s a r e w r i t t e n along each c e n t r a l bond. The information contained i n such a sequence i s both q u a l i t a t i v e and q u a n t i t a t i v e : The simple sequence of t h e s i g n s of t h e t o r s i o n angles i n d i c a t e s t h e t y p e of conformation; t h e a b s o l u t e v a l u e s of t h e t o r s i o n angles allow t h e deformation with r e s p e c t t o a r e f e r e n c e conformation t o be estimated. For example, t h e sum of t h e a b s o l u t e v a l u e s of t h e t o r s i o n a n g l e s of a r i n g may be taken a s a r e l a t i v e measure of t h e puckering o r f l a t t e n i n g of a deformed conformation: t h e g r e a t e r t h e sum t h e g r e a t e r t h e puckering, and conversely, t h e smaller t h e sum t h e g r e a t e r t h e f l a t t e n i n g . Such a sum may a l s o be c a l c u l a t e d f o r j u s t p a r t of a r i n g , t h e same r u l e applying t o t h e estimat i o n of t h e puckering o r f l a t t e n i n g of t h e p a r t under conside r a t i o n . But more p r e c i s e information may be obtained on a p a r t i c u l a r r e g i o n o r s i t e of a r i n g ( 3 ) a s follows: Let u s consider t h e system of f o u r consecutive bonds shown i n Figure 3a which form p a r t of a r i n g and suppose w e wish t o know t h e shape of t h e r i n g i n t h e r e g i o n of A i and t h e o r i e n t a t i o n of a p o s s i b l e a x i a l s u b s t i t u e n t on A;." Following t h e sequence of t h e t o r s i o n a n g l e s of t h e r i n g , i n a clockwise d i r e c t i o n , we note t h e a l g e b r a i c v a l u e Q and 9 ' of t h e t o r s i o n angles which precede and follow A i l r e s p e c t i v e l y . When t h e difference 9 Q' equals zero o r i s very small

-

Q

-

Q' = 0 ( o r :0 )

t h e r i n g atom A i l i e s i n t h e mean plane? defined by t h e f i v e r i n g atoms A i - 2 , A i - 1 , A i , A i + l , and A i + 2 and i t s two subs t i t u e n t s a r e symmetrically p o s i t i o n e d ( e q u a l l y i n c l i n e d ) above and below t h i s plane: they a r e c a l l e d b i s e c t i o n a l o r i s o c l i n a l . The shape of t h i s r i n g r e g i o n i s shown i n Figure 3b. *We assume t h a t A< i s a t e t r a g o n a l atom bearing two subs t i t u e n t s . I t could a l s o be a nonplanar t r i g o n a l atom such a s t h e n i t r o g e n atom, t h e lone p a i r being considered a s a substituent. +The mean plane i s t h e l e a s t squares plane through t h e f i v e r i n g atoms A{-2, A i - 1 , A i l A i + l , A i + 2 , a l s o c a l l e d "best" plane by c r y s t a l l o g r a p h e r s ( 9 ) . *The e d i t o r s p r e f e r t h e term i s o c l i n a l ( c f . t h e f o o t n o t e on page 236, Chapter 3 ) b u t both terms a r e i n use.

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Ai-2-Ai-l

Fig. 3. angles.

Geometry a s a f u n c t i o n of successive t o r s i o n

When O - O ' Z O A i i s o u t of t h e mean plane defined by t h e f i v e r i n g atoms. If t h e d i f f e r e n c e i s p o s i t i v e , A i l i e s above t h e mean plane and i t s

a x i a l s u b s t i t u e n t i s f3 o r i e n t a t e d (above t h e r i n g , Fig. 3d): i f negative, A i l i e s below t h e mean plane and i t s a x i a l s u b s t i t u e n t i s ct o r i e n t a t e d (below t h e r i n g , Fig. 3 f ) . The magnitude of t h e d i f f e r e n c e i s a l s o of importance s i n c e t h e g r e a t e r t h e d i f f e r e n c e , t h e g r e a t e r t h e d i s t a n c e of Ai from t h e mean plane and t h e more a x i a l t h e s u b s t i t u e n t t h a t i s t o say, t h e more puckered i s t h i s r e g i o n of t h e r i n g . A s a standard reference f o r an a x i a l s u b s t i t u e n t we w i l l t a k e t h e a x i a l subs t i t u e n t s of t h e i d e a l c h a i r form (see below), They a r e known t o be perpendicular t o t h e mean plane of t h e c y c l e (which i s a l s o t h e mean plane f o r f i v e r i n g atoms). The r e f e r e n c e v a l u e for the difference O O' f o r a pure a x i a l s u b s t i t u e n t i s t h e r e f o r e +120°, a s t h e t o r s i o n angles of t h i s form equal 60' and a r e of o p p o s i t e sign. Should t h e two t o r s i o n angles surrounding a r i n g atom be of o p p o s i t e s i g n , t h e d i f f e r e n c e has t h e s i g n of t h e f i r s t angle encountered i n a clockwise d i r e c t i o n . An arrangement of opposite s i g n s f r e q u e n t l y corresponds t o s u b s t a n t i a l a x i a l c h a r a c t e r . The two

-

-

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165

possibilities are shown in Figures 3c and e . Consequently inspection of the sequence of signs alone can yield useful information. Briefly, the sequence +, - indicates that the ring atom and its axial substituent are pointing upward; conversely, the inverse sequence -, + corresponds to a ring atom and its axial substituent pointing downward.*

111.

A. 7.

MONOCYCLIC MOLECULES

Cyclohexane and Cyclohexanone

Chair Form and Its Deformations

The rigid or chair form of cyclohexane is characterized by the regular alternation of the signs of its torsion angles (Fig. 4). In an undistorted chair form all the torsion angles have the same absolute value. These two properties reflect the high degree of symmetry of this conformation. It possesses, among other elements of symmetry, a center of inversion and a threefold rotation axis perpendicular to the mean plane of the molecule and passing through its center. As a consequence, the torsion angles in the 1,4 positions are of opposite sign, whereas they are of the same sign in the 1,3 positions.

choir form

Fig. 4. The signs of the torsion angles in cycionexane (chair form). Perfect chair form: 0 = 109'28', 0 = 60'; real chair form: 0 = lll', 9 = 56'. In the ideal chair form, which is that of common molecular models, the absolute value of the torsion angles (9) is 60', corresponding to the theoretical C-C-C valence angle (0)of 109'28'. Such a geometry is free of torsional strain (Pitzer strain) as the torsional arrangement has minimal energy when With respect to the angle strain (Baeyer strain), Q = 60'. *As a mnemonic aid for this rule, we can make a comparison with topography: a positive value of Q - 9', or encountering a positive torsion angle before reaching the ring atom Ai, is comparable to an elevation above sea level (positive height).

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however, t h e s i t u a t i o n i s d i f f e r e n t . A s it i s known t h a t t h e "normal" valence angle C-CH2-C must have t h e value of 112.4', which i s t h e experimentally determined v a l u e f o r t h e n-alkanes (101, t h e i d e a l c h a i r form with 0 = 109'28' must s u f f e r an On t h e o t h e r hand, a c h a i r angle s t r a i n of about 1 kcal/mole. form with t h e normal valence angle of 112.4' would have a t o r s i o n angle of 52'*, giving r i s e t o a P i t z e r s t r a i n of about 0.7 t o 0.8 kcal/mole. I f it i s assumed t h a t t h e minimal energy conformation i s c h i e f l y governed by t h e balance between Baeyer and P i t z e r s t r a i n s , t h e p o i n t of equilibrium i s reached with t h e v a l u e s of 111.1 and 55.8O f o r 0 and @, r e s p e c t i v e l y ( 1 2 ) . I t happens t h a t a t t h i s p o i n t t h e t o t a l s t r a i n i s roughly e q u a l l y d i s t r i b u t e d (0.2 kcal/mole f o r each kind of s t r a i n ) . This very u n s o p h i s t i c a t e d explanation of t h e s l i g h t f l a t t e n i n g of t h e c h a i r form of cyclohexane i s very c l o s e t o t h e t r u e p i c t u r e , a s w i l l be seen l a t e r . The expansion of t h e valence a n g l e i n cyclohexane was pred i c t e d i n 1960 by t h e o r e t i c a l c a l c u l a t i o n ( 1 3 ) . Three y e a r s l a t e r t h i s was confirmed (0 = 111.55') by e l e c t r o n d i f f r a c t i o n (141, and t h e concept of a f l a t t e n e d c h a i r form was t h u s i n t r o duced. A paper was published i n 1964 (15) which described t h e f l a t t e n e d forms of cyclohexene and cyclohexane obtained by c a l c u l a t i o n of minimum energy conformations, and t h i s was s h o r t l y followed by a p u b l i c a t i o n (16) which showed t h e p o s s i b l e physic a l and chemical consequences of t h i s f l a t t e n i n g . Since then, many t h e o r e t i c a l approaches employing i n c r e a s i n g l y r e f i n e d methods have a l s o supported t h e f l a t t e n e d c h a i r form (17-23). The most r e c e n t r e s u l t s show a t r e n d toward s l i g h t l y g r e a t e r t o r s i o n angle v a l u e s , = 56' (18-211, as compared t o p r e v i o u s l y reported values of ~ 5 4 . 5 ' (17, 2 2 , 23). Recent experimental 58' by nrnr (24, 25) and determinations show t h e same trend: 55.9' by e l e c t r o n d i f f r a c t i o n (26). The round f i g u r e of 56' f o r t h e cyclohexane c h a i r form w i l l t h e r e f o r e be chosen h e r e a s t h e most probable value. As a consequence of t h e r i n g f l a t t e n i n g , t h e a x i a l bonds a r e bent s l i g h t l y outward; t h e a x i a l bonds a r e no longer p a r a l l e l , a s i n t h e p e r f e c t c h a i r form, b u t a t an angle of 7 O w i t h r e s p e c t t o each o t h e r . I n cyclohexanone t h e c h a i r i s i n a l l l i k e l i h o o d n o t very d i f f e r e n t from t h a t of cyclohexane b u t probably s l i g h t l y f l a t t e r owing t o two f a c t s : t h e g r e a t e r normal valence aFgle C-C(0)-C (116') and t h e s h o r t e r bond l e n g t h C-C(O) (1.51 A ) a s compared t o t h e v a l u e s found i n n-alkanes (112.4' and 1.53 A ) *Value given by t h e equation cos

0 -2 = -2 cos 2 @

which can be derived from a more g e n e r a l r e l a t i o n (11).

ROBERT BUCOURT

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( 1 0 ) . Among t h e t h e o r e t i c a l c a l c u l a t i o n s published (27-29), t h e one r e p o r t i n g t o r s i o n angle v a l u e s ( 2 7 ) s u b s t a n t i a t e s t h i s f u r t h e r f l a t t e n i n g of cyclohexanone i n t h e region of t h e carbony1 group ( s e e Fig. 5 ) .

Fig. 5. Differences between t h e a b s o l u t e t o r s i o n a n g l e v a l u e s of t h e cyclohexanone and cyclohexane f l a t t e n e d c h a i r f oms. A deformation of t h e cyclohexane c h a i r form may arise l o c a l l y , e.g., as t h e r e s u l t of t h e f u s i o n with another c y c l e o r through t h e presence of a x i a l s u b s t i t u e n t s s u f f e r i n g van d e r Waals r e p u l s i o n s . For i n s t a n c e , one may assume t h a t i n t h e c a s e of f u s i o n with another c y c l e t h e t o r s i o n a n g l e @ of Figure 6a i s made t o c l o s e o r open. The q u e s t i o n a s t o t h e consequences of such a l o c a l deformation on t h e geometry of t h e c h a i r form of t h e r i n g t h u s a r i s e s . The r e s u l t s obtained by c a l c u l a t i o n of minimum energy conformations ( 1 2 ) a r e b r i e f l y summarized i n Figure 6b. I f t h e amplitude of t h e i n i t i a l deformation ( A @ ) i s taken a s u n i t y , t h e a b s o l u t e v a l u e s of t h e t o r s i o n a n g l e s s i t u a t e d i n 1,2 p o s i t i o n s ( @ ( 1 , 2 ) ) change i n t h e same d i r e c t i o n * b u t t o a lesser e x t e n t (about 60% of t h e amplitude of t h e i n i t i a l deformation). The t o r s i o n a n g l e s i n 1 , 3 p o s i t i o n s a r e l i t t l e a f f e c t e d , while t h e t o r s i o n angle i n 1 , 4 p o s i t i o n ( @ ( 1 , 4 ) ) v a r i e s i n v e r s e l y + and t o a much l e s s e r e x t e n t (about 3 0 % ) . The energy i n c r e a s e introduced i n t h e r i n g by t h e t o r s i o n of Q away from i t s equilibrium value can be roughly approximated

*That i s t o say, a c l o s i n g i f t h e i n i t i a l deformation (AQ) i s a c l o s i n g ( a decrease i n t h e a b s o l u t e v a l u e s of @ and Q ( 1 , 2 ) ) ; an opening of @ g i v e s an opening of @ ( 1 , 2 ) . +An opening i f t h e i n i t i a l deformation i s a c l o s i n g , and vice versa.

168

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la I

Fig. 6. E f f e c t of deformation of t h e c h a i r form of cyclohexane on t o r s i o n angles. by t h e two following equatiqns:"

(A@)

m = T i T for

a

2/3(A9)2

100

an opening f o r a closing

where i s i n kcal/mole i f A@ i s i n degrees. The l I 3 - d i w i a l d i s t a n c e s a r e a l t e r e d by t h e s e v a r i a t i o n s of t h e t o r s i o n angle v a l u e s . The g r e a t e s t changes occur between t h e a x i a l subs t i t u e n t s borne by t h e r i n g atoms which determine t h e t o r s i o n angle A c l o s i n g of 9 r e s u l t s i n t h e same i n c r e a s e i n t h e two 1 , 3 - d i a x i a l d i s t a n c e s i n d i c a t e d i n F i g u r e 6c; an opening r e s u l t s i n a decrease. This i s a consequence of t h e g e n e r a l r u l e s t a t e d i n t h e foregoing s e c t i o n : A decrease i n t h e absolute values of t h e t o r s i o n angles corresponds t o a

@.

-These equations (and t h e s e t of v a r i a t i o n s i n Fig. 6 b ) a r e approximations of curves given i n r e f . 1 2 f o r A9 v a l u e s from -25 t o +20°.

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f l a t t e n i n g of t h e r i n g ; simultaneously t h e a x i a l s u b s t i t u e n t s a r e b e n t f u r t h e r away from each o t h e r . An i n c r e a s e corresponds t o a puckering and t h e a x i a l s u b s t i t u e n t s are brought c l o s e r t o g e t h e r . A s seen i n F i g u r e 6 b , t h e deformation i s p r i m a r i l y l o c a t e d i n t h e left-hand s i d e of t h e r i n g , w h i l e t h e r i g h t hand s i d e i s a f f e c t e d i n t h e o p p o s i t e way t o a much lesser extent. Conversely, a v a r i a t i o n i n t h e d i s t a n c e between two 1,3d i a x i a l s u b s t i t u e n t s w i l l a f f e c t t h e t o r s i o n a n g l e v a l u e s of t h e c y c l e . T h i s may be due t o t h e r e p u l s i o n between two bulky syn-axial s u b s t i t u e n t s ; t h e two 1 , 3 - d i a x i a l bonds ( i . e . , t h e bonds connected t o t h e r i n g atoms x and y i n F i g s . 6d and e ) a r e b e n t away from each o t h e r . According t o t h e preceding s t a t e m e n t s , such a displacement of t h e d i a x i a l bonds w i l l i n duce a c l o s i n g of t h e two t o r s i o n a n g l e s s i t u a t e d between them (between t h e r i n g atoms x and y of Fig. 6 d ) . Thus it i s necessary t o analyze t h e kind of deformation t h e cyclohexane c h a i r form w i l l undergo when two c o n s e c u t i v e t o r s i o n a n g l e s a r e simultaneously closed. The s e t of v a r i a t i o n s i n F i g u r e 6 b can serve f o r t h i s a n a l y s i s . I t h a s indeed been found (30) t h a t t h e d i s t o r t i o n r e p r e s e n t e d i n F i g u r e 6 b induced by t h e deformat i o n of t h e t o r s i o n angle 4 can be used as a b a s i c u n i t of d i s t o r t i o n f o r l i n e a r combinations, when two o r more t o r s i o n a n g l e s are simultaneously submitted t o a g i v e n deformation. Good approximate r e p r e s e n t a t i o n of deformations may be o b t a i n e d i n t h i s way and have been v e r i f i e d by c a l c u l a t i o n . I n t h e p r e s e n t c a s e b o t h t o r s i o n a n g l e s l o c a t e d between x and y have t o be considered a s t h e a n g l e 4 of F i g u r e 6 a , each inducing t h e s e t of v a r i a t i o n s shown i n F i g u r e 6b. The a d d i t i o n of t h e s e two b a s i c u n i t s g i v e s t h e new r e l a t i v e set of v a r i a t i o n s shown i n F i g u r e 6 d . T h i s second type of deformation has a p l a n e of symmetry r e p r e s e n t e d by a dashed l i n e i n F i g u r e 6d. I t i s i n t e r e s t i n g t o n o t e t h a t t h e deformations of t h e two t o r s i o n a n g l e s between x and y induce an i n v e r s e deformation of t h e two t o r s i o n a n g l e s f a r t h e s t away from them ( s i t u a t e d between t h e r i n g atoms x ' and y ' of t h e f i g u r e ) . A s t h e i n i t i a l deformation i s a t o r s i o n a n g l e c l o s i n g ( a f l a t t e n i n g ) , t h e i n duced deformation i n t h e o t h e r p a r t of t h e r i n g i s a t o r s i o n a n g l e opening (a p u c k e r i n g ) . Thus an i n c r e a s e i n t h e separat i o n between two 1 , 3 - d i a x i a l s u b s t i t u e n t s must induce a decrease i n t h e s e p a r a t i o n between t h e two 1 , 3 - d i a x i a l s u b s t i t u e n t s symmetrically disposed on t h e o t h e r f a c e of t h e r i n g , a s shown i n F i g u r e 6 e . T h i s i s t h e c h a r a c t e r i s t i c of t h e " r e f l e x e f f e c t " which o r i g i n a t e s i n t h e mutual r e p u l s i o n of two bulky a x i a l s u b s t i t u e n t s (31, 3 2 ) . The i n v e r s i o n of t h e t o r s i o n angle v a r i a t i o n s of t h e F i g u r e 6 d t y p e should t h e r e f o r e

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p l a y a p a r t i n t h e r e f l e x e f f e c t . * I t was r e f e r r e d t o i n e a r l y t h e o r e t i c a l c a l c u l a t i o n s c a r r i e d o u t on t h i s s u b j e c t (33) and i s indeed s u b s t a n t i a t e d by X-ray determinations. From c r y s t a l l o g r a p h i c d a t a on 2-bromo-3,3,5,5-tetramethylcyclohexanone (I) (34) and 2,2,6,6-tetramethylpiperidin-4-ol-l-oxyl ( 2 ) (351, t h e t o r s i o n a n g l e v a l u e s shown i n formulas 1 and 2 were c a l c u l a t e d .

B+\

53' *55

I f t h e v a l u e of 54O i s taken a s t h e mean v a l u e of t h e t o r s i o n angles f o r t h e c h a i r form of cyclohexanone (241, i t can be seen from formula I+ t h a t t h e two a x i a l methyl groups produce a c l o s i n g of both t o r s i o n a n g l e s between them and induce an opening of t h e two t o r s i o n a n g l e s f u r t h e s t away. Here t h i s e f f e c t i s more pronounced than i n F i g u r e 6b and i s proba b l y due t o t h e lower b a r r i e r t o r o t a t i o n about t h e C-C(=O) bond a s compared t o t h a t about t h e C-C moiety i n alkanes. A s has a l r e a d y been pointed o u t (31, 3 6 ) , t h e same kind of e f f e c t , b u t r e s u l t i n g from an i n v e r s e p r o c e s s , a r i s e s i n *In f a c t , valence a n g l e deformations a l s o p l a y a p a r t . As i n a l l deformations of t h e cyclohexane c h a i r form, t o r s i o n

angle and valence angle v a r i a t i o n s a r e always r e l a t e d . F l a t t e n i n g i s g e n e r a l l y accompanied by a valence angle expans i o n , and puckering by a reduction. Thus an expansion of 0 and a reduction of 0 ' (Fig. 6d) a r e o t h e r c h a r a c t e r i s t i c s of t h e r e f l e x e f f e c t (33) and a r e a l s o found i n t h e computation of t h e type of deformation described here. +Torsion angle v a l u e s of a r i n g must be w r i t t e n along each c e n t r a l bond and within t h e r i n g t o which they r e f e r (e.g., formulas 1 and 2 ) . They a r e so i n d i c a t e d f o r p o l y c y c l i c molecules. Where no ambiguity can a r i s e , f o r example, i n t h e case of i s o l a t e d r i n g s , t h e v a l u e s may be w r i t t e n along t h e c e n t r a l bond, b u t o u t s i d e t h e r i n g a s shown i n Figure 9.

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ROBERT BUCOURT

cyclohexane d e r i v a t i v e s i n which two syn-axial s u b s t i t u e n t s a r e brought c l o s e r together by a d i r e c t linkage (Fig. 7 ) .

f

Fig. 7.

Reflex e f f e c t due t o 1 , 3 bridging.

The decrease i n t h e 1 , 3 - d i a x i a l d i s t a n c e t o which such a b r i d g e formation l e a d s r e s u l t s i n an opening of t h e two proximal t o r s i o n angles of t h e r i n g . According t o t h e s e t of v a r i a t i o n s of Figure 6 b , t h i s w i l l induce a c l o s i n g of both t o r s i o n a n g l e s f u r t h e s t away and consequently an i n c r e a s e i n t h e s e p a r a t i o n of both a x i a l s u b s t i t u e n t s symmetrically p o s i t i o n e d on t h e o t h e r f a c e of t h e r i n g a s shown i n F i g u r e 7. This e f f e c t is encountered i n glaucarubin p-bromobenzoate ( 3 ) . Torsion angle values obtained from t h e atomic c o o r d i n a t e s given by X-ray study ( 3 7 ) show a pronounced r e f l e x e f f e c t f o r t h e r i n g bearing t h e three-bond bridge. I n t h i s p a r t i c u l a r c a s e t h e e f f e c t i s probably r e i n f o r c e d by t h e presence of two bulky d i a x i a l subs t i t u e n t s on t h e o t h e r f a c e of t h e molecule: t h e 0-H group on C12 and t h e carbon 1 5 on C 1 4 .

172

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

14

0

Another more obvious type of deformation of t h e cyclohexane c h a i r form i s c h a r a c t e r i z e d by a g r a d u a l d i s t o r t i o n without i n v e r s i o n of t h e t o r s i o n a n g l e v a r i a t i o n s . This i s t h e c a s e of t h e w i a l m e t h y l c y c l o h e x a n e f o r which t h e t h e o r e t i c a l geometry of Figure 8 has been c a l c u l a t e d (18). From t h e rounded v a l u e s of t h e f i g u r e , i t appears t h a t t h e v e r y s l i g h t a d d i t i o n a l f l a t t e n i n g of t h e r i n g around t h e a x i a l methyl group d e c r e a s e s t o zero f o r t h e most d i s t a n t p a r t of t h e r i n g .

Fig. 8. Torsion a n g l e s i n methylcyclohexane. The d i f f e r e n c e s i n comparison with t h e t o r s i o n a n g l e v a l u e of t h e f l a t t e n e d c h a i r form of cyclohexane a r e g i v e n i n parentheses.

ROBERT BUCOURT

173 2.

Flexible Form

Whereas the torsion angles in the 1,4 positions in the chair form of cyclohexane are of opposite sign, those in the flexible form are identical. This identity reflects the presence of a two-fold symmetry axis perpendicular to the ring at its center. The sequence of signs is shown in Figure 9a: There are two pairs of torsion angles of the same sign separated on either side by a torsion angle of the opposite sign. Owing to the flexibility of this form, a continuous variation of all the torsion angle values gives rise to an infinite number of conformations. Among these, the two of highest degree of symmetry are the twist form or skew boat (38) (Fig. 9b) which possesses two further two-fold symmetry axes (as indicated in the Figure), and the boat form (Fig. SC) with two planes of symmetry (represented by dashed lines in the figure). From all published theoretical values (2, 12,

Fig. 9. The flexible form of cyclohexane. 21, 231, those selected for the torsion angles of the two particular conformations in Figure 9 have been taken only from those publications (12, 21) which also give the value nearest to the 56O adopted here for the chair form.* For the common conformation, represented in Figure 9a, the two pairs of torsion angles of the same sign are always smaller (<54O) than the two of opposite sign ( > 5 4 O ) . The pseudorotation of the flexible form of cyclohexane, which interconverts all the -The torsion angle values which would correspond to the ideal flexible conformations, i.e., with tetrahedral valence angles, are 33 and 71' for the twist form, and 60' for the boat form.

1 74

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

p o s s i b l e t w i s t and boat forms, has been e x t e n s i v e l y s t u d i e d ( 2 , 3 , 39-41). The most r e c e n t paper ( 4 1 ) p r e s e n t s a simple method of determining t h e geometry of any one conformation appearing i n t h e pseudorotation c i r c u i t , by t h e following equation:

i n which Qmax r e p r e s e n t s t h e g r e a t e s t v a l u e a t o r s i o n angle can reach during pseudorotation*; A i s a p s e u d o r o t a t i o n a l parameter varying from 0 t o 360O; j i s an i n t e g e r (0-5) ref e r r i n g t o each t o r s i o n angle; 6 = 120O. During t h e pseudorotation t h e t o r s i o n angles vary simultaneously between -65 and +65O a s i n d i c a t e d i n Scheme 1.

0

Scheme 1. C o r r e l a t i o n of v a r i a t i o n of t o r s i o n a n g l e s i n 01, 02, and Q 3 a r e t h e t o r s i o n a n g l e s of pseudorotation. Figure 9a. For example, i n t h e passage of t h e t w i s t form of Figure 9b t o t h e boat form of Figure 9C, t h e t o r s i o n a n g l e s 01 diminish t o O o , while t h e Q3's i n c r e a s e , and t h e 0 2 ' s decrease simultaneously t o reach 54O. Scheme 1 shows t h a t s i x t w i s t forms and s i x b o a t forms are encountered i n t h e pseudorotat i o n i t i n e r a r y . For each form t h e clockwise s i g n sequence immediately p r e s e n t s t h e shape of t h e conformation considered and t h e o r i e n t a t i o n s of i t s a x i a l s u b s t i t u e n t s (see, e.g., t h e * I n t h e paper quoted ( 4 1 ) amax = 61.5' i n s t e a d of 6bU given here. There a r e two reasons f o r t h i s discrepancy: (a) t h e geometry of t h e model used i n t h e paper w a s f l a t t e r , and ( b ) t h e equation i s probably n o t s t r i c t l y a p p l i c a b l e owing t o t h e presence of a p s e u d o r o t a t i o n a l b a r r i e r (accordingly Omax i s c a l c u l a t e d a s t h e " b e s t " v a l u e ) .

ROBERT BUCOURT

175

perspective views corresponding to the conformations of Figs. 9b and c ) . With regard to the energies at the different conformations of the flexible form, the twist form has minimum energy, the boat form maximum energy. The difference can only be theoretically estimated and it is difficult to gain an exact idea of its real magnitude; the published values range from near 0 to 1.8 kcal/mole (2, 12, 21-23, 42-44). We will adopt here the rounded value of 1 kcal/mole. As experimental determinations of the enthalpy difference between the chair and twist forms have given values of around 5 kcal/mole (38), the energy of the boat form may be assumed to be about 6 kcal/mole. On the basis of a AHo value of 5.3 kcal/mole and a Aso value of 4.9 cal/deg.-mole , the A G O value of the transformation chair twist form has been estimated to be about 3.8 kcal/mole at 25' (38). This value agrees well with the ratio chair form/ twist form given elsewhere ( 4 5 ) . Thus flexible conformations are practically absent in solution at room temperature unless a bulky axial substituent destabilizes the chair form (38, 46, 47). In cyclohexanone the problem is somewhat more complex, because the presence of the carbonyl group gives rise to two types of twist and boat forms. One twist form (Fig. 10a) retains one of the three axes of symmetry of the cyclohexane twist form whereas the other (Fig. 100) has no symmetry. Of the two possible boat forms, one has no symmetry (Fig. lob), while the other has one plane of symmetry (Fig. lod). A s the

AH=3 2

32 (a I

AH=6 6.3

bl

AH=& ( 0 )

AH-5.0 57

-

(d

1

Fig. 10. Calculated energies of the cyclohexanone boat forms as compared with the chair as a function of torsion angle values as given in ref. 27. The alternative energy values (underlined) are taken from ref. 48; the geometry is not described in that paper, but should be quite similar to that shown here. main part of the energy of the flexible form arises from bond eclipsing, lower energies.are expected for the flexible

176

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

conformations having m a l l t o r s i o n a n g l e s i n t h e v i c i n i t y OF t h e carbonyl, because t h e b a r r i e r t o r o t a t i o n about t h e C-C(=O) bond i s lower than t h a t about t h e C-C bond i n alkanes. I n f a c t , t h e conformations shown i n F i g u r e s l O a , b , and c a r e much lower i n energy than those i n cyclohexane. The succession of t h e f o u r conformations of Figure 10 i n t h e o r d e r a -b-c --d r e p r e s e n t s one-quarter of t h e e n t i r e pseudorot a t i o n c i r c u i t of t h e f l e x i b l e form of cyclohexanone. Accordi n g t o t h e v a l u e s of Figure 1 0 , t h e energy p r o f i l e of t h e pseudorotation i s d i f f e r e n t (Fig. 1 l b ) from t h a t of cyclohexane (Fig. l l a ) . As t h e e n e r g i e s of two successive forms (conformations i n F i g s . l o b and c) have been estimated t o be t h e same, t h e curve must be f l a t i n t h e r e g i o n between them.

Pseudorotational

pororneter

(a)

(b)

Fig. 11. H a l f - i t i n e r a r y of pseudorotation i n (a) cyclohexane and (b1 cyclohexanone

.

Consequently t h e r e e x i s t h a l f a s many extrema a s i n cyclohexane. Moreover, t h e energy d i f f e r e n c e between t h e extrema i s more pronounced. I n Figure 11 t h e energy i s p l o t t e d a g a i n s t a pseudorotational parameter such as t h e one r e p o r t e d i n t h e d e s c r i p t i o n of pseudorotation i n t h e cyclohexanone f l e x i b l e form (49).

3.

Inversion

I n terms of t o r s i o n a n g l e s , i n v e r s i o n i s a conformational change which transforms a r i n g conformation by i n v e r s i o n of a l l i t s t o r s i o n angle values. I n o t h e r words, it i s an i n t e r conversion between two forms of t h e same type having t o r s i o n angles of t h e same a b s o l u t e v a l u e s b u t of o p p o s i t e s i g n . The

XOBERT BUCOURT

177

case of the inversion of the cyclohexane chair form is illustrated in E'igure 12. The activation energy associated with

Fig. 12. Signs of torsion ang-ss in c air-chair inversion of cyclohexane. this transformation is of interest and its theoretical approach has been t h e subject of many papers (2, 21, 40, 42). Since a torsion angle must pass through the value zero in order to be inverted, the different possible ways of inversion can be characterized by those conformations having one or more zero torsion angle values involved in the inversion process. Symmetric and asymmetric modes of inversion can be considered. In the symmetric modes, one symmetry element (fixed with respect to the ring) is retained throughout the inversion process. If, in the case of the cyclohexane chair form, the center of symmetry is retained, all the torsion angles have to pass through zero simultaneously. Such a process is very unlikely because it involves a completely planar transition state of very high energy ( z 23 kcal/mole) ( 2 ) . An inversion process which retains a two-fold symmetry axis is depicted in Scheme 2 (6'2 mode of inversion). The torsion angles related to each

€om.

Scheme 2.

C2

mode of inversion of the cyclohexane chair

178

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

o t h e r by t h i s e l e m e n t of synnnetry (symmetrically p o s i t i o n e d a c r o s s t h e symmetry l i n e i n t h e scheme) w i l l r e t a i n equal v a l u e s throughout t h e i n v e r s i o n process. The t o r s i o n angle $ 1 ~ 2i s f i r s t i n v e r t e d , and t h e r i n g p a s s e s through t h e monop l a n a r form 5* ( h a l f - c h a i r form) t o g i v e t h e form 6 with t h r e e consecutive t o r s i o n angles of t h e same s i g n . Subsequently, t h e two t o r s i o n angles @2,3 and @ 1 , 6 i n v e r t simultaneously, and t h e r i n g passes through t h e 1 , 3 - d i p l a n a r form ? t o g i v e t h e form 8 , which belongs t o t h e f l e x i b l e form because it has t h e c h a r a c t e r i s t i c s i g n sequence of t h a t form. The c o n t i n u a t i o n of t h e i n v e r s i o n process involves t h e same types of conformat i o n encountered before: 8 - 7 " 6' - 5 ' , t o give f i n a l l y t h e inverted c h a i r form 4 ' . Another symmetric mode of i n v e r s i o n i s shown i n Scheme 3 . A plane of symmetry i s r e t a i n e d during t h e i n v e r s i o n process (c, mode). The t o r s i o n a n g l e s r e l a t e d t o each o t h e r by t h i s symmetry element always have o p p o s i t e values. The p a r t i c u l a r forms involved a r e t h e 1,a-diplanar forms 10 and 10' , and t h e l I 4 - d i p l a n a r form 1 2 (boat form).

Scheme 3. form.

C, mode of i n v e r s i o n of t h e cyclohexane c h a i r

An asymmetric mode of i n v e r s i o n can b e derived from a deformation of t h e r i n g which involves t h e i n v e r s i o n of only one t o r s i o n angle a t any time. The i n i t i a l deformation i s then proposed nomenclature f o r conformations showing one o r more zero t o r s i o n angles i s used h e r e (see r e f . 3 , pg. 2082). The term planar i n d i c a t e s t h e presence i n t h e r i n g of a plane r e s u l t i n g from a zero t o r s i o n angle. The conformation i s called multiplanar i f there a r e several zero torsion angles; t h e i r r e l a t i v e l o c a t i o n i s given by t h e numbering convention proposed e a r l i e r (see page 162).

A-

ROBERT BUCOURT

179

propagated along t h e r i n g t o induce, s u c c e s s i v e l y , t h e invers i o n of t h e o t h e r t o r s i o n angles. Let u s assume t h a t t h e t o r s i o n angle 01,2 of t h e c h a i r form 13 (Scheme 4 ) changes i t s s i g n t o g i v e 15, and passes through zero i n t h e monoplanar form 14. I n a conformation such a s 15, with t h r e e consecutive t o r s i o n angles of t h e same s i g n , c a l c u l a t i o n i n d i c a t e s t h a t t h e s e t o r s i o n a n g l e s a r e always smaller than t h e o t h e r s ( 2 ) . Therefore t h e second most l i k e l y t o r s i o n angle t o i n v e r t must be one of t h e two a d j a c e n t t o r s i o n a n g l e s @ 2 , 3 o r $ 1 , ~ . I f it i s @ 2 , 3 , i n v e r s i o n l e a d s t o t h e new monoplanar form 16, which then g i v e s conformation 17. I n 1 7 two consecutive t o r s i o n angles of l i k e s i g n a r e d i r e c t l y followed by two t o r s i o n a n g l e s of opposite s i g n . C a l c u l a t i o n shows t h a t t h e s e two p a i r s of

Scheme 4 . c h a i r form.

Asymmetric mode of i n v e r s i o n of t h e cyclohexane

t o r s i o n angles have smaller v a l u e s than t h e remaining two. I f it i s Thus t h e t h i r d i n v e r s i o n must a f f e c t @3,4 o r @1,6. @3,4, t h e monoplanar form I8 i s obtained and l e a d s t o con'format i o n 19. This conformation belongs t o t h e f l e x i b l e form. I f @ 4 , 5 i s next i n v e r t e d , t h e deformation w i l l propagate f u r t h e r i n t h e same d i r e c t i o n , passing through t h e same types of forms a s b e f o r e , t o g i v e f i n a l l y t h e i n v e r t e d c h a i r 1 3 ' . The i t i n e r a r y depicted i n Scheme 4 may be considered t o be t h e r e s u l t of a deformation r o t a t i n g along t h e r i n g . The d i r e c t i o n of propagation of t h i s deformation might have been r e v e r s e d during t h e process. Other asymmetric p a t h s of i n v e r s i o n a r e thus imaginable, b u t they would involve t h e same i n t e r m e d i a t e conformations a s shown i n Scheme 4 . I n such a p r o c e s s t h e r e i s no symmetry r e s t r i c t i o n . I t would be p o s s i b l e t o imagine a symmetry element f o r c e r t a i n i n t e r m e d i a t e conformations b u t t h i s would be v a l i d a t a given moment only. Furthermore, i n t e r mediate conformations 16 and 18 a r e e s s e n t i a l l y asymmetric.

180

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

As it appears i n Schemes 2 , 3, and 4 , t h e f l e x i b l e form i s always midway i n t h e c h a i r I c h a i r interconversion. A s it corresponds t o an energy trough, t h e i n v e r s i o n process can be i n t e r r u p t e d a t t h i s p o i n t . The r i n g can expend i t s excess energy (by v i b r a t i o n s f o r example), and very probably a second molecular c o l l i s i o n i s necessary t o convert t h e i n t e r m e d i a t e f l e x i b l e form e i t h e r back t o t h e o r i g i n a l o r on t o t h e i n v e r t e d c h a i r form. The b a r r i e r t o t h e change from a c h a i r t o a f l e x i b l e form can he assessed by c a l c u l a t i o n of minimum energy conformations corresponding t o a s e t of d i f f e r e n t geometric s t a t e s through which t h e r i n g must pass. Each s t a t e i s defined by t h e s i g n sequence and by one o r two t o r s i o n angle values. These v a l u e s a r e g r a d u a l l y v a r i e d , p a r t i c u l a r l y i n t h e r e g i o n of t h e b a r r i e r , i n order t o f i n d o u t with p r e c i s i o n t h e energy and t h e geometry of t h e t r a n s i t i o n s t a t e . Figure 13 shows t h e energy p r o f i l e s of t h e change leading from a c h a i r t o a f l e x i b l e form i n t h e two symmetric modes of i n v e r s i o n (2). I t can be seen from t h e f i g u r e t h a t t h e two p r o f i l e s a r e q u i t e similar. The monoplanar and d i p l a n a r forms a r e s i t u a t e d near t h e b a r r i e r . The b a r r i e r , i n f a c t , corresponds t o forms which have three l i k e s i g n s ( i n t h e C2 mode) o r a p a i r of l i k e s i g n s followed by a p a i r of t h e

Fig. 13. Energy p r o f i l e s of t h e two symmetric modes of t h e c h a i r e f l e x i b l e form i n t e r c o n v e r s i o n f o r cyclohexane.

181

ROBERT BUCOURT

opposite sign (in the C, mode) (2, 21, 40). The respective geometry of these two transition states is given by formulas 20 and 21 in Figure 14. Formula 20 is an intermediate form between the monoplanar form 22 and the 1,3-diplanar form 2 3 , while formula 21 is very near the 1,2-diplanar form 24. All five forms are very close in energy. The asymmetric mode of inversion would not represent a more economical route to inversion as it involves the conformations 15 and 17 (Scheme 4) which are of the same type as the conformations of highest energy in the symmetric modes. Indeed, calculation on asymmetric conformations in the region of the barrier has substantiated this idea (2, 21). Thus the energy profile which is relatively flat in the region of the transition state should not show a dependence on symmetry. This is in accord with a new mode of calculation which leads to the conclusion that "the molecule must be considered to be pseudorotating freely in the transition state" (50).

AH=10.1, (2se'

Fig. 14. Transition states for chair inversion and their energies. The values are taken from refs. 2 and 40. (The somewhat higher energy values given in ref. 4 0 are underlined.) Similar results are given in ref. 21. The values given in Figure 14 for the energies of the transition states are in good agreement with the experimental AH values of 10.8 (51) and 10.4 (47) (see also ref. 52). In cyclohexanone the presence of the carbonyl group gives more flexibility to this part of the ring, because the barrier to rotation about a C,p2-C,p3 bond is lower than that about a

182

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

bond. Thus t h e i n v e r s i o n process i s more l i k e l y t o occur i n t h e region of t h e carbonyl group and must have a lower b a r r i e r than i n cyclohexane. Such a p r e f e r e n t i a l mode of i n v e r s i o n is depicted i n Scheme 5 ( 2 ) . Csp3-Csp3

0

0

6 n

- 0

(301

Scheme 5. A p r e f e r e n t i a l mode of i n v e r s i o n of t h e cyclohexanone c h a i r form. I f t h e two t o r s i o n angles i n t h e v i c i n i t y of t h e carbonyl group of t h e cyclohexanone c h a i r form 25 are simultaneously i n v e r t e d , t h e 1,2-diplanar form 26 i s involved, and it l e a d s t o t h e t r a n s i t i o n s t a t e 27 i n which t h e s m a l l e s t t o r s i o n angles are centered on t h e carbonyl group (see t h e d e t a i l e d geometry of t h e t r a n s i t i o n s t a t e 27 i n Fig. 1 5 ) . Subsequently t h e boat form 28 can be reached a s i n t h e case of cyclohexane (Scheme 3 ) . A t t h i s s t a g e t h e two t o r s i o n a n g l e s f u r t h e s t away from t h e carbonyl group can be i n v e r t e d by means of a pseudorotation involving t h e f l e x i b l e forms 29, 30, 31, 30', 2 9 ' , and 28'. From t h e l a s t of t h e s e forms t h e p a t h t o t h e i n v e r t e d c h a i r form 25' involves t h e same i n t e r m e d i a t e s a s b e f o r e , 27' and 26'. The mode of i n v e r s i o n shown i n Scheme 5 should be t h e most economical r o u t e t o i n v e r t t h e cyclohexanone c h a i r form. I t s energy p r o f i l e i s given i n Figure 16 (2); a l l t h e f l e x i b l e forms have lower energy than t h e t r a n s i t i o n s t a t e , a s i n cyclohexane. However, t h e energy s e p a r a t i o n between t h e t r a n s i t i o n s t a t e and t h e f l e x i b l e form of higher energy (boat 28) i s r e l a t i v e l y low: 0.7 kcal/mole.

183

ROBERT BUCOURT

3 1 & l;J61'

-

(26) A H = 5.6

*by (27)

A H = 6.1

Fig. 15. Intermediate conformations i n t h e i n v e r s i o n of t h e cyclohexanone c h a i r form.

Fig. 16. Energy p r o f i l e of t h e i n v e r s i o n of t h e cyclohexanone c h a i r form. The geometry r e p o r t e d here i s t h a t of F i g u r e s 10 and 15. An experimental determination (53) has r e s u l t e d i n a v a l u e of 4.9 kcal/mole a t -170' f o r t h e f r e e energy of a c t i v a t i o n of t h e i n v e r s i o n process of cyclohexanone. The entropy term has n o t been measured, b u t it h a s been estimated t o be t h a t f o r t h e c h a i r - t o - c h a i r i n t e r c o n v e r s i o n i n cyclohexane, i . e . , 1.4e.u. Thus t h e probable v a l u e f o r AH should be around 5 kcal/mole.

B.

Cycl ohexene

Many r e c e n t conformational c a l c u l a t i o n s have been performed on cyclohexene ( 2 , 12, 15, 54, 5 5 ) . An e x h a u s t i v e

184

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

exploration of all the possible conformations can be achieved by gradually varying all the torsion angles of the ring. These angles will thus be decreased and inverted, one after the other, similarly as in the asymmetric mode of inversion of cyclohexane (Scheme 4). Starting from the monoplanar conformation 32 (Scheme 6) (half-chair form), which has long been recognized as the more stable conformation of cyclohexene, one diminishes, in a stepwise fashion, the value of the torsion angle @2,3 (located in the 1,2 position to the double bond). For each value assigned to @2,3 the corresponding minimum energy conformation is computed. One observes that the decrease of @2,3 induces a decrease of the absolute values of the two f_ollowing torsion angles: @3,4 and @4,5. The energy of the ring increases slowly and the 1,2-diplanar form.33 is reached. If negative and stepwise increasing values are then given to @2,3 (conformations 3 4 ) , the corresponding values of @3,4 continue to decrease and reach zero in the 1,3-diplanar form 35. Increasing positive values of @3,4 (conformations 36) lead to the boat form* 37 (l14-diplanarform).

Scheme 6. The possible types of conformation of cyclohexene. The torsion angle values and the relative energies (in kcal/mole) are those of ref. 2. If the process is continued in the same way, successively decreasing and inverting the two remaining torsion angles @ 5 , 6 and 06 1 , the half-chair form will be restored, but the torsion angies will have inverted signs. The transformation thus performed is an inversion process of the half-chair form. Its energy profile is given in Figure 17. *We prefer to name this conformation a "boat" instead of a "half-boat" because it is shaped like a full boat. As the "half-chair'' has half of the character of a chair, the tern "half-boat" might impart the erroneous idea that it has half of the character of a boat.

ROBERT BUCOURT

185

0

+ 15

0

-20 -39 -37

AH

'= 6.9kcol/mule

-27

-15

02.3

Fig. 17. Energy profile of the inversion of the cyclohexene half-chair form (2). The energy increases regularly in the transformation leading from the half-chair form to the boat form. Thus the energy profile of the inversion has only one maximum and is different from the energy profile of inversion of cyclohexane and cyclohexanone. Because of this, the concept of flexible forms situated in a trough of energy cannot apply to cyclohexene. The boat form of cyclohexene constitutes the transition state in the half-chair half-chair interconversion.* In the calculations of the minimum energy conformations of cyclohexene so far reported the double-bond moiety is always maintained planar. It is known, however, that a twisting of the double bond is possible and the corresponding energy has been estimated (56). Recent calculations, which differ from the earlier ones chiefly by taking into account *Another possible transition state is the fully planar form (all six atoms in a plane). However, it is not likely to be involved, owing to its high energy of 9.3 kcal/mole (2). Qualitatively speaking, the fact that the half-chair is the energy maximum in the inversion itinerary of cyclohexane and the boat is a (high) energy minimum whereas the opposite situation obtains in cyclohexene is related to the fact that the half-chair has more eclipsed bonds than the boat. In the (saturated) cyclohexane, this extra eclipsing of S 3 - S bonds is unfavorable; in contrast, in cyclohexene the Sp'-~$~bond eclipsing is energetically favored.

186

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

such t w i s t i n g of t h e double bond, imply (57) a n o t a b l e l e s s e n ing of t h e energy of t h e 1,2-diplanar form 39 (Fig. 1 8 ) . Thus, t h i s form, o f t e n c a l l e d “ s o f a “ (581, i s a b l e t o compete with t h e h a l f - c h a i r form (20% i n an equilibrium involving both forms 38 and 39). Other d i f f e r e n c e s i n t h e f o r c e f i e l d , used f o r t h e

Fig. 18. Geometry and energy of t h e t y p i c a l forms of cyclohexene involving p o s s i b l e t w i s t i n g of t h e double bond. c a l c u l a t i o n , have a l s o c o n t r i b u t e d t o a lowering of t h e energ i e s , a s shown by t h e b o a t form 4 1 , b u t t o a r e l a t i v e l y l e s s e r e x t e n t (11% f o r t h e boat form a g a i n s t 30% f o r t h e 1,2-diplanar form). The new v a l u e of 6.1 kcal/mole f o r t h e boat form i s c l o s e t o t h e c a l c u l a t e d value of 5.97 kcal/mole given e l s e where (55). The v a l i d i t y of t h e r e s u l t s obtained by t h e t h e o r e t i c a l c a l c u l a t i o n s can be estimated i n two manners. With regard t o t h e geometry, t h e t o r s i o n angle values c a l c u l a t e d from t h e c r y s t a l l o g r a p h i c d a t a (59) of a cyclohexene d e r i v a t i v e , 42, compare favorably with t h e t h e o r e t i c a l v a l u e s f o r t h e h a l f c h a i r form. Electron d i f f r a c t i o n s t u d i e s (60, 61) of cyclohexene i n t h e vapor phase (43) g i v e v a l u e s which a r e a l s o i n good agreement with theory (see Fig. 1 9 ) .

Fig. 19. Experimental determinations of cyclohexene geometry. For 43 t h e v a l u e s i n parentheses a r e those of r e f . 61. With r e s p e c t t o energy, t h e comparison between t h e measured b a r r i e r t o i n v e r s i o n , 5.3 kcal/mole (62) and t h e

187

ROBERT BUCOURT

c a l c u l a t e d v a l u e s (6.1 and 5.97 kcal/mole) i s a l s o f a v o r a b l e . The pathway of t h e i n v e r s i o n shown i n Figure 17 i s a t variance with o t h e r proposals (62, 54) which s t a t e t h a t t h e boat form i s n o t a p o t e n t i a l m a x i m u m on t h e r e a c t i o n c o o r d i n a t e b u t r a t h e r l i e s i n an energy trough, a s does t h e boat form of cyclohexane (Figure 1 3 ) . This c o n t r o v e r s i a l p o i n t , which has been f u l l y discussed elsewhere ( 6 3 ) , a r o s e from e a r l i e r s p e c i f i c h e a t measurements suggesting a v a l u e of 2.7 kcal/mole f o r t h e energy of t h e boat form of cyclohexene ( 6 4 ) . I t now seems, however, t h a t t h e boat form i s t h e most l i k e l y t r a n s i t i o n s t a t e f o r h a l f - c h a i r i n v e r s i o n i n cyclohexene and d e r i v a t i v e s , i n view of t h e f a c t t h a t energy b a r r i e r s t o i n v e r s i o n a r e highly s e n s i t i v e t o t h e b u l k i n e s s of s u b s t i t u e n t s s i t u a t e d on carbons 4 and 5 (65) ( s e e Fig. 20).

A$= 5.3

5.3

6.3

7.4

Fig. 20. B a r r i e r t o i n t e r c o n v e r s i o n of cyclohexene d e r i v a t i v e s ( i n kcal/mole) ( 6 5 ) . I f t h e t r a n s i t i o n s t a t e i s a boat form, a l l C-4 and C-5 bonds a r e t o t a l l y e c l i p s e d . The e c l i p s i n g i n t e r a c t i o n s should t h u s i n c r e a s e i n t h e sequence: F * * * H< C l * * * H < CO$H3***C02CH3, a s i s i n f a c t found f o r t h e b a r r i e r t o i n v e r s i o n of t h e cyclohexene d e r i v a t i v e s shown i n Figure 20.

C.

Small Rings

Cyclobutane d e r i v a t i v e s appear t o be e i t h e r p l a n a r o r puckered, depending on t h e i n d i v i d u a l c a s e ( 6 6 ) . For cyclobutane i t s e l f , t h e puckered form has been found, experimentally, t o be more s t a b l e , by 1.28 kcal/mole, than t h e p l a n a r one ( 6 7 ) . With an experimental value of 35' (67, 68) f o r t h e puckering angle of cyclobutane (angle c1 i n Fig. 21) t h e corresponding t o r s i o n angle v a l u e is 25' (formula 4 4 ) . T h e o r e t i c a l c a l c u l a t i o n s a l s o i n d i c a t e t h e puckered form t o be t h e most s t a b l e b u t with a lower energy d i f f e r e n c e and a l e s s e r degree of puckering (44, 6 9 ) . Cyclopentane i s a puckered f l e x i b l e r i n g c h a r a c t e r i z e d by "pseudorotation." The puckering r o t a t e s around t h e r i n g without an 'energy b a r r i e r , t h u s g i v i n g r i s e t o an i n f i n i t y of conformations which d i f f e r only i n bond and

188

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

Fig. 21.

Torsion angles in cyclobutane and cyclopentane.

torsion angles (70). It has been the subject of many theoretical calculations (20, 43, 44, 71, 72). A recent electron diffraction study (73) is in accord with a puckering amplitude which corresponds to the geometry of formulas 45 and 46 of Figure 21 for the envelope (C, symmetry) and the half-chair form (Cg symmetry), respectively. These two typical symmetric forms are only two particular points along the strain-free pseudorotation circuit. In order to determine the torsion angles of any of the infinity of forms which a regular cyclopentane ring can assume in the pseudorotation course, a simple method of calculation has been devised (74). It is based on the maximum value, $ m a , which a torsion angle can adopt. This maximum is reached in the half-chair form (for example, $ m a = 42O in the case of Fig. 21). A conformational parameter, "the phase angle A , " is introduced to define the coordinate along the pseudorotation circuit. If the phase angle A is set to zero at the half-chair form, then the following equation: A 03 = Qmax c o d 5 + j6)wherej = 0, 1, 2, 3, 4; 6 = 144O

gives the simultaneous variations of the torsion angles 00, 01, 02, 03, and 04 of the cyclopentane 47. A variation of A from 0 to 720' gives a description of the entire pseudorotation circuit. (Values of A varying from 360 to 720' yield the mirror images of the conformations already encountered from 0 to 360O.)

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ROBERT BUCOURT

Cyclopentene , w i t h i t s z e r o t o r s i o n a n g l e imposed by t h e double bond, can only adopt t h e envelope conformation. From microwave i n v e s t i g a t i o n s (75) and t h e o r e t i c a l approaches ( 6 4 , 76, 7 7 ) , t h e s t r u c t u r e shown i n 48 i s t h e most p r o b a b l e (see pp. 101 and 108 i n r e f . 7 8 ) . The d e g r e e of f l a t t e n i n g i s

g r e a t e r f o r cyclopentene t h a n f o r cyclopentane.

D. Medium R i n g s This s e c t i o n i s l i m i t e d t o an i n d i c a t i o n of how t h e probl e m of t h e geometry of medium r i n g s can be approached i n terms of t o r s i o n angles. The geometry of medium r i n g s h a s been w e l l s t u d i e d theor e t i c a l l y and d e s c r i b e d i n terms of t h e magnitude of t h e i r t o r s i o n a n g l e s (72, 7 9 ) . The f l e x i b i l i t y of t h e s e r i n g s allows them t o adopt a g r e a t number of shapes. A t o p o l o g i c a l convention has been devised f o r d e f i n i n g a l l t h e p o s s i b l e symmetric conformations of medium r i n g s and t h e i r i n t e r r e l a t i o n s ( 7 9 ) . An a x i s o r a p l a n e of symmetry i s denoted by a h o r i z o n t a l symmetry l i n e and above and below t h i s l i n e one p l a c e s t h e s i g n s of t h e t o r s i o n a n g l e s ( a z e r o t o r s i o n a n g l e i s r e p r e s e n t e d by 0 ) . When a bond i s b i s e c t e d by t h e element of symmetry, i t s s i g n ( o r 0 ) appears a t t h e end of t h e symmetry l i n e ( i n t h e c a s e of a p l a n e of symmetry it can o n l y be 0 ) . The u s e of t h i s n o t a t i o n i s i l l u s t r a t e d i n Fig. 22 by t h e r e p r e s e n t a t i o n of both t h e C, and C2 conformations of cyclopentane (compare with conformations 45 and 46 of F i g . 2 1 ) and b o a t conversion of by t h e r e p r e s e n t a t i o n of t h e c h a i r cyclohexane a l r e a d y shown i n Scheme 3 (see page 1 7 8 ) .

-

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

190

Cyciopeiituiie

--+ 90 --+

envelope (Cs) Ilolf-choir ( C z )

*--

Cyclohexone

0-+

o+-

Choir

Fig. 22.

++-

-0+

-+o-

Boot

Topological convention for ring compounds.

The four possible symmetric conformations of cycloheptane are given in Figure 23 with the detailed geometry of the most stable one, the twist-chair form. The chair and twist-chair forms as well as the boat and twist-boat forms are interconvertible by pseudorotation.

Chair

Twlst-chuir

Twtst-chair

y=ap ++-0

Boat

1 :

++

Twist-boot

Fig. 2 3 . Symmetric conformations of cycloheptane. The simplified conventional notations (by means of the signs of the torsion angles) which are given here reflect the dispositions of the perspective views in the figure. Because the views of the twist-chair and twist-boat forms are seen along the symmetry axis their conventional notations have been oriented in the same way. The conformations of cyclooctane may be divided into three families of interconvertible symmetric forms. The familiar crown form belongs to a family characterized by the regular

ROBERT BUCOURT

191

alternation of all the signs of their torsion angles (formula In the symmetric crown form, all torsion angle values equal 92'. Among two other less symmetric forms, the 0 2 form 50 represents the minimum energy form of this family. The interconvertible symmetric forms of the second family are (a)the familiar chair form 52 with its derivated D, form 52 of lower energy, ( b ) a centrosymmetric form 55 which represents a maximum in the interconversion energy profile of this family, and ( c ) the boat-chair form 5 4 . This latter form is the lowest energy member of the second family of conformations and also of all the symmetric forms of cyclooctane here described. The highest energy member is represented by the tub form 55 which, with the boat form 56, belongs to the third family of conformations. As the transition barriers from one family to the others are relatively low, cyclooctane is a very mobile conformational mixture at ordinary temperature (79) 49 in Fig. 24).

.

W -+-+ +-+-

Cmwn f o r m

(49)

- i - e ' Q O

S

O

-++- -++- ,

Fig. 24. Symmetric forms of cyclooctane. The simplified conventional notations by means of the signs of the torsion angles reflect the dispositions of the perspective views. Thus the notation of 52 is rotated by 90'.

192

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

IV.

A.

P O L Y C Y C L I C MOLECULES

S t e r i c R e l a t i o n s h i p s a t a Ring J u n c t i o n

In a polycyclic molecule a fusion between two rings represents a region where the deformation of one ring can be transmitted to the other. This is of prime importance in the phenomenon of conformational transmission (3-5) and is discussed here in detail. 1.

trans Fusion

When two rings are fused in a trans manner (drawings 57 and 60 of Fig. 2 5 ) their Newman projections 58 and 61 show that the "torsion angles of junction," 0 and O', are of opposite signs. (A "torsion angle of junction" is the torsion angle in each ring which has the common bond as its central bond.) The signs are determined by the a or B orientations of

* ax R o x

R

ox ROX.

Signs ox R'ax R'

(60)

:

opposite and fixed.

Deformations

:

in opposite directions

(59) R'

Fig. 25. Rules of conformational transmission at a trans junction. Signs: opposite and fixed. Deformations: in opposite directions. the angular substituents R and R' and are consistent with the fact that, in the case of a trans fusion, the angular substituents are always axially orientated to both rings. We

193

ROBERT BUCOURT

have seen b e f o r e (Sect. 11-B, Figs. 3c and e , page 164) t h a t , i f one follows t h e sequence of t h e s i g n s of t h e t o r s i o n a n g l e s of a r i n g i n a clockwise f a s h i o n , a B a x i a l s u b s t i t u e n t i s preceded by + and followed by -, and v i c e v e r s a f o r an a a x i a l s u b s t i t u e n t . I t can be seen from t h e drawings 57 and 60 of Figure 2 5 t h a t t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n a r e accordingly r e l a t e d t o t h e o r i e n t a t i o n s of t h e a x i a l s u b s t i t uents. (The dashed arrows r e p r e s e n t t h e d i r e c t i o n of observat i o n of t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n . ) The Newman p r o j e c t i o n 59 shows t h e r e s u l t of a r i n g deformation. When t h e geometry of t h e r i n g on t h e left-hand s i d e i s a l t e r e d i n such a way t h a t it causes an opening of t h e t o r s i o n angle of j u n c t i o n @, t h e f i g u r e i n d i c a t e s t h a t t h e t o r s i o n angle of j u n c t i o n @ ' i n t h e r i n g on t h e right-hand s i d e undergoes a closing.* Conversely, a r i n g deformation which causes a c l o s i n g of t h e t o r s i o n angle of j u n c t i o n w i l l induce an opening of t h e t o r s i o n angle of j u n c t i o n i n t h e o t h e r r i n g . A t a t r a n s j u n c t i o n , t h e deformation i s t r a n s m i t t e d i n t h e opposite d i r e c t i o n t o t h e one by which it i s induced. From a q u a n t i t a t i v e p o i n t of view, t h e t r a n s m i t t e d deformation should have t h e same magnitude a s t h e inducing one. I n o t h e r words, if each system of t h r e e bonds ( b l , b2, b3 and b i , b i , b$ i n Fig. 26a) connected t o t h e common bond c were symmetrically disposed around it (Fig. 2 6 b ) , t h e sum of t h e a b s o l u t e v a l u e s of t h e t o r s i o n a n g l e s of j u n c t i o n should equal 120'. However, t h i s symmetry c o n d i t i o n h o l d s p r a c t i c a l l y

R

Fig. 26.

Ring junction.

*The t h r e e bonds i n f r o n t of t h e Newman p r o j e c t i o n form a r e l a t i v e l y r i g i d system because they a r e connected t o t h e same carbon atom; t h u s a r o t a t i o n of one bond must induce a r o t a t i o n of t h e o t h e r two i n t h e same d i r e c t i o n .

194

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

never f o r disymmetric s u b s t i t u t i o n (R # R') (80, 81) o r noni d e n t i c a l valency angle deformations i n both rings. When a t l e a s t one of t h e two angular s u b s t i t u e n t s i s hydrogen (R and/ or R' = H) an approximative value of 110' may be empirically chosen a s giving l e s s e r r o r than t h e 120° value (see p. 451 i n r e f . 81). Only when R and R ' a r e both a l k y l groups may t h e approximative value of 120' be used.

2.

cis Fusion

I n t h e Newman projection 63 corresponding t o t h e c i s fusion 62, both t o r s i o n angles of junction a r e p o s i t i v e (see Fig. 2 7 ) . When one t o r s i o n angle i s closed, a s shown i n t h e projection 6 4 , t h e t o r s i o n angle of junction i n t h e other r i n g

eq Rox.

ox Req

Fig. 27. Rules o f conformational transmission a t a c i s junction. Signs : i d e n t i c a l ; can be inverted simultaneously. Deformations : i n same d i r e c t i o n .

ROBERT BUCOURT

195

i s a l s o c l o s e d (and conversely, an opening would have g i v e n r i s e to an opening i n t h e o t h e r r i n g ) . I f t h e r o t a t i o n i n d i c a t e d i n p r o j e c t i o n 64 i s continued, t h e three bonds i n f r o n t of t h e p r o j e c t i o n can p a s s over t h e r e a r bonds, g i v i n g t h e new d i s p o s i t i o n 65 i n which t h e t o r s i o n a n g l e s of j u n c t i o n are b o t h negative. Thus, a t t h e s i t e of c i s f u s i o n t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n can be simultaneously i n v e r t e d . Contrary to t h e s i t u a t i o n i n t r a n s f u s i o n , t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n i n c i s f u s i o n are n o t f i x e d ( t h e y This i s t h e r e a s o n why a c i s f u s e d can be both + o r b o t h -1. j u n c t i o n i s f l e x i b l e while a t r a n s f u s e d j u n c t i o n i s r i g i d . I n c i s f u s i o n t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n a r e n o t r e l a t e d to t h e a o r f3 o r i e n t a t i o n s of t h e a n g u l a r subs t i t u e n t s , a s i n t r a n s f u s i o n . T h i s can be s e e n from F i g u r e 27: I f t h e drawing 63 i s r o t a t e d by 180' i n t h e p l a n e of t h e f i g u r e , t h e r e r e s u l t s t h e p r o j e c t i o n 66 which corresponds to t h e c i s f u s i o n 67 w i t h b o t h a n g u l a r s u b s t i t u e n t s R and R ' a o r i e n t a t e d . However, t h e a x i a l i t y of R and R ' i s always r e l a t e d to t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n . As i n d i c a t e d i n t h e r e p r e s e n t a t i o n s 62 and 67, each a n g u l a r subs t i t u e n t i s a x i a l to one r i n g and e q u a t o r i a l to t h e o t h e r , according to t h e s i g n s of t h e t o r s i o n a n g l e s of j u n c t i o n . A s shown i n F i g u r e 27, t h e v a l u e s of t h e two t o r s i o n a n g l e s of j u n c t i o n a t a c i s f u s i o n should be t h e same; t h e t r a n s m i t t e d deformations should a l s o be i d e n t i c a l . However, € o r t h e same r e a s o n s a s b e f o r e , t h i s r u l e must be regarded as an approximation. A s w i l l be seen i n Sect. V , t h e r u l e s given h e r e f o r t r a n s and c i s f u s i o n , although approximative, c o n s t i t u t e a good b a s i s f o r t h e a n a l y s i s of conformational t r a n s m i s s i o n .

3.

mas i- tr an s and &uasi-cis Fusions

I f a j u n c t i o n i n v o l v e s one t r i g o n a l carbon atom, as i n ( a ) one F i g u r e 28, t h e r e a r e two p o s s i b i l i t i e s of j u n c t i o n : having o p p o s i t e s i g n s f o r t h e t o r s i o n a n g l e s of j u n c t i o n as i n a t r a n s f u s i o n , which f o r t h i s r e a s o n i s c a l l e d a quasi-trans f u s i o n ( 6 8 ) , and ( b ) a n o t h e r having t h e same s i g n s f o r t h e t o r s i o n a n g l e s of j u n c t i o n , as i n a c i s f u s i o n , and which i s c a l l e d a quasi-cis f u s i o n (69) ( 8 2 ) . A c a s e of q u a s i - c i s f u s i o n i s g i v e n by 26-acetoxytestost e r o n e ( 7 0 ) ; an X-ray a n a l y s i s of i t s 1 7 - a c e t a t e d e r i v a t i v e (83) has shown an i n v e r t e d h a l f - c h a i r conformation f o r t h e A r i n g which corresponds to t h e q u a s i - c i s f u s i o n 7 1 . Testost e r o n e i t s e l f e x h i b i t s t h e normal h a l f - c h a i r conformation f o r r i n g A (841, corresponding to t h e q u a s i - t r a n s f u s i o n 72.

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

196

R

Fig. 28.

R

Fusion involving an 8p2-carbon atom.

(71)

2 p-acetoxytestmtemne

0

A I-

de hydrutestosterune

(73)

Testosterone

(72)

A quasi-cis fusion should, a priori, be of higher energy than the corresponding quasi-trans fusion as the result of the

197

ROBERT BUCOURT

opening of the torsion angle of junction @ ' (formula 69). Consequently, a quasi-cis fusion would normally occur only when conformational parameters unfavorable to the quasi-trans fusion are present. This is the case of 2%-acetoxytestosterone in which the 2%-acetoxy group is equatorial in 71. In conformation 72 it would be axial and give rise to a severe 1,3diaxial interaction with the angular methyl group. Formula 7 3 shows an example of a quasi-cis fusion caused by a geometrical change (an additional double bond in ring A of testosterone) (85). As can be seen from Figure 29, profiles b and C of quasicis fused molecules show a characteristic folding at the site of junction between rings A and B in comparison with profile U of a quasi-trans fusion. The similarities between these

I _

0. 1-

a) testosterone (yum/-tmmfision)

b)

A'- dehydrotestostemne (yuosi-crsfision)

4

c) 2

p - ocetoxytestosterone (yuosicjs thsion)

Fig. 29. Profiles of quasi-trans and quasi-cis fusions from X-ray determinations (83, 8 5 ) .

198

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

profiles and those of the classical trans and cis fusions account for the proposed nomenclature of quasi-cis and quasitrans fusions. Another point of analogy lies in the axiality of the angular substituent. In a quasi-trans fusion, the angular substituent is axial to both rings, as in a trans fusion; in a quasi-cis fusion it is axial only to one ring, as in a cis fusion (see the torsion angle values in formulas PI, 72, and 73 and the profiles a, b, and c in Fig. 2 9 ) . The appearance of quasi-cis fusion is not as rare as might be thought. The "folded" conformation of levopharic acid ( 7 4 ) , for example, is another case of quasi-cis fusion (86) (see also ref. 87).

B.

Conformation of Polycyclic Molecules

As the aim of the present chapter is to show how the torsion angle concept can be fruitfully used in conformational analysis rather than to give an exhaustive report of all its applications, the following discussion is frequently limited to the more typical examples.

1.

Steroid Structures

In this part, it is shown how the torsion angle concept can be used to analyze, in a logical way, all the conformations which a polycyclic molecule can adopt. The steroid skeleton is chosen as an example of a polycyclic compound. The androstane ring system has the trans-anti-trans-antitrans stereochemistry shown in formula 75. At each of the three trans junctions, A/B, B/C, and C / D , the signs of the torsion angles of junction are fixed by the orientations of the angular substituents. The signs are indicated in formula 75, according to the rule discussed above. In rings B and C the two torsion angles in the 1,3 position show the same sign,

199

ROBERT BUCOURT

& &: +

A-+B H

-+

-

- + : -

(75)

A

(76)

and t h e r e f o r e , both r i n g s can adopt a c h a i r form (formula 76)". They could a l t e r n a t i v e l y adopt f l e x i b l e forms, because i n such forms t h e two t o r s i o n a n g l e s i n 1 , 3 p o s i t i o n can a l s o have i d e n t i c a l s i g n s . However, t h i s s i t u a t i o n should correspond t o a higher energy l e v e l and w i l l n o t be discussed h e r e ( f o r a f u l l discussion see r e f . 3 ) . Much more i n t e r e s t i n g t o analyze i s t h e case of 9-iSOandrostane i n which t h e hydrogen a t Cg has t h e B c o n f i g u r a t i o n . The f u s i o n between r i n g s B and C i s c i s , and t h e s i g n s of t h e t o r s i o n angles of j u n c t i o n can be both + o r -, a s i n d i c a t e d i n formulas 77 and 78, r e s p e c t i v e l y . Because two t o r s i o n angles i n t h e 1 , 3 p o s i t i o n i n r i n g C of formula 77 are of o p p o s i t e s i g n s , t h i s r i n g can no l o n g e r e x i s t i n a c h a i r form; it i s f o r c e d t o adopt a f l e x i b l e form. Ring B can exist i n e i t h e r a c h a i r form o r i n a f l e x i b l e form. Thus, f o r 7 7 , t h e r e a r e two combinations: B-chair, C - f l e x i b l e and B - f l e x i b l e , S i m i l a r l y , r i n g B i n formula 78 can only adopt a C-flexible. f l e x i b l e form, and two combinations are p o s s i b l e : B-flexible

*The c h a i r form w i l l always be chosen f o r t h e conformat i o n of r i n g A ; f l e x i b l e forms a r e a l s o p o s s i b l e b u t t h e a n a l y s i s here w i l l be r e s t r i c t e d t o t h e most s t a b l e form of t h e A r i n g . Ring D w i l l always be r e p r e s e n t e d i n t h e h a l f c h a i r form although two e n e r g e t i c a l l y e q u i v a l e n t envelope forms a r e a l s o p o s s i b l e (each corresponding to one of t h e z e r o s i n d i c a t e d i n parentheses i n formula 7 6 ) .

200

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

C-chair and B-flexible, C-flexible. Consequently, it i s possible t o consider four types of conformational arrangements f o r t h e B, C p a r t of t h e molecule: two f o r 77 and two f o r 78. Among t h e three imaginable f l e x i b l e forms c,, c2, and c 3 f o r r i n g C of 77 (see Fig. 301, t h e l a s t two, C2 and C3, are not plausible. I n C3 t h e t o r s i o n angle of junction of r i n g C corresponds t o a small angle of t h e with r i n g D (@12,13,14,8) t w i s t form (31', see page 173). This is i n c o n f l i c t with t h e demand of t h e C/D t r a n s fusion which r e q u i r e s a l a r g e value f o r t h e t o r s i o n angle of junction of r i n g C , a s can be seen i n t h e Newman p r o j e c t i o n 81. The t w i s t form c1 is more adapted t o t h e C / D t r a n s fusion because t h e t o r s i o n angle of junction The corresponds t o t h e l a r g e angle of t h e t w i s t form (65'). boat form C2 cannot occur because t h e angular methyl group on

I

Fig. 30.

. I

F l e x i b l e forms of r i n g C.

carbon -13 occupying a "flagpole" p o s i t i o n would g i v e r i s e t o a too severe i n t e r a c t i o n with t h e 98-hydrogen i n "bowsprit" position. However, a rocking toward t h e t w i s t form C1 which enables a r e l i e f of t h e "flagpole-bowsprit" i n t e r a c t i o n i s possible. Such an intermediate conformation between C1 and C2 is very l i k e l y t o occur i n t h e B-chair, C-flexible arrangement 79. A pure t w i s t form such a s C1 would g i v e a value of 31' f o r t h e t o r s i o n angle of junction of r i n g B i n 79, inducing a l a r g e d i s t o r t i o n of t h e c h a i r form. An intermediate value between 31 and 54' ( i n t h e boat form) i s better adapted. The combination B-flexible, C-flexible i s shown i n formula 80. The f l e x i b l e forms involved a r e probably not pure t w i s t forms. A t t h e A/B t r a n s fusion, a value O f 31' i n r i n g B would induce an unfavorably l a r g e opening of t h e t o r s i o n angle of

201

ROBERT BUCOURT

j u n c t i o n i n r i n g A. A r o t a t i o n of t h e f l e x i b l e forms of 80 toward t h e boat forms of 82 i s more probable. However, owing t o an unfavorable “bowsprit-flagpole’’ i n t e r a c t i o n i n r i n g B which involves t h e angular methyl group, t h i s l a t t e r conformat i o n 82 cannot be a t t a i n e d . Thus t h e e n e r g e t i c a l l y p r e f e r r e d geometry f o r t h e combination of C - f l e x i b l e , B-flexible must be an i n t e r m e d i a t e form between 80 and 82.

I n t h e c a s e of t h e B/C f u s i o n r e p r e s e n t e d by formula 78, t h e t h r e e imaginable f l e x i b l e forms f o r r i n g B a r e B l r B,, B , (Fig. 3 1 ) . B1 i s unfavorable because it induces a l a r g e

H, I

Fig. 31.

C

H -.

I

F l e x i b l e forms of r i n g B.

opening i n t h e a d j a c e n t A r i n g . I n t h i s r e s p e c t t h e t w i s t form B2 i s b e t t e r adapted b u t , on t h e o t h e r hand, it l e a d s t o a severe c l o s i n g a t t h e B/C junction. The boat B3 would g i v e b e t t e r values ( 5 4 O ) f o r t h e t o r s i o n a n g l e s of j u n c t i o n with r i n g s A and C , b u t it i s d e s t a b i l i z e d by a very s t r o n g

202

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

"bowsprit-flagpole" i n t e r a c t i o n between t h e 14a-methine group and t h e 5a-hydrogen. Thus an i n t e r m e d i a t e conformation between t h e t w i s t form B 2 and t h e boat form B3 i s more probable. A combination of such a conformation with a c h a i r form f o r r i n g C i s depicted i n formula 83. The o t h e r combination: B-flexi b l e , C-flexible, shown i n formula 8 4 , can be r u l e d o u t because t h e t o r s i o n angle of junction of r i n g C w i t h r i n g D corresponds t o t h e small t o r s i o n angle of t h e f l e x i b l e form, and t h i s i s opposite t o t h e demand of t h e C/D t r a n s f u s i o n 81. I n conclusion, of t h e f o u r t h e o r e t i c a l l y p o s s i b l e types of conformational arrangements, only t h r e e a r e p l a u s i b l e : t h e B-chair, C-flexible 79, t h e B-flexible, C - f l e x i b l e 80, and t h e B-flexible, C-chair 83. A s t h e f l e x i b l e form of cyclohexane has more energy c o n t e n t than t h e c h a i r form, t h e arrangements containing only one f l e x i b l e form, 79 and 8 3 , should be favored a priori. The i n t e r p r e t a t i o n of t h e Cotton e f f e c t of a 3-keto d e r i v a t i v e i n d i c a t e s , however, t h a t t h e B-flexible, C-flexible arrangement 8 0 must e x i s t and should a t l e a s t be i n equilibrium with one o r both of t h e c h a i r / f l e x i b l e forms 7 9 and 83 ( 8 8 ) . An X-ray a n a l y s i s of a 9-isoandrostane, possessing an u n s a t u r a t i o n i n r i n g A , has shown t h e presence of f l e x i b l e forms f o r both r i n g s B and C , 8 5 ( 8 9 ) . I t i s worth noting t h a t t h e presence of a t r i g o n a l carbon atom a t t h e A/B j u n c t i o n , which allows a low value f o r t h e t o r s i o n angle of j u n c t i o n of r i n g B with r i n g A , can more e a s i l y a c c e p t t h e B-flexible, C - f l e x i b l e conformation than t h e s a t u r a t e d A ring i n 80.

From t h e example above it must be concluded t h a t conformat i o n a l a n a l y s i s by means of t h e s i g n s of t h e t o r s i o n a n g l e s makes p o s s i b l e t h e l o g i c a l a n a l y s i s of a l l t h e t h e o r e t i c a l l y imaginable conformations of a p o l y c y c l i c molecule. Some of t h e s e conformations can be r u l e d o u t f o r obvious conformational o r s t e r i c reasons. However, energy d i f f e r e n c e s between t h e remaining p l a u s i b l e conformations cannot be determined without taking i n t o account a l l t h e i n t e r a c t i o n s between nonbonded

203

ROBERT BUCOURT

atoms. This can be done by f o r c e - f i e l d c a l c u l a t i o n s with t h e a i d of a computer a s i s o u t l i n e d i n t h e following p a r t . 2.

Application t o Structure-Activity Re Zationship

The n a t u r a l l y occurring s t e r o i d hormones have t h e a n t i t r a n s - a n t i - t r a n s stereochemistry between carbons 1 0 and 13, a s shown i n formula 8 6 . A g r e a t number of s y n t h e t i c analogs with a change of configuration a t t h e c h i r a l c e n t e r s have been prepared i n r e c e n t y e a r s , b u t have not l e d t o t h e r a p e u t i c a l l y valuable compounds, except f o r a s p e c i a l c l a s s of s t e r o i d s c a l l e d r e t r o s t e r o i d s which have t h e two c e n t e r s a t C g and C10 i n v e r t e d : Retroprogesterone (87) i s more a c t i v e than prog e s t e r o n e (86) (90).

0

n

The change of stereochemistry a t C q and C1o considerably a l t e r s t h e shape of t h e molecule. I n s t e a d of being p l a n a r , a s i s progesterone ( 8 8 ) , r e t r o p r o g e s t e r o n e has a b e n t shape, 89, a s has been confirmed by x-ray a n a l y s i s (91). The i n t r i guing p o i n t i s t h a t i n s p i t e of t h i s dramatic change of t h e shape of t h e molecule, r e t r o p r o g e s t e r o n e e x h i b i t s t h e a c t i v i t i e s of Progesterone. This has been t e n t a t i v e l y explained by t h e suggestion ( 9 2 ) t h a t t h e e n t i r e s t e r o i d molecule i s only of secondary importance i n t h a t it provides t h e a p p r o p r i a t e d i s t a n c e between c r u c i a l a r e a s of proper e l e c t r i c d e n s i t y and s t e r i c configuration. This apparent c o n t r a d i c t i o n between t h e b i o l o g i c a l and p h y s i c a l f i n d i n g s can be r e c o n c i l e d by t h e hypothesis t h a t , a t t h e b i o l o g i c a l r e c e p t o r s i t e , t h e molecule of r e t r o p r o gesterone undergoes a conformational change simultaneously

204

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

involving r i n g s B and C , the two r i n g s passing from c h a i r forms t o f l e x i b l e forms (Fig. 3 2 ) . A s can be demonstrated by molecular models, t h i s change can r e s t o r e t h e p l a n a r shape of t h e molecule. The e n t i r e conformation of t h e s t e r o i d molecule becomes f l e x i b l e and t h e molecule i s a b l e t o adopt an o v e r a l l shape such a s t h a t of progesterone ( s e e formula 92 and perspect i v e view 9 3 ) . I f an a n a l y s i s i s performed a s i n t h e foregoing

Fig. 32.

Conformational change i n r e t r o p r o g e s t e r o n e .

p a r t , t h r e e p l a u s i b l e conformational arrangements 90, 91, and 92 a r e obtained. The -, B/C f u s i o n can g i v e t h e double c h a i r form 90 (corresponding t o t h e p e r s p e c t i v e view 89) o r t h e twist-chair form 91. Ring C cannot adopt a f l e x i b l e form f o r t h e same reason a s before, (owing t o C/D t r a n s f u s i o n which cannot accept a small v a l u e f o r t h e t o r s i o n angle of j u n c t i o n i n the ring C). The +, + B/C f u s i o n can g i v e only t h e double t w i s t form 92 and only t h i s l a t t e r form can have a p l a n a r shape 93. Here, t h e question a r i s e s a s t o whether such a conformation i s n o t too high i n energy t o be biologica1,ly s i g n i f i c a n t . A c a l c u l a t i o n with t h e a i d of a computer program (93) gave t h e following r e s u l t s (94) f o r t h e conformations of minimum energy:

-

double t w i s t ( q u a s i - c i s ) :

AH = 7 . 3 kcal/mole

double t w i s t ( q u a s i - t r a n s ) :

AH = 2 . 7 kcal/mole

double c h a i r ( q u a s i - c i s ) :

AH = 0 . 8 kcal/mole

double c h a i r ( q u a s i - t r a n s ) :

AH = 0

kcal/mole

ROBERT BUCOURT

205

As discussed before, the notation quasi-trans and quasi-cis corresponds to the two possibilities for the A/B junction. From values shown above it is clear that the double twist form, with an energy of only 2.7 kcal/mole above the chair form, cannot be excluded from playing a part in the biological action of retroprogesterone. Indeed it is known that the energy of binding of progesterone with its receptor is about 15 kcal/mole (95). The low energy value for the double twist form of retroprogesterone is not actually surprising because in this form the severe nonbonded interactions engendered by the l0a-methyl group in the double chair form 89 are relieved.

V.

CONFORMATIONAL TRANSMISSION

In a polycyclic molecule, the distortion of one ring can exert an effect upon the reactivity at a point situated in another ring remote from the original distortion. This phenomenon was first recognized by Barton (96) and called "conformational transmission." It implies that the geometric states of the rings of a polycyclic molecule must be interdependent. The following examples will show how this phenomenon can be explained in terms of torsion angles.

A.

Octahydronaphthalene Compounds

The question to be discussed here is the following: Is it possible to predict the relative stability of the double bond in octalin, as concerns its location (1,3 or 1,4 to the position of the bond common to both rings), shown in Figure 33 for the case of a trans fusion? 1.

trans Fusion

@J(yJ@J s+ ~

(94)

Fig. 3 3 . fusion.

(95) R'

-

-

(96) R'

Torsion angles in octahydronaphthalenes - trans

206

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

When R = R ' , t h e systems 95 and 96 are i d e n t i c a l . When R # R ' , c a s e s 95 and 96 can show some d i f f e r e n c e s . But t h e geometrical d i f f e r e n c e s which can e x i s t between than are of secondary importance compared t o those e x i s t i n g with t h e isomer 94. For t h i s reason, they w i l l be considered h e r e a s e q u i v a l e n t and only one of them w i l l be r e f e r r e d t o , i . e . , t h e isomer 95. The geometrical d i f f e r e n c e s between 94 and 95 may be depicted i n terms of t o r s i o n angles of j u n c t i o n , t h e transd e c a l i n (97) being taken a s t h e b a s i s of comparison. According t o t h e empirical r u l e given f o r a t r a n s f u s i o n w i t h a t l e a s t one hydrogen a s angular s u b s t i t u e n t ( t h e sum of t h e a b s o l u t e values of t h e t o r s i o n angles of j u n c t i o n equaling l l O ' ) , t h e values of t h e t o r s i o n angles of j u n c t i o n i n t h e t r a n s - d e c a l i n (97) should be 55'. As t h i s v a l u e i s v e r y c l o s e t o t h e 56O value of t h e r e a l c h a i r form, t r a n s - d e c a l i n r e p r e s e n t s a system f r e e of geometrical s t r a i n .

I f t h e cyclohexene moiety of t h e o c t a l i n s 94 and 95 i s considered i n i t s most s t a b l e form ( t h e h a l f - c h a i r form 38 of Fig. 1 8 ) , it would induce a v a l u e of 49' f o r t h e t o r s i o n a n g l e of j u n c t i o n i n t h e s a t u r a t e d r i n g of 94 ( s e e formula 98) and a value of 65' i n 95 ( s e e formula 9 9 ) . Thus, r e l a t i v e t o t h e s t r a i n - f r e e t r a n s - d e c a l i n (97) , t h e o c t a l i n (98) can be schematically c h a r a c t e r i z e d by a c l o s i n g of 6 ' of t h e t o r s i o n angle of j u n c t i o n i n t h e s a t u r a t e d cyclohexane r i n g , whereas 99 i s c h a r a c t e r i z e d by an opening of 10'. A s t h e deformation induced i n t h e s a t u r a t e d r i n g i s more severe i n 99 (and furthermore i s an opening)*than i n 98 it may be concluded t h a t t h e t r a n s - o c t a l i n 94 should be more s t a b l e than t h e transo c t a l i n 95. I n r e a l i t y t h e deformation i s spread through both r i n g s and t h e v a l u e s of t h e t o r s i o n a n g l e s noted i n formulas 98 and 99 merely serve t o convey a g e n e r a l understanding of t h e process.

*See t h e equations on page 168 which show t h a t t h e energy i n c r e a s e of t h e cyclohexane c h a i r form i s g r e a t e r f o r an opening of t h e t o r s i o n a l angle than f o r a c l o s i n g of t h e same magnitude.

207

ROBERT BUCOURT

The e n t h a l p y d i f f e r e n c e between 94 and 95 (when R=R'=H) was a t f i r s t approximated t o l i e i n t h e r a n g e of 0.8 kcal/mole, i n f a v o r of 94 ( 1 2 ) . A r e c e n t thorough c o m p u t a t i o n a l s t u d y of t h e e q u i l i b r i u m between a l l t h e d i f f e r e n t isomers of o c t a l i n h a s g i v e n t h e v a l u e of 0.7 kcal/mole i n good agreement w i t h t h e experimental r e s u l t s (54). The c o n t r i b u t i o n of t h e a n g u l a r s u b s t i t u e n t s t o t h e s t a b i l i t y r e l a t i o n s h i p can a l s o b e e x p l a i n e d . If a t l e a s t one of t h e a n g u l a r s u b s t i t u e n t s h a s a l a r g e s t e r i c demand (such a s a methyl group, f o r example), t h e f l a t t e n i n g of t h e r i n g i n i t s v i c i n i t y , which i s imposed by t h e c l o s i n g of t h e t o r s i o n w i l l o f f e r some r e l i e f f o r i t s a n g l e of j u n c t i o n i n 98 (-6'1, 1 , 3 - d i a x i a l i n t e r a c t i o n i n t h e s a t u r a t e d r i n g and w i l l c o n t r i b u t e t o t h e s t a b i l i z a t i o n of t h i s isomer. On t h e o t h e r hand, i n 99, t h e puckering imposed by t h e t o r s i o n a n g l e opening ( + l o o ) w i l l r e i n f o r c e t h e 1 , 3 - d i a x i a l i n t e r a c t i o n s of t h e a n g u l a r s u b s t i t u e n t and w i l l c o n t r i b u t e t o t h e d e s t a b i l i z a t i o n of t h i s p a r t i c u l a r isomer ( 5 ) . A l l t h e s e p r e d i c t i o n s a r e i n good agreement w i t h t h e e x p e r i m e n t a l f i n d i n g s . The 3-OX0 A/B t r a n s - s t e r o i d s ( f o g ) g i v e a t e q u i l i b r i u m two p a r t s of t h e A2-eno1 ( 1 0 1 ) , and one The A2-en01 i s e x c l u s i v e p a r t of t h e A3-en01 ( 1 0 2 ) when R = H. l y formed when R = CH3 ( 9 7 ) . 6-Decalone i t s e l f (which would b e 3-decalone i n formula 1 0 0 , R = H , i n t h e absence of t h e remaind e r of t h e s t e r o i d ) g i v e s a A 2 / A 3 e n o l r a t i o of 72/28 ( 9 8 ) .

2.

cis Fusion

The problem i s somewhat d i f f e r e n t i n t h e case of t h e c i s fusion. Assuming t h a t t h e B r i n g of c i s - d e c a l i n i s r i g i d l y h e l d i n conformation 106 d e p i c t e d i n F i g u r e 34, one c o u l d d i r e c t l y p r e d i c t t h a t ( f o r s t e r i c r e a s o n s ) t h e A 3 isomer 104 s h o u l d be more s t a b l e t h a n t h e A2 and A' isomers 103 and 105. The double bond of t h e A 3 isomer s u p p r e s s e s two c i s - d e c a l i n - t y p e i n t e r a c t i o n s among t h e t h r e e which a r e i n d i c a t e d by arrows i n formula 1 0 6 . I n t h e A2 and A' isomers, o n l y one i n t e r a c t i o n i s suppressed. The p a r t a g e o m e t r i c a l e f f e c t of t h e t y p e

2 08

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

2 r n 8 y J fyJ

3

- -

4 R '

Fig. 34. cis fusion.

9 --

-*

+ -

R'

R'

Torsion angles in octahydronaphthalenes -

discussed for the trans isomer can play here is very difficult to estimate, because small geometrical deformations can have a great influence on the distances between the interacting hydrogens on the a face of the molecule. Such an effect could, for example, override the steric effect discussed above. A theoretical approach had reported both the A' isomer and A 3 isomer as more stable than the A2 isomer (12). However, the classification of the three isomers in the order of increasing stability had not been made. A recent force-field calculation (99) has given the following order of stability with the corresponding enthalpy differences (when R=R'=H): A?- isomer :

AH

1.2 kcal/mole

A 3 isomer:

M

1.0 kcal/mole

~1 isomer:

AH

0

This result demonstrates that the geometric effect is of paramount importance, since the A 3 isomer, which has the smallest number of interactions, is not the most stable. In the study mentioned before, ref. 5 4 , an energy increment of 0.8 kcal/mole has been attributed to the A2 isomer 103 in comparison with 204 and 705 (when R=R'=H) Such an order of stability of the three isomers is in relatively good agreement with an experimental determination of the ratios, at equilibrium, between the enol forms of the

.

209

ROBERT BUCOURT

(100).

f o u r decalones (107-110)

i

I n examples 107, 108, and 110,

H

0

(107) H ~ * - e n o t 40% A3-enol 60%

(109)

A2-enol 65% AJ-enol 35%

H

(110)

Az-enol 0% A'-enol 100%

t h e A2-enol i s t h e l e a s t s t a b l e one, and, i n accord w i t h t h e s t a b i l i t y o r d e r shown above, t h e d i f f e r e n c e i s g r e a t e r between A2- and A'-enols than between A2- and A3-enols. The decalone 1 0 9 shows a r a t i o which i s r e v e r s e t o t h e one expected, b u t it should be noted t h a t t h e t h e o r e t i c a l d i f f e r e n c e , 0.2 k c a l / mole, i s so small t h a t s l i g h t g e o m e t r i c a l d i s t o r t i o n s i n t r o duced by s u b s t i t u e n t s can e a s i l y i n f l u e n c e t h e s t a b i l i t y o r d e r . This might be t h e o r i g i n of t h e d i s c r e p a n c y between examples 107 and 1 0 9 . Furthermore, t h e c a l c u l a t i o n s a r e perhaps n o t s u f f i c i e n t l y a c c u r a t e t o c o n s i d e r such a small energy d i f f e r ence a s r e l i a b l e .

B.

Hexahydronaphthalene Compounds

A very i n t e r e s t i n g problem o c c u r s i n t h e c a s e o f t h e f u s i o n of two cyclohexene r i n g s i n t h e manner d e p i c t e d i n F i g u r e 35. I n o r d e r t o have s t a b l e isomers, t h e deformation induced by one r i n g i n a n o t h e r must correspond t o t h e demand i n t h e second r i n g . This i s t h e c a s e f o r t h e three isomers 111, 112, and 113 where both r i n g s are c i s fused. For t h e t r a n s f u s i o n 1 1 4 , t h e induced t o r s i o n a n g l e of j u n c t i o n of 65' i n t h e r i n g on t h e right-hand s i d e i s v e r y c l o s e t o t h e v a l u e of 61°, corresponding t o t h e demand of t h i s r i n g . The arrangements of double bonds shown i n formulas I l l , 112, and 113 should r e p r e s e n t u n s t a b l e isomers i n t r a n s f u s i o n compared w i t h t h e arrangement of formula 1 1 4 . Conversely, t h e arrangement of formula 114 i n c i s f u s i o n should r e p r e s e n t a n u n s t a b l e isomer compared w i t h t h e arrangements o f formulas 111, 112, and 113. The p r e f e r e n c e f o r arrangement 114 f o r a t r a n s f u s i o n

210

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

&

stable in cis fusion

65'=61'

R.

(114 stable in tmru fusion

Fig. 35.

Stability of hexahydronaphthalenes.

is substantiated by the following experimental results: The steroid ketones 1 1 5 and 1 1 6 were methylated in alkaline medium, in which the two possible enols are in equilibrium. In each case, the methylated products (101) correspond to the methylation of the stable enol predicted by the arrangement of formula 114. An analysis of the conformational transmission effect of a double bond in steroids, based on a conceptually similar method to the one given here, has also been used to explain reactivity differences at C - 2 (102). When the statements illustrated in Figure 35 were published ( 5 ) , there was no example of cis fusions corresponding to formulas 111, 112, and 113, but since then, three experimental investigations have confirmed the predictions:

ROBERT BUCOURT

211

0

0

H

Methylation of t h e s t e r o i d ketone 117 g i v e s e x c l u s i v e l y t h e type of rnethylated p r o d u c t s corresponding t o t h e arrangement 112 f o r t h e e n o l (103).

90.5 "!.

9.5

z

The e n o l a c e t y l a t i o n of t h e same s t e r o i d ketone 117 under e q u i l i b r a t i n g c o n d i t i o n s g i v e s 90.5% of t h e e n o l having t h e d i s p o s i t i o n of t h e doubl'e bonds a s i n 1 1 2 (104).

212

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

Equilibration of the enol ether of uis-A5-octalone-2 gives a mixture of the two isomers in which the one corresponding to the arrangement 113 largely predominates (105).

C.

Hydrindane Compounds

The type of compounds discussed in this part may be described as resulting from a fusion of cyclopentane with cyclohexene. Cyclopentane is a relatively flattened ring in which the torsion angle may reach a maximum of 42O without increase of the energy content (see page 188). The Newman projection 118 shows the demands of cyclopentane at a trans and cis junction. From this projection it can be seen that the torsion

angles of the half-chair form of cyclohexene (see formula 38, page 186) which best accommodate these demands are 61° for the trans fusion and 45' for the cis fusion. Therefore, the disposition of the double bond shown in formula 119 should correspond to the most stable position for a trans fusion, and that of formula 1 2 0 for a cis fusion. The disposition of 1 2 0 should represent an unstable isomer for a trans fusion, and likewise, 119 should correspond to an unstable disposition of the double bond for a cis fusion. The chlorination of the hydrindanones 121 and 122 (106) gives in each case the chlorinated product corresponding to the enol with the double bond as in 119 and 120, respectively. The nitric acid oxidation of the cis-hydrindanone ( 1 2 2 ) (107) gives exclusively the cleavage product which corresponds to the enol double-bond position corresponding to 1 2 0 . Another example can be found in steroid chemistry. It is known ( 3 ) that the double bond of A'-estrone ( 1 2 3 ) migrates

213

ROBERT BUCOURT

to position to give 124 under acidic conditions. However, this migration is not complete and is at variance with the results of chlorination of the trans-hydrindanone ( 1 2 1 )

0

(121)

H

which gives only one compound. This may be due to a steric repulsion between the hydrogens at C-11 and C-1 in 1 2 4 which destabilizes this isomer and perhaps also to greater stability of the tetrasubstituted double bond in 1 2 3 as compared to the trisubstituted one in 1 2 4 . If the geometric effect of the C/D trans fusion were reinforced by a greater f attening of ring D, the equilibrium between the 'A and compounds should be shifted toward the isomer. This is indeed the case, as shown in Figure 36 (108). Cyclopentene is flatter than cyclopentane (maximum torsion angle value of 24' as against 42O, see page 189) and, because of this, the presence of a double bond in ring D ( 1 2 5 ) causes a shift of equilibrium in favor of the A 9 ( " ) compound 226. However, this does not completely overcome the H-l/H-ll repulsion. Only with a cyclobutane ring instead of the cyclopentane ring D is the counteracting steric parameter totally overridden. The D-nor-A9(11) compound 128 gives none of the isomeric product 127 under acid treatment. Cyclobutane being probably less deformable than cyclopentene induces such a large opening of the torsion angle of ring C at the C/D trans fusion, that the 'A compound is much more destabilized than in the two former examples. Such a destabilizing effect of the C/D trans fusion toward the A8 compound is an important factor in the thermal isomerization of precalciferol ( 1 2 9 ) into calciferol ( 1 3 0 ) (109). The equilibrium mixture contains 808 of the isomerized product 1 3 0 . For the cis analog 131 the equilibrium lies far

214

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

-'A conipouriu

Fig. 36.

Ag"'!Com~und

Equilibria of A 8 and A 9 ( 1 1 ) compounds.

to the precalciferol side, (109, 1101, whereas for the D-nor compound 1 3 2 the results are in accord with a complete transformation at room temperature into the calciferol-like

ROBERT BUCOURT

215

product 133 ( 1 1 0 ) .

VI.

CONTRIBUTIONS FROM X-RAY A N A L Y S I S

S t r u c t u r e determinations by X-ray c r y s t a l l o g r a p h y a r e of extreme value a s a source of information about t h e geometry of p o l y c y c l i c molecules, b u t t h e d i s c u s s i o n here i s l i m i t e d t o only a few c a s e s , s u f f i c i e n t t o bring t o l i g h t t h e importance of X-ray c o n t r i b u t i o n s i n t h i s a r e a . The problem of t h e conformation of r i n g A i n 4,4-dimethyl3-OX0 s t e r o i d s has been t h e s u b j e c t of much d i s c u s s i o n (111). These compounds s u f f e r from a severe 1 , 3 - d i w i a l i n t e r a c t i o n i n r i n g A ( c h a i r form) between t h e angular methyl group and t h e 6-orientated methyl group a t C-4 (formula 1 3 4 ) . I t has been assumed t h a t t h e severe crowding of t h e s e two s u b s t i t u e n t s , syn-axial i n t h e c h a i r form, could d e s t a b i l i z e it i n f a v o r of a f l e x i b l e form i n which such a crowding i s avoided ( 1 1 2 ) . X-Ray d i f f r a c t i o n s t u d i e s (113) have, however, shown (formula 1 3 4 ) t h a t t h e geometry adopted by r i n g A i s a f l a t t e n e d c h a i r form. The comparison of i t s t o r s i o n a n g l e values with those i n formula 136 ( 1 1 4 ) , which corresponds t o a compound without t h e gem-dimethyl s u b s t i t u t i o n , i n d i c a t e s some degree of f l a t t e n i n g f o r 134 ( c l o s i n g of t o r s i o n a n g l e v a l u e s ) . I t

216

TORSION ANGLE IN CONFORMATIONAL ANALYSIS

ox.

46

A

-51

ox.

J ax.

OX

(134)

a f f e c t s , as expected, t h e p a r t of t h e r i n g s i t u a t e d between t h e t w o i n t e r a c t i n g a x i a l methyl groups ( t o r s i o n a n g l e v a l u e s of -51 and 47O a g a i n s t -57 and 56'1, b u t t o a g r e a t e r e x t e n t t h e r e g i o n of gem-dimethyl s u b s t i t u t i o n (go d i f f e r e n c e ) r a t h e r

ROBERT BUCOURT

217

than t h e r e g i o n of j u n c t i o n (6' d i f f e r e n c e ) . T h i s l a t t e r f a c t i s due t o t h e r i g i d i t y imparted by a t r a n s f u s i o n a t t h e s i t e of j u n c t i o n ; away from t h e j u n c t i o n t h e c y c l e i s more f l e x i b l e . I n t h e compound which l a c k s t h e a n g u l a r methyl group, formula 135, (113) t h e 1 , 3 - d i a x i a l i n t e r a c t i o n i s l e s s s e v e r e and accordingly t h e f l a t t e n i n g of t h e r i n g i s l e s s pronounced. Another i n t e r e s t i n g example i s g i v e n by l a b d a n o l i c a c i d ( 1 3 7 ) , a b i c y c l i c d i t e r p e n e (115). Ring A , b e a r i n g gem-dimethyl s u b s t i t u e n t s , shows f l a t t e n i n g analogous t o 134, b u t s l i g h t l y less prominent. T h i s may be due t o t h e f a c t t h a t i n 134 t h e presence of a carbonyl group l e n d s more f l e x i b i l i t y t o the r i n g . Another f a c t o r which can c o n t r i b u t e t o less f l a t t e n ing i n 1 3 7 i s t h e presence of an a d d i t i o n a l d i a x i a l methylmethyl i n t e r a c t i o n i n r i n g B of 1 3 7 . A s can be seen i n formula 1 3 7 , t h e c l o s i n g of t h e t o r s i o n a n g l e of j u n c t i o n i n r i n g A , due t o t h e r i n g f l a t t e n i n g , t r a n s m i t s a n opening t o t h e t o r s i o n angle of j u n c t i o n i n r i n g B. This opening t e n d s t o i n t r o d u c e a puckering i n r i n g B i n t h e v i c i n i t y of r i n g A (see Fig. 6 ) . Such a puckering i s opposed t o t h e f l a t t e n i n g t h a t t h e d i w i a l methyl-methyl i n t e r a c t i o n i n r i n g B would i n t r o d u c e i n i t s a r e a . Thus t h e geometric e f f e c t s a r e i n o p p o s i t i o n a t t h e t r a n s f u s i o n . The two 1 , 3 - d i a x i a l i n t e r a c t i o n s should induce a simultaneous f l a t t e n i n g i n both r i n g s , b u t t h i s i s incompati b l e w i t h a t r a n s f u s i o n ; o n l y one r i n g a t a t i m e can be f l a t t e n e d . To s o l v e t h i s c o n f l i c t , one of t h e a x i a l methyl groups must r e l i e v e i t s i n t e r a c t i o n s by v a l e n c e a n g l e deformat i o n s alone (without t o r s i o n a n g l e c l o s i n g ) . A s shown i n formula 1 3 8 t h e v a l e n c e a n g l e s of t h e a x i a l methyl group i n r i n g B a r e more extended (116 and 111') t h a n i n t h e f i r s t r i n g (115 and 110'). This g i v e s r i s e t o a g r e a t e r bending outward of t h e methyl group i n r i n g B and t h i s o c c u r s p r e c i s e l y i n t h e r i n g which shows no f l a t t e n i n g . I t i s u s e f u l t o n o t e t h a t t h e puckering imposed i n t h e second r i n g by t h e f l a t t e n i n g of t h e f i r s t r i n g i s confined t o t h e p a r t of t h e r i n g which does n o t bear t h e a x i a l s u b s t i t u e n t s ( t o r s i o n a n g l e v a l u e s of 61 and 5 9 O ) . I t remains t o be explained why it i s t h e r i n g A which i s f l a t t e n e d and n o t r i n g B. T h i s could be due t o t h e chain a t t a c h e d t o r i n g B: A f l a t t e n i n g o f r i n g B would inc r e a s e t h e gauche i n t e r a c t i o n s of t h e c h a i n w i t h t h e two c i s - s i t u a t e d a x i a l methyl groups. These examples show t h a t v a l e n c e a n g l e deformations can participate i n relieving steric interactions, but usually i n combination with t o r s i o n a n g l e deformations. Only when t o r s i o n angle deformations a r e f o r b i d d e n , f o r g e o m e t r i c a l r e a s o n s , w i l l valence a n g l e deformations a l o n e s u s t a i n t h e e n t i r e deformation necessary. I n formula 1 3 7 , t h e conformation of t h e s i d e c h a i n h a s a l s o been d e s c r i b e d by means of C-C-C-C t o r s i o n a n g l e values.

218

TORSION ANGLE I N CONFORMATIONAL ANALYSIS

It i s an e q u a t o r i a l , a n t i - p e r i p l a n a r b u t y l chain w i t h a carboxymethyl group g r a f t e d on t h e end. The l a s t example i s t h a t of a p e n t a c y c l i c t r i t e r p e n e d e r i v a t i v e : 2a-bromoarborinone ( 1 3 9 ) (116). This product a l s o shows a f l a t t e n e d c h a i r form f o r r i n g A , b u t with a degree of f l a t t e n i n g somewhat less than i n 1 3 4 . This may be due to t h e presence of a double bond i n r i n g C of 139 which e l i m i n a t e s t h e b u t t r e s s i n g 118-axial hydrogen of 1 3 4 . By i t s presence i n 1 3 4 , t h e 11$-axial hydrogen p r e v e n t s t h e angular methyl group from escaping t h e syn-axial Me/Me i n t e r a c t i o n by bending away from t h e a x i a l methyl group. I n 139 t h e valence angle v a l u e s , i n r e f e r e n c e to t h e angular methyl group, show some rocking toward t h e 11 p o s i t i o n . A s t h i s causes a p a r t i a l r e l i e f of t h e s t e r i c i n t e r a c t i o n s , t h e c o n t r i b u t i o n a r i s i n g from a f l a t t e n i n g of t h e r i n g i n 1 3 9 need n o t be as important a s i n 1 3 4 . Another i n t e r e s t i n g f e a t u r e i n 1 3 9 i s t h e geometry of t h e cyclohexene (C) r i n g which i s t h a t of t h e h a l f - c h a i r form, b u t with a t o r s i o n angle i n t h e 1,4 p o s i t i o n t o t h e double bond of much g r e a t e r magnitude (68O) than t h e normal value of 61O. A methyl-methyl d i w i a l i n t e r a c t i o n i n r i n g D tends t o introduce a f l a t t e n i n g i n t h i s r i n g . The v a l u e of 54O f o r i t s t o r s i o n angle of j u n c t i o n , which corresponds t o a very s l i g h t f l a t t e n i n g , s e r v e s a s an e x p l a n a t i o n f o r t h e value of 68' i n r i n g C . (The sum of t h e a b s o l u t e v a l u e s of t h e t o r s i o n angles of j u n c t i o n must be about 120' here-see page 194.) Another consequence of t h e s l i g h t f l a t t e n i n g of r i n g D a t t h e j u n c t i o n with r i n g E i s t h e puckering of t h e trans-fused cyclopentane i n comparison to t h e geometry of t h e equally trans-fused cyclopentane i n s t e r o i d 136. I t i s v e r y l i k e l y t h a t t h e very s l i g h t f l a t t e n i n g of r i n g D , i n s p i t e of t h e d i a x i a l methyl-methyl i n t e r a c t i o n it s u s t a i n s , i s a consequence of t h e l a r g e d i s t o r t i o n s t h a t a more pronounced f l a t t e n i n g would produce i n t h e a d j a c e n t r i n g s . The a c t u a l geometric s t a t e of r i n g D a l r e a d y induces e n e r g e t i c a l l y unfavorable deformations i n r i n g s C and E. The conformations which a r e discussed here a r e t h o s e determined f o r t h e compounds i n t h e c r y s t a l l i n e s t a t e . I n s o l u t i o n , t h e conformations a r e not n e c e s s a r i l y t h e same, b u t they a r e very o f t e n comparable. For example, it has been s t a t e d (113) t h a t t h e conformations i n s o l u t i o n of t h e s t e r o i d compounds 134 and 135 a r e with a high degree of p r o b a b i l i t y t h e same a s , o r a t l e a s t v e r y s i m i l a r to, t h e conformations found i n the c r y s t a l l i n e s t a t e .

V I I.

CONCLUSION

Although an e x a c t d e s c r i p t i o n of t h e geometry of a molecule r e q u i r e s a knowledge of bond l e n g t h s and valence

219

ROBERT BUCOURT

angles a s w e l l a s t o r s i o n angles it has been shown i n t h i s chapter t h a t t h e t o r s i o n angle v a l u e s r e p r e s e n t t h e most s e n s i t i v e parameters f o r t h e d e s c r i p t i o n of molecular shape. Their v a r i a t i o n s can be e a s i l y i n t e r p r e t e d and expressed i n terms which a r e very f a m i l i a r t o t h e organic chemist, e.g., type of conformation, n a t u r e of geometric d i s t o r t i o n , a x i a l i t y of s u b s t i t u e n t s , and e f f e c t s of conformational transmission. The concept of t h e t o r s i o n angle i s more and more frequentl y used i n t h e l i t e r a t u r e by c r y s t a l l o g r a p h e r s , who now v e r y o f t e n r e p o r t t h e i r r e s u l t s i n terms of t o r s i o n a n g l e v a l u e s (113, 1 1 4 ) , a s w e l l a s by those organic chemists who a r e approaching t h e geometry of organic molecules by t h e o r e t i c a l calculations. However, f o r t h e m a j o r i t y of organic chemists who d e a l mostly with molecular models, of t h e Dreiding t y p e , t h e concept can a l s o be of g r e a t value. The e s t i m a t i o n of t o r s i o n a n g l e s can e a s i l y be achieved i n such models by means of a p r o t r a c t o r ( 1 1 7 ) , and t h e r e s u l t i n g v a l u e s can s e r v e a s a b a s i s f o r t h e d e s c r i p t i o n and a n a l y s i s of molecular geometry more p r e c i s e than simple i n s p e c t i o n of t h e model.

ACKNOWLEDGMENT I would l i k e t o t a k e t h i s opportunity t o e x p r e s s my a p p r e c i a t i o n t o D r . N. C. Cohen and D r . D. Hainaut f o r t h e i r valuable c o l l a b o r a t i o n i n s e v e r a l of t h e s t u d i e s r e p o r t e d here.

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Klyne and V. Prelog, Experientia, 1 6 , 521 (1960). R. Bucourt and D. Hainaut, B u z z . SOC. Chim. France, 1967, 4562. R. Bucourt, Buzz. SOC. Chirn. France, 1964, 2000. R. Bucourt, BUZZ. SOC. Chim. France, 1962, 1903. R. Bucourt, BUZZ. SOC. Chim. France, 1963, 1262. E. L. E l i e l , N. L. A l l i n g e r , S. J. Angyal, and G. A . Morrison, ConforrnationuZ Analysis, I n t e r s c i e n c e , N e w York, 1965, p. 6. C. Romers, C. Altona, H. R. Buys, and E. Havinga, "Geometry and Conformational P r o p e r t i e s of Some Five- and Six-Membered Heterocyclic Compounds Containing Oxygen o r S u l f u r , " i n Topics i n Stereochemistry, Vol. 4 , E. L. E l i e l and N. L. A l l i n g e r , Eds., I n t e r s c i e n c e , N e w York, 1969, p. 43. J. M. Ohrt, B. A . Haner, and D. A. Norton, NahPe, 199, 1180 (1963); D. A. Norton, G. Kartha, and Chia Tang Lu, W.

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38.

39. 40. 41. 42. 43.

44. 45. 46. 47 * 48. 49. 50. 51. 52.

53. 54. 55. 56. 57. 58. 59. 60.

221

E . L. E l i e l , N. I,. A l l i n g e r , S. J. Angyal, and G. A. Morrison, Conformatiowl Analysis, Interscience, New York, 1965, pp. 38-40. P. Hazebroek and L. J. O o s t e r h o f f , Discuss. Faraday Soc., 10, 87 (1951). J. B. Hendrickson, J . h e r . Chem. Soc., 89, 7047 (1967). H. R. Buys and H. J. Geise, Tetrahedron L e t t . , 1968, 5619. N . L. A l l i n g e r , M. A. M i l l e r , F. A. Van C a t l e d g e , and J. A. H i r s c h , J . h e r . Chem. Soc., 89, 4345 ( 1 9 6 7 ) . N. L. A l l i n g e r , J. A. H i r s c h , M. A. M i l l e r , I. J . Tyminski, and F. A. Van C a t l e d g e , J . h e r . Chem. Soc., 90, 1199 (1968). N. L. A l l i n g e r , M . T. T r i b b l e , M. A. M i l l e r , and D. H. Wertz, J . Amer. Chem. Soc., 93, 1637 (1971). V. Tabacik, Tetrahedron L e t t . , 1968, 561. H. Booth and G. 2. G i d l e y , Tetrahedron L e t t . , 1964, 1449. H. Kessler, V. Gusowski, and M. Hanack, Tetrahedron L e t t . , 1968, 4665. N. L. A l l i n g e r , J. A. H i r s c h , M. A. Miller, and I. J . Tyminski, J . Amer. Chem. Soc., 91, 337 (1969). N. L. A l l i n g e r , J. A l l i n g e r , and M. A . D a Rooge, J . h e r . Chem. Soc., . 86, 4061 (1964). H. M. P i c k e t t and H. L. S t r a u s s , J . h e r . Chem. Soc., 92, 7281 (1970). F. A. L. A n e t and A. J. R. Bourn, J . h e r . Chem. SOC., 89, 760 (1967). S . L. Spassov, D. L. G r i f f i t h , E. S. Glazer, K. Nagarajan, and J. D. R o b e r t s , J . h e r . Chem. soc., 89, 88 (1967); F. A. Bovey, F. P. Hood, 111, E. W. Anderson, and R. L. Kornegay, J . Chem. Phys., 41, 2041 ( 1 9 6 4 ) ; F. A. L. Anet, M. Ahmsd, and L. D. H a l l , B O C . Chem. SOC., 1964, 145. F. R. J e n s e n and B. H. Beck, J . h e r . Chem. SOC., 90, 1066 (1968). N . L. A l l i n g e r , J. A . H i r s c h , M. A. Miller, and I . J. Tyminski, J . Amer. Chm. Soc., 90, 5773 (1968). G. F a v i n i , G. Bueni, and M. Raimondi, J . MOZ. StPuCt., 2, 137 (1968). F. H. A l l e n , E. D. Brown, D. Rogers, and J. K. S u t h e r l a n d , Chem. Commun., 1967, 1116. R. Bucourt and N. C . Cohen, u n p u b l i s h e d work. E. M. P h i l b i n and T. S. Wheeler, B O C . Chem. soc., 1958, 167. I . L. K a r l e , K. B r i t t s , and S. Brenner, Acta Crystal1OgP., 1 7 , 1506 (1964). J. F. Chiang and S. H. Bauer, J . h e r . Chem. SOC., 91, 1898 (1969).

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61. L. H. Scharpen, J. E. Wollrab, and D. P. Ames, J . Chem, Phys., 49, 2368 (1968). 62. F. A. L. Anet and M. 2. Haq, J . Amer. Chem. SOC., 87, 3147 (1965). 63. J. E. Anderson and J. D. Roberts, J . h e r . Chem. SOc., 92, 97 (1970). 64. C. W. Beckett, N. K. Freeman, and K. S. Pitzer, J . h e r . Chem. SOC., 70, 4227 (1948). 65. F. R. Jensen and C. H. Bushweller, J. h e r . Chem. soc., 92, 5774 (1969). 66. E. Adman and T. N. Margulis, J . h e r . Chem. soc., 90, 4517 (1968). 67. T. Ueda and T. Shimanouchi, J . Chem. Phys., 49, 470 (1968). 68. A. W. Burgstahler, J. Gawronski, T. F. Niemann, and B. A. Feinberg, Chem. COmn., 1971, 121. 69. J. S . Wright and L. Salem, Chem. C o m n . , 1969, 1370. 70. E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, ConformationaZ Analysis, Interscience, New York, 1965, p. 200. 71. K. S. Pitzer and W. E. Donath, J . h e r . Chem. Soc., 81, 3213 (1959). 72. J. B. Hendrickson, J . h e r . C k m . soc., 83, 4537 (1961); 85, 4059 (1963). 73. W. J. Adams, H. J. Geise, and L. S. Bartell, J . h e r . Chem. SOC., 92, 5013 (1970). 74. C. Altona, H. J. Geise, and C. Romers, Tetrahedron, 24, 13 (1968). 75. G. W. Rathjens Jr., J . Chem. P h p . , 36, 2401 (1962); S . S. Butcher and C. C. Costain, J . Idol. SpeCtPOSC., 15, 40 (1965). 76. E. L. James, "The Conformation of Cyclopentene," Thesis, University of Pennsylvania, Philadelphia, Pennsylvania, 1963; Diss. Abstr., 24, 1398 (1963). 77. D. A. Usher, E. A. Dennis, and F. H. Westheher, J . h e r . Chem. SOC., 87, 2320 (1965). 78. H. R. Buys, "Confornational Investigations on FiveMembered Ring Compounds," Thesis, University of Leiden, Leiden, The Netherlands, 1968, p. 101. 79. J. B. Hendrickson, J . h e r . Chem. SOc., 86, 4854 (1964). 80. See ref. 17, p. 504. 81. H. J. Geise, C. Altona, and C. Romers, Tetrahedron, 23, 439 (1967). 82. H. Christ01 and Y. Pietrasanta, Buzz. Soc. Chim. France, 1967, 1030. 83. w. L. Duax, C. Eger, S. Pokrywiecki, and Y. Osawa, J . Med. Chem., 14, 295 (1971). 84. A. Cooper, G. Kartha, E. M. Gopalakrishna, and

ROBERT BUCOURT 85. 86.

87. 88.

89.

90.

91. 92.

93. 94. 95. 96. 97. 98. 99. 100. 101* 102. 103. 104. 105.

223

D. A. Norton, Acta Crystalzogr., B 25, 2409 (1969). W. L. Duax, D. A. Norton, S. Pokrywiecki, and C. Eger, Steroids, 18, 525 (1971). J. M. R. Stone and I. M. Mills, Moz. Phys., 18, 631 (1970); U. Weiss, W. B. Whalley, and I. L. Karle, Chem. C o m n . , 1972, 16. H. J. C. Jacobs, "Cotton Effects and Conformations of Some Skeletally Isomeric Steroids," Thesis, University of Leiden, Leiden, The Netherlands, 1972, p. 61. H. J. C. Jacobs and E. Havinga, Tetrahedron, 28, 135 (1972). B. Hesper, H. J. Geise, and C. Ramers, Rec. Trav. Chim., 88, 871 (1969). P. Westerhof, Rec. Trav. Chim., 79, 771 (1960); E. H. Reerink, H. F. L. Schsler, P. Westerhof, A. Querido, A. A. H. Kessenaar, E. Diczfalusy and K. C. Tillinger, Nature, 186, 168 (1960). W. E. Oberhlnsli and J. M. Robertson, HeZv. Chim. Acta, 50, 53 (1967). T. Miyake and W. H. Rooks, 11, "The Relation between the Structure and Physiological Activity of Progestational Steroids," in Methods i n Hormone Research, Vol. V, Part C, R. I. Dorfman, Ed., Academic Press, New York, 1966, p. 73. R. Bucourt and N. C. Cohen, Buzz. SOC. Chim. France, 1970, 2015; N. C. Cohen, Tetrahedron, 27, 789 (1971). R. Bucourt and N. C. Cohen, unpublished results. B. W. O'Malley, M. R. Sherman, and D. 0. Toft, B O C . NatZ. Acad. S c i . U. S., 67, 501 (1970). D. H. R. Barton, XIV International Congress of Pure and Applied Chemistry; Experientia, Suppl. I1, 1955, 121; Science, 169, 539 (1970). B. Berkoz, E. P. Chavez, and C. Djerassi, J . them. S O C . , 1962, 1323. H. 0. House and B. M. Trost, J . h g . Chem., 30, 1341 (1965). R. Bucourt, N. C. Cohen, and G. Lemoine, to be published. H. Favre and A. J. Liston, Can. J . Chm., 47, 3233 (1969). F. Sondheimer, Y. Klibansky, Y. M. Y. Haddad, G. H. R. Summers, and W. Klyne, J . Chern. Soc., 1961, 767. , M. J. T. Robinson and W. B. Whalley, Tetrahedron, 2123 (1963). P. Morand, J. M. Lyall, and H. Stollar, J . Chem. SOC. (C), 1970, 2117. A. J. Liston, P. Toft, P. Morand, and H. Stollar, J . Chem. SOC. ( C ) , 1970, 2121. J. A. Berson and E. J. Walsh, Jr., J . h e r . Chem. soc., 90, 4729 (1968).

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R. Granger, M. Corbier, and P. Nau, Buzz. SOC. Chim. France, 1955, 479; 1956, 247; R. Granger and J. P. Girard, ibid., 1962, 695. 107. A. H . Cook and R. P. Linstead, J . Chem. soc., 1934,

106.

946. 108. R. Bucourt and D. Hainaut, to be published. 109. J. L. M. A. Schlatmann, J. Pot, and E. Havinga, Rec. Trav. Chim., 83, 1173 (1964). 110. H. J. Takken, Thesis, University of Leiden, 1971. 111. D. L. Robinson and D. W. Theobald, Q. Rev., 21, 314 (1967). 112. J. S. E. Holker and W. B. Whalley, B o c . Chem. Soc., 1961, 464. 113. G. Ferguson, E. W. Macaulay, J. M. Midgley, J. M. Robertson, and W. B. Whalley, Chem. Cotrormn., 1970, 954. 114. B. Busetta, C. Courseille, J. M. Fornies-Marquina, and M. Hospital, Cryst. S t m c t . corn., 1 , 4 3 (1972). 115. K. Bjher, G. Ferguson, and R. D. Melville, Acta Crystazlogr., B24, 855 (1968). 116. 0 . Kennard, L. Riva di Sanseverino, and J. S. Rollett, Tetrahedron, 23, 131 (1967). 117. R. Bucourt, B u z z . SOC. Chim. France, 1967, 1000.

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS G.

M.

KELLIE" AND F. G. RIDDELL

Department of C h e m i s t r y The University S t i r l i n g , Scotland

. . . . . . . . . . . . . . 226 The S t r u c t u r e o f Non-Chair Conformations . . . . . . 226 A. H i s t o r i c a l . . . . . . . . . . . . . . . . . . . 226 B. Geometric Consi dera t ions . . . . , . . . . . . . 228 C. Energy C o n s i d e r a t i o n s , . . . . . . . . . . . . 230 D. S u b s t i t u t e d Six-Membered Rings . . . . . . . . . 233 E. S u b s t i t u t i o n P a t t e r n s i n T w i s t Conformations . . 236 C l a s s i f i c a t i o n o f Non-Chair Conformations . . . . . 237

I. The Scope o f t h e Review 11.

111.

A. B. C.

IV.

Molecules Forced i n t o Non-Chair Forms by t h e Magnitude o f t h e S t r a i n P r e s e n t i n T h e i r C h a i r Conformations

. . . . . . . . . . . . . . 239

. . . . . . . . . . . . . . 240 X-Ray and E l e c t r o n D i f f r a c t i o n . . . . . . . . . 241 NMR Spectroscopy . . . . . . . . . . . . . . . . 242

The A p p l i c a t i o n o f P h y s i c a l Methods t o t h e Study o f Non-Chai r Conformations A. B.

No.

. . . . . . . . . . . . . . 237 Molecules w i t h an I n h e r e n t Preference f o r Nonchair Forms . . . . . . . . . . . . . . . . . 238 Molecules Constrained i n t o Non-Chair Forms by Chemical Bonding

* P r e s e n t address: c/o P r o c t o r and G a m b l e L t d . , 1, T r a f f o r d P a r k , Manchester M 1 7 1NX.

P.O.

BOX

225

Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

226

V.

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

D i p o l e Moments

D.

Vibrational

The Non-Chair Conformations o f V a r i o u s Ring Systems. 245

. . . . . . . . 245 B. N i trogen-Containing Rings . . . . . . . . . . . 252 C. Oxygen-Containing Rings . . . . . . . . . . . . 252 0. Sul f u r - C o n t a i n i ng R i ngs . . . . . . . . . . . . 258 E. Phosphorus-Containing Rings . . . . . . . . . . 260 M o l e c u l a r Mechanics C a l c u l a t i o n s . . . . . . . . . . 260 Discussion . . . . . . . . . . . . . . . . . . . . . 262 References . . . . . . . . . . . . . . . . . . . . . 264 A.

VI. VII.

. . . . . . . . . . . . . . . . . 243 Spectroscopy . . . . . . . . . . . . 244

C.

Cyclohexane and I t s D e r i v a t i v e s

I.

THE SCOPE OF THE REVIEW

Considerably less is known about the non-chair conformations of six-membered rings than is known about the generally more stable chair conformations, as a result, mainly, of the instability of non-chair forms. The literature on the subject is confused in many respects. In order to clarify much of the available material, and to rationalize this rather complicated but important area of conformational analysis, we devote the major part of this chapter to monocyclic systems, though some reference is made to polycyclic and bridged rings. This article does not pretend to represent a complete compilation of data and references, though an attempt has been made to cover important publications up to May 1972.

11.

THE STRUCTURE OF NON-CHAIR CONFORMATIONS A.

Historical

The origins of conformational analysis may be found in the work of Sachse (1) who first suggested that cyclohexane could adopt two possible arrangements, free of angle strain,

G. M. KELLIE AND F. G.

227

RIDDELL

l a t e r termed t h e c h a i r and boat conformations.* Sachse's t h e o r i e s , echoed by Mohr ( 2 1 , were, a t l e a s t i n p a r t , v e r i f i e d by HUckel's work (3) on t h e d e c a l i n s and t h e l a t e r e l e c t r o n d i f f r a c t i o n s t u d i e s of Hassel (4). H a s s e l ' s work and t h e c a l c u l a t i o n s of P i t z e r ' s group (5) demonstrated t h a t i n cyclohexane, and i n most of i t s d e r i v a t i v e s , t h e c h a i r form was by f a r t h e most s t a b l e arrangement, an i d e a which r a p i d l y gained widespread acceptance. However, it was n o t u n t i l 1950 t h a t t h e fundamental r e l a t i o n s h i p between conformation and chemical behavior was pointed o u t by Barton ( 6 ) . Although Johnson (7) noted i n 1951 t h a t c e r t a i n p o l y c y c l i c molecules would, a s a consequence of t h e i r s t r u c t u r e s , cons t r a i n a t l e a s t one six-membered r i n g i n t o a non-chair form it was not u n t i l 1957 t h a t examples were found of molecules p r e f e r r i n g t o e x i s t i n a non-chair conformation, where c h a i r conformations, a l b e i t highly s t r a i n e d , w e r e a v a i l a b l e . Barton and h i s co-workers (8) demonstrated t h a t 2-$-bromo-lanost-8ene-3-one (2 1 had an " e q u a t o r i a l " bromine atom, a s i t u a t i o n only r e c o n c i l a b l e with a nonchair conformation of r i n g A. This r e s u l t was subsequently v e r i f i e d i n an nmr study by Abraham and Holker ( 9 ) . A t about t h e same time Lyle (10) found t h a t 1,2,2,6,6-pentamethyl-4-hydroxy-4-phenylpiperidine ( 2 ) possessed an i n t e r n a l hydrogen bond, c o n s i s t e n t with t h i s compound e x i s t i n g with s u b s t a n t i a l p r o p o r t i o n s of nonchair conformations i n which hydrogen bonds can form.

1

2

*Sachse's i n t u i t i o n i n t o t h e n a t u r e of t h e two forms of cyclohexane was outstanding. He was aware t h a t one form was r i g i d and t h e o t h e r mobile, he suggested t h a t t h e mobile form was of higher energy because of "intramolecular f o r c e s , " and he observed from models t h a t t h e r e was a b a r r i e r t o t h e i n t e r conversion of one form t o t h e o t h e r .

228

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Subsequent work by o t h e r r e s e a r c h groups has been s u f f i c i e n t t o warrant, a t v a r i o u s times, reviews of t h e s u b j e c t by L e v i s a l l e s (11), Barton and Morrison ( 1 2 ) , Balasubramanian (131, E l i e l , A l l i n g e r , Angyal, and Morrison ( 1 4 ) , and Robinson and Theobald ( 1 5 ) . Despite these attempts a t a c o r r e l a t i o n of d a t a and i d e a s , a g r e a t many terms remain i n use t o d e s c r i b e t h e various non-chair forms, and many groups of workers p e r s i s t i n representing non-chair conformations a s c l a s s i c a l boats.* The need f o r a c r i t i c a l and up-to-date review becomes i n c r e a s i n g l y apparent a s one scans t h e c u r r e n t l i t e r a t u r e . Before proceeding t o examine t h e experimental evidence f o r non-chair conformations it i s important t o c l e a r l y d e f i n e t h e terms and o u t l i n e t h e concepts employed i n t h i s c h a p t e r . t

B.

Geometric Considerat ions

I t i s simplest t o consider f i r s t t h e p o s s i b l e arrangements of s i x p o i n t s c o n s t r a i n e d , a s i n cyclohexane, by t h r e e condi( a ) t h e p o i n t s a r e joined i n a r i n g , ( b ) t h e d i s t a n c e s tions: between a d j a c e n t p o i n t s a r e e q u a l , and ( c ) t h e angle subtended a t any one p o i n t by i t s two neighbors i s t e t r a h e d r a l (109O28'). I t i s p o s s i b l e t o demonstrate (16) t h a t t h e r e a r e two s e t s of arrangements t h a t f u l f i l l t h e s e r e s t r i c t i o n s . + The f i r s t s e t has only one member and i s r i g i d . This i s known a s t h e c h a i r conformation (31, of symmetry D3d. The second s e t has an inf i n i t e number of members (17) a l l of which possess a C g axis, and includes forms of symmetry C2v (boat arrangement) ( 4 ) and D 2 ( t w i s t conformation) ( 5 ) . This s e t has one degree of freedom, allowing i n t e r c o n v e r s i o n between a l l of i t s members. We d e f i n e t h i s second set a s t h e boat-twist (BT) family. This chapter i s concerned with t h i s BT family. Interconversion

*The r e p r e s e n t a t i o n of non-chair forms a s c l a s s i c a l b o a t s p e r s i s t s i n t h e l i t e r a t u r e p o s s i b l y due t o t h e l a c k of a s t e n c i l of t h e t w i s t form. Although many workers a r e a t p a i n s t o p o i n t o u t t h e inadequacy of t h i s r e p r e s e n t a t i o n , confusion must i n e v i t a b l y follow. + I n t h i s connection we s h a l l employ conformation i n t h e sense of a form having a f i n i t e e x i s t e n c e , i . e . , e x i s t i n g i n t h e v i c i n i t y of t h e minimum of a p o t e n t i a l energy w e l l . (Other authors have used "conf ormational isomer" o r "conformer" i n t h i s context.) A l l o t h e r forms of molecules w i l l be c a l l e d arrangements. *Although t h e s e r e s t r i c t i o n s do not conform t o t h e a c t u a l s i t u a t i o n i n which bond l e n g t h s and angles can change, and bond angles a r e n o t i n f a c t p e r f e c t l y t e t r a h e d r a l , they form a convenient background f o r t h e subsequent argument.

G. M.

229

KELLIE AND F. G. RIDDELL

3

4

between t h e unique m e m b e r of t h e c h a i r s e t and any member of t h e BT s e t involves breaking a t l e a s t one of t h e t h r e e condit i o n s l a i d o u t above.*

c-3 5

- =+ 6

The symmetries Dgd and C2 a r e s u f f i c i e n t t o d e f i n e t h e c h a i r and BT sets i n cyclohexane b u t do not hold with s u b s t i t u t ed six-membered r i n g s . I n t h e s e c a s e s it i s convenient t o look a t t h e s i g n s of t h e t o r s i o n a n g l e s i n t h e r i n g . For c h a i r conformations (6) t h e s e s i g n s a l t e r n a t e a s one moves round t h e r i n g s , i n t h e BT family (7, 8 ) they do not ( c f . Chap. 2 ) .

+w0

7

*On going from t h e cyclohexane system with equal bond l e n g t h s and a n g l e s t o a r i n g with unequal l e n g t h s and a n g l e s , it i s p o s s i b l e t o show (16) t h a t i n g e n e r a l t h e p r e v i o u s l y i n f i n i t e set now has only c e r t a i n allowable p o s i t i o n s u n l e s s it possesses an a x i s of symmetry ( i . e . , lI2-dioxane i s r e s t r i c t e d b u t lI4-dioxane has a continuously v a r i a b l e i n f i n i t e set).

230

NON-CHAIR

C.

CONFORMATIONS OF SIX-MEMBERED RINGS

Energy Considerations

Changing from t h e a b s t r a c t concepts of p o i n t s joined by f i x e d d i s t a n c e s and angles t o t h e p h y s i c a l r e a l i t y of molecules i n which t h e s e parameters can vary involves c o n s i d e r a t i o n of t h e r e l a t i v e e n e r g i e s of t h e s p e c i e s involved. The changes between c h a i r , boat, and t w i s t forms a r e most r e a d i l y understood i n terms of an energy map of t h e type suggested by Hendrickson (la) (Figure 1). The two p o l e s of t h e sphere

Fig. 1. S p h e r i c a l r e p r e s e n t a t i o n of chair-twist-boat interconversions i n cyclohexane. r e p r e s e n t c h a i r conformations which a r e separated by energy mountain chains from t h e BT family around t h e equator. A p r o j e c t i o n of t h i s i n two dimensions due t o P i c k e t t and S t r a u s s (19) i s shown i n Figure 2. I f a plane of symmetry i s maintained during t h e changes from a c h a i r form, t h e i n t e r conversion l e a d s t o a boat arrangement. I f an a x i s of symmetry

G.

M. KELLIE AND F. G. RIDDELL

01

231

I

I

4

20

8 12

40

0"

180 1 0

I

120

I

240

360

7

Fig. 2. Conformation map of cyclohexane Reproduced from H. M. Pickett and H. L. Straws, J . h e r . Chem. SOC., 92, 7281 (1970) by permission of the editor. Chair conformations are at 0 = 0 and 180'. The boat-twist forms are near 0 = 90°. (passing through the midpoints of two C-C bonds on opposite sides of the ring) is maintained, the interconversion leads to a twist conformation. It has been suggested (19) that the relative energies of the transition states (TS and TS') for these two processes are comparable. Interconversion between the twist and boat forms takes place around the equator of the diagram, the boat corresponding to a transition state between two twist conformations. The potential energy profiles of these processes are shown in Figures 3 and 4. Calculations (see Sect. VI) suggest that relative to the chair conformation

232

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

E ,\

/

>

lnterconversion coordinate, 8"

Fig. 3.

Chair-chair i n t e r c o n v e r s i o n i n cyclohexane.

t h e boat arrangement i s ca. 6 kcal/mole less s t a b l e and t h e t w i s t form ca. 5 kcal/mole l e s s s t a b l e . This small energy d i f f e r e n c e between boat and t w i s t forms means t h a t t h e r e i s extremely r a p i d i n t e r c o n v e r s i o n between t w i s t conformations a t room temperature. This i n t e r c o n v e r s i o n i s g e n e r a l l y c a l l e d pseudorotation, a term o r i g i n a l l y adopted by P i t z e r e t a l . ( 2 0 ) t o d e s c r i b e t h e r o t a t i o n of t h e out-of-plane displacements i n a puckered cyclopentane but now used i n a v a r i e t y of senses. We s h a l l u s e t h e term pseudorotation t o d e s c r i b e t h e process t h a t continuously i n t e r c o n v e r t s members of t h e BT family, involves motions around t h e equator of F i g u r e 1, and p r e s e r v e s a C2 axis i n cyclohexane. The entropy of a t w i s t conformation can be high r e l a t i v e t o a c h a i r f o r t h r e e reasons: (1) t h e t w i s t may have a low symmetry number r e l a t i v e t o t h e c h a i r ; ( 2 ) t h e r e could be an entropy of mixing of s e v e r a l d i f f e r e n t t w i s t conformations of s i m i l a r energy; and ( 3 1 , t h e r e may be low-frequency v i b r a t i o n s , which could be c a l l e d p s e u d o l i b r a t i o n s , about t h e mean t w i s t

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Boat

Twist

Pseudorqtation coordinate,

Fig. 4.

0"

Pseudorotation i n cyclohexane.

p o s i t i o n . I n most cases it i s u n l i k e l y t h a t c o n s i d e r a t i o n 1 i s important. Consideration 2 may a l s o be unimportant f o r reasons o u t l i n e d below. Consideration 3 i s t h e r e f o r e t h e most l i k e l y cause of any high r e l a t i v e entropy found i n t w i s t forms. A small p s e u d o l i b r a t i o n about t h e mean t w i s t p o s i t i o n may be t h e b e s t sense i n which t w i s t forms can be c a l l e d f l e x i b l e .

D.

S u b s t i t u t e d Six-Membered Rings

I f t h e six-membered r i n g c a r r i e s s u b s t i t u e n t s o r i n c l u d e s heteroatoms, then t h e symmetry and energy c o n s i d e r a t i o n s outl i n e d above no longer s t r i c t l y apply. There w i l l be s e v e r a l d i f f e r e n t t w i s t conformations of varying energy, and t h e p o s s i b l e boat arrangements w i l l a l s o d i f f e r i n energy. The symmetry of t h e s p h e r i c a l energy s u r f a c e described e a r l i e r becomes d i s t o r t e d and t h e t w i s t - t w i s t i n t e r c o n v e r s i o n b a r r i e r w i l l no longer be a s i n Figure 4 b u t may be more l i k e Figure 5. The c a l c u l a t e d p r o j e c t i o n of t h e energy s u r f a c e f o r 1,3dioxane, by P i c k e t t and S t r a u s s ( 1 9 ) , i s shown i n F i g u r e 6 ,

234

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Psuedorotation coordinate, 0"

*

Fig. 5. Possible energy graph for pseudorotation in a hetero-substituted six-membered ring. and it is seen that they calculate that there are two pairs of minimum energy non-chair conformations available of very different energies.* Although one may, with some justification, talk of the BT family in cyclohexane as "flexible ," this may be an inappropriate and misleading term for substituted rings. Related to each of the twist forms shown in Figure 5 there is a chair-twist enthalpy (and entropy) difference (AHct). Wherever possible a value of AHct should be related to a particular twist conformation although in practice it may be difficult to determine which twist conformation(s) are important. The chair-boat energy difference, which corresponds to an activation energy may be defined similarly (AHcb). By the definitions and clarifications discussed above it is hoped that much of the ambiguity associated with expressions *Althcmgh for 1,3-dioxane the calculated and experimental values differ considerably, and although four and not six minima are found by these calculations, the argument is not seriously affected.

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Fig. 6. Conformation map of lI3-dioxane. Reproduced from H. M. Pickett and H. L. Strauss, J . h e r . Chem. SOC., 92, 7281 (1970) by permission of the editor. such as "flexible" (14)I "stretched" (21)I "skewed" (22) and "twisted" (24) will disappear. If a molecule is so encumbered as to be forced into a twist conformation, the encumbrance will raise the energy of most possible twists leaving very few possible twist conformations from the original pseudorotation circuit open to the molecule. For such molecules which exist in or near the minima of potential energy wells we suggest "twist conformation" as the most appropriate description as it avoids the misleading connotations of other terms that have been used.

236

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED R I N G S

E.

Substitution Patterns i n Twist Conformations

I n c o n t r a s t t o t h e c h a i r conformation, with only two posit i o n s a v a i l a b l e f o r s u b s t i t u e n t s ( a x i a l and e q u a t o r i a l ) , t h e t w i s t conformation has t h r e e (Figure 7 ) . These a r e pseudoe q u a t o r i a l (YE) , pseudoaxial ("A) , and i s o c l i n a l * ( I c ) Although it i s d i f f i c u l t t o a s s i g n r e l a t i v e e n e r g i e s t o conformations with s u b s t i t u e n t s i n any of t h e s e p o s i t i o n s , it

.

Fig. 7 .

S u b s t i t u e n t p o s i t i o n s f o r t h e t w i s t conformation.

appears from t h e c a l c u l a t i o n s of Hendrickson (181, t h a t a methyl group i s s u b s t a n t i a l l y more hindered i n t h e YA p o s i t i o n t h a t i n e i t h e r t h e YE o r I c p o s i t i o n s and w i l l t h e r e f o r e pref e r t h e l a t t e r s i t u a t i o n s . A geminal grouping w i l l favor t h e I c p o s i t i o n s , once again avoiding t h e YA s u b s t i t u e n t . With c i s - v i c i n a l s u b s t i t u e n t s of such a s i z e a s t o i n t e r f e r e with one another, t h e t w i s t conformation o f f e r s l i t t l e r e l i e f . Three p o s s i b l e arrangements e x i s t , a l l of which have e n e r g e t i c drawbacks: YE-'PA, with an unfavorable YA group; YA-Ic, again unfavorable; and YE-Ic i n which t h e t o r s i o n angle between t h e groups i s considerably l e s s than 60' making t h e combination *This term seems t o have o r i g i n a t e d with P r o f e s s o r M. C . Whiting; c f . Hendrickson (141b).

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RIDDELL

e n e r g e t i c a l l y u n s u i t a b l e . With bulky t r a n s - v i c i n a l s u b s t i t u e n t s two t w i s t conformations m e r i t c o n s i d e r a t i o n : YE-YE, w i t h a d i h e d r a l a n g l e between t h e groups of a b o u t 60'; and YE-Ic which may be favored because of t h e l a x g e r than 60° t o r s i o n angle. I n c o n s t r u c t i n g a p p r o p r i a t e t w i s t forms of molecules t h e s e r e s t r i c t i o n s should be borne i n mind.

111.

CLASSIFICATION OF NON-CHAIR CONFORMATIONS

I t i s u s e f u l and i n s t r u c t i v e t o p l a c e molecules w i t h nonc h a i r conformations i n t h r e e nonexclusive c l a s s e s . T h i s d i v i s i o n corresponds b a s i c a l l y t o t h a t o r i g i n a l l y proposed by L a m b e r t (23).

A.

Molecules Constrained into Non-Chair Forms by Chemical Bonding

Well-known examples of such molecules a r e t w i s t a n e ( 9 ) (25) and bicyclo[2.2.2]octane ( 1 0 ) which a r e f o r c e d t o adopt non-chair forms due t o bridging. Whereas t w i s t a n e i s r i g i d l y c o n s t r a i n e d t o an almost i d e a l t w i s t form, s u b s t i t u t e d b i c y c l o [2.2.2]octanes a r e observed t o become d i s t o r t e d t o a c e r t a i n e x t e n t t o avoid t h e s t r a i n r e s u l t i n g from t h e b o a t arrangements of t h e i r r i n g s (26).

9

I n Sect. I1 it w a s noted t h a t c e r t a i n p o l y c y c l i c molecules could, by t h e n a t u r e of t h e s t e r e o c h e m i s t r y of t h e i r r i n g

11

12

238

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

junctions, force one or more rings into non-chair conformations. Trans-anti-trans-Perhydroanthracene (21) (27) and the lactone ( 2 2 ) (24) must have ring B in a boat-twist conformation. In contrast the trans-syn-trans isomers have this ring in a chair form. By measuring the enthalpy differences between the pairs of isomers (from their heats of combustion) and applying certain corrections, Johnson et al. were able to estimate M C t in cyclohexane to be 4.8 and 5.5 kcal/mole, respectively (27, 24). It is also possible to include in this class organometallic complexes such as the piperazine-palladium chloride adduct studied by Hassel and Pedersen (28). However, for the purposes of this chapter such molecules will be disregarded.

B.

Molecules w i t h an Inherent Preference f o r Non-Chair Forms

Molecules in this class tend to be rather rare as it would appear that most six-membered ring systems prefer the chair conformation for the parent compounds (14). The most studied molecule of this type is cyclohexane-lI4-dione. Dipole moments (29), Raman (29-32) and ir (31) spectroscopy, and X-ray (33) and electron diffraction (34) indicate that this molecule exists in twist conformation 13 in the solid, solution, and gas phases. The X-ray structure reveals that the carbonyl groups are inclined at an angle of 154' to one another (180' in a perfect twist). This may be the result of crystal packing forces or is perhaps indicative of a certain amount of pseudolibrating or twisting about the perfect twist form. A molecular beam deflection experiment (35) suggests that this molecule is nonpolar in the gas phase, and it has been postulated (35) that the compound exists in a chair conformation. However, the results equally fit a twist form with the carbonyl groups inclined at an angle of 180' (or one pseudolibrating rapidly about this conformation), and in view of the weight of evidence from other sources, it would appear that cyclohwane-l,4dione prefers a twist conformation. An X-ray study of the analogous cyclohexane-l,4-dioxime reveals that it also exists in a twist conformation (36).

13

14

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Kumler and Huitric (37) proposed that molecules with two or more atoms in a six-membered ring, with other than sp3 hybridization, favored twist conformations. In support of this Lautenschlaeger and Wright (38) suggested that 1,4dimethylenecyclohexane ( 1 4 ) , and its exo-tetramethyl and tetraphenyl analogs existed in non-chair forms. However, an X-ray diffraction study of the exo-tetracyano derivative (39) and a vibrational spectroscopic study of the parent molecule (30) indicated that the chair conformation is the most stable form of these molecules. Further, a dynamic process (AG = 7.5 kcal/mole) has been observed by nmr spectroscopy for the parent molecule (40). This is consistent with a chair-chair ring inversion process. The related 4-methylenecyclohexanone may also favor a chair form (41).

*

C. Molecules Forced i n t o Non-Chair Forms by t h e Magnitude o f t h e S t r a i n Present i n T h e i r C h a i r Conformations

This is the most important class of molecules to be considered in this chapter. The best known molecules in this category are those possessing axial t-butyl groups in their chair conformations, e.g. , tPanS-1,3- and Cis-lf4-di-t-butylcyclohexanes. The severe 1,3-diaxial nonbonded repulsions present in their chair conformations (e.g., 1 5 ) may be substantially relieved in certain of the twist forms (e.g., 1 6 )

t -Bu

15

which can be envisaged, i.e., those with the t-butyl groups in YE or Ic positions. A s a result these molecules may prefer to exist in twist conformations. In certain cases not only can the strains present in the chair conformations be relieved but certain stabilizing interactions may only take place in some of the twist conformations, e.g., r-1-cis-4-di-t-butylcis-2,5-dihydroxycyclohexane ( 1 7 ) (42) and the previously discussed 1,2,2,6,6-pentamethyl-4-hydroxy-4-phenylpiperidine (2) in which hydrogen bonds may be formed in twist conformations. It is important to note that compounds in this class will

240

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

R = I-Naphthyl

17

18

only prefer to exist in twist conformations if there is available a twist form (or forms) in which some or all of the strains encumbering the chair forms are substantially relieved. Although this may be valid for some of the molecules described above it does not appear so likely for r-1,3,3-trans-5-tetramethyl-l-hydroxy-c~s-5-(l’-naphthyl)-cyclohexane (43) and r-l-cis-2,3,4,5,6,-hexamethylcyclohexane ( 4 4 ) . For neither compound can one construct a twist form which does not possess two pseudoaxial substituents e.g., 18 and 1 9 . As a result, in spite of the strain due to nonbonded repulsions being greater than 6 kcal/mole (i.e., greater than AHct in cyclohexane itself) they both appear to prefer chair conformations.

19

IV.

THE APPLICATION OF PHYSICAL METHODS TO THE STUDY OF NON-CHAIR CONFORMATIONS

One of the major problems in the conformational analysis of molecules with non-chair conformations has been the lack of an exact method of assessing whether or not a molecule exists in a non-chair conformation and for examining such forms in detail. In this section we consider and examine sane of the methods applied to the study of these molecules and some of the results obtained.

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The methods available for the detection of conformational ambiguities can be ordered into a list of roughly decreasing reliability. Diffraction and microwave techniques head the list, nmr and other spectroscopic methods follow, and ORD-CD, dipole moments, and kinetic methods are among the least reliable, although still useful in suggesting anomalies for further investigation.

A.

X-Ray and E l e c t r o n D i f f r a c t i o n

Diffraction methods offer, in general, the most accurate means available for the determination of molecular geometries in the solid and gas phases (45, 46). In order to obtain meaningful results from more readily applied methods, e.g., nmr spectroscopy and dipole moments, it is vital to be able to relate parameters such as coupling constants to certain accurately known stereochemical arrangements. However, both X-ray and electron diffraction have been largely neglected as tools for the study of compounds with non-chair conformations, and it is to be hoped that the advent of more sophisticated techniques, e.g., direct methods in X-ray diffraction (471, will lead to more work in the future. Cyclohexane-l,4-dione and some of its derivatives have been studied by both techniques (33, 34). Twistane (341, bicyclo[2.2.2]octane (261, and l,4-diazabicyclo[2.2.2loctane (48) have been analyzed by gas-phase electron diffraction.

20

The use of this method for conformational studies has been reviewed by Bastiansen and co-workers (34). Certain polycyclic molecules have been shown by X-ray diffraction to possess sixmembered rings with boat-twist conformations in their structure, e.g., 22,23-dibromo-cl,8-ergost-4-en-3-one (20) has rings B and C in twist conformations (49) and lunarine hydrobromide hydrate ( 2 1 ) has ring A in a twist form (50).

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CONFORMATIONS OF SIX-MEMBERED RINGS

21

H

So far as we are aware, only two studies have been undertaken on any canpounds in category C (i.e., Sect. 1 1 1 - C ) of our classification of non-chair conformations. Both studies, by electron diffraction (51, 5 2 ) , have been on cis-l,4-di-t-butylcyclohexane which has been considered to exist in a twist conformation. Both research groups unfortunately could not unambiguously interpret the radial distribution curve obtained for this compound in terms of either a twist or chair conformation. As it now seems likely that this molecule exists with appreciable proportions of both forms, it is possible that a better theoretical curve might have been obtained by assuming a value for the chair-twist equilibrium constant.

B.

NMR Spectroscopy

As discussed above the use of nmr spectroscopy in obtaining information on non-chair conformations has been hindered by the lack of accurate structural information on model compounds suitable for nmr work. Despite this shortccnning Lambert has developed his "R" value method based on the vicinal coupling constants in six-membered rings (23, 53). He considers that values near 2.0 are indicative of almost perfect chair conformations, whereas values of R near 1.0 suggest the presence of either flattened chairs or non-chairs. However, this approach cannot distinguish between the latter two cases; thus cyclohexane-l,4-dione monoketal, which most likely prefers a chair conformation, has an identical R value (1.29) to cyclohexane-l,4-dione. Buys (54) extended this treatment to the calculation of ring torsion angles. Although his method has been very successful for compounds with chair conformations it cannot be used to evaluate the torsion angles for non-chair

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conformations. The importance of t h i s approach i s t h a t , when used a s a purely empirical t o o l , it does serve t o g i v e some i n d i c a t i o n of t h e presence of d i s t o r t e d c h a i r o r non-chair conformations. Another method has been proposed by Dalling and Grant ( 5 5 ) and developed b t h e p r e s e n t a u t h o r s (56). Dalling and Grant recorded t h e nmr s p e c t r a of a series of methylcyclohexanes and r a t i o n a l i z e d t h e s h i f t s of t h e r i n g carbon atoms using s u b s t i t u e n t parameters.* When t h e s e parameters w e r e used t o c a l c u l a t e t h e chemical s h i f t s of t h e r i n g carbon atoms of compounds considered t o adopt c h a i r conformations, e x c e l l e n t agreement was found between t h e experimental and c a l c u l a t e d values. However, f o r 1,1,2-trimethylcyclohexane r e g a r d l e s s of t h e value assumed f o r t h e equilibrium c o n s t a n t between t h e two p o s s i b l e c h a i r conformations, poor agreement w a s found. Accordingly it was suggested t h a t t h i s compound e x i s t s t o an

']5,

22

appreciable e x t e n t i n t h e t w i s t conformation 22. However, it seems u n l i k e l y t h a t t h e gauche t o r s i o n a l i n t e r a c t i o n s p r e s e n t i n t h e c h a i r conformations would be of s u f f i c i e n t magnitude t o make t h e twist t h e favored form.? I n a d d i t i o n it i s d i f f i c u l t t o construct a t w i s t form i n which much of t h i s s t r a i n can be relieved.

C.

Dipole Moments

Although Allinger and Freiberg (29) s u c c e s s f u l l y employed t h i s technique t o examine cyclohexane-l,4-dione, i t s usefulness remains l i m i t e d due t o a lack of a c c u r a t e s t r u c t u r a l informat i o n on t w i s t conformations. Care must be taken when i n t e r p r e t i n g dipole moment data. Thus Balasubramanian and D'Souza (58) determined t h e d i p o l e moment of 3- (4 '-bromophenyl) -3 ,5,5"For a discussion of t h e use of t h e s e parameters i n I 3 C nmr spectroscopy see r e f . 57. ?Two explanations can be advanced t o account f o r Dalling and Grant's observation: e i t h e r t h e molecules have a d i s t o r t e d c h a i r conformation, o r t h e parameter s e t used was n o t appropriate.

244

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

trimethylcyclohexanone and compared it with values calculated for "perfect" chair conformations as shown in Figure 0 . As their observed and calculated values for either conformation

d

CH3

A

B

R = 4-Bromophenyl pcalc'd = 2

470

walc'd

=

4.19D

polis. = 3.8212

Fig. 8. Observed and calculated dipole moments for 3-(4'-bramophenyl)-3,5,5-trimethylcyclohexanone. were not in close agreement, they proposed that the molecule adopted a twist conformation. However, allowing for some distortions in the chair forms it is possible to demonstrate that the observed figures best fit conformation B with an axial aryl group. This has now been confirmed by the X-ray (59) and nnu (60) studies of Shapiro et al., and by Allinger and Tribble's molecular mechanics calculations (61).

D.

Vibrational Spectroscopy

Infrared spectroscopy has proved to be very useful in the study of non-chair conformations. The presence of internal hydrogen bonds in molecules such as compound 2 provides extremely good evidence for the existence of substantial proportions of non-chair conformations. Moreover, this technique can be used to give quantitative information. Stolow et al. (62, 63) have been able to estimate the percentage of non-chair conformations in r-l-cis-4-dialkyl-c~s-2,5-dihydroxycyclohexanes from the intensity of the absorption due to internally hydrogen-bonded hydroxyl. Raman spectroscopy is also becoming popular as a tool for conformational studies (29, 30, 64-67). It seems likely that

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vibrational spectroscopic methods will become increasingly important in confcrmational analysis as further studies are undertaken to assign specific vibrational bands to definite molecular conformations

.

V. THE NON-CHAIR CONFORMATIONS OF VARIOUS R I N G SYSTEMS A.

Cyclohexane and I t s D e r i v a t i v e s

As cyclohexane is commonly considered the "classical" conformational analysis system it is not surprising that a large number of studies have been carried out on the non-chair conformations of substituted cyclohexanes, cyclohexanones, and cyclohexanols. Following the suggestion of Winstein and Holness (68) that the t-butyl group strongly prefers the equatorial position in cyclohexanes, attempts were made to synthesize molecules which would possess axial t-butyl groups, in order to observe whether or not they existed in non-chair forms. Allinger and Freiberg (69) contended that trans-1,3-dit-butylcyclohexane existed largely in a twist conformation and therefore estimated AHct for cyclohexane by equilibrating cis- and trans-1,3-di-t-butylcyclohexane. The figure they obtained (5.7 kcal/mole) has been adopted as a standard value but now is slightly suspect as it seems that the trans isomer exists with appreciable quantities of both chair and twist conformations. On the basis of a recent infrared spectroscopic study of the trans isomer (70) it has been proposed that the twist form is only 0.3 kcalhole more stable than the chair conformation. On this basis it would appear that AHct is slightly less than 5.7 kcalhole. This also accounts €or a proportion of the large ent.ropydifference (4.9 cal/deg-mole) between the two isomers. van Bekkum et al. ( 5 2 ) obtained heats of combustion for cis- and trans-1,4-di-t-butylcyclohexanes and found that the cis isomer was less stable than the trans by 4.7 kcal/mole. However, for reasons discussed in Sect. IV-A this cannot be considered as an estimate of AHct.

23

246

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

24

Several workers have examined Cis-4-t-butylcyclohexyltrimethylammonium iodide (23) and have considered that substantial proportions of chair conformations are present (71, 72). An nmr and ir study of compound 24 proved inconclusive (73) although it might be expected to show a slightly greater preference for the chair conformation compared with the equivalent di-t-butyl compound. r-l-tran8-3,5-Tri-t-butylcyclohexane displays an interesting nrnr spectrum (74). Only one t-butyl resonance is observed and the ring protons display a pattern inconsistent with a preponderance of the chair conformation. It is possible that a buttressing effect of the type described by Eliel (75) and Allinger (76) and their respective groups renders the chair form less stable than the chair conformation of the equivalent di-t-butyl compound. It would therefore seem likely that a useful estimate of AHct might be obtained by equilibrating the diastereoisomeric trit-butylcyclohexanes. Johnson et al. (24, 27) obtained values of M C t of 5.5 and 4.8 kcal/mole using the perhydroanthracenes and their derivatives as models for twist forms as described in Sect. 111. While this approach relies on a large n-er of assumptions, the values obtained would appear to be good approximations. During an mnr study of ring-flattening effects in cyclohexanes it was observed that for cis-1-t-butyl-4-phthalhidocyclohexane the methine proton adjacent to the phthalimido

R = Phthalimido

2s

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group had two equal vicinal couplings of 5.9 Hz (77, 78). It was demonstrated by an elegant argument that these couplings could not have arisen from a chair-chair equilibrium and the conclusion was drawn that this molecule exists in a number of twist conformations, e.g., 25. Although the nmr results indicate that non-chair forms are involved in the conformational equilibrium of this compound the possibility cannot be overlooked that a chair-twist equilibrium could have resulted in the observed couplings. Similar difficulties arise in the interpretation of the nmr spectrum of r-1-hydroxy-cis-3-trans5-di-t-butylcyclohexane considered by Feltkamp et al. to be indicative of a chair-twist equilibrium (79). Further complications inherent in the use of nmr spectroscopy can be seen in the case of c~s-1,2-di-t-butylcyclohexane (80). Two coalescences were observed, one at 35O (AG+ = 16.3 f 0.3 kcal/mole) and a second at -81' (AG* = 10.1 kcal/mole). The first process was attributed to a twist-twist interconversion and the second to a chair-twist interconversion. However, it has been shown that ring inversion barriers in cyclohexanes with large torsional interactions may be as high as 17.0 kcal/mole (44) and hence this could account for the former rate process. The second coalescence could well have arisen from slow rotation of one or both of the t-butyl groups (81). It is difficult to see how the strains present in the chair forms of this molecule can be relieved to any major extent in any twist conformation. The suggestion that l-dimethylamino-3,3-trans-5-trimethyland dimethylamino-3,3,5,5-tetramethylcyclohexane (26 and 27) exist in non-chair forms (82) seems rather unlikely as the more stable chair conformations of these molecules are unlikely to

26

27

28

have a strain energy of more than 3.5 kcal/mole due to 1,3diwial interactions. The anomalous methylation rates observed for these compounds may be accounted for by ring distortions and by the presence of axial methyl groups hindering approach of the methylating agent. Some rather interesting studies have been carried out on

248

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

cyclohexanols by Stolow et al. (42, 62, 63) and by Pasto and Rao (83, 84). Both groups found that a substantial destabilizing interaction takes place when t-butyl and hydroxyl groups are in trans-vicinal positions in chair conformations.* The magnitude of this interaction is such as to assist compounds like r-l-cis-4-di-t-butyl-c~s-2-hydroxycyclohexane (28) and r-l-t-butyl-trans-2,5-dihydroxy-cis-4-methylcyclohexane ( 2 9 ) to exist with large proportions ot twist conformations. Pasto obtained an estimate of the enthalpy difference between trans1,4-di-t-butylcyclohexane and the twist conformations of the cis-l,4 isomer from equilibration studies on 2,5-di-t-butylcyclohexanols (84). His value of 7.7 kcal/mole differs greatly from the figure determined by van Bekkum (4.7 kcal/ mole) for the enthalpy difference between the compounds. This appears to indicate either that one of the estimates is inaccurate or that c~s-1,4-di-t-butylcyclohexane exists predcnninantly in a chair conformation. For r-1-cis-4-di-t-butyltrans-2-hydroxycyclohexane (30) both chair and twist forms were identified from the ir spectrum (83). The low value of AS found for interconversion between the two conformations led the authors to suggest that the twist form of this molecule is restricted to only a small portion of its pseudorotational itinerary; i.e., the compound exists to a large extent in only one twist conformation.

I

29

t-BI: 30

31

A s early calculations indicated that M C t in cyclohexanone could be ae low as 2.7 kcal/mcle (85) many workers examine2 this systm. in a search for compounds with nonchair conformations. Aliinger et al. (31, 86) equilibrated the cis- and

*It has been inferred by the present authors and Professor Stolow, frm, an examination of r,olecular models, that although substantial strain is present in a cis-vicinal arrangement this cannot be relieved to any major extent by any possible twist conformation (see Section. 1 1 - E ) .

G. M.

KELLIE AND F. G. RIDDELL

249

trans-3,5- and -2,4-di-t-butylcyclohexanones. They proposed that trans-3,5- (31) and trans-2,4- (86) di-t-butylcyclohexanones (31 and 32) preferred twist conformations and determined M C t for cyclohexanone to be 2.7 kcal/mole, i.e., in agreement with the calculated value. The suggestion (85) that 2-t-butylcyclohexanone exists with appreciable non-chair populations, due to interactions between the t-butyl and carbonyl groups, has been criticized by Stolow (87). From an examination of certain analogous compounds Stolow concluded that the nonchair populations for this compound must be less than 10%.

1-Eu 32

33

OCH3 34

OH

A number of studies have been carried out on cyclohexanones with the destabilizing trans-vicinal interaction described above. trans-3-t-Butyl-4-hydroxycyclohexanone (33) (88) and its methyl ether 34 exist with appreciable proportions of non-chair forms. Indeed it would appear that the magnitude of this interaction increases proceeding from hydroxyl to methoxyl. Further studies have revealed that compounds 35, 36, and 37 all exist substantially in non-chair conformations

n 1-BU t -Bu

t

-

B

'OH

35

N OH

36

(89) and their epimers 38, 39, and 40, which should have more stable chair conformations, also possess substantial non-chair populations.

250

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

37

38

A considerable body of evidence now exists to demonstrate that c~s-2,5-dialkylcyclohexane-1,4-diones are more stable than their trans isomers (90, 911, in contrast to the situation in

39

40

the analogous cyclohexanes. It also seems very likely that the cis isomers exist predominantly in twist conformations, whereas the trans isomers may have large populations of both chair and twist forms, the proportion of chair conformations increasing with increasing bulk of the alkyl group. These results can be rationalized in the light of the knowledge that the parent dione prefers a twist conformation as discussed earlier (Sect. 111-B). Hence if two groups are placed in pseudoequatorial positions (as in the cis isomer 41) it is likely that this molecule will be more stable than the trans isomer which must exist either in a twist form 42 with one group pseudoaxial (assuming the carbonyl groups occupy Ic positions) or in a chair conformation with both groups equatorial, 43. The latter form, although it places the groups in unhindered positions, requires the ring to exist in a higher energy conformation; hence the cis isomers must be more

G. M. KELLIE AND F. G. RIDDELL

251

o ;==o R

'R 41

42

stable than the trans. This is precisely the reverse of what may take place in the diastereoisomeric 1,4-di-t-butylcyclohexanes in which the cis isomer can only place the groups in unhindered positions in the less stable twist conformation. The small entropy difference between the Cis- and tPan82,5-di-t-butylcyclohexane-l,4-diones (0.2 cal/deg.) may well indicate that the cis isomer exists preferentially in one twist conformation (91). This is quite possible as the conformation depicted ( 4 1 ) with the t-butyl groups in YE positions appears to be more stable than any other form which can be constructed for this molecule.

43

44

Several workers have examined 2,2,4,4,6,6-hexamethylcyclohexane-1,3,5-trione (92, 93). Dipole moment and Kerr constant measurements indicate that this molecule adopts a twist conformation, 44. In this twist conformation, although there are two YA methyl groups, they are transannularly placed with respect to carbonyl groups and therefore will experience less steric repulsions than they would in a cyclohexane twist. In addition the chair conformation has three syn-axial methyl groups and will be effectively destabilized by this interaction.

252

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

B. Nitrogen-Containing Rings At present only relatively few nitrogen compounds have been shown to exist in nonchair conformations. In many cases where twist conformations are favored, e.g., 1,2,2,6,6-pentamethyl-4-hydroxy-4-phenylpiperidine (lo), Y-tropine (94), and 2-hydroxy-2-phenylquinolizidine (951, the molecules possess internal hydrogen bonds which stabilize these conformations. Casy et al. have examined a number of 4-phenylpiperidinols. They originally suggested (see ref. 96) that trans-2,5-dimethyl4-phenyl-r-4-hydroxy-N-methylpiperidine existed in a twist form but withdrew this suggestion after a 1 3 C nmr study (97) had revealed that this compound prefers a chair form. However, for the protonated derivatives of certain compounds Casy considers that non-chair populations are appreciable in some solvents (98). The nmr spectrum of N-t-butyl-trans-3,5-dimethylpiperidone (45) has been interpreted in terms of non-chair conformations (99). However, this nmr analysis was based on first-order

t-Bu 46

40

coupling constants and therefore must be considered suspect. On a priori grounds, contributions of non-chair forms to the structure of 45 are nonetheless plausible, as severe interactions may occur between the t-butyl and methyl groups in the chair form. It is also interesting to note the recent appearance of syntheses (100) of the nitrogen analog of twistane, l-azatwistane ( 4 6 ) .

C.

Oxygen-Containing Rings

The bulk of the studies on oxygen-containing six-membered rings in terms of non-chair conformations have been carried out on the 1,3-dioxane series. So far as we are aware no tetrahydropyrans, 1,2-dioxanes, 1,4-dioxanes, and 1,3,5-trioxanes

G. M.

KELLIE AND F. G. RIDDELL

253

have been shown to prefer non-chair conformations. As a result this section is exclusively devoted to the lI3-dioxanes although some compounds with oxygen and other heteroatoms are considered in later sections. The conformational analysis of 1,3-dioxanes has been widely studied and a number of useful reviews have been published (66,101-103). Table 1 shows some of the values proposed for AHct in 1,3-dioxane. The initial suggestion made in 1965 (14) of 2.2 kcal/mole was based on the rotational barrier in methanol (1.1 kcal/mole) which was subsequently (105) shown to be an inappropriate model. The multitude of values given for this parameter are partly accounted for by a lack of concrete evidence as to which 1,3-dioxanes exist in twist conformations. Also 1,3-dioxane itself has two possible twist conformations termed (119) the 1,4 twist 47 and the 2,5 twist 48 which may well be of different energies. Hence it is possible that different workers have used different twist conformations as models of 1,3-dioxane non-chair forms.

47

48

49

Delmau and Duplan (115) considered that 4-t-butyl-4methyl-lI3-dioxane adopted a twist conformation in order to relieve the strain caused by the presence of an axial 4-methyl group. However, 'H nmr evidence proved that the preferred conformation of this molecule is a chair conformation (104, 116). Eliel et al. (109, 110) and Pihlaja and Ayras (117) proposed that molecules which would possess syn-diaxial methyl groups in their chair conformations might be more likely to have appreciable twist populations. 'H nmr coupling constants and solvent shifts (117), thermochemical (1081, and molecular rotation (118) studies tended to support this contention. Tavernier and Anteunis (116) have tackled the problem by preparing model compounds which would be forced to have an axial t-butyl (or another group of similar bulk) group in their chair conformations. In order to develop a criterion to enable a distinction to be made between chair and twist conformations they examined the sum of the vicinal coupling constants in compounds with a trans-4,6-dialkyl grouping. For the chair conformations they anticipated that the sum of the vicinal couplings between the 4, 6 and 5 protons should be

254

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Table 1. Proposed Values of MCt f o r 1,3-Dioxane

Met, kcal/mole

Date

Ref.

E l i e l , A l l i n g e r , Angyal, and Morrison

1965

14

>3.0

Anderson , e t a l .

1967

104

>3.0

R i d d e l l and Robinson

1967

105

6.8

Pihlaja

1968

106

6.2

Anteunis and Swaelensa

1970

107

6.2

Eccleston and Wyn-Jonesa

1971

113

7.2

P i h l a j a and Lucuna

1968

108

>7.2

E l i e l and Powers

1969

llob

>8.0

Nader and E l i e l

1970

109

8.3

Pihlaj a

1971

112

8.5

P i h l a j a and Jalonen

1971

111

Clay, e t a l .

1972

114

2.2

<8.9

Proposed by

a s t r i c t l y speaking t h e s e v a l u e s apply t o s p e c i f i c CMpounds which c o n t a i n a x i a l groups i n t h e i r c h a i r conformations and are t h u s more s t r a i n e d than t h e c h a i r form of 1,3-dioxane i t s e l f . A s a r e s u l t AHct estimated by t h e s e methods w i l l be a t l e a s t 3 k c a l h o l e l a r g e r than t h e v a l u e quoted. bE. L. E l i e l , J. R. Powers, Jr., and F. W. Nader, Tetrahedron, i n p r e s s . The a u t h o r s have r e p o r t e d a s l i g h t l y r e v i s e d v a l u e of >7.4 kcal/mole.

G. M. KELLIE AND F. G . RIDDELL

255

about 11 Hz,* whereas for the twist conformation 49, with the groups in pseudoequatorial positions, a value of about 15 Hz would be more likely. Table 2 presents values obtained for this parameter in a number of molecules. It can be seen that for most simple alkyl groups the chair form is favored but for trans-4,6-di-t-butyl- and tran8-4-t-butyl-6-(l'-adamantyl)1,3-dioxanes (50) the conditions for a twist conformation are met. 2,2-tran8-4,6-tetramethyl-l,3-dioxane (49) (R = R' = R" = Me) has the required 8yn-diwial methyl groups to destabilize the chair conformation (119). For unsymmetrically substituted tran8-4,6-dialkyl-lI3dioxanes the geminal coupling constant between the protons at C(2) is sensitive to conformation. The temperature variation of this coupling constant for certain 1,3-dioxanes has been measured and used to obtain an estimate of AHct in lI3-dioxane (107). Kellie and Riddell (56) modified the 1 3 C n m r method of Grant in an examination of some methyl and gem-diethyl-1,3dioxanes. Substituent parameters were evaluated for a large number of compounds which had previously been demonstrated to exist in chair forms. These parameters were then used to calculate the shifts of the ring carbon atoms of compounds suspected of existing in non-chair conformations. For 1,3dioxanes which would have a 2,4-8yn-diaxial methyl interaction in their chair forms, large deviations were observed between the experimental and calculated values, whereas for molecules with a 4,6 interaction small differences were noted. From a knowledge of the geometry of the 1,3-dioxane chair conformation it is apparent that the strain generated by the 2,4 repulsion is rather more severe than that generated by the 4,6 interaction. On this basis the authors concluded that the former compounds prefer non-chair forms, whereas those with the 4,6 interaction exist either in distorted chair forms or with appreciable proportions of both chair and twist conformations. As it is difficult to construct a twist conformation for the compounds with a 4,6 interaction, in which much of the strain present in the chair conformation is relieved, it seems more likely that distorted chair forms are favored. A similar analysis to that applied to the 13C nmr shifts has been used in a study of the boiling points and molar volumes of some 1,3-dioxanes (120). Substantial deviations between experimental and calculated values have been found for the lI3-dioxanes considered to prefer nonchair conformations. However, due to the complex nature of the forces determining such properties, care must be taken in drawing conclusions from these results.

256

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS Table 2. Vicinal Coupling Constants for lI3-Dioxanes with a trans-4,6-Dialkyl Grouping

R1

R2

R3

E 3 J ~ HZa ~,

Ref.

H

Me

Me

10.8

116

H

Et

Et

10.7

116

H

n-pr

n-Pr

10.5

116

H

i-pr

i-pr

10.9

116

H

~-Bu

i-Bu

10.6

116

H

SeC-Bu

SeC-Bu

11.1

116

H

t-Bu

t-Bu

15.6

116

H

t-Bu

1-Adamantyl

16.4

107

Me

14.8

119

Me

Me

asurn of the vicinal coupling constants between the 4, 6 and 5 protons.

G.

M.

KELLIE AND F. G.

I

I

1 -Ada man i y I 50

257

RIDDELL

51

52

In a 'H nmr study of some of these nonchair conformations (119) it has been found that the coupling constants for many of these molecules can be interpreted in terms of certain twist forms, e.g., 2,2-r-4-trans-5-cis-6-pentamethyl-l,3dioxane has couplings of 7.8 and 5.3 Hz between the 4 , 6 and 5 protons. This is inconsistent with a chair conformation but can be demonstrated to fit well the twist conformation shown (51). For certain 1,3-dioxanes it was observed that the coupling constants were temperature invariant, indicating that they exist largely in only one twist conformation. in 1,3-dioxane has been obtained from An estimate of Ah& ultrasonic relaxation experiments (113). However, at present the exact nature of the relaxation processes observed has not been unambiguously assigned. A novel method of obtaining conformational energetics using appearance potentials in the mass spectra of certain 1,3-dioxanes has been used to estimate AHct (111). This technique may well prove to be very useful for further studies on nonchair molecules. Perhaps the most interesting 1,3-dioxane studied has been trans-2,4,4,6-tetramethyl-l,3-dioxane. From an analysis of the variable-temperature nmr spectrum of this compound Eliel and Nader (109) proposed that at room temperature it existed as a 5 : lmixture of the chair and twist forms 52 and 5 3 , respectively. However, it was subsequently shown (119), from a rigorous analysis of the 220 MHz nmr spectrum of this molecule, that the twist form was the most stable conformation. In an attempt to estimate M C t for 1,3-dioxane,trans-2,4,4,6tetramethyl-lI3-dioxanewas equilibrated (109) with its cis isomer, which was known to prefer the chair conformation. However, using gzc techniques no trans isomer could be detected at equilibrium and hence the energy difference could not be determined. This problem was solved by application of a microcalorimetric method for determining conformational enthalpies (114). The enthalpy difference between the isomers was found

258

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

to be 5.8 kcal/mole and as the cis isomer has about 3.1 kcal/ mole strain due to the axial methyl group, M C t was estimated to be 8.9 kcal/mole less the strain present in 53. Although no crystal structure has been determined for a l13-dioxanewith a non-chair conformation* an X-ray diffraction study has been carried out on r-2-4,4-cis-6-tetramethyl2-(4'-bromophenyl)-l,3-dioxane (121). This cornpound has a 2,4diaxial interaction between a phenyl and a methyl group and might well have favored a twist conformation. However, the crystal structure clearly reveals that this molecule exists in a deformed chair conformation 54 in the solid state and the nmr parameters indicated that this was also the case in solution. As this molecule was at least 2 kcal/mole more stable than its trans epimer, with a 2,4-syn-diaxial methyl interaction in the chair form, it is likely that compounds with this latter interaction prefer twist conformations.

t -Bu

53

64

66

Tavernier and Anteunis (124) have recently carried out further NRT studies on l13-dioxanes. For r-2-cis-4-dimethyltrans-6-t-butyl-l,3-dioxanes they consider the nmr parameters to be consistent with a twist conformation. Anteunis et al. (125) have also studied a number of bicyclic dioxanes in which the chair conformation is highly strained. For certain of these molecules they consider that at least one ring may be forced into a twist conformation.

0. Sulfur-Containing Rings

As the 1,3-dithianesI like the 1,3-dioxanes, possess a number of features which render them attractive as a system *This is partly due to the difficult of obtaining crystalline 1,3-dioxanes suitable for an X-ray diffraction study (122, 123).

G.

M. KELLIE AND F. G. RIDDELL

259

for conformational analysis studies, a number of investigations have been carried out on their non-chair conformation. Abraham and Thomas (126) suggested that molecules such as 55 could adopt twist forms. Eliel and Hutchins (127) obtained accurate values for the conformational energies of substituents at each of the ring positions in the chair conformations. In contrast to cis-2,5-di-t-butyl-l,3-dioxane which exists in a chair conformation with an axial 5-t-butyl group (1051, C<8-2,5-dit-butyl-1,3-dithiane appears to prefer a twist conformation. From an equilibration of cis- and trans-2,5-di-t-butyl-lI3dithianes AHct was determined (127) to be 3.4 kcalbole. In the equilibration of cis- and trans-r-2-t-b~tyl-4~6-dimethyl1,3-dithianes only a small entropy difference was found. As the trans isomer appears to favor a twist conformation this tends to imply that one twist form is particularly favored, e.g., conformation 56 in which all the groups are in pseudoequatorial or isoclinal positions.

56

57

Wood and Miskow (128) considered that trimethylene sulfite might exist in a non-chair conformation but later nmr (129) and X-ray (130) diffraction studies showed that this molecule prefers a chair form with the S=O group in an axial position. t~anS-4,6-Diisopropyl-5,5-dimethyltrimethylene sulfite displays an nmr spectrum consistent with a non-chair conformation (131). In a numher of studies on 8-tetrathianes (132-134) Bushweller et al. concluded that tetramethyl-8-tetrathiane is involved in a chair-twist equilibrium. A line-shape analysis indicated that the twist form was more stable by 0.8 kcal/mole In contrast other derivatives appear to prefer chair forms. The X-ray crystal structure of the tetramethyl compound (135) does indeed reveal that it exists in a non-chair form, but it is a boat conformation and not the twist form depicted by Bushweller. At present the general implications of these results remain a little difticult to interpret, but in view of the fact that the potential energy curve for rotation about heteroatom-heteroatm bonds is vastly different (14) to

260

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

that in C-C or C-heteroatam bonds, it is possible that either twist or boat forms will be favored for such molecules. Pasanen and Pihlaja (1361, in a study of the conformational to be preferences of the 1,3-oxathianes, have estimated Uct about 6 kcal/mole in this system. This is strictly an enlightened guess, based on the value of the U c t parameter in 1,3dioxane and 1,3-dithiane.

E.

Phosphorus-Contai ni ng Ri ngs

Conformational analysis studies on six-membered ring compounds containing phosphorus are now becaning more numerous, and although few cases of non-chair conformations have been reported, some of the features of the stereochemistry of these molecules, e.g., the preference of substituents attached to phosphorus to be axial, may result in many molecules adopting twist conformations. Bentrude and Hargis (137) have examined the conformational preferences of 1,3,2-dioxaphosphorinans and have suggested that twist forms may be involved in the conformational equilibrium of tran8-2-methoxy-5-t-butyl-l,3,2dioxaphosphorinan. In the case of cis-2,5-di-t-butyl-l,3,2dioxaphosphorinan-2-one, the nmr spectrum clearly points to a non-chair form (138) and the coupling constants may be reconciled with a preponderance of the twist form 57.

VI.

MOLECULAR MECHANICS CALCULATIONS

The use of molecular mechanics methods to calculate the geometries and energies of molecules has attracted many workers. As the twist form of cyclohexane was not easily studied experimentally, the use of semiempirical and more rigorous calculations to determine relative energies and conformations became important. Pitzer (see ref. 5) was able to deduce that the chair conformation was the most stable form of cyclohexane, and Hazebroek and Oosterhoff (21) demonstrated that the twist form was more stable than the boat arrangement. The use of semiempirical techniques was developed by Hendrickson (1411, Wiberg (142), and Lifson and Warshel (143). The nature of some of these methods has been discussed by Schleyer (see ref. 144). This section is concerned with results rather than methods applied to date. In order to demonstrate the accuracy of the various calculations Table 3 shows various values calculated for AHct and m c b in cyclohexane. Hendrickson (141) first tackled the nature of the twist and boat conformations in detail. He obtained data on the exact geametry of each conformation and clearly delineated the various modes of interconversion (18) between the chair and

G. M. KELLIE AND F. G. RIDDELL

261

Table 3. Calculated Potential Energy Differences between the Chair, Twist, and Boat Forms of Cyclohexane

Chair-twist, kcal/mole

Chair-boat, kcal/mole

5.6

--

4.8

5.3

Ref.

5 21

5.1

--

6.5

6.6

139

5.6

6.4

18

5.1

6.4

76

4.9

6.6

70

4.9

6.7

140

7.9

8.5

19

85

boat-twist family and within the boat-twist family, i.e., pseudorotation. He has calculated the relative energies of methyl groups in various positions on the twist conformation. The pseudoequatorial position is of lowest energy although the Ic positions engender only slightly more strain. In contrast a methyl group in a pseudoaxial situation experiences repulsion of a similar magnitude to those found in the axial position in the chair conformation. Allinger developed Wiberg's calculation scheme and has produced some interesting results. He has calculated the effect of an axial t-butyl group on the cyclohexane ring. Although early results (76) indicated severe destabilization compared with a twist form with the group in a YE or Ic position, later predictions suggest that the conformational energy of a t-butyl group in cyclohexane is 5.4 kcal/mole (70). This indicated that trans-1,3-di-t-butylcyclohexane should contain appreciable amounts of both chair and twist forms, a result which infrared spectroscopy appears to confirm (70). Allinger and other workers have attempted by calculations, to show whether or not compounds with strained chair

262

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

conformations exist preferentially in chair or twist conformations. Cyclohexanes with a l13-8yn-diaxial methyl interaction, e.g., l,lI3,3-tetramethyl- and 1,l-tran8-3,5-tetramethylcyclohexane, are clearly shown to favor slightly deformed chair (70, 145) conformations in agreement with experiment. 3,3,5,5Tetramethylcyclohexanone also can be calculated to exist in a chair (145) conformation and most interestingly 3-phen~l-3~5~5trimethylcyclohexanone and l-phenyl-1,3,3-trimethylcyclohexane should exist in chair conformations with axial phenyl groups (61). These interesting predictions have recently been confirmed experimentally (59, 60) and the explanations offered can be applied to demonstrating that r-2,4,4-ci8-6-tetramethyl6-(4'-bromophenyl)-l13-dioxane should be more stable than its trans epimer (121). Recent calculations of M C t indicate that cyclohexane-1,4dione should be slightly more stable in the twist than the chair conformations (140),although the experimental evidence tends to point to quite a substantial free energy difference. One of Allinger's early calculations on cyclohexanone (85) indicated that M C t should be about 2.7 kcal/mole. Later determinations gave a value of 3.3 kcalhole (146), rather nearer the experimental value. M c t in silacyclohexane has been considered (147) to be about 3 kcal/mole and this may well lead to some interesting experimental work on this system. During a study of 1,3-diaxial interactions in cyclohexanes Lambert et al. (148) carried out some interesting calculations which reveal high interaction energies between a methyl group syn-axial with a bromine or iodine atom. Therefore it is possible that certain molecules with this interaction in their chair conformations may well exist in twist forms. Pickett and Strauss (19) have carried out detailed studies on cyclohexane and related oxanes using a potential energy function derived from vibrational and geometric data. At present this method gives values of AHc. which are somewhat higher than those evaluated using other techniques. However, with further refinement this method could prove very useful.

VII.

DISCUSSION

It is apparent fran many of the examples given in the previous sections that in order for a compound in section C of our classification (cf. Sect. 111-C) to prefer a twist conformation considerable strain must be present in the chair conformations and this must be substantially relieved in some of the available twist conformations. Many of the canpounds that have been put forward as examples of non-chair conformations in fact possess deformed chair conformations. Much of

G. M. KELLIE AND F. G. RIDDELL

263

the evidence has been extremely tenuous; in particular, mis interpretation of nmr spectra has led to some erroneous conclusions. In many cases ancmalous results have not been scrutinized carefully and instead the twist form has been used as a universal panacea to explain everything. In order to decide whether or not it is reasonable to consider non-chair conformations for a particular molecule all the possible forms should be examined either using models or by application of molecular mechanics computer programs. The forms of minimum energy should then be closely examined to see whether or not they fit the experimental results. Another important conclusion which may be drawn from the examples given is that for sane compounds one twist form may be considerably more stable than all others. This appears to be likely for certain cyclohexanes, 1,3-dioxanes, 1,3-dithianes, and 1,3,2,-dioxaphosphorinans. This is a good reason for abandoning the term "flexible" previously used to describe the boat-twist family. However, it should always be remembered that the molecule may be able to pseudolibrate around one twist form and hence gain some of the entropic stabilization commonly associated with the twist form. It has frequently been assumed that ASc. should be large for most molecules and hence this has become adopted as a criterion of whether or not a molecule exists in a twist form. Clearly the discussion above shows that this may not be universally true, and indeed it appears that the greatest factor favoring twist forms is the relief of strain in the chair conformations, not entropic factors. It is interesting to note that M c t rises proceeding from 1,3-dithiane through cyclohexane to 1,3-dioxane. A possible explanation for these differences may lie in the fact that the twist forms become more "compact" proceeding up the list as bond lengths in the molecule decrease, and the energy differences may reflect increased transannular interactions in the twist conformations (101).

ACKNOWLEDGMENTS It is a pleasure to acknowledge the help of many people who have assisted in the preparation of this chapter. Particular thanks must be extended to Dr. M. J. T. Robinson for his helpful and constructive comments, to our colleagues Drs. J. S. Roberts and P. Murray Rust, who read and commented on the draft manuscript, and to Professor J. Leech for several interesting discussions on the geometry of six-membered rings.

264

NON-CHAIR

CONFORMATIONS OF SIX-MEMBERED RINGS

REFERENCES 1. 2.

3. 4. 5. 6.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17.

18. 19. 20.

21. 22.

H. Sachse, Ber., 23, 1363 (18901, Z. Phys. Chem., 10, 203 (1892). E. Mohr, J . Prackt. Chem., [21 98, 315 (1918); Ber., 55, 230 (1922). W. HCickel, Ann. Chem., 441, 1 (1925). Cf. 0. Hassel, Q. Rev., 7, 2 2 1 (1953). C. W. Beckett, K. S. P i t z e r , and R. S p i t z e r , J . h e r . Chem. Soc., 69, 2488 (1947). D. H. R. Barton, Experientia, 6, 316 (1950); Science, 169, 539 (1970). W. S. Johnson, Experientia, 7, 315 (1951). D. H. R. Barton, D. A. Lewis, and J. F. McGhie, J . Chem. SOC., 1957, 2907. R. J. Abraham and J. S. E. Holker, J . Chem. Soc., 1963, 806. R. E. Lyle, J . &g. them., 22, 1280 (1957). J. L e v i s a l l e s , B u l l . SOC. Chim. France, 1960, 551. D. H. R. Barton and G. A. Morrison, -09. Chem. Org. Nut. Prod., 19, 165 (1961). M. Balasubramanian, Chem. Rev., 62, 591 (1962). E. L. E l i e l , N. L. A l l i n g e r , S. J. Angyal, and G. A. Morrison, ConfomationaZ Analysis, I n t e r s c i e n c e , N e w York, 1965. D. L. Robinson and D. W. Theobald, Q. Rev., 21, 314 (1967). Professor Leech of t h i s u n i v e r s i t y has produced a proof of t h i s and has extended t h e argument t o r i n g s with nonequal bond l e n g t h s and angles. A proof has a l s o been published by Professor J. D. Dunitz, J . Chem. Educ., 47, 488 (1970) i n an a r t i c l e g i v i n g r e f e r e n c e s t o e a r l i e r work. W e acknowledge r e c e i p t of two p r e p r i n t s from Professor Dunitz d e a l i n g w i t h t h e s e and r e l a t e d m a t t e r s . The six p o i n t s t h a t we a r e considering c o n s t i t u t e t h e v e r t i c e s of an octahedron. The c o n d i t i o n s under which octahedra a r e deformable have been i n v e s t i g a t e d by G. T. Bennett, Proc. bondon Math. Soc. (21, 10, 309 (19121, and R. Bricard, J . Math. a r e s A p p l . (51, 3, 113 (1897). J. B. Hendrickson, J . h e r . Chem. SOC., 89, 7047 (1967). H. M. P i c k e t t and H. L. S t r a u s s , J . h e r . Chem. Soc., 92, 7281 (1970); H. L. S t r a u s s , J . Chem. Educ., 48, 2 2 1 (1971). J. E. K i l p a t r i c k , K. S. P i t z e r , and R. S p i t z e r , J . h e r . Chem. Soc., 69, 2483 (1947). P. Hazebroek and L. J. Oosterhoff, Dismss. Faraday Soc., 10, 87 (1951). R. E. Reeves, Ann, Rev, Biochem. 27, 1 5 (1958).

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44. 45.

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kzz.

266

NON-CWLIR CONFORMATIONS OF SIX-MEMBERED RINGS

47. 48.

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i n Topic8 i n Stereochemistry, V o l . 4 , E. L. E l i e l and

49 50. 51. 52.

53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

72 (1971). B. Hesper, H. J. Geise, and C. Romers, Rec. !7”ruv. Chh., 88, 871 (1969). c. Tamura and G. A. sim, J. Chem. Sac. ( B I , 1970, 991. A. Haaland and L. S c h l f e r , Acta Chem. Scafld., 21, 2474 (1967). H. van Bekkm, M. A. Hoefnagel, L. de L a v i e t e r , A. Van Veen, P. E. Verkade, A. Wemmers, B. M. Wepster, J. H. Palm, L. S c h l f e r , H. Dekker, C. Mosselman, and G. Scansen, Rec. Trav. Chim., 86, 1363 (1967). J. B. L a m b e r t , Acc. Chem. Res., 4, 87 (1971). H. R. BUYS, Rec. Trav. Chim., 88, 1003 (1969). D. K. D a l l i n g and D. M. Grant, J. h e r . Chm. SOC., 89, 6612 (1967). G. M. Kellie and F. G. R i d d e l l , J. chem. SOC., ( B ) , 1971, 1030. D. E. Donnan, M. J a u t e l a t , and J. D. Roberts, J. @g. C h . , 36, 2757 (1971). M. Balasubramanian and A. D ’Souza, Tetrahedron, 25, 2973 (1969). R. L. R. Towns and B. L. S h a p i r o , & y S t . StPuCt. COVUn., 1, 1 5 1 (1972). B. L. Shapiro, M. J. Gatluso, N. F. Hepfinger, R. L. Shone, and W. L. White, Tetrahedron Lett., 1971, 219. N. L. A l l i n g e r and M. T. T r i b b l e , Tetrahedron htt., 1971, 3259. R. D. Stolow and M. M. Bonaventura, J . Amer. Chem. SOC., 85, 3636 (1963). R. D. stolow, P. M. McDonagh, and M. M. Bonaventura, J. h e r . C h m . SOC., 86, 2165 (1964). K. B. Wiberg and A. Shrake, Spectrochim. Acta, 27A, 1139 (1971). 0 . H. E l l e s t a d , P. Klaboe, and G. Hagen, Spectrochim. A c t a , 27A, 1025 (1971). 0 . H. E l l e s t a d , P. Klaboe, and G. Hagen, Spectrochim. Acta, 28A, 137 (1972). 0. H. E l l e s t a d , P. Klaboe, G. Hagen, and T. S t r o y e r Hansen, Spectroch-im. A c h , 28A, 149 (1972). S . Winstein and N. J. Holness, J, h e r . chem. SOC., 77, 5562 (1955). N. L. A l l i n g e r and L. A. F r e i b e r g , J. Amer. Chm. SOc., 82, 2393 (1960). N. L. A l l i n g e r , J. A..Hirsh, M. A. Miller, I. Tyminski, and F. A. Van C a t l e d g e , J . Amer. Chm. SOC., 90, 1199 (1968).

J.

G. M.

71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

81. 82. 83. 84. 85 * 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97.

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267

A l l i n g e r and J. C. Graham, J . @g. Chem., 36, (1971). C u r t i n , R. D. Stolow, and W. Maya, J . h e r . Chem. 81, 3330 (1959). R. D. Stolow and C. B. Boyce, J . erg. chem., 26, 4726 (1961). H. van Bekkum, H. M. A. Buunnans, G. Van Minnen-Pathius, and B. M. Wepster, Rec. Trav. Chim., 88, 779 (1969). E. L. E l i e l , S. H. S c h r o e t e r , T. J. B r e t t , F. J. B i r o s , and J. C. R i c h t e r , J . h e r . Chem. SOC., 88, 3327 (1966). N. L. A l l i n g e r , M. A. Miller, F. A. Van C a t l e d g e , and J. A . Hirsh, J . h e r . Chem. soc., 89, 4345 (1967). H. Booth and P. R. Thornburrow, J . Chem. SOC. ( B ) , 1971, 1051. H. Booth, G. C. G r i d l e y and P. R. Thornburrow, J . them. SOC. ( B ) , 1971, 1047. H. Feltkamp, N. C. F r a n k l i n , M. Hanack, and K. M. Heinz, Tetrahedron Lett., 1964, 3335. H. K e s s l e r , V. Gusowski, and M. Hanack, Tetrahedron Lett., 1968, 4665. A. Rieker and H. Kessler, Tetrahedron Lett., 1969, 1227. K. Ramalingam, M. Balasubramanian, and V. B a l i a h , J . C h . SOC. ( B ) , 1971, 2287. D. J. P a s t o and D. R. R a o , J . h e r . C%m. SoC., 92, 5151 (1970). D. Pasto and D. R. Rao, J . h e r . Chem. SOC., 91, 2790 (1969). N. L. A l l i n g e r , J . h e r . chem. Soc., 81, 5727 (1959). N. L. A l l i n g e r and H. M. Blatter, J. h e r . them. SOC., 83, 994 (1961). R. D. stolow, T. Groom, and M. Gerace, J . h e r . Chem. Soc., 90, 3290 (1968). R. D. Stolow, A. A. G a l l o , and J. L. Marini, Tetrahedron Lett., 1969, 4655. R. D. S t o l o w , T. Groom, and D. I. Lewis, Tetrahedron Lett., 1969, 913. R. D. s t o l o w and M. M. Bonaventura, Tetrahedron Lett., 1964, 95. R. D. Stolow and C. B. Boyce, J . h e r . chem. soc., 83, 3722 (1961). J. Dale, J . Chem. Soc., 1965, 1028. R. J. W. L e Fsvre, J . Chem. SOC. ( B ) , 1968, 697. G. Fodor and K. Nador, Nature, 169, 462 (1952). J. Sam, J. D. England, and D. Temple, J . Med. chem., 12, 144 (1969). A . F. Casy and K. M. J. McErlane, J . c. Perkin I, 1972, 334. A. J. J o n e s , A. F. Casy, and K. M. J. McErlane, L. 1688 D. Y. Soc., N.

J.

s.

268

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Tetrahedron Lett., 1972, 1727. 98. A. F. Casy, personal communication. 99. M. M. A. Hassan and A. F. Casy, Tetrahedron, 26, 4517 (1970). 100. K. Heusler, Tetrahedron Lett., 1970, 97; P. Perelman, S. Sicsic, and 2. Welvat, {bid., 1970, 103; S . Dub6 and P. Deslongchamps, ibid., 1970, 101. 101. E. L. Eliel, Ace. Chem. R m . , 3, 1 (1970). 102. F. G. Riddell, Q. Rev., 21, 364 (1967). 103. H. Booth, in Progress in SpeCi!ZPO6COpy, Vol. 5, J. W. Emsley, J. Feeney, and L. H. Sutcliffe, Eds., Pergamon, London, 1969, p. 149. 104. J. E. Anderson, F. G. Riddell, and M. J. T. Robinson, Tetrahedron L e t t , , 1967, 2017. 105. F. G. Riddell and M. J. T. Robinson, Tetrahedron, 23, 3417 (1967). 106. K. Pihlaja, Acta Chem. Scand., 22, 716 (1968). 107. M. Anteunis and G. Swaelens, Org. Magn. Re~onunce, 2, 389 (1970). 108. K. Pihlaja and S. Lucma, Acta Chm. S c a d . , 22, 2401 (1968). 109. F. W. Nader and E. L. Eliel, J . h l e r . chem. SOC., 92, 3050 (1970). 110. E. L. Eliel, Pure A p p l . Chem., 25, 509 (1971). 111. K. Pihlaja and J. Jalonen, Org. Ma66 @ectrOm., 5, 1363 (1971). 112. K. Pihlaja, personal communication. 113. G. Eccleston and E. Wyn-Jones, J . chem. SOC. ( B ) , 1971, 2469. 114. R. M. Clay, G. M. Kellie, and F. G. Riddell, J . .her. Chem. Soc., 95, 4632 (1973). 115. J. Delmau and J. Duplan, Tetrahedron Lett., 1966, 2693. 116. D. Tavernier and M. Anteunis, Buzz. Soc. Chim. Belge6, 76, 157 (1967). 117. K. Pihlaja and P. Ayras, Acta Chem. Scand., 24, 531 (1970). 118. J. Tocanne, B u l l . SOC. Chim. France, 1970, 750. 119. K. Pihlaja, G. M. Kellie, and F. G. Riddell, J. c. s. Perkin 11, 1972, 252. 120. G. M. Kellie and F. G. Riddell, Chem. COmnrUn., 1972, 42. 121. G . M. Kellie, P. Murray-Rust, and F. G. Riddell, J . c. S. Perkin 11, 1972, 2384. 122. E. L. Eliel and F. W. Nader, personal communication. 123. G. M. Kellie, J. Murray-Rust, P. Murray-Rust, and F. G. Riddell, unpublished results. 124. D. Tavernier and M. Anteunis, Tetrahedron, 27, 1677 (1971).

G. M. KELTSE AND F. G. RIDDELL

269

125. M. Anteunis, G. Swaelens, F. Anteunis-de Ketelaere, and P. Dirinck, &cll. SOC. Chim. BeZges, 80, 409 (1971). 126. R. J. Abraham and W. A. Thomas, J . Chem. soc., 1965, 335. 127. E. L. Eliel and R. 0. Hutchins, J . Amer. Chem. Soc., 91, 2703 (1969). 128. G. Wood and M. Miskow, Tetrahedron Lett., 1966, 4433. 129. C. H. Green and D. G. Hellier, J . c. S. Perkin 11, 1972, 458. 130. C. Altona, H. J. Geise, and C. Ramers, Rec. Trav. Chim., 85, 1197 (1966). 131. L. Cazaux and P. Maroni, T e t r a k d r o n Lett., 2969, 3667. 132. C . H. Bushweller, J . Amer. Chem. Soc., 89, 5978 (1967); 90, 2450 (1968); 91, 6019 (1969). 133. C. H. Bushweller, J. Golini, G. U. Rao, and J. W. O'Neil, J . h e r . Chem. Soc., 92, 3055 (1970). 134. C . H. Bushweller, G. U. Rao, and F. H. Bissett, J . h e r . Chem. Soc., 93, 3058 (1971); Int. J . Sulfur Chem., 1, 216 (1971). 135. A . Fredga, Acta Chem. S c a d . , 12, 891 (1958). 136. P. Pasanen and K. Pihlaja, Tetrahedron, 28, 2617 (1972). 137. W. G. Bentrude and J. H. Hargis, J . h e r . Chm. Soc., 92, 7136 (1970). 138. W. Bentrude and K. C . Yee, Chem. C o m n . , 1972, 169. 139. M. Bixon and S . Lifson, Tetrahedron, 23, 769 (1967). 140. N. L. Allinger, M. T. Tribble, and M. A. Miller, Tetrahedron, 28, 1173 (1972). 141. J. B. Hendrickson, J . Amer. C h m . SOc., (a) 83, 4537 (1961); (b) 86, 4854 (1964); ( c ) 89, 7036, 7043 (1967). 142. K. B. Wiberg, J . h e r . Chem. SOC., 87, 1070 (1965). 143. S. Lifson and A. Warshel, J . Chem. Phys., 49, 5116 (1968). 144. J. E. Williams, P. J. Stang, and P. Von R. Schleyer, Ann. Rev. Phys. Chem., 19, 531 (1968). 145. J. Fournier and B. Waegell, Tetrahedron, 26, 3195 (1970). 146. N. L. Allinger, J. A . Hirsch, M. A . Miller, and I. J. Tyminski, J . h e r . Chem. SOC., 91, 337 (1969). 147. M. T. Tribble and N. L. Allinger, Tetrahedron, 28, 2147 (1972); see also R. J. Ouelette, D. Baron, J. Stoffo, A . Rosenblum, and P. Weber, ibid., 28, 2163 (1972). 148. D. S. Bailey, J. A. Walder, and J. B. Lambert, J . h e r . Chem. Soc., 94, 177 (1972).

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS G.

M.

KELLIE" AND F. G. RIDDELL

Department of C h e m i s t r y The University S t i r l i n g , Scotland

. . . . . . . . . . . . . . 226 The S t r u c t u r e o f Non-Chair Conformations . . . . . . 226 A. H i s t o r i c a l . . . . . . . . . . . . . . . . . . . 226 B. Geometric Consi dera t ions . . . . , . . . . . . . 228 C. Energy C o n s i d e r a t i o n s , . . . . . . . . . . . . 230 D. S u b s t i t u t e d Six-Membered Rings . . . . . . . . . 233 E. S u b s t i t u t i o n P a t t e r n s i n T w i s t Conformations . . 236 C l a s s i f i c a t i o n o f Non-Chair Conformations . . . . . 237

I. The Scope o f t h e Review 11.

111.

A. B. C.

IV.

Molecules Forced i n t o Non-Chair Forms by t h e Magnitude o f t h e S t r a i n P r e s e n t i n T h e i r C h a i r Conformations

. . . . . . . . . . . . . . 239

. . . . . . . . . . . . . . 240 X-Ray and E l e c t r o n D i f f r a c t i o n . . . . . . . . . 241 NMR Spectroscopy . . . . . . . . . . . . . . . . 242

The A p p l i c a t i o n o f P h y s i c a l Methods t o t h e Study o f Non-Chai r Conformations A. B.

No.

. . . . . . . . . . . . . . 237 Molecules w i t h an I n h e r e n t Preference f o r Nonchair Forms . . . . . . . . . . . . . . . . . 238 Molecules Constrained i n t o Non-Chair Forms by Chemical Bonding

* P r e s e n t address: c/o P r o c t o r and G a m b l e L t d . , 1, T r a f f o r d P a r k , Manchester M 1 7 1NX.

P.O.

BOX

225

Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

226

V.

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

D i p o l e Moments

D.

Vibrational

The Non-Chair Conformations o f V a r i o u s Ring Systems. 245

. . . . . . . . 245 B. N i trogen-Containing Rings . . . . . . . . . . . 252 C. Oxygen-Containing Rings . . . . . . . . . . . . 252 0. Sul f u r - C o n t a i n i ng R i ngs . . . . . . . . . . . . 258 E. Phosphorus-Containing Rings . . . . . . . . . . 260 M o l e c u l a r Mechanics C a l c u l a t i o n s . . . . . . . . . . 260 Discussion . . . . . . . . . . . . . . . . . . . . . 262 References . . . . . . . . . . . . . . . . . . . . . 264 A.

VI. VII.

. . . . . . . . . . . . . . . . . 243 Spectroscopy . . . . . . . . . . . . 244

C.

Cyclohexane and I t s D e r i v a t i v e s

I.

THE SCOPE OF THE REVIEW

Considerably less is known about the non-chair conformations of six-membered rings than is known about the generally more stable chair conformations, as a result, mainly, of the instability of non-chair forms. The literature on the subject is confused in many respects. In order to clarify much of the available material, and to rationalize this rather complicated but important area of conformational analysis, we devote the major part of this chapter to monocyclic systems, though some reference is made to polycyclic and bridged rings. This article does not pretend to represent a complete compilation of data and references, though an attempt has been made to cover important publications up to May 1972.

11.

THE STRUCTURE OF NON-CHAIR CONFORMATIONS A.

Historical

The origins of conformational analysis may be found in the work of Sachse (1) who first suggested that cyclohexane could adopt two possible arrangements, free of angle strain,

G. M. KELLIE AND F. G.

227

RIDDELL

l a t e r termed t h e c h a i r and boat conformations.* Sachse's t h e o r i e s , echoed by Mohr ( 2 1 , were, a t l e a s t i n p a r t , v e r i f i e d by HUckel's work (3) on t h e d e c a l i n s and t h e l a t e r e l e c t r o n d i f f r a c t i o n s t u d i e s of Hassel (4). H a s s e l ' s work and t h e c a l c u l a t i o n s of P i t z e r ' s group (5) demonstrated t h a t i n cyclohexane, and i n most of i t s d e r i v a t i v e s , t h e c h a i r form was by f a r t h e most s t a b l e arrangement, an i d e a which r a p i d l y gained widespread acceptance. However, it was n o t u n t i l 1950 t h a t t h e fundamental r e l a t i o n s h i p between conformation and chemical behavior was pointed o u t by Barton ( 6 ) . Although Johnson (7) noted i n 1951 t h a t c e r t a i n p o l y c y c l i c molecules would, a s a consequence of t h e i r s t r u c t u r e s , cons t r a i n a t l e a s t one six-membered r i n g i n t o a non-chair form it was not u n t i l 1957 t h a t examples were found of molecules p r e f e r r i n g t o e x i s t i n a non-chair conformation, where c h a i r conformations, a l b e i t highly s t r a i n e d , w e r e a v a i l a b l e . Barton and h i s co-workers (8) demonstrated t h a t 2-$-bromo-lanost-8ene-3-one (2 1 had an " e q u a t o r i a l " bromine atom, a s i t u a t i o n only r e c o n c i l a b l e with a nonchair conformation of r i n g A. This r e s u l t was subsequently v e r i f i e d i n an nmr study by Abraham and Holker ( 9 ) . A t about t h e same time Lyle (10) found t h a t 1,2,2,6,6-pentamethyl-4-hydroxy-4-phenylpiperidine ( 2 ) possessed an i n t e r n a l hydrogen bond, c o n s i s t e n t with t h i s compound e x i s t i n g with s u b s t a n t i a l p r o p o r t i o n s of nonchair conformations i n which hydrogen bonds can form.

1

2

*Sachse's i n t u i t i o n i n t o t h e n a t u r e of t h e two forms of cyclohexane was outstanding. He was aware t h a t one form was r i g i d and t h e o t h e r mobile, he suggested t h a t t h e mobile form was of higher energy because of "intramolecular f o r c e s , " and he observed from models t h a t t h e r e was a b a r r i e r t o t h e i n t e r conversion of one form t o t h e o t h e r .

228

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Subsequent work by o t h e r r e s e a r c h groups has been s u f f i c i e n t t o warrant, a t v a r i o u s times, reviews of t h e s u b j e c t by L e v i s a l l e s (11), Barton and Morrison ( 1 2 ) , Balasubramanian (131, E l i e l , A l l i n g e r , Angyal, and Morrison ( 1 4 ) , and Robinson and Theobald ( 1 5 ) . Despite these attempts a t a c o r r e l a t i o n of d a t a and i d e a s , a g r e a t many terms remain i n use t o d e s c r i b e t h e various non-chair forms, and many groups of workers p e r s i s t i n representing non-chair conformations a s c l a s s i c a l boats.* The need f o r a c r i t i c a l and up-to-date review becomes i n c r e a s i n g l y apparent a s one scans t h e c u r r e n t l i t e r a t u r e . Before proceeding t o examine t h e experimental evidence f o r non-chair conformations it i s important t o c l e a r l y d e f i n e t h e terms and o u t l i n e t h e concepts employed i n t h i s c h a p t e r . t

B.

Geometric Considerat ions

I t i s simplest t o consider f i r s t t h e p o s s i b l e arrangements of s i x p o i n t s c o n s t r a i n e d , a s i n cyclohexane, by t h r e e condi( a ) t h e p o i n t s a r e joined i n a r i n g , ( b ) t h e d i s t a n c e s tions: between a d j a c e n t p o i n t s a r e e q u a l , and ( c ) t h e angle subtended a t any one p o i n t by i t s two neighbors i s t e t r a h e d r a l (109O28'). I t i s p o s s i b l e t o demonstrate (16) t h a t t h e r e a r e two s e t s of arrangements t h a t f u l f i l l t h e s e r e s t r i c t i o n s . + The f i r s t s e t has only one member and i s r i g i d . This i s known a s t h e c h a i r conformation (31, of symmetry D3d. The second s e t has an inf i n i t e number of members (17) a l l of which possess a C g axis, and includes forms of symmetry C2v (boat arrangement) ( 4 ) and D 2 ( t w i s t conformation) ( 5 ) . This s e t has one degree of freedom, allowing i n t e r c o n v e r s i o n between a l l of i t s members. We d e f i n e t h i s second set a s t h e boat-twist (BT) family. This chapter i s concerned with t h i s BT family. Interconversion

*The r e p r e s e n t a t i o n of non-chair forms a s c l a s s i c a l b o a t s p e r s i s t s i n t h e l i t e r a t u r e p o s s i b l y due t o t h e l a c k of a s t e n c i l of t h e t w i s t form. Although many workers a r e a t p a i n s t o p o i n t o u t t h e inadequacy of t h i s r e p r e s e n t a t i o n , confusion must i n e v i t a b l y follow. + I n t h i s connection we s h a l l employ conformation i n t h e sense of a form having a f i n i t e e x i s t e n c e , i . e . , e x i s t i n g i n t h e v i c i n i t y of t h e minimum of a p o t e n t i a l energy w e l l . (Other authors have used "conf ormational isomer" o r "conformer" i n t h i s context.) A l l o t h e r forms of molecules w i l l be c a l l e d arrangements. *Although t h e s e r e s t r i c t i o n s do not conform t o t h e a c t u a l s i t u a t i o n i n which bond l e n g t h s and angles can change, and bond angles a r e n o t i n f a c t p e r f e c t l y t e t r a h e d r a l , they form a convenient background f o r t h e subsequent argument.

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3

4

between t h e unique m e m b e r of t h e c h a i r s e t and any member of t h e BT s e t involves breaking a t l e a s t one of t h e t h r e e condit i o n s l a i d o u t above.*

c-3 5

- =+ 6

The symmetries Dgd and C2 a r e s u f f i c i e n t t o d e f i n e t h e c h a i r and BT sets i n cyclohexane b u t do not hold with s u b s t i t u t ed six-membered r i n g s . I n t h e s e c a s e s it i s convenient t o look a t t h e s i g n s of t h e t o r s i o n a n g l e s i n t h e r i n g . For c h a i r conformations (6) t h e s e s i g n s a l t e r n a t e a s one moves round t h e r i n g s , i n t h e BT family (7, 8 ) they do not ( c f . Chap. 2 ) .

+w0

7

*On going from t h e cyclohexane system with equal bond l e n g t h s and a n g l e s t o a r i n g with unequal l e n g t h s and a n g l e s , it i s p o s s i b l e t o show (16) t h a t i n g e n e r a l t h e p r e v i o u s l y i n f i n i t e set now has only c e r t a i n allowable p o s i t i o n s u n l e s s it possesses an a x i s of symmetry ( i . e . , lI2-dioxane i s r e s t r i c t e d b u t lI4-dioxane has a continuously v a r i a b l e i n f i n i t e set).

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NON-CHAIR

C.

CONFORMATIONS OF SIX-MEMBERED RINGS

Energy Considerations

Changing from t h e a b s t r a c t concepts of p o i n t s joined by f i x e d d i s t a n c e s and angles t o t h e p h y s i c a l r e a l i t y of molecules i n which t h e s e parameters can vary involves c o n s i d e r a t i o n of t h e r e l a t i v e e n e r g i e s of t h e s p e c i e s involved. The changes between c h a i r , boat, and t w i s t forms a r e most r e a d i l y understood i n terms of an energy map of t h e type suggested by Hendrickson (la) (Figure 1). The two p o l e s of t h e sphere

Fig. 1. S p h e r i c a l r e p r e s e n t a t i o n of chair-twist-boat interconversions i n cyclohexane. r e p r e s e n t c h a i r conformations which a r e separated by energy mountain chains from t h e BT family around t h e equator. A p r o j e c t i o n of t h i s i n two dimensions due t o P i c k e t t and S t r a u s s (19) i s shown i n Figure 2. I f a plane of symmetry i s maintained during t h e changes from a c h a i r form, t h e i n t e r conversion l e a d s t o a boat arrangement. I f an a x i s of symmetry

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M. KELLIE AND F. G. RIDDELL

01

231

I

I

4

20

8 12

40

0"

180 1 0

I

120

I

240

360

7

Fig. 2. Conformation map of cyclohexane Reproduced from H. M. Pickett and H. L. Straws, J . h e r . Chem. SOC., 92, 7281 (1970) by permission of the editor. Chair conformations are at 0 = 0 and 180'. The boat-twist forms are near 0 = 90°. (passing through the midpoints of two C-C bonds on opposite sides of the ring) is maintained, the interconversion leads to a twist conformation. It has been suggested (19) that the relative energies of the transition states (TS and TS') for these two processes are comparable. Interconversion between the twist and boat forms takes place around the equator of the diagram, the boat corresponding to a transition state between two twist conformations. The potential energy profiles of these processes are shown in Figures 3 and 4. Calculations (see Sect. VI) suggest that relative to the chair conformation

232

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

E ,\

/

>

lnterconversion coordinate, 8"

Fig. 3.

Chair-chair i n t e r c o n v e r s i o n i n cyclohexane.

t h e boat arrangement i s ca. 6 kcal/mole less s t a b l e and t h e t w i s t form ca. 5 kcal/mole l e s s s t a b l e . This small energy d i f f e r e n c e between boat and t w i s t forms means t h a t t h e r e i s extremely r a p i d i n t e r c o n v e r s i o n between t w i s t conformations a t room temperature. This i n t e r c o n v e r s i o n i s g e n e r a l l y c a l l e d pseudorotation, a term o r i g i n a l l y adopted by P i t z e r e t a l . ( 2 0 ) t o d e s c r i b e t h e r o t a t i o n of t h e out-of-plane displacements i n a puckered cyclopentane but now used i n a v a r i e t y of senses. We s h a l l u s e t h e term pseudorotation t o d e s c r i b e t h e process t h a t continuously i n t e r c o n v e r t s members of t h e BT family, involves motions around t h e equator of F i g u r e 1, and p r e s e r v e s a C2 axis i n cyclohexane. The entropy of a t w i s t conformation can be high r e l a t i v e t o a c h a i r f o r t h r e e reasons: (1) t h e t w i s t may have a low symmetry number r e l a t i v e t o t h e c h a i r ; ( 2 ) t h e r e could be an entropy of mixing of s e v e r a l d i f f e r e n t t w i s t conformations of s i m i l a r energy; and ( 3 1 , t h e r e may be low-frequency v i b r a t i o n s , which could be c a l l e d p s e u d o l i b r a t i o n s , about t h e mean t w i s t

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Boat

Twist

Pseudorqtation coordinate,

Fig. 4.

0"

Pseudorotation i n cyclohexane.

p o s i t i o n . I n most cases it i s u n l i k e l y t h a t c o n s i d e r a t i o n 1 i s important. Consideration 2 may a l s o be unimportant f o r reasons o u t l i n e d below. Consideration 3 i s t h e r e f o r e t h e most l i k e l y cause of any high r e l a t i v e entropy found i n t w i s t forms. A small p s e u d o l i b r a t i o n about t h e mean t w i s t p o s i t i o n may be t h e b e s t sense i n which t w i s t forms can be c a l l e d f l e x i b l e .

D.

S u b s t i t u t e d Six-Membered Rings

I f t h e six-membered r i n g c a r r i e s s u b s t i t u e n t s o r i n c l u d e s heteroatoms, then t h e symmetry and energy c o n s i d e r a t i o n s outl i n e d above no longer s t r i c t l y apply. There w i l l be s e v e r a l d i f f e r e n t t w i s t conformations of varying energy, and t h e p o s s i b l e boat arrangements w i l l a l s o d i f f e r i n energy. The symmetry of t h e s p h e r i c a l energy s u r f a c e described e a r l i e r becomes d i s t o r t e d and t h e t w i s t - t w i s t i n t e r c o n v e r s i o n b a r r i e r w i l l no longer be a s i n Figure 4 b u t may be more l i k e Figure 5. The c a l c u l a t e d p r o j e c t i o n of t h e energy s u r f a c e f o r 1,3dioxane, by P i c k e t t and S t r a u s s ( 1 9 ) , i s shown i n F i g u r e 6 ,

234

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Psuedorotation coordinate, 0"

*

Fig. 5. Possible energy graph for pseudorotation in a hetero-substituted six-membered ring. and it is seen that they calculate that there are two pairs of minimum energy non-chair conformations available of very different energies.* Although one may, with some justification, talk of the BT family in cyclohexane as "flexible ," this may be an inappropriate and misleading term for substituted rings. Related to each of the twist forms shown in Figure 5 there is a chair-twist enthalpy (and entropy) difference (AHct). Wherever possible a value of AHct should be related to a particular twist conformation although in practice it may be difficult to determine which twist conformation(s) are important. The chair-boat energy difference, which corresponds to an activation energy may be defined similarly (AHcb). By the definitions and clarifications discussed above it is hoped that much of the ambiguity associated with expressions *Althcmgh for 1,3-dioxane the calculated and experimental values differ considerably, and although four and not six minima are found by these calculations, the argument is not seriously affected.

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Fig. 6. Conformation map of lI3-dioxane. Reproduced from H. M. Pickett and H. L. Strauss, J . h e r . Chem. SOC., 92, 7281 (1970) by permission of the editor. such as "flexible" (14)I "stretched" (21)I "skewed" (22) and "twisted" (24) will disappear. If a molecule is so encumbered as to be forced into a twist conformation, the encumbrance will raise the energy of most possible twists leaving very few possible twist conformations from the original pseudorotation circuit open to the molecule. For such molecules which exist in or near the minima of potential energy wells we suggest "twist conformation" as the most appropriate description as it avoids the misleading connotations of other terms that have been used.

236

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED R I N G S

E.

Substitution Patterns i n Twist Conformations

I n c o n t r a s t t o t h e c h a i r conformation, with only two posit i o n s a v a i l a b l e f o r s u b s t i t u e n t s ( a x i a l and e q u a t o r i a l ) , t h e t w i s t conformation has t h r e e (Figure 7 ) . These a r e pseudoe q u a t o r i a l (YE) , pseudoaxial ("A) , and i s o c l i n a l * ( I c ) Although it i s d i f f i c u l t t o a s s i g n r e l a t i v e e n e r g i e s t o conformations with s u b s t i t u e n t s i n any of t h e s e p o s i t i o n s , it

.

Fig. 7 .

S u b s t i t u e n t p o s i t i o n s f o r t h e t w i s t conformation.

appears from t h e c a l c u l a t i o n s of Hendrickson (181, t h a t a methyl group i s s u b s t a n t i a l l y more hindered i n t h e YA p o s i t i o n t h a t i n e i t h e r t h e YE o r I c p o s i t i o n s and w i l l t h e r e f o r e pref e r t h e l a t t e r s i t u a t i o n s . A geminal grouping w i l l favor t h e I c p o s i t i o n s , once again avoiding t h e YA s u b s t i t u e n t . With c i s - v i c i n a l s u b s t i t u e n t s of such a s i z e a s t o i n t e r f e r e with one another, t h e t w i s t conformation o f f e r s l i t t l e r e l i e f . Three p o s s i b l e arrangements e x i s t , a l l of which have e n e r g e t i c drawbacks: YE-'PA, with an unfavorable YA group; YA-Ic, again unfavorable; and YE-Ic i n which t h e t o r s i o n angle between t h e groups i s considerably l e s s than 60' making t h e combination *This term seems t o have o r i g i n a t e d with P r o f e s s o r M. C . Whiting; c f . Hendrickson (141b).

G. M.

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RIDDELL

e n e r g e t i c a l l y u n s u i t a b l e . With bulky t r a n s - v i c i n a l s u b s t i t u e n t s two t w i s t conformations m e r i t c o n s i d e r a t i o n : YE-YE, w i t h a d i h e d r a l a n g l e between t h e groups of a b o u t 60'; and YE-Ic which may be favored because of t h e l a x g e r than 60° t o r s i o n angle. I n c o n s t r u c t i n g a p p r o p r i a t e t w i s t forms of molecules t h e s e r e s t r i c t i o n s should be borne i n mind.

111.

CLASSIFICATION OF NON-CHAIR CONFORMATIONS

I t i s u s e f u l and i n s t r u c t i v e t o p l a c e molecules w i t h nonc h a i r conformations i n t h r e e nonexclusive c l a s s e s . T h i s d i v i s i o n corresponds b a s i c a l l y t o t h a t o r i g i n a l l y proposed by L a m b e r t (23).

A.

Molecules Constrained into Non-Chair Forms by Chemical Bonding

Well-known examples of such molecules a r e t w i s t a n e ( 9 ) (25) and bicyclo[2.2.2]octane ( 1 0 ) which a r e f o r c e d t o adopt non-chair forms due t o bridging. Whereas t w i s t a n e i s r i g i d l y c o n s t r a i n e d t o an almost i d e a l t w i s t form, s u b s t i t u t e d b i c y c l o [2.2.2]octanes a r e observed t o become d i s t o r t e d t o a c e r t a i n e x t e n t t o avoid t h e s t r a i n r e s u l t i n g from t h e b o a t arrangements of t h e i r r i n g s (26).

9

I n Sect. I1 it w a s noted t h a t c e r t a i n p o l y c y c l i c molecules could, by t h e n a t u r e of t h e s t e r e o c h e m i s t r y of t h e i r r i n g

11

12

238

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

junctions, force one or more rings into non-chair conformations. Trans-anti-trans-Perhydroanthracene (21) (27) and the lactone ( 2 2 ) (24) must have ring B in a boat-twist conformation. In contrast the trans-syn-trans isomers have this ring in a chair form. By measuring the enthalpy differences between the pairs of isomers (from their heats of combustion) and applying certain corrections, Johnson et al. were able to estimate M C t in cyclohexane to be 4.8 and 5.5 kcal/mole, respectively (27, 24). It is also possible to include in this class organometallic complexes such as the piperazine-palladium chloride adduct studied by Hassel and Pedersen (28). However, for the purposes of this chapter such molecules will be disregarded.

B.

Molecules w i t h an Inherent Preference f o r Non-Chair Forms

Molecules in this class tend to be rather rare as it would appear that most six-membered ring systems prefer the chair conformation for the parent compounds (14). The most studied molecule of this type is cyclohexane-lI4-dione. Dipole moments (29), Raman (29-32) and ir (31) spectroscopy, and X-ray (33) and electron diffraction (34) indicate that this molecule exists in twist conformation 13 in the solid, solution, and gas phases. The X-ray structure reveals that the carbonyl groups are inclined at an angle of 154' to one another (180' in a perfect twist). This may be the result of crystal packing forces or is perhaps indicative of a certain amount of pseudolibrating or twisting about the perfect twist form. A molecular beam deflection experiment (35) suggests that this molecule is nonpolar in the gas phase, and it has been postulated (35) that the compound exists in a chair conformation. However, the results equally fit a twist form with the carbonyl groups inclined at an angle of 180' (or one pseudolibrating rapidly about this conformation), and in view of the weight of evidence from other sources, it would appear that cyclohwane-l,4dione prefers a twist conformation. An X-ray study of the analogous cyclohexane-l,4-dioxime reveals that it also exists in a twist conformation (36).

13

14

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KELLIE AND F. G. RIDDELL

Kumler and Huitric (37) proposed that molecules with two or more atoms in a six-membered ring, with other than sp3 hybridization, favored twist conformations. In support of this Lautenschlaeger and Wright (38) suggested that 1,4dimethylenecyclohexane ( 1 4 ) , and its exo-tetramethyl and tetraphenyl analogs existed in non-chair forms. However, an X-ray diffraction study of the exo-tetracyano derivative (39) and a vibrational spectroscopic study of the parent molecule (30) indicated that the chair conformation is the most stable form of these molecules. Further, a dynamic process (AG = 7.5 kcal/mole) has been observed by nmr spectroscopy for the parent molecule (40). This is consistent with a chair-chair ring inversion process. The related 4-methylenecyclohexanone may also favor a chair form (41).

*

C. Molecules Forced i n t o Non-Chair Forms by t h e Magnitude o f t h e S t r a i n Present i n T h e i r C h a i r Conformations

This is the most important class of molecules to be considered in this chapter. The best known molecules in this category are those possessing axial t-butyl groups in their chair conformations, e.g. , tPanS-1,3- and Cis-lf4-di-t-butylcyclohexanes. The severe 1,3-diaxial nonbonded repulsions present in their chair conformations (e.g., 1 5 ) may be substantially relieved in certain of the twist forms (e.g., 1 6 )

t -Bu

15

which can be envisaged, i.e., those with the t-butyl groups in YE or Ic positions. A s a result these molecules may prefer to exist in twist conformations. In certain cases not only can the strains present in the chair conformations be relieved but certain stabilizing interactions may only take place in some of the twist conformations, e.g., r-1-cis-4-di-t-butylcis-2,5-dihydroxycyclohexane ( 1 7 ) (42) and the previously discussed 1,2,2,6,6-pentamethyl-4-hydroxy-4-phenylpiperidine (2) in which hydrogen bonds may be formed in twist conformations. It is important to note that compounds in this class will

240

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

R = I-Naphthyl

17

18

only prefer to exist in twist conformations if there is available a twist form (or forms) in which some or all of the strains encumbering the chair forms are substantially relieved. Although this may be valid for some of the molecules described above it does not appear so likely for r-1,3,3-trans-5-tetramethyl-l-hydroxy-c~s-5-(l’-naphthyl)-cyclohexane (43) and r-l-cis-2,3,4,5,6,-hexamethylcyclohexane ( 4 4 ) . For neither compound can one construct a twist form which does not possess two pseudoaxial substituents e.g., 18 and 1 9 . As a result, in spite of the strain due to nonbonded repulsions being greater than 6 kcal/mole (i.e., greater than AHct in cyclohexane itself) they both appear to prefer chair conformations.

19

IV.

THE APPLICATION OF PHYSICAL METHODS TO THE STUDY OF NON-CHAIR CONFORMATIONS

One of the major problems in the conformational analysis of molecules with non-chair conformations has been the lack of an exact method of assessing whether or not a molecule exists in a non-chair conformation and for examining such forms in detail. In this section we consider and examine sane of the methods applied to the study of these molecules and some of the results obtained.

G. M. KELLIE AND F. G. RIDDELL

241

The methods available for the detection of conformational ambiguities can be ordered into a list of roughly decreasing reliability. Diffraction and microwave techniques head the list, nmr and other spectroscopic methods follow, and ORD-CD, dipole moments, and kinetic methods are among the least reliable, although still useful in suggesting anomalies for further investigation.

A.

X-Ray and E l e c t r o n D i f f r a c t i o n

Diffraction methods offer, in general, the most accurate means available for the determination of molecular geometries in the solid and gas phases (45, 46). In order to obtain meaningful results from more readily applied methods, e.g., nmr spectroscopy and dipole moments, it is vital to be able to relate parameters such as coupling constants to certain accurately known stereochemical arrangements. However, both X-ray and electron diffraction have been largely neglected as tools for the study of compounds with non-chair conformations, and it is to be hoped that the advent of more sophisticated techniques, e.g., direct methods in X-ray diffraction (471, will lead to more work in the future. Cyclohexane-l,4-dione and some of its derivatives have been studied by both techniques (33, 34). Twistane (341, bicyclo[2.2.2]octane (261, and l,4-diazabicyclo[2.2.2loctane (48) have been analyzed by gas-phase electron diffraction.

20

The use of this method for conformational studies has been reviewed by Bastiansen and co-workers (34). Certain polycyclic molecules have been shown by X-ray diffraction to possess sixmembered rings with boat-twist conformations in their structure, e.g., 22,23-dibromo-cl,8-ergost-4-en-3-one (20) has rings B and C in twist conformations (49) and lunarine hydrobromide hydrate ( 2 1 ) has ring A in a twist form (50).

242

NON-CHAIR

CONFORMATIONS OF SIX-MEMBERED RINGS

21

H

So far as we are aware, only two studies have been undertaken on any canpounds in category C (i.e., Sect. 1 1 1 - C ) of our classification of non-chair conformations. Both studies, by electron diffraction (51, 5 2 ) , have been on cis-l,4-di-t-butylcyclohexane which has been considered to exist in a twist conformation. Both research groups unfortunately could not unambiguously interpret the radial distribution curve obtained for this compound in terms of either a twist or chair conformation. As it now seems likely that this molecule exists with appreciable proportions of both forms, it is possible that a better theoretical curve might have been obtained by assuming a value for the chair-twist equilibrium constant.

B.

NMR Spectroscopy

As discussed above the use of nmr spectroscopy in obtaining information on non-chair conformations has been hindered by the lack of accurate structural information on model compounds suitable for nmr work. Despite this shortccnning Lambert has developed his "R" value method based on the vicinal coupling constants in six-membered rings (23, 53). He considers that values near 2.0 are indicative of almost perfect chair conformations, whereas values of R near 1.0 suggest the presence of either flattened chairs or non-chairs. However, this approach cannot distinguish between the latter two cases; thus cyclohexane-l,4-dione monoketal, which most likely prefers a chair conformation, has an identical R value (1.29) to cyclohexane-l,4-dione. Buys (54) extended this treatment to the calculation of ring torsion angles. Although his method has been very successful for compounds with chair conformations it cannot be used to evaluate the torsion angles for non-chair

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M. KELLIE AND F. G. RIDDELL

243

conformations. The importance of t h i s approach i s t h a t , when used a s a purely empirical t o o l , it does serve t o g i v e some i n d i c a t i o n of t h e presence of d i s t o r t e d c h a i r o r non-chair conformations. Another method has been proposed by Dalling and Grant ( 5 5 ) and developed b t h e p r e s e n t a u t h o r s (56). Dalling and Grant recorded t h e nmr s p e c t r a of a series of methylcyclohexanes and r a t i o n a l i z e d t h e s h i f t s of t h e r i n g carbon atoms using s u b s t i t u e n t parameters.* When t h e s e parameters w e r e used t o c a l c u l a t e t h e chemical s h i f t s of t h e r i n g carbon atoms of compounds considered t o adopt c h a i r conformations, e x c e l l e n t agreement was found between t h e experimental and c a l c u l a t e d values. However, f o r 1,1,2-trimethylcyclohexane r e g a r d l e s s of t h e value assumed f o r t h e equilibrium c o n s t a n t between t h e two p o s s i b l e c h a i r conformations, poor agreement w a s found. Accordingly it was suggested t h a t t h i s compound e x i s t s t o an

']5,

22

appreciable e x t e n t i n t h e t w i s t conformation 22. However, it seems u n l i k e l y t h a t t h e gauche t o r s i o n a l i n t e r a c t i o n s p r e s e n t i n t h e c h a i r conformations would be of s u f f i c i e n t magnitude t o make t h e twist t h e favored form.? I n a d d i t i o n it i s d i f f i c u l t t o construct a t w i s t form i n which much of t h i s s t r a i n can be relieved.

C.

Dipole Moments

Although Allinger and Freiberg (29) s u c c e s s f u l l y employed t h i s technique t o examine cyclohexane-l,4-dione, i t s usefulness remains l i m i t e d due t o a lack of a c c u r a t e s t r u c t u r a l informat i o n on t w i s t conformations. Care must be taken when i n t e r p r e t i n g dipole moment data. Thus Balasubramanian and D'Souza (58) determined t h e d i p o l e moment of 3- (4 '-bromophenyl) -3 ,5,5"For a discussion of t h e use of t h e s e parameters i n I 3 C nmr spectroscopy see r e f . 57. ?Two explanations can be advanced t o account f o r Dalling and Grant's observation: e i t h e r t h e molecules have a d i s t o r t e d c h a i r conformation, o r t h e parameter s e t used was n o t appropriate.

244

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

trimethylcyclohexanone and compared it with values calculated for "perfect" chair conformations as shown in Figure 0 . As their observed and calculated values for either conformation

d

CH3

A

B

R = 4-Bromophenyl pcalc'd = 2

470

walc'd

=

4.19D

polis. = 3.8212

Fig. 8. Observed and calculated dipole moments for 3-(4'-bramophenyl)-3,5,5-trimethylcyclohexanone. were not in close agreement, they proposed that the molecule adopted a twist conformation. However, allowing for some distortions in the chair forms it is possible to demonstrate that the observed figures best fit conformation B with an axial aryl group. This has now been confirmed by the X-ray (59) and nnu (60) studies of Shapiro et al., and by Allinger and Tribble's molecular mechanics calculations (61).

D.

Vibrational Spectroscopy

Infrared spectroscopy has proved to be very useful in the study of non-chair conformations. The presence of internal hydrogen bonds in molecules such as compound 2 provides extremely good evidence for the existence of substantial proportions of non-chair conformations. Moreover, this technique can be used to give quantitative information. Stolow et al. (62, 63) have been able to estimate the percentage of non-chair conformations in r-l-cis-4-dialkyl-c~s-2,5-dihydroxycyclohexanes from the intensity of the absorption due to internally hydrogen-bonded hydroxyl. Raman spectroscopy is also becoming popular as a tool for conformational studies (29, 30, 64-67). It seems likely that

G. M.

KELLIE AND F. G. RIDDELL

245

vibrational spectroscopic methods will become increasingly important in confcrmational analysis as further studies are undertaken to assign specific vibrational bands to definite molecular conformations

.

V. THE NON-CHAIR CONFORMATIONS OF VARIOUS R I N G SYSTEMS A.

Cyclohexane and I t s D e r i v a t i v e s

As cyclohexane is commonly considered the "classical" conformational analysis system it is not surprising that a large number of studies have been carried out on the non-chair conformations of substituted cyclohexanes, cyclohexanones, and cyclohexanols. Following the suggestion of Winstein and Holness (68) that the t-butyl group strongly prefers the equatorial position in cyclohexanes, attempts were made to synthesize molecules which would possess axial t-butyl groups, in order to observe whether or not they existed in non-chair forms. Allinger and Freiberg (69) contended that trans-1,3-dit-butylcyclohexane existed largely in a twist conformation and therefore estimated AHct for cyclohexane by equilibrating cis- and trans-1,3-di-t-butylcyclohexane. The figure they obtained (5.7 kcal/mole) has been adopted as a standard value but now is slightly suspect as it seems that the trans isomer exists with appreciable quantities of both chair and twist conformations. On the basis of a recent infrared spectroscopic study of the trans isomer (70) it has been proposed that the twist form is only 0.3 kcalhole more stable than the chair conformation. On this basis it would appear that AHct is slightly less than 5.7 kcalhole. This also accounts €or a proportion of the large ent.ropydifference (4.9 cal/deg-mole) between the two isomers. van Bekkum et al. ( 5 2 ) obtained heats of combustion for cis- and trans-1,4-di-t-butylcyclohexanes and found that the cis isomer was less stable than the trans by 4.7 kcal/mole. However, for reasons discussed in Sect. IV-A this cannot be considered as an estimate of AHct.

23

246

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

24

Several workers have examined Cis-4-t-butylcyclohexyltrimethylammonium iodide (23) and have considered that substantial proportions of chair conformations are present (71, 72). An nmr and ir study of compound 24 proved inconclusive (73) although it might be expected to show a slightly greater preference for the chair conformation compared with the equivalent di-t-butyl compound. r-l-tran8-3,5-Tri-t-butylcyclohexane displays an interesting nrnr spectrum (74). Only one t-butyl resonance is observed and the ring protons display a pattern inconsistent with a preponderance of the chair conformation. It is possible that a buttressing effect of the type described by Eliel (75) and Allinger (76) and their respective groups renders the chair form less stable than the chair conformation of the equivalent di-t-butyl compound. It would therefore seem likely that a useful estimate of AHct might be obtained by equilibrating the diastereoisomeric trit-butylcyclohexanes. Johnson et al. (24, 27) obtained values of M C t of 5.5 and 4.8 kcal/mole using the perhydroanthracenes and their derivatives as models for twist forms as described in Sect. 111. While this approach relies on a large n-er of assumptions, the values obtained would appear to be good approximations. During an mnr study of ring-flattening effects in cyclohexanes it was observed that for cis-1-t-butyl-4-phthalhidocyclohexane the methine proton adjacent to the phthalimido

R = Phthalimido

2s

G. M. KELLIE AND F. G. RIDDELL

247

group had two equal vicinal couplings of 5.9 Hz (77, 78). It was demonstrated by an elegant argument that these couplings could not have arisen from a chair-chair equilibrium and the conclusion was drawn that this molecule exists in a number of twist conformations, e.g., 25. Although the nmr results indicate that non-chair forms are involved in the conformational equilibrium of this compound the possibility cannot be overlooked that a chair-twist equilibrium could have resulted in the observed couplings. Similar difficulties arise in the interpretation of the nmr spectrum of r-1-hydroxy-cis-3-trans5-di-t-butylcyclohexane considered by Feltkamp et al. to be indicative of a chair-twist equilibrium (79). Further complications inherent in the use of nmr spectroscopy can be seen in the case of c~s-1,2-di-t-butylcyclohexane (80). Two coalescences were observed, one at 35O (AG+ = 16.3 f 0.3 kcal/mole) and a second at -81' (AG* = 10.1 kcal/mole). The first process was attributed to a twist-twist interconversion and the second to a chair-twist interconversion. However, it has been shown that ring inversion barriers in cyclohexanes with large torsional interactions may be as high as 17.0 kcal/mole (44) and hence this could account for the former rate process. The second coalescence could well have arisen from slow rotation of one or both of the t-butyl groups (81). It is difficult to see how the strains present in the chair forms of this molecule can be relieved to any major extent in any twist conformation. The suggestion that l-dimethylamino-3,3-trans-5-trimethyland dimethylamino-3,3,5,5-tetramethylcyclohexane (26 and 27) exist in non-chair forms (82) seems rather unlikely as the more stable chair conformations of these molecules are unlikely to

26

27

28

have a strain energy of more than 3.5 kcal/mole due to 1,3diwial interactions. The anomalous methylation rates observed for these compounds may be accounted for by ring distortions and by the presence of axial methyl groups hindering approach of the methylating agent. Some rather interesting studies have been carried out on

248

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

cyclohexanols by Stolow et al. (42, 62, 63) and by Pasto and Rao (83, 84). Both groups found that a substantial destabilizing interaction takes place when t-butyl and hydroxyl groups are in trans-vicinal positions in chair conformations.* The magnitude of this interaction is such as to assist compounds like r-l-cis-4-di-t-butyl-c~s-2-hydroxycyclohexane (28) and r-l-t-butyl-trans-2,5-dihydroxy-cis-4-methylcyclohexane ( 2 9 ) to exist with large proportions ot twist conformations. Pasto obtained an estimate of the enthalpy difference between trans1,4-di-t-butylcyclohexane and the twist conformations of the cis-l,4 isomer from equilibration studies on 2,5-di-t-butylcyclohexanols (84). His value of 7.7 kcal/mole differs greatly from the figure determined by van Bekkum (4.7 kcal/ mole) for the enthalpy difference between the compounds. This appears to indicate either that one of the estimates is inaccurate or that c~s-1,4-di-t-butylcyclohexane exists predcnninantly in a chair conformation. For r-1-cis-4-di-t-butyltrans-2-hydroxycyclohexane (30) both chair and twist forms were identified from the ir spectrum (83). The low value of AS found for interconversion between the two conformations led the authors to suggest that the twist form of this molecule is restricted to only a small portion of its pseudorotational itinerary; i.e., the compound exists to a large extent in only one twist conformation.

I

29

t-BI: 30

31

A s early calculations indicated that M C t in cyclohexanone could be ae low as 2.7 kcal/mcle (85) many workers examine2 this systm. in a search for compounds with nonchair conformations. Aliinger et al. (31, 86) equilibrated the cis- and

*It has been inferred by the present authors and Professor Stolow, frm, an examination of r,olecular models, that although substantial strain is present in a cis-vicinal arrangement this cannot be relieved to any major extent by any possible twist conformation (see Section. 1 1 - E ) .

G. M.

KELLIE AND F. G. RIDDELL

249

trans-3,5- and -2,4-di-t-butylcyclohexanones. They proposed that trans-3,5- (31) and trans-2,4- (86) di-t-butylcyclohexanones (31 and 32) preferred twist conformations and determined M C t for cyclohexanone to be 2.7 kcal/mole, i.e., in agreement with the calculated value. The suggestion (85) that 2-t-butylcyclohexanone exists with appreciable non-chair populations, due to interactions between the t-butyl and carbonyl groups, has been criticized by Stolow (87). From an examination of certain analogous compounds Stolow concluded that the nonchair populations for this compound must be less than 10%.

1-Eu 32

33

OCH3 34

OH

A number of studies have been carried out on cyclohexanones with the destabilizing trans-vicinal interaction described above. trans-3-t-Butyl-4-hydroxycyclohexanone (33) (88) and its methyl ether 34 exist with appreciable proportions of non-chair forms. Indeed it would appear that the magnitude of this interaction increases proceeding from hydroxyl to methoxyl. Further studies have revealed that compounds 35, 36, and 37 all exist substantially in non-chair conformations

n 1-BU t -Bu

t

-

B

'OH

35

N OH

36

(89) and their epimers 38, 39, and 40, which should have more stable chair conformations, also possess substantial non-chair populations.

250

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

37

38

A considerable body of evidence now exists to demonstrate that c~s-2,5-dialkylcyclohexane-1,4-diones are more stable than their trans isomers (90, 911, in contrast to the situation in

39

40

the analogous cyclohexanes. It also seems very likely that the cis isomers exist predominantly in twist conformations, whereas the trans isomers may have large populations of both chair and twist forms, the proportion of chair conformations increasing with increasing bulk of the alkyl group. These results can be rationalized in the light of the knowledge that the parent dione prefers a twist conformation as discussed earlier (Sect. 111-B). Hence if two groups are placed in pseudoequatorial positions (as in the cis isomer 41) it is likely that this molecule will be more stable than the trans isomer which must exist either in a twist form 42 with one group pseudoaxial (assuming the carbonyl groups occupy Ic positions) or in a chair conformation with both groups equatorial, 43. The latter form, although it places the groups in unhindered positions, requires the ring to exist in a higher energy conformation; hence the cis isomers must be more

G. M. KELLIE AND F. G. RIDDELL

251

o ;==o R

'R 41

42

stable than the trans. This is precisely the reverse of what may take place in the diastereoisomeric 1,4-di-t-butylcyclohexanes in which the cis isomer can only place the groups in unhindered positions in the less stable twist conformation. The small entropy difference between the Cis- and tPan82,5-di-t-butylcyclohexane-l,4-diones (0.2 cal/deg.) may well indicate that the cis isomer exists preferentially in one twist conformation (91). This is quite possible as the conformation depicted ( 4 1 ) with the t-butyl groups in YE positions appears to be more stable than any other form which can be constructed for this molecule.

43

44

Several workers have examined 2,2,4,4,6,6-hexamethylcyclohexane-1,3,5-trione (92, 93). Dipole moment and Kerr constant measurements indicate that this molecule adopts a twist conformation, 44. In this twist conformation, although there are two YA methyl groups, they are transannularly placed with respect to carbonyl groups and therefore will experience less steric repulsions than they would in a cyclohexane twist. In addition the chair conformation has three syn-axial methyl groups and will be effectively destabilized by this interaction.

252

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

B. Nitrogen-Containing Rings At present only relatively few nitrogen compounds have been shown to exist in nonchair conformations. In many cases where twist conformations are favored, e.g., 1,2,2,6,6-pentamethyl-4-hydroxy-4-phenylpiperidine (lo), Y-tropine (94), and 2-hydroxy-2-phenylquinolizidine (951, the molecules possess internal hydrogen bonds which stabilize these conformations. Casy et al. have examined a number of 4-phenylpiperidinols. They originally suggested (see ref. 96) that trans-2,5-dimethyl4-phenyl-r-4-hydroxy-N-methylpiperidine existed in a twist form but withdrew this suggestion after a 1 3 C nmr study (97) had revealed that this compound prefers a chair form. However, for the protonated derivatives of certain compounds Casy considers that non-chair populations are appreciable in some solvents (98). The nmr spectrum of N-t-butyl-trans-3,5-dimethylpiperidone (45) has been interpreted in terms of non-chair conformations (99). However, this nmr analysis was based on first-order

t-Bu 46

40

coupling constants and therefore must be considered suspect. On a priori grounds, contributions of non-chair forms to the structure of 45 are nonetheless plausible, as severe interactions may occur between the t-butyl and methyl groups in the chair form. It is also interesting to note the recent appearance of syntheses (100) of the nitrogen analog of twistane, l-azatwistane ( 4 6 ) .

C.

Oxygen-Containing Rings

The bulk of the studies on oxygen-containing six-membered rings in terms of non-chair conformations have been carried out on the 1,3-dioxane series. So far as we are aware no tetrahydropyrans, 1,2-dioxanes, 1,4-dioxanes, and 1,3,5-trioxanes

G. M.

KELLIE AND F. G. RIDDELL

253

have been shown to prefer non-chair conformations. As a result this section is exclusively devoted to the lI3-dioxanes although some compounds with oxygen and other heteroatoms are considered in later sections. The conformational analysis of 1,3-dioxanes has been widely studied and a number of useful reviews have been published (66,101-103). Table 1 shows some of the values proposed for AHct in 1,3-dioxane. The initial suggestion made in 1965 (14) of 2.2 kcal/mole was based on the rotational barrier in methanol (1.1 kcal/mole) which was subsequently (105) shown to be an inappropriate model. The multitude of values given for this parameter are partly accounted for by a lack of concrete evidence as to which 1,3-dioxanes exist in twist conformations. Also 1,3-dioxane itself has two possible twist conformations termed (119) the 1,4 twist 47 and the 2,5 twist 48 which may well be of different energies. Hence it is possible that different workers have used different twist conformations as models of 1,3-dioxane non-chair forms.

47

48

49

Delmau and Duplan (115) considered that 4-t-butyl-4methyl-lI3-dioxane adopted a twist conformation in order to relieve the strain caused by the presence of an axial 4-methyl group. However, 'H nmr evidence proved that the preferred conformation of this molecule is a chair conformation (104, 116). Eliel et al. (109, 110) and Pihlaja and Ayras (117) proposed that molecules which would possess syn-diaxial methyl groups in their chair conformations might be more likely to have appreciable twist populations. 'H nmr coupling constants and solvent shifts (117), thermochemical (1081, and molecular rotation (118) studies tended to support this contention. Tavernier and Anteunis (116) have tackled the problem by preparing model compounds which would be forced to have an axial t-butyl (or another group of similar bulk) group in their chair conformations. In order to develop a criterion to enable a distinction to be made between chair and twist conformations they examined the sum of the vicinal coupling constants in compounds with a trans-4,6-dialkyl grouping. For the chair conformations they anticipated that the sum of the vicinal couplings between the 4, 6 and 5 protons should be

254

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

Table 1. Proposed Values of MCt f o r 1,3-Dioxane

Met, kcal/mole

Date

Ref.

E l i e l , A l l i n g e r , Angyal, and Morrison

1965

14

>3.0

Anderson , e t a l .

1967

104

>3.0

R i d d e l l and Robinson

1967

105

6.8

Pihlaja

1968

106

6.2

Anteunis and Swaelensa

1970

107

6.2

Eccleston and Wyn-Jonesa

1971

113

7.2

P i h l a j a and Lucuna

1968

108

>7.2

E l i e l and Powers

1969

llob

>8.0

Nader and E l i e l

1970

109

8.3

Pihlaj a

1971

112

8.5

P i h l a j a and Jalonen

1971

111

Clay, e t a l .

1972

114

2.2

<8.9

Proposed by

a s t r i c t l y speaking t h e s e v a l u e s apply t o s p e c i f i c CMpounds which c o n t a i n a x i a l groups i n t h e i r c h a i r conformations and are t h u s more s t r a i n e d than t h e c h a i r form of 1,3-dioxane i t s e l f . A s a r e s u l t AHct estimated by t h e s e methods w i l l be a t l e a s t 3 k c a l h o l e l a r g e r than t h e v a l u e quoted. bE. L. E l i e l , J. R. Powers, Jr., and F. W. Nader, Tetrahedron, i n p r e s s . The a u t h o r s have r e p o r t e d a s l i g h t l y r e v i s e d v a l u e of >7.4 kcal/mole.

G. M. KELLIE AND F. G . RIDDELL

255

about 11 Hz,* whereas for the twist conformation 49, with the groups in pseudoequatorial positions, a value of about 15 Hz would be more likely. Table 2 presents values obtained for this parameter in a number of molecules. It can be seen that for most simple alkyl groups the chair form is favored but for trans-4,6-di-t-butyl- and tran8-4-t-butyl-6-(l'-adamantyl)1,3-dioxanes (50) the conditions for a twist conformation are met. 2,2-tran8-4,6-tetramethyl-l,3-dioxane (49) (R = R' = R" = Me) has the required 8yn-diwial methyl groups to destabilize the chair conformation (119). For unsymmetrically substituted tran8-4,6-dialkyl-lI3dioxanes the geminal coupling constant between the protons at C(2) is sensitive to conformation. The temperature variation of this coupling constant for certain 1,3-dioxanes has been measured and used to obtain an estimate of AHct in lI3-dioxane (107). Kellie and Riddell (56) modified the 1 3 C n m r method of Grant in an examination of some methyl and gem-diethyl-1,3dioxanes. Substituent parameters were evaluated for a large number of compounds which had previously been demonstrated to exist in chair forms. These parameters were then used to calculate the shifts of the ring carbon atoms of compounds suspected of existing in non-chair conformations. For 1,3dioxanes which would have a 2,4-8yn-diaxial methyl interaction in their chair forms, large deviations were observed between the experimental and calculated values, whereas for molecules with a 4,6 interaction small differences were noted. From a knowledge of the geometry of the 1,3-dioxane chair conformation it is apparent that the strain generated by the 2,4 repulsion is rather more severe than that generated by the 4,6 interaction. On this basis the authors concluded that the former compounds prefer non-chair forms, whereas those with the 4,6 interaction exist either in distorted chair forms or with appreciable proportions of both chair and twist conformations. As it is difficult to construct a twist conformation for the compounds with a 4,6 interaction, in which much of the strain present in the chair conformation is relieved, it seems more likely that distorted chair forms are favored. A similar analysis to that applied to the 13C nmr shifts has been used in a study of the boiling points and molar volumes of some 1,3-dioxanes (120). Substantial deviations between experimental and calculated values have been found for the lI3-dioxanes considered to prefer nonchair conformations. However, due to the complex nature of the forces determining such properties, care must be taken in drawing conclusions from these results.

256

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS Table 2. Vicinal Coupling Constants for lI3-Dioxanes with a trans-4,6-Dialkyl Grouping

R1

R2

R3

E 3 J ~ HZa ~,

Ref.

H

Me

Me

10.8

116

H

Et

Et

10.7

116

H

n-pr

n-Pr

10.5

116

H

i-pr

i-pr

10.9

116

H

~-Bu

i-Bu

10.6

116

H

SeC-Bu

SeC-Bu

11.1

116

H

t-Bu

t-Bu

15.6

116

H

t-Bu

1-Adamantyl

16.4

107

Me

14.8

119

Me

Me

asurn of the vicinal coupling constants between the 4, 6 and 5 protons.

G.

M.

KELLIE AND F. G.

I

I

1 -Ada man i y I 50

257

RIDDELL

51

52

In a 'H nmr study of some of these nonchair conformations (119) it has been found that the coupling constants for many of these molecules can be interpreted in terms of certain twist forms, e.g., 2,2-r-4-trans-5-cis-6-pentamethyl-l,3dioxane has couplings of 7.8 and 5.3 Hz between the 4 , 6 and 5 protons. This is inconsistent with a chair conformation but can be demonstrated to fit well the twist conformation shown (51). For certain 1,3-dioxanes it was observed that the coupling constants were temperature invariant, indicating that they exist largely in only one twist conformation. in 1,3-dioxane has been obtained from An estimate of Ah& ultrasonic relaxation experiments (113). However, at present the exact nature of the relaxation processes observed has not been unambiguously assigned. A novel method of obtaining conformational energetics using appearance potentials in the mass spectra of certain 1,3-dioxanes has been used to estimate AHct (111). This technique may well prove to be very useful for further studies on nonchair molecules. Perhaps the most interesting 1,3-dioxane studied has been trans-2,4,4,6-tetramethyl-l,3-dioxane. From an analysis of the variable-temperature nmr spectrum of this compound Eliel and Nader (109) proposed that at room temperature it existed as a 5 : lmixture of the chair and twist forms 52 and 5 3 , respectively. However, it was subsequently shown (119), from a rigorous analysis of the 220 MHz nmr spectrum of this molecule, that the twist form was the most stable conformation. In an attempt to estimate M C t for 1,3-dioxane,trans-2,4,4,6tetramethyl-lI3-dioxanewas equilibrated (109) with its cis isomer, which was known to prefer the chair conformation. However, using gzc techniques no trans isomer could be detected at equilibrium and hence the energy difference could not be determined. This problem was solved by application of a microcalorimetric method for determining conformational enthalpies (114). The enthalpy difference between the isomers was found

258

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

to be 5.8 kcal/mole and as the cis isomer has about 3.1 kcal/ mole strain due to the axial methyl group, M C t was estimated to be 8.9 kcal/mole less the strain present in 53. Although no crystal structure has been determined for a l13-dioxanewith a non-chair conformation* an X-ray diffraction study has been carried out on r-2-4,4-cis-6-tetramethyl2-(4'-bromophenyl)-l,3-dioxane (121). This cornpound has a 2,4diaxial interaction between a phenyl and a methyl group and might well have favored a twist conformation. However, the crystal structure clearly reveals that this molecule exists in a deformed chair conformation 54 in the solid state and the nmr parameters indicated that this was also the case in solution. As this molecule was at least 2 kcal/mole more stable than its trans epimer, with a 2,4-syn-diaxial methyl interaction in the chair form, it is likely that compounds with this latter interaction prefer twist conformations.

t -Bu

53

64

66

Tavernier and Anteunis (124) have recently carried out further NRT studies on l13-dioxanes. For r-2-cis-4-dimethyltrans-6-t-butyl-l,3-dioxanes they consider the nmr parameters to be consistent with a twist conformation. Anteunis et al. (125) have also studied a number of bicyclic dioxanes in which the chair conformation is highly strained. For certain of these molecules they consider that at least one ring may be forced into a twist conformation.

0. Sulfur-Containing Rings

As the 1,3-dithianesI like the 1,3-dioxanes, possess a number of features which render them attractive as a system *This is partly due to the difficult of obtaining crystalline 1,3-dioxanes suitable for an X-ray diffraction study (122, 123).

G.

M. KELLIE AND F. G. RIDDELL

259

for conformational analysis studies, a number of investigations have been carried out on their non-chair conformation. Abraham and Thomas (126) suggested that molecules such as 55 could adopt twist forms. Eliel and Hutchins (127) obtained accurate values for the conformational energies of substituents at each of the ring positions in the chair conformations. In contrast to cis-2,5-di-t-butyl-l,3-dioxane which exists in a chair conformation with an axial 5-t-butyl group (1051, C<8-2,5-dit-butyl-1,3-dithiane appears to prefer a twist conformation. From an equilibration of cis- and trans-2,5-di-t-butyl-lI3dithianes AHct was determined (127) to be 3.4 kcalbole. In the equilibration of cis- and trans-r-2-t-b~tyl-4~6-dimethyl1,3-dithianes only a small entropy difference was found. As the trans isomer appears to favor a twist conformation this tends to imply that one twist form is particularly favored, e.g., conformation 56 in which all the groups are in pseudoequatorial or isoclinal positions.

56

57

Wood and Miskow (128) considered that trimethylene sulfite might exist in a non-chair conformation but later nmr (129) and X-ray (130) diffraction studies showed that this molecule prefers a chair form with the S=O group in an axial position. t~anS-4,6-Diisopropyl-5,5-dimethyltrimethylene sulfite displays an nmr spectrum consistent with a non-chair conformation (131). In a numher of studies on 8-tetrathianes (132-134) Bushweller et al. concluded that tetramethyl-8-tetrathiane is involved in a chair-twist equilibrium. A line-shape analysis indicated that the twist form was more stable by 0.8 kcal/mole In contrast other derivatives appear to prefer chair forms. The X-ray crystal structure of the tetramethyl compound (135) does indeed reveal that it exists in a non-chair form, but it is a boat conformation and not the twist form depicted by Bushweller. At present the general implications of these results remain a little difticult to interpret, but in view of the fact that the potential energy curve for rotation about heteroatom-heteroatm bonds is vastly different (14) to

260

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

that in C-C or C-heteroatam bonds, it is possible that either twist or boat forms will be favored for such molecules. Pasanen and Pihlaja (1361, in a study of the conformational to be preferences of the 1,3-oxathianes, have estimated Uct about 6 kcal/mole in this system. This is strictly an enlightened guess, based on the value of the U c t parameter in 1,3dioxane and 1,3-dithiane.

E.

Phosphorus-Contai ni ng Ri ngs

Conformational analysis studies on six-membered ring compounds containing phosphorus are now becaning more numerous, and although few cases of non-chair conformations have been reported, some of the features of the stereochemistry of these molecules, e.g., the preference of substituents attached to phosphorus to be axial, may result in many molecules adopting twist conformations. Bentrude and Hargis (137) have examined the conformational preferences of 1,3,2-dioxaphosphorinans and have suggested that twist forms may be involved in the conformational equilibrium of tran8-2-methoxy-5-t-butyl-l,3,2dioxaphosphorinan. In the case of cis-2,5-di-t-butyl-l,3,2dioxaphosphorinan-2-one, the nmr spectrum clearly points to a non-chair form (138) and the coupling constants may be reconciled with a preponderance of the twist form 57.

VI.

MOLECULAR MECHANICS CALCULATIONS

The use of molecular mechanics methods to calculate the geometries and energies of molecules has attracted many workers. As the twist form of cyclohexane was not easily studied experimentally, the use of semiempirical and more rigorous calculations to determine relative energies and conformations became important. Pitzer (see ref. 5) was able to deduce that the chair conformation was the most stable form of cyclohexane, and Hazebroek and Oosterhoff (21) demonstrated that the twist form was more stable than the boat arrangement. The use of semiempirical techniques was developed by Hendrickson (1411, Wiberg (142), and Lifson and Warshel (143). The nature of some of these methods has been discussed by Schleyer (see ref. 144). This section is concerned with results rather than methods applied to date. In order to demonstrate the accuracy of the various calculations Table 3 shows various values calculated for AHct and m c b in cyclohexane. Hendrickson (141) first tackled the nature of the twist and boat conformations in detail. He obtained data on the exact geametry of each conformation and clearly delineated the various modes of interconversion (18) between the chair and

G. M. KELLIE AND F. G. RIDDELL

261

Table 3. Calculated Potential Energy Differences between the Chair, Twist, and Boat Forms of Cyclohexane

Chair-twist, kcal/mole

Chair-boat, kcal/mole

5.6

--

4.8

5.3

Ref.

5 21

5.1

--

6.5

6.6

139

5.6

6.4

18

5.1

6.4

76

4.9

6.6

70

4.9

6.7

140

7.9

8.5

19

85

boat-twist family and within the boat-twist family, i.e., pseudorotation. He has calculated the relative energies of methyl groups in various positions on the twist conformation. The pseudoequatorial position is of lowest energy although the Ic positions engender only slightly more strain. In contrast a methyl group in a pseudoaxial situation experiences repulsion of a similar magnitude to those found in the axial position in the chair conformation. Allinger developed Wiberg's calculation scheme and has produced some interesting results. He has calculated the effect of an axial t-butyl group on the cyclohexane ring. Although early results (76) indicated severe destabilization compared with a twist form with the group in a YE or Ic position, later predictions suggest that the conformational energy of a t-butyl group in cyclohexane is 5.4 kcal/mole (70). This indicated that trans-1,3-di-t-butylcyclohexane should contain appreciable amounts of both chair and twist forms, a result which infrared spectroscopy appears to confirm (70). Allinger and other workers have attempted by calculations, to show whether or not compounds with strained chair

262

NON-CHAIR CONFORMATIONS OF SIX-MEMBERED RINGS

conformations exist preferentially in chair or twist conformations. Cyclohexanes with a l13-8yn-diaxial methyl interaction, e.g., l,lI3,3-tetramethyl- and 1,l-tran8-3,5-tetramethylcyclohexane, are clearly shown to favor slightly deformed chair (70, 145) conformations in agreement with experiment. 3,3,5,5Tetramethylcyclohexanone also can be calculated to exist in a chair (145) conformation and most interestingly 3-phen~l-3~5~5trimethylcyclohexanone and l-phenyl-1,3,3-trimethylcyclohexane should exist in chair conformations with axial phenyl groups (61). These interesting predictions have recently been confirmed experimentally (59, 60) and the explanations offered can be applied to demonstrating that r-2,4,4-ci8-6-tetramethyl6-(4'-bromophenyl)-l13-dioxane should be more stable than its trans epimer (121). Recent calculations of M C t indicate that cyclohexane-1,4dione should be slightly more stable in the twist than the chair conformations (140),although the experimental evidence tends to point to quite a substantial free energy difference. One of Allinger's early calculations on cyclohexanone (85) indicated that M C t should be about 2.7 kcal/mole. Later determinations gave a value of 3.3 kcalhole (146), rather nearer the experimental value. M c t in silacyclohexane has been considered (147) to be about 3 kcal/mole and this may well lead to some interesting experimental work on this system. During a study of 1,3-diaxial interactions in cyclohexanes Lambert et al. (148) carried out some interesting calculations which reveal high interaction energies between a methyl group syn-axial with a bromine or iodine atom. Therefore it is possible that certain molecules with this interaction in their chair conformations may well exist in twist forms. Pickett and Strauss (19) have carried out detailed studies on cyclohexane and related oxanes using a potential energy function derived from vibrational and geometric data. At present this method gives values of AHc. which are somewhat higher than those evaluated using other techniques. However, with further refinement this method could prove very useful.

VII.

DISCUSSION

It is apparent fran many of the examples given in the previous sections that in order for a compound in section C of our classification (cf. Sect. 111-C) to prefer a twist conformation considerable strain must be present in the chair conformations and this must be substantially relieved in some of the available twist conformations. Many of the canpounds that have been put forward as examples of non-chair conformations in fact possess deformed chair conformations. Much of

G. M. KELLIE AND F. G. RIDDELL

263

the evidence has been extremely tenuous; in particular, mis interpretation of nmr spectra has led to some erroneous conclusions. In many cases ancmalous results have not been scrutinized carefully and instead the twist form has been used as a universal panacea to explain everything. In order to decide whether or not it is reasonable to consider non-chair conformations for a particular molecule all the possible forms should be examined either using models or by application of molecular mechanics computer programs. The forms of minimum energy should then be closely examined to see whether or not they fit the experimental results. Another important conclusion which may be drawn from the examples given is that for sane compounds one twist form may be considerably more stable than all others. This appears to be likely for certain cyclohexanes, 1,3-dioxanes, 1,3-dithianes, and 1,3,2,-dioxaphosphorinans. This is a good reason for abandoning the term "flexible" previously used to describe the boat-twist family. However, it should always be remembered that the molecule may be able to pseudolibrate around one twist form and hence gain some of the entropic stabilization commonly associated with the twist form. It has frequently been assumed that ASc. should be large for most molecules and hence this has become adopted as a criterion of whether or not a molecule exists in a twist form. Clearly the discussion above shows that this may not be universally true, and indeed it appears that the greatest factor favoring twist forms is the relief of strain in the chair conformations, not entropic factors. It is interesting to note that M c t rises proceeding from 1,3-dithiane through cyclohexane to 1,3-dioxane. A possible explanation for these differences may lie in the fact that the twist forms become more "compact" proceeding up the list as bond lengths in the molecule decrease, and the energy differences may reflect increased transannular interactions in the twist conformations (101).

ACKNOWLEDGMENTS It is a pleasure to acknowledge the help of many people who have assisted in the preparation of this chapter. Particular thanks must be extended to Dr. M. J. T. Robinson for his helpful and constructive comments, to our colleagues Drs. J. S. Roberts and P. Murray Rust, who read and commented on the draft manuscript, and to Professor J. Leech for several interesting discussions on the geometry of six-membered rings.

264

NON-CHAIR

CONFORMATIONS OF SIX-MEMBERED RINGS

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NON-CWLIR CONFORMATIONS OF SIX-MEMBERED RINGS

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STEREOCHEMISTRY OF CYCLOBUTANE AND HETEROCYCLIC ANALOGS ROBERT M

. MORIARTY

Department of Chemistry University of Illinois a t Chicago Circle. Chicago. Illinois

.

I

.

I1

.

I11

. V.

IV

VI

.

. . . . . . . . . . . . . . . . . . . . 273 The Shape o f the Four-Membered Ring . . . . . . . . 274 Reason f o r Puckering o f t h e Cyclobutane Ring . . . . 284 Monosub s t i t u t e d Cycl obutanes . . . . . . . . . . . . 289 D i s u b s t i t u t e d Cyclobutanes . . . . . . . . . . . . . 297 A . 1. 1-Disubstituted Cyclobutanes . . . . . . . . . 297 B . l Y 2 - D i s u b s t i t u t e d Cyclobutanes . . . . . . . . . 299 C . l Y 3 - D i s u b s t i t u t e d Systems . . . . . . . . . . . 302 Tetrasubsti t u t e d Cyclobutanes . . . . . . . . . . . 318 A . Substituted Ethylene Dimers . . . . . . . . . . 318 B . Tricyclo[4.2.0.02~~]octane . . . . . . . . . . . 322 C. 6-Unsaturated Carbonyl Dimers . . . . . . . . 326 0 . Thymine and U r a c i l Photodimers . . . . . . . . . 333 Introduction

a.

VII

.

E

.

1.1.2.2.-

T e t r a s u b s t i t u t e d Cyclobutanes

. . . . . 341

Cyclobutane as a Member o f a Simple Fused Ring System

. . . . . . . . . . . . . . . . . . . . 344 A . B i c y c l o [ l . l .Olbutane . . . . . . . . . . . . . . 344 B . Bicyclo[2.1 .Olpentane . . . . . . . . . . . . . 347 C . B i c y c l o[ 2.2.03 hexane . . . . . . . . . . . . . . 348

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Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

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CYCLOBUTANE AND HETEROCYCLIC ANALOGS

. E.

. . . . . . . . . . . . . 349 Bicyclo[7.2.0]undecane . . . . . . . . . . . . 353 V I I I . 1. 3.Disubstituted Systems i n Which t h e Cyclobutane I s P a r t o f a Bridged P o l y c y c l i c System . . . 360 A . B i c y c l o [ l .1 .l l p e n t a n e . . . . . . . . . . . . . 360 B . Bicyclo[P.l .llhexane . . . . . . . . . . . . . 361 C . Bicyclo[3.1 .13 heptane . . . . . . . . . . . . . 363 D . Tricyclo[3.3.0.02~~]octane . . . . . . . . . . 368 E . Tricyclo[3.2.1.0~~5]octane . . . . . . . . . . 372 I X . The Cyclobutyl Carbocation . . . . . . . . . . . . 373 X . Heterocyclic Four-Membered Ring D e r i v a t i v e s . . . . 383 A . Trimethylene Oxide (Oxetane) . . . . . . . . . 383 B . Trimethylene Sulfide (Thietane) . . . . . . . . 386 C . Trimethyl ene Sel enide . . . . . . . . . . . . . 387 D . S i 1acycl obu tane . . . . . . . . . . . . . . . . 389 E . Trimethylene Imine (Azetane) . . . . . . . . . 390 F . Substituted Oxetanes . . . . . . . . . . . . . 393 G . Substituted Azetanes . . . . . . . . . . . . . 394 H . Substituted Thietanes . . . . . . . . . . . . . 397 I. Substituted 1. 2.0xazetidines . . . . . . . . . 402 J . Phosphorane and Phosphetane D e r i v a t i v e s . . . . 404 K . Ferretane . . . . . . . . . . . . . . . . . . . 407 D

Bicyclo[4.2.0]octane

Acknowledgements

408

References

408

ROBERT M.

273

MORIARTY

I, INTRODUCTION The s u b j e c t of t h e stereochemistry of cyclobutane and i t s d e r i v a t i v e s r e c e i v e s r e l a t i v e l y l i t t l e a t t e n t i o n i n standard t e x t s on conformational theory (1, 2 ) . I t i s completely overshadowed by d i s c u s s i o n of cyclohexane. Nonetheless t h e r e e x i s t s a l a r g e l i t e r a t u r e on t h e four-membered r i n g which has n c t r e c e n t l y been brought t o g e t h e r i n a comprehensive way ( 3 ) . The aim of t h i s chapter i s t o do so. I n a p r e s e n t a t i o n of t h e conformational a n a l y s i s of cyclobutane one i s i n e v i t a b l y !.ed t o s t u d i e s on four-membered h e t e r o c y c l i c compounds such a s trimethylene oxide (oxetane) trimethylene imine ( a z e t a n e ) , trimethylene s u l f i d e ( t h i e t a n e ) , trimethylene s e l e n i d e , and silacyclobutane. This i s because t h e s e compounds p o s s e s s d i p o l e moments, and t h e r e f o r e may be s t u d i e d by microwave spectroscopy which g i v e s extremely a c c u r a t e molecular parameters. Cyclobutarie i t s e l f cannot be s t u d i e d by microwave techniques because it has v i r t u a l l y no d i p o l e moment. Furthermore, r i n g puckering ( o r t h e out-of-plane r i n g v i b r a t i o n ) i s i n f r a r e d i n a c t i v e , and t h e r e f o r e no f a r - i n f r a r e d spectrum can be expected. However, t h e puckering fundamental is Raman allowed and Raman spectroscopy has been used e x t e n s i v e l y i n t h e study of cyclobutane and i t s d e r i v a t i v e s . A f e a t u r e of t h e l i t e r a t u r e on t h e four-membered r i n g i s t h e predominance of t h e u s e of p h y s i c a l methods i n t h e e l u c i d a t i o n of i t s conformational p r o p e r t i e s . Microwave, i n f r a r e d , and Raman s p e c t r a , t o g e t h e r with e l e c t r o n and X-ray d i f f r a c t i c n , have supplied t h e e s s e n t i a l conformational p i c t u r e . Dipole moment and nuclear magnetic resonance s t u d i e s have a l s o yielded v a l u a b l e information, b u t i n c o n t r a s t t o t h e course of development of t h e conformational a n a l y s i s of cyclohexane, standard organic chemical methods have n o t a s y e t played a key r o l e i n our knowledge of t h e stereochemistry of t h e fourmembered r i n g . Two a r e a s of t h e chemistry of cyclobutane have nevertheless been i n v e s t i g a t e d f r u i t f u l l y . These are t h e e q u i l i b r a t i o n of d i s u b s t i t u t e d diastereomers, and s o l v o l y t i c r e a c t i o n s of v a r i o u s simple and fused r i n g cyclobutyl d e r i v a t i v e s . Considerable promise l i e s i n t h e a p p l i c a t i o n of computer methods based on Westheiner-type f u n c t i o n s t o t h e conformational problen. Also ab initio and extended H k k e l t h e o r y c a l c u l a t i o n undoubtedly w i l l y i e l d important stereochemical information about cyclobutane. F i n a l l y , a l a t e n t i n t e r e s t i n cyclobutane has always e x i s t ed among o r q a n i c chemists because of t h e occurrence of t h i s r i n g i n c e r t a i n n a t u r a l products. Very e a r l y t h e problem of t h e s t r u c t u r e of t h e t r u x i l l i c and t r u x i n i c a c i d s was s o r t e d o u t on t h e b a s i s of more o r less c l a s s i c a l stereochemical

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

274

analysis. This work gave sane important i n s i g h t s i n t o t h e stereochemical p o s s i b i l i t i e s f o r substituted cyclobutanes. The very complex f i e l d of caryophyllene and i t s rearrangement products derived from r i n g a l t e r a t i o n of the four-membered r i n g has offered some general stereochemical patterns f o r cyclobutane rearrangements. Also, t h e extensive X-ray work done on these cmpounds has shed a good deal of l i g h t on t h e struct u r a l problem of fused r i n g cyclobutanes. Pinane chemistry has a l s o supplied important information about conformational control i n cyclobutane r i n g expansion. A renewed i n t e r e s t i n t h e stereochemistry of cyclobutane has arisen because of the surge of research a c t i v i t y on t h e stereochemical aspects of photochemical and thermal o l e f i n cycloaddition reactions which lead t o four-membered rings. Recently t h e four-membered ring containing photodimers from i r r a d i a t i o n of DNA have been investigated by a combination of physical methods and very good s t r u c t u r a l parameters have been obtained. The cyclobutyl-cyclopropylcarbinyl cation problem i s being reexamined, and it appears t h a t the conformational aspects of the four-membered r i n g may supply a r a t i o n a l e f o r t h e diverse r e s u l t s obtained i n t h i s series. The approach used i n t h i s chapter i s t o r e p o r t and evaluate information frcan the various f i e l d i n which s t r u c t u r a l data about the cyclobutane r i n g have been generated. Hopefully t h i s w i l l r e s u l t i n a f u l l y developed description of the stereochemical f a c t o r s which govern t h e s t r u c t u r e and reactivi t y of the four-membered ring.

11.

THE SHAPE OF THE FOUR-MEMBERED R I N G

Cyclobutane may e x i s t i n two limiting conformational forms. One i s planar ( 2 ) having D4h symmetry, and t h e other is a bent or puckered form (2) having Dpd symmetry (see Scheme 1). The point group designation indicates t h a t they both possess dihedral symmetry, t h a t is, a v e r t i c a l principal axis, and twofold subsidiary axes perpendicular t o the principal axis. I n the planar form t h e r e is a fourfold principal axis and a horizontal plane of symmetry which contains the subsidiary axes. There a r e a l s o four v e r t i c a l planes of symmetry perpendicular t o the horizontal plane. The puckered form has a twofold v e r t i c a l principal a x i s and two v e r t i c a l planes of symmetry. A very important s t r u c t u r a l parameter f o r the puckered form i s the angle of pucker, 4 . Some confusion a r i s e s over terminology i n designating t h i s angle. I f it i s termed the dihedral angle, then it should properly r e f e r t o t h e angle made by t h e i n t e r s e c t i o n of

27 5

ROBERT M. MORIARTY

a rn

I "

b

I

rn

1

2

a

Scheme 1. Symmetry elements f o r p l a n a r and puckered (1) a = p r i n c i p a l v e r t i c a l axis and b = twofold cyclobutane: s u b s i d i a r y axes; ( 2) m = p r i n c i p a l twofold a x i s , n = two v e r t i c a l p l a n e s of symmetry, and 4 = a n g l e of pucker. V e r t i c a l p l a n e s of symmetry c o n t a i n t h e s u b s i d i a r y b axes.

-

p l a n e s C1C2C4 with C2C3C4 and equal 180' 0. The pucker angle 4 i s t h e angle of displacement of t h e C2C3C4 plane above t h e C1C2C4 plane. Unfortunately, both d e f i n i t i o n s a r e used f o r t h e term d i h e d r a l angle by v a r i o u s a u t h o r s , and s i n c e no consensus e x i s t s on t h i s p o i n t , both are used i n this chapter according t o t h e choice of t h e a u t h o r s of t h e work discussed. The f o l d i n g of t h e r i n g i s accomplished by a t w i s t i n g of carbon-carbon bonds, r e s u l t i n g i n d i r e c t e d s u b s t i t u e n t bonds analogous t o t h e a x i a l and e q u a t o r i a l bonds i n cyclohexane. I n t h e l i g h t of modern conformational theory one would regard t h e equilibrium s t r u c t u r e of cyclobutane t o be t h e r e s u l t of t h e counterplay of two l a r g e opposing f o r c e s . The p l a n a r form i s d e s t a b i l i z e d by t h e e c l i p s i n g of t h e a d j a c e n t methylene hydrogen atoms. This i s r e l i e v e d by r i n g puckering, which i n c r e a s e s the t o r s i o n a l angle between t h e a d j a c e n t hydrogens, b u t a l s o d e c r e a s e s t h e CCC bond a n g l e s , r e s u l t i n g i n an i n c r e a s e i n angle s t r a i n . I t i s of h i s t o r i c a l i n t e r e s t t o trace t h e changes i n concept regarding t h e shape of cyclobutane. von Baeyer cons i d e r e d a l l c y c l i c cornpounds t o be p l a n a r . Sachse around 1890 p u t f o r t h h i s i d e a of a nonplanar cyclohexane, and a l s o pointed o u t t h e p o s s i b i l i t y of a nonplanar form f o r cyclobutane.

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CYCLOBUTANE AND HETEROCYCLIC ANALOGS

Sachse's originally discredited ideas on the boat and chair form of cylohexane were vindicated by Mohr in 1918 and eventually fully accepted through the work of Hassel, Barton, and others in the early 1950s. No such denouement occurred for cyclobutane. Rather, its stereochemistry has matured much more slowly, and in comparison with cyclohexane it is at a considerably less well developed stage. The earliest Raman and infrared study on cyclobutane led to the conclusion that the molecule was planar ( 4 ) . This suggestion influenced a number of subsequent studies. For example, Edge11 (5a) investigated the Raman spectrum of octafluorocyclobutane in both liquid and gaseous states and based the interpretation and normal coordinate analysis on the assumption of a planar model. The same conclusion was reached from analysis of the infrared spectrum of octafluorocyclobutane (6). Credit for first recognizing that cyclobutane might be a nonplanar molecule must go to R. P. Bell who published a very important theoretical paper in 1945 (7). Bell found that for a molecule of the type 3 , the potential energy change for

3

a vibrational mode such that one of the atoms A, B, C, or D moves by a small displacement X toward a at right angles to the plane of the ring is governed by the relationship: V ( x ) = bx4 where b is a force constant Bell reasoned that the restoring force for the vibrational displacement depended on the ring angle bending constants. Since angles 0.i are related to the ring-puckering coordinate x, the distortion of the ring from planarity is given by A${=x', and the potential energy of the vibration depends on ( A 4 y 1 2 ; therefore it must be quartic in the form x 4 . He stated ciearly that cyclobutane ought to be a prime example of this fourth-power vibrational dependency, and also that any torsional

ROBERT M.

MORIARTY

277

c o n t r i b u t i o n t o t h e ring-puckering v i b r a t i o n should e n t e r a s a q u a d r a t i c term. B e l l had found an equation f o r t h e d e s c r i p t i o n of a phenomenon t h a t apparently d i d n o t occur, f o r Wilson ( 4 ) had concluded t h a t cyclobutane was a p l a n a r molecule. Even though B e l l could n o t apply h i s fourth-power molecular v i b r a t i o n a l r e l a t i o n s h i p irmnediately t o cyclobutane, t h i s same equation has been used by v i r t u a l l y a l l subsequent workers t o c o n s t r u c t p o t e n t i a l energy curves by f i t t i n g observed v i b r a t i o n a l f r e q u e n c i e s t o a r e l a t i o n s h i p of t h e form V(x) = ax4 bx2 (see Table 19, page 393). The smaller q u a d r a t i c term i s added i n t h e p o t e n t i a l t o match experimental observations. Somewhat l a t e r , Edge11 r e v i s e d h i s view on t h e p l a n a r i t y of octafluorocyclobutane on t h e b a s i s of Raman d a t a u s i n g b e t t e r equipment (5b). If C4Fg were p l a n a r with symmetry D 4 h r 11 fundamentals would be Raman a c t i v e . Under c o n d i t i o n s of b e t t e r r e s o l u t i o n he was a b l e t o observe almost twice t h a t number of l i n e s . The D4h model possesses a c e n t e r of symmetry, and t r a n s i t i o n s allowed i n t h e Raman spectrum are forbidden i n t h e i n f r a r e d . However, some r e g i o n s of t h e Raman spectrum had i n f a c t an e x a c t correspondence i n t h e i n f r a r e d spectrum.* A t about t h e same t h e an e l e c t r o n d i f f r a c t i o n (ED) study of t h i s molecule forced t h e conclusion t h a t it was i n f a c t nonplanar ( 8 ) . The ED method assumes a c e r t a i n model and then f i t s t h e c a l c u l a t e d i n t e n s i t y curve f o r t h e model with t h e observed d i f f r a c t i o n p a t t e r n . The p a t t e r n w a s c o n s i s t e n t with a d i h e d r a l angle between 17 and 23O. A more r e c e n t and f a r more d e t a i l e d ED study on octafluorocyclobutane i s d i s c u s s e d l a t e r (23). Soon t h e r e a f t e r octachlorocyclobutane was shown t o have a puckered s t r u c t u r e by means of X-ray d i f f r a c t i o n . A d i h e d r a l angle of about 22O was determined ( 9 a ) . Owen and Hoard were unwilling t o extend t h e i r concept of a nonplanar s t r u c t u r e t o cyclobutane i t s e l f . I n 1952 Dunitz and Schomaker (lOa) reported on t h e molecular s t r u c t u r e of cyclobutane a s determined by e l e c t r o n d i f f r a c t i o n . They concluded t h a t on t h e gverage They t h e r i n g i s nonplanar with a d i h e d r a l a n g l e of 200+&. d i d n o t camnit themselves on t h e q u e s t i o n of t h e e q u i l i b r i u m symmetry, noting t h a t t h e i r d a t a d i d n o t warrant an unequivocal choice between a D2d (puckered) r i n g o r p l a n a r r i n g w i t h a *This correspondence of v i b r a t i o n a l t r a n s i t i o n s has played a key r o l e i n t h e many s t u d i e s t o follow i n e s t a b l i s h i n g p o t e n t i a l f u n c t i o n s f o r r i n g puckering. Also, it has been used t o enable a choice of s t r u c t u r e i n c e r t a i n h i g h l y s u b s t i t u t e d examples where diastereomers are r e l a t e d by e i t h e r t h e presence o r absence of a c e n t e r of symmetry, e.g., r e f . 108.

279

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

very low r i g i d i t y leading t o a l a r g e out-oE-plane bending. A l though t h i s paper i s f r a n k l y inconclusive with r e s p e c t to the equilibrium c o n f i g u r a t i o n , it marks t h e i n c e p t i o n of the s e r i o u s c o n s i d e r a t i o n of a puckered Eorm € o r cyclobutane i t s e l € . I n 1953 Rathjens snd Gwinn (11) measured the heat c a p a c i t y of s o l i d and l i q u i d cyclobutane from 1 4 t o 285.67OK ( 1 2 3 ) . F r o m t h e s e d a t a t h e entropy was c a l c u l a t e d , and i t was found t o be appreciably higher than t h a t expected f o r 3 planar structure.* This r e s u l t prompted a r e i n v e s t i g a t i o n 9 E the inErared and Raman s p e c t r a ( 1 3 ) . The s p e c t r a were s l i g h t l y temperature dependent i n t h e sense t h a t s e v e r a l bands showed a diminution i n i n t e n s i t y over t h e temperature range employed. This behavior agrees with a puckered Eorm and a s u f f i c i e n t l y low b a r r i e r t o r i n g i n v e r s i o n such t h a t an s p p r e c i & l e Eraction oE .nolecules would e x i s t above t h e b a r r i e r i n t h e p l s n v E ~ x m . The change i n population causes a loss of i n t e n s i t y of a l l i n f r a r e d bands which a r e allowed f o r D2d symmetry but srs f o r bidden € o r D4h symmetry. The p o t e n t i a l f u n c t i o n shown i n Figure 1 was c a l c u l a t e d using a perturbed harmonic o s c i l l a t o r €unction of t h e form V (cm-l) = 2800z2 + 400e'500z2 where z is the d i s t a n c e i n angstroms of a l t e r n a t i v e carbon atoms above and below the average plane ( 1 3 ) . They r e a l i z e d t h a t a q u a r t i c term should have been added b u t chose t o omit it because of the u n c e r t a i n t i e s i n t h e i r d a t a . I n f r a r e d ( 1 4 ) and Raman s p e c t r a (15) and normal c o o r d i n a t e a n a l y s i s confirmed t h e puckered foim b u t d i d not y i e l d an accurate value f o r t h e d i h e d r a l angle. I n p r i n c i p l e t h e molecular s t r u c t u r e of cyclobutane could be completely d e t e r mined by i t s Raman spectrum. The c l a s s i c a l a p p l i c a t i o n of t h i s "The n a t u r e of the phase t r a n s i t i o n s has been i n v e s t i g a t e d . Kaarsemaker and Coops (12b) found t h a t t h e r e i s a s t a t e t r a n s i t i o n a t 146.3'K. Rathjens and Gwinn (11) found a t r a n s i t i o n beginning a t 120'K and ending s h a r p l y a t 145.7'K. They r e p o r t a melting p o i n t of 182.3'K. C a r t e r and Templeton (12c) s t u d i e d the c r y s t a l s t r u c t u r e of cyclobutane using X-ray diEEraction. I n the high-temperature s o l i d phase t h e s t r u c t u r e v a s bodycentered cubic. The molecules possess r o t a t i o n a l d i s o r d e r vrithin the l a t t i c e . They could n o t s o l v e t h e c r y s t a l s t r u c t u r e of the low-temperature fonn, although it i s n o t cubic. An nmr study of t h e phase t r a n s i t i o n s a t 130 and 146'K has been reported, and from s p i n - l a t t i c e r e l a x a t i o n times it was possib l e t o determine a c t i v a t i o n e n e r g i e s f o r molecular r e o r i e n t a t i o n i n t h e low-temperature s o l i d phase (E, = 10.5 + 1.3 kcal/ mole) and f o r s e l f - d i f f u s i o n i n t h e high-temperature s o l i d phase (4.1 ? 0.6 kcal/mole) (12d).

ROBERT Y. YORIARTY

273

Fig. 1. P o t e n t i a l energy P m c t i o n and v i b r a t i o n a l l e v e l s €or out-of-plane bending motion i n cyclobutane. The b a r r i e r to inversion is roughly 400 m-' $1 k c a l h o l e ) . [From 3athjer.s s t 31. (13j, with permission oP the e d i t o r . ] nethod was the demonstration of the pyramidal s t r u c t u r e €or ammonia (16). The i n t e n s i t y of the 8aman spectrum was Eound t o be too l ~ fwo r determination Df the d i h e d r a l angle. This a l s o precluded determination of the b a r r i e r h e i g h t s f o r the sending v i b r a t i o n . The low i n t e n s i t y i s due t o a small anisotropy i n t h e p o l a r i z a b i l i t y because of d e p a r t u r e from a s p h e r i c a l p o l a r i z a b i l i t y symmetry of an e l l i p s o i d a l shape. This i s understood i n terms oE a D2d symmetry of cyclobutane. Very r e c e n t l y iiaman s p e c t r a of s u f e i c i e n t i n t e n s i t y have Seen c h t a i n e d , and t h i s has nade p o s s i b l e a c a l c u l a t i o n of t h e P u l l p o t e n t i a l energy curve f o r r i n g puckering. The gas-phase iiaman study of C I + H ~l e d t o d e t e c t i o n of bands between 30 and 200 cm-' due t o t h e highly anharmonic puckering m o d e ( 1 7 ) . The out-of-plane v i b r a t i o n €or C4Hg occurs a t 207 m-' Eor the l i q u i d and a t 208 cm" f o r t h e s o l i d . For l i q u i d C4Dg it i s 157 cm-l and for s o l i d C4Dg it occurs around 144 an". Srom t h e i r d a t a Miller and Capwell (17a) were able to c a l c u l a t e the r i n g i n v e r s i o n b a r r i e r . The twofold symmetric p o t e n t i a l

280

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

w e l l f o r t h e puckering mode was r e p r e s e n t e d by t h e f u n c t i o n o r i g i n a l l y suggested by B e l l ( 7 ) :

where z i s t h e dimensionless reduced coordinate. This f u n c t i o n w a s s u b s t i t u t e d i n t o t h e one-dimensional Schradinger equation, and energy s o l u t i o n s were obtained computationally by empiri c a l l y varying t h e c o n s t a n t s A and B u n t i l t h e c a l c u l a t e d energy s e p a r a t i o n matched t h e observed frequencies. The h e i g h t The p o t e n t i a l c o n s t a n t s of t h e p o t e n t i a l b a r r i e r i s AB2/4. i n t h e equation above were evaluated from both Raman and midi n f r a r e d s p e c t r a . The p o t e n t i a l f u n c t i o n which gave t h e b e s t f i t was

V (an‘’) = 26.16(Z4

-

8.90Z2)

and t h e b a r r i e r h e i g h t AB2/4 i s 518 f 5 cm-’ (1481 k 1 4 c a l / mole). Applied t o C4D8, t h e best f i t t o t h e s i x Raman f r e quencies was

V (cm-l) = 18.51(z4

-

10.48Z2)

C o e f f i c i e n t s A and B g i v e a b a r r i e r h e i g h t of 508 f 8 cm” (1452 k 23 cal/mole). I n o r d e r t o c o n s t r u c t a p o t e n t i a l energy diagram f o r t h e s e two molecules, t h e reduced c o o r d i n a t e z i s transformed t o t h e normal coordinate x where x , t h e out-of-plane displacement, i s h a l f t h e d i s t a n c e s e p a r a t i n g t h e r i n g d i a g o n a l s i n angstroms i s zero a t t h e planar conformation). The p o t e n t i a l funct i o n i n terms of t h e coordinate x i s

(x

V (cm-l) = 6.932 X 105x4

-

3.790 X 104x2

and a p l o t of t h i s f u n c t i o n is shown i n Figure 2 , where x = f0.166 fl and t h e d i h e d r a l angle i s 35.0°. Work by Stone and M i l l s (18) g i v e s similar r e s u l t s . Even though t h e ringpuckering v i b r a t i o n f o r C4Hg i s i n f r a r e d i n a c t i v e , puckerin l e a d s t o s i d e bands on t h e i n f r a r e d fundamental a t 1453 cm- , and t h i s was analyzed i n terms of a q u a r t i c - q u a d r a t i c p o t e n t i a l f u n c t i o n f o r r i n g puckering, y i e l d i n g a b a r r i e r t o i n v e r s i o n of 503 cm’l (1440 cal/mole) i n t h e ground s t a t e and 491 cm-l i n t h e e x c i t e d s t a t e . The equilibrium d i h e d r a l a n g l e was determined t o be 35’ (18). I n an e a r l i e r and s i m i l a r i n v e s t i g a t i o n , Ueda and Shimanouchi (19) observed puckering s i d e bands on t h e lowwave-number s i d e of t h e 2878 cm-l band i n t h e CH s t r e t c h i n g

9

ROBERT M.

MORIARTY

281

I

I

1

I

I

Cvclobutsne

uIMn

I

I

'

I

_

loo0

800

600

v

(cm ' j

400

200

0

I

-0.3

I

-0.2

1

-0.1 -X-

I

0

1

I

+0.1

M.2

t0.3

Fig. 2. P o t e n t i a l f u n c t i o n and energy l e v e l s f o r r i n g puckering i n cyclobutane. Observed Raman t r a n s i t i o n s a r e shown on t h e r i g h t and some c a l c u l a t e d i n f r a r e d t r a n s i t i o n s a r e shown on t h e l e f t . [From Miller and Capwell ( 1 7 a ) , w i t h permission of t h e e d i t o r . ] r e g i o n of C4H8, from which t h e y d e r i v e d a n i n v e r s i o n b a r r i e r of 448 cm-' i n t h e puckering c o o r d i n a t e and a d i h e d r a l a n g l e of 34 0.5'. T h i s work has been d i s c u s s e d by Miller and Capwell ( l i a ) who concluded t h a t many of t h e combination t o n e s which Ueda and Shimanouchi used involved o t h e r modes and t h u s were misassigned. Stone and M i l l s reanalyzed Ueda and Shimanouchi's o b s e r v a t i o n s on t h e 2878 an-' band (18). They p r e f e r t o r e g a r d t h i s band a s an overtone of t h e CH2 s c i s s o r i n g mode. Other c a l c u l a t i o n s of t h e d i h e d r a l a n g l e of t h e puckered r i n g have been based on t h e r e l a t i v e i n t e n s i t i e s of CH2 rocking v i b r a t i o n s of C4H8 a t 21'K i n an argon m a t r i x (20). The

*

2Ei

CYCLCEL'TAXE

Iwc HETERDCYCLIC ANALOG5

derive? d i h e d r a l anqle is 37 t $', t h e out-of-plane carbor displacement beinq C.l@ k C.02 k. A s a consequence cf t h e non$anarity of cyclobutane, t l x hydrossn atoms ouqbt t c group thenseivec i n t o a x i a l and e q u a t o r i a l s e t s wkic€- carr be detectec' ir t h e vibratione: spectrurr by B s p i i t t l n q cf t h e frequencies. This has been locked f o r i r : t h e kaman and i n f r a r e ? spectrum of cyclobctane and mcnodeuteriocyclobutaxe i n t h e c;as, l i q u i d I and s o l i t ; phases I2C:. I n t h e R a m s spectrum, e l i n e a t 213 cm-l bas assigned t o t h e out-of-Fiane v i b r a t i o r of t h t r i n g . T h i s i s Raman allowed an? l n f r a r e e forbidden and a g r e e s with c a l c u l e tior. ( 2 0 ~ )of t h e frequency a c 20C c m - l a s w e l l a s t h e Ramar work c i t e d i n r e f s . i7e a d lE. Ir t h e vapor-phase i n f r a r e t spectrurr., Aleksanym e t a l . f20alb) a s s i g n a d o u b l e t band a t 627 cm-1 t o twc v i b r a t i o n s of a x i a l and eguatoria: groups. This c o n t r a s t s with t h e assignment of Lord and Nakagawa ( 2 4 ) whc a s s i g n t h i s band t o a s i n g l e fundamental frequency for a rocking v i b r a t i o r , . The band due t o t h e C-D s t r e t c h i n g v i b r a t i o n i n t h e l i q u i d and gaseous i n f r a r e d s p e c t r a of monodevteriocyclobutane i s c l e a r l y s p l i t (Av = 5 cm-') , and t h e t w c bands show approximately equal i n t e n s i t i e s . This s t r o n g l y i n d i c a t e s a nonplanar s t r u c t u r e . The s t r u c t u r e of cyclobutane has a l s o been determined frorr, t h e nmx s p e c t m r i n a l i q u i d c r y s t a l (nematic) s o l v e n t (21, 2 2 ) . I n t h i s method an equilibrium geometry and a motional constant are assumed and a t h e o r e t i c a l spectrum i s computed. The assumed parameters a r e a d j u s t e d e m p i r i c a l l y u n t i l a match i s obtained between t h e c a l c u l a t e d and experimental spectrum. The observed cyclobutane spectrum can only be reproduced using a puckered Dgd model. From t h e absence of l i n e broadening, t h e conformational l i f e t i m e i s assumed t o be l e s s than sec. The derived d i h e d r a l angle i s 35O (21) , which was l a t e r revised (Table 1) t o v a l u e s which range between 23 and 27' (22). The molecular s t r u c t u r e of cyclobutane which t h e s e authors obtained i s shown i n Figure 3 and Table 1. A f u r t h e r i n t e r e s t i n g f e a t u r e i s t h a t Meiboom and Snyder r e p o r t t h a t t h e C-C-C planes do not b i s e c t t h e HCH angle. The H1 and H 5 atoms a r e bent toward each o t h e r with a tilt o r "rocking" angle of 4'. The angle of tilt of t h e a x i a l atoms i n cyclobutane, which was i n d i c a t e d by t h e r e s u l t s of Snyder and Meiboom ( 2 1 , 2 2 ) and demanded by t h e c a l c u l a t i o n s of Wright and Salem, (32a) and Nelson and F r o s t (320) ( s e e below), was a l s o d e t e r mined t o e x i s t i n octafluorocyclobutane from a r e c e n t and very p r e c i s e e l e c t r o n d i f f r a c t i o n study (23). The e a r l i e r e l e c t r o n d i f f r a c t i o n study on t h i s compound has a l r e a d y beexi discussed (8). The d i h e d r a l angle $ was determined t o be 17.4O;

ROEERT K. MOIIIARTY

283

Fig. 3 . Molecular s t r u c t u r e of cyclobutane determined by nmr i n t h e nematic phase. [From Meiboom and Snyder (221, w i t h permission of t h e editor.: Table 1. Determined and Assumed Molecular Parameters

for Cyclobutane

Assumption

Coordinate R 0

RCH(l)

RCC'A


A

A

CE (1)=

1.133 1.133

(1.548)a 108.1'

122.10 27.00

2)

RcH (I)= RCH ( 2) +c .Od 1.1229

1.083

(1.548) 109.5O

118.5' 22.7'

aparenthesized parameters are assumptions.

A

HCH = 109'47'

1.1233

1.085

(1.548)

(109.47) 118.7' 22 .go

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

284

t h e tilt angle ( B ) o r rocking angle of t h e a x i a l s u b s t i t u e n t s i s 5.4' with t h e C-F bonds b e n t toward each o t h e r .

F

F

P L e m a i r e and Livingstone ( 8 ) r e p o r t e d a d i h e d r a l a n g l e ($1 f 4' f o r CqFg, and a r e c e n t study on t h i s compound i n d i c a t e s a d i h e d r a l angle of 20 f 3" ( 2 4 ) . Both i n v e s t i g a t i o n s assumed a ' 0 tilt angle B. Recently Miller and Capwell ( 2 5 ) and Bauman and Bulkin (26) have determined and i n t e r p r e t e d t h e i n f r a r e d and Raman s p e c t r a of octafluorocyclobutane (27) and octachlorocyclobutane i n terms of a D p d s t r u c t u r e . Octahydroxycyclobutane i n aqueous s o l u t i o n gave a Raman spectrum c o n s i s t e n t with a D4h s t r u c t u r e ( 2 7 ) . An X-ray study confirmed t h e p l a n a r s t r u c t u r e , and a Raman spectrum i n t h e s o l i d s t a t e agreed w i t h t h i s model (28). The p l a n a r i t y is most l i k e l y due t o i n t r a m o l e c u l a r hydrogen bonding. From t h e X-ray d a t a of Bock (281, one can c a l c t l a t e an oxygen-oxygen d i s t a n c e f o r t h e hydrogen bond of 2.66 A . The energy required t o execute t h e puckering mode of v i b r a t i o n would involve a l a r g e term for s t r e t c h i n g .

of 20

111.

REASON FOR PUCKERING OF THE CYCLOBUTANE R I N G

The inescapable conclusion t o be drawn from t h e r e s u l t s summarized above i s t h a t cyclobutane and i t s o c t a s u b s t i t u t e d d e r i v a t i v e s a r e nonplanar molecules, with t h e exception of octahydroxycyclobutane. The reason f o r d e v i a t i o n from p l a n a r i t y i s not completely understood. Wiberg and Lampman ( 2 9 ) have c a r r i e d o u t some i n t e r e s t i n g c a l c u l a t i o n s on t h i s problem. The reason suggested e a r l i e r f o r t h e puckering was b a s i c a l l y r e l i e f of nonbonded i n t e r a c t i o n s . However, t h e equilibrium p o t e n t i a l energy of cyclobutane w i l l depend upon a minimizat i o n of o t h e r f a c t o r s , namely t o r s i o n a l a n g l e s , d e s c r i b e d by

V = 1.5(1 where by

'I

-

cos 3'1) kcal/mole

i s t h e t o r s i o n a l a n g l e , and t h e C-C-C

bond a n g l e s , given

285

ROBERT M. MORIARTY

V = 0.064 (AO)

kcal/mole

where 0 i s t h e d e v i a t i o n from 90°, and t h e H-H nonbonded i n t e r actions. Wiberg and Lampman determined t h e v a r i a t i o n i n t h e t o r s i o n a l s t r a i n energy (curve A , Fig. 4 ) , bond a n g l e s t r a i n energy (curve B, Fig. 41, and H-H nonbonded i n t e r a c t i o n energy (curve c, F i g . 4 ) a s a f u n c t i o n of d e v i a t i o n from p l a n a r i t y with t h e a i d of a computer program designed f o r t h e purpose ( 3 0 ) . Curve D (Fig. ,4) i s t h e sum of A , B, and C. The minimum o c c u r s a t 33O, which a g r e e s e x c e l l e n t l y w i t h t h e a n g l e of 35' (18) , 34' ( 1 9 ) , 37 6 O (20) , and 35' ( l o b ) . The c a l c u l a t e d s t a b i l i z a t i o n of t h e nonplanar form i s about 2 kcal/mole. This a g r e e s w i t h t h e i n f r a r e d b a r r i e r s of 1.481 i- 0.014 kcal/mole (17a). +_

32-

-3 -4

0

5

10

15 20 25 30 35 40 45

Deviation from planarity, @'

Fig. 4. Energy v a r i a t i o n f o r cyclobutane as a f u n c t i o n o f d e v i a t i o n from p l a n a r i t y . A i s t o r s i o n a l energy, B i s t h e C-C-C bond bending term, c i s t h e H-H nonbonded i n t e r a c t i o n , and D i s t h e sum of A, B, and C. [From Wiberg and Lampman (29) , w i t h permission of t h e e d i t o r . ] F i g u r e 5 d e p i c t s t h e v a r i a t i o n of t o r s i o n a l a n g l e and bond a n g l e with d e v i a t i o n from p l a n a r i t y . I t can be concluded from t h e s e c a l c u l a t i o n s t h a t t h e dominant f o r c e i n causing puckering i s t h e minimization of t h e C-C-C-C torsional energy.

C-C-C

2EE

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

U

Deviation from planarity,

0"

Fig. 5. R e l a t i o n between t h e bond a n g l e s (curve E ) , t h e t o r s i o n a l angles (curve F ) , and t h e d e v i a t i o n from p l a n a r i t y f o r t h e cyclobutane r i n g . [From Wiberg and Lampman (291, w i t h permission of t h e e d i t o r . ] A l l i n g e r e t a l . ( 3 1 ) , using t h e c l a s s i c a l mechanical method of Westheimer, have c a l c u l a t e d t h e energy d i f f e r e n c e between t h e p l a n a r and puckered form (4 = 20') of cyclobutane t o be 0.9 kcal/mole, which i s lower t h a n t h e s p e c t r o s c o p i c v a l u e of 1.48 kcal/mole and much s m a l l e r t h a n t h e 2.0 kcal/mole d i f f e r e n c e c a l c u l a t e d by Wiberg and Lampman ( 2 9 ) . Wright and Salem (32a) used t h r e e quantum mechanical approaches [ab i n i t i o , extended H k k e l t h e o r y (EHT), and CNDO/2 methods] f o r t h e c a l c u l a t i o n of t h e p o t e n t i a l energy curve f o r r i n g puckering based on two h y p o t h e t i c a l nonplanar models. The f i r s t u s e s a model which was a p p l i e d s u c c e s s f u l l y by Gwinn and co-workers ( s e e page 384) t o reproduce t h e double-minimum p o t e n t i a l of 0-, S-, and S e - s u b s t i t u t e d four-membered r i n g s . This treatment assumes t h a t t h e CC and CH bond l e n g t h s remain c o n s t a n t a s does t h e HCH angle during t h e puckering v i b r a t i o n . Also they r e q u i r e t h a t t h e methylene groups remain b i s e c t e d by t h e i r l o c a l CCC angle. Using t h e s e r e s t r i c t i o n s , Wright and

ROBERT

M. MORIARTY

2Ei

Salem (?2a: c a l c v l a t e d t h e p o t e n t i a l energy curve by t h e CNDC/Z, EHl, and ak inztio approaches. Thc p o t e n t l a i curves a r e showr. i n Figure 6 . Remarkably, t h e energy minimur i s st t h e p l a n a r forn. and puckering i n c r e a s e s t h e energy.

Angle o i pucker ('1

Fig. 6. P o t e n t i a l curves f o r t h e puckering motion by t h r e e d i f f e r e n t methods. Experimental bond d i s t a n c e s and HCH a n g l e s a r e used. [From Wright and Salem (32a) , w i t h permission of t h e e d i t o r . ] The only way t o g e n e r a t e a curve which resembled experimental r e a l i t y , namely a b a r r i e r a t t h e planar form and a double energy minimum, was t o i n t r o d u c e an a d d i t i o n a l d i s t o r t i o n , namely, rocking of t h e methylene group r e l a t i v e t o t h e CCC plane, which i n c r e a s e s t h e s t a g g e r i n g of t h e a d j a c e n t methylene hydrogens, Addition of t h i s rocking f a c t o r i n t h e CND0/2 c a l c u l a t i o n g i v e s t h e curve shown i n Figure 7. The p o t e n t i a l energy minimum occurs a t a d i h e d r a l angle of 20'. The b a r r i e r , however, i s only 0.31 kcal/mole, which i s obviously t o o small. The r e s u l t of t h e CNDO/2 c a l c u l a t i o n was l a t e r confirmed by an ab initio c a l c u l a t i o n (32n). I t should be noted t h a t i n t h e e l e c t r o n d i f f r a c t i o n s t u d i e s CHCH) , on cyclobutane it was always assumed t h a t B = 1/2(360 which of course would not be t h e case i n t h e rocking methylene model. The e l e c t r o n i c s t r u c t u r e of cyclobutane has been a s u b j e c t of considerable study (32b-0). Recently Hoffmann and Davidson (321111have discussed a model fashioned on t h e Walsh cyclopropane p i c t u r e .

-

288

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

1

Angle of pucker ('1

Fig. 7. Optimized CND0/2 p o t e n t i a l curves f o r t h e puckering motion, with and without rocking of methylene groups. [From Wright and Salem ( 3 2 a ) , with permission of t h e e d i t o r . ] A D4h r i n g i s used and f o u r sp2-methylene groups a r e f i l l e d in.

P

The o r b i t a l symmetry c o r r e l a t i o n diagram is shown i n Figure 8. The u p a r t overlaps a t t h e c e n t e r of t h e r i n g and t h e p o r b i t a l s overlap around t h e periphery. These a r e shown t o t h e l e f t and r i g h t , r e s p e c t i v e l y , i n F i g u r e 8. The u p a r t s combine t o y i e l d a bonding alg, nonbonding e,, and antibonding bZg o r b i t a l . The p p a r t s combine to form a bonding big, a nonbonding e,, and antibonding a2g o r b i t a l . The h i g h e s t occupied molecular o r b i t a l s a r e a degenerate e,

ROBERT M.

289

MORIARTY

Fig. 8. O r b i t a l c o r r e l a t i o n diagram f o r cyclobutane. [From Hoffmann and Davidson (321111, with permission of t h e editor. I pair.

The 1-3 and 2-4 71 s e t s a r e antibonding. Herein may l i e an a d d i t i o n a l b a s i c reason f o r r i n g puckering. Bending may cause a d i s t o r t i o n which lowers t h e energy of t h e eu degenerate set. Nelson and F r o s t (320) have used a f l o a t i n g s p h e r i c a l Gaussian o r b i t a l (FSGO) model t o c a l c u l a t e t h e geometry of cyclobutane. Minimization on a p l a n a r D4h s t r u c t u r e l e a d s t o a s t a b l e form i f methylene rocking occurs. The minimum energy D2d model had a d i h e d r a l a n g l e of 32' and a rocking angle of 7'. The b a r r i e r h e i g h t f o r i n v e r s i o n was 3.5 kcal/mole, which i s t o o high by a f a c t o r of about 2.

IV.

MONOSUBSTITUTED CYCLOBUTANES

A geometric consequence of puckering of t h e cyclobutane r i n g i s t h e e x i s t e n c e of a x i a l and e q u a t o r i a l d i r e c t e d bonds. Therefore, f o r a monosubstituted cyclobutyl d e r i v a t i v e one would expect an equilibrium mixture of t h e two conformers. The energy maximum s e p a r a t i n g t h e two would be due t o t o r s i o n a l

CYCLOBUTANE AND HETEROCYCLIC )ANALOGS

290

H3

I

i

;I5

Equatorial. fcrm 93

I

I

x

Hg

I

d7

U i a 1 form 34 I

gauche-Butane i n t e r a c t i o n s and van d e r Waals s t r a i n p r e s e n t i n t h e p l a n a r €orm. The a x i a l conformer i s d e s t a b i l i z e d r e l a t i v e to t h e equator i a 1 form by two gauche-butane-type i n t e r a c t i o n s and also by a 1,3 i n t e r a c t i o n between the a x i a l s u b s t i t u e n t and the C 3 atom. 3f c m r s e , energy i s minimized i n the equilibrium conformation, and the a x i a l form might have a s t r u c t u r e q u i t e d i f f e r e n t Prom the i d e a l i z e d model, f o r example, a n e a r l y p l a n a r form. The e a r l i e s t s t r u c t u r a l i n v e s t i g a t i o n of a monosubstituted zyclobutane was the e l e c t r o n d i f f r a c t i o n study on methylcyclobutane ( 8 b ) . although good carbon-carbon d i s t a n c e s were determined i n t h i s study (1.56 f 0.03 f o r t h e r i n g ) , the d i h e d r a l angle oE r i n g puckering could not be determined with c e r t a i n t y . The s n g l e was s e t within t h e limits 20 t o 30'. Most of the s t r u c t u r a l work has been done on monohalocyclobutanes. I n t r o d u c t i o n of a halogen atom i n t o t h e cyclobutane ring reduces the molecular symmetry from D2d t o Timple C,5 symmetry. Since the r e s u l t i n g molecule possesses a d i p o l e luoment it can be s t u d i e d by means of microwave spectroscopy. I f an zquilibrium e x i s t s among the E q u a t o r i a l , p l a n a r , and a x i a l Eorms, i n p r i n c i p l e t r a n s i t i o n s could be observed Eor oach. I n p r a c t i c e , t h i s depends on the p o t e n t i a l energy function zonnecting these species. Since t h e e q u a t o r i a l form i s probably the more s t a b l e , one would expect an asymmetric

ROBERT M.

MORIARTY

291

double-minimum p o t e n t i a l energy curve. Of course, i f the equil i b r i u m c o n c e n t r a t i o n of t h e l e s s s t a b l e form i s v e r y low, i t may f a l l o u t s i d e t h e range of d e t e c t i o n of t h e microwave spectrometer. Microwave s t u d i e s on bromocyclobutane d e s c r i b e the molec u l e a s e x i s t i n g i n a bent e q u a t o r i a l form ( 3 3 ) . N o evidence f o r t h e a x i a l form was obtained. I f t h e energy diEference between t h e e q u a t o r i a l and a x i a l forms i s sbove 1.5 kcal/mole, then t h e c o n c e n t r a t i o n of t h e l e s s s t a b l e form would be below the limits of s e n s i t i v i t y of the microwave spectrometer. By zomparison, t h e energy d i f f e r e n c e between t h e a x i a l and equat o r i a l forms of bromocyclohexane i s 0.48 kzal/mole ( 3 4 ) . A s a p o s s i b l e reason f o r t h e nondetection of t h e a x i a l form Rothschild and Dailey (33) suggested t h a t e x c i t e d v i b r a t i o n a l s t a t e s of t h e e q u a t o r i a l bromocyclobutane would be expected t o be i n c r e a s i n g l y p l a n a r , and i f a second p o t e n t i a l energy minimum e x i s t e d f o r an a x i a l form, tunneling through t h e p o t e n t i a l b a r r i e r could occur. Tunneling by such a heavy atom a s bromine appears q u e s t i o n a b l e , however. Rothschild subsequently continued t h e s e a r c h f o r the a x i a l conformation of bromocyclobutane using Raman spectroscopy ( 3 5 ) . He was a b l e t o i d e n t i f y t h e fundamental of t h e puckering mode a s o c c u r r i n g a t 1 4 4 cm-’ and f i t t h e d a t a t o an asymmetric p o t e n t i a l f u n c t i o n with o n l y one minimum. From t h e e a r l i e r microwave d a t a t h e pucker a n g l e s f o r t h e f i r s t t h r e e v i b r a t i o n a l s t a t e s a r e n = 0 (ground s t a t e ) , 4 = 29.3’; TZ = 1, $ = 27.0’; and n = 2 , 0 = 24.6O. L a t e r Rothschild s t u d i e d t h e i n f r a r e d s p e c t r a of bromocyclobutane and chlorocyclobutane a s a f u n c t i o n of temperature between 30 and 172’ ( 3 6 ) . The r e s u l t s i n d i c a t e two conformers f o r bromocyclobutane. The two conformers, however, a r e n o t simple e q u a t o r i a l and a x i a l forms b u t r a t h e r an e q u a t o r i a l € o m and a l e s s s t a b l e e s s e n t i a l l y p l a n a r form. T h i s a n a l y s i s i s based on t h e temperature v a r i a t i o n of t h e carbon-bromine frequency which was assigned a s 487.5 rn-l f o r t h e e q u a t o r i a l and 551 cm-’ f o r t h e e s s e n t i a l l y p l a n a r form. I n chlorocyclobutane, t h e s e occur a t 532.5 an-’ f o r t h e e q u a t o r i a l and 631 an-1 f o r t h e p l a n a r form. A p l o t of t h e i n t e n s i t y r a t i o of t h e two peaks v e r s u s t h e r e c i p r o c a l of t h e a b s o l u t e temperature over t h e temperature range l e a d s t o an energy d i f f e r e n c e LIE 1 kcal/mole. The i n f r a r e d s p e c t r a of bromocyclobutane and s e v e r a l d e u t e r a t e d d e r i v a t i v e s have been s t u d i e d i n both t h e l i q u i d Also the Raman s p e c t r a and vapor phases from 4000 t o 250 cm-’. were measured a t 35 t o -83O ( 3 7 ) . These r e s u l t s support t h e f i n d i n g s of Rothschild, namely, t h a t bromocyclobutane e x i s t s i n two conformations, one of which i s e q u a t o r i a l and another a l e s s s t a b l e near-planar conformation. The two conformers

292

CYCLOBUTAW AND HETEROCYCLIC ANALOGS

correspond t o two d i f f e r e n t v i b r a t i o n a l s t a t e s of t h e r i n g puckering fundamental. Two C-Br s t r e t c h i n g v i b r a t i o n s were observed i n t h e Raman spectrum and one was found t o disappear a t -185O. The frequencies of t h e s e two bands, which were a l s o observed by Rothschild, occur a t 534 and 481 cm-l ( 3 8 ) . The l a t t e r , which i s assigned t o t h e e q u a t o r i a l C-Br s t r e t c h , i s about four times a s i n t e n s e a t 31OC a s t h e former, and t h i s i n d i c a t e s t h e e q u a t o r i a l form predominates t o t h e e x t e n t of about 80% over t h e near-planar form (-20%) (provided t h e ext i n c t i o n c o e f f i c i e n t s of t h e two bands a r e t h e same). A microwave study of chlorocyclobutane and fluorocyclobutane has r e s u l t e d i n v e r y a c c u r a t e s t r u c t u r a l parameters (39). A bent e q u a t o r i a l s t r u c t u r e was found f o r t h e c h l o r o compound, and t h e a x i a l conformer was not observed. The d i h e d r a l angle equals 20 2 1'. For t h e f l u o r o compound a d i h e d r a l angle i n t h e ground s t a t e of 20' was i n d i c a t e d and a d i p o l e of 1.94 2 0.01 D was obtained. These a u t h o r s a l s o d i s c u s s two p o s s i b l e p o t e n t i a l f u n c t i o n s f o r chlorocyclobutane a s shown i n Figure 9.

Fig. 9. P o s s i b l e p o t e n t i a l f u n c t i o n s f o r cyclobutyl c h l o r i d e . [Kim and Gwinn ( 3 9 a ) , with permission of t h e e d i t o r . ]

ROBERT M.

MORIARTY

293

Case A i s c h a r a c t e r i z e d by a high-energy p l a n a r conformat i o n and a r e l a t i v e l y l a r g e energy gap between t h e a x i a l and e q u a t o r i a l forms. Case B , on t h e o t h e r hand, has a low-energy p l a n a r c o n f i g u r a t i o n (39a). I t was found t h a t t h e ring-puckering angles c a l c u l a t e d from t h e moments of i n e r t i a f o r t h e ground s t a t e , f i r s t , and second e x c i t e d s t a t e s were 20, 17 and 1 4 O , r e s p e c t i v e l y . I n c a s e A , t h e v i b r a t i o n s a r e n e a r l y symmetrical about t h e e q u i l i brium conformation, while i n B t h e p o t e n t i a l energy curve i s asymmetric. The shape of t h e curve f o r t h e a x i a l conformation i s completely h y p o t h e t i c a l , s i n c e t h i s form was n o t observed. The most r e c e n t f a r - i n f r a r e d study on chlorocyclobutane, bromocyclobutane, and cyanocyclobutane r e v e a l s t h a t t r a n s i t i o n s between ring-puckering v i b r a t i o n s could be f i t t e d t o an e t r i c s i n le-minimum p o t e n t i a l f u n c t i o n of t h e form v(X) = bX2 + CX where X i s t h e ring-puckering c o o r d i n a t e (39b). The single-minimum p o t e n t i a l f u n c t i o n corresponds t o t h e e q u a t o r i a l isomer. N o evidence f o r an a x i a l isomer could be found (39b). A r e c e n t i n f r a r e d and Raman study of fluorocyclobutane agrees with t h e d e s c r i p t i o n j u s t o u t l i n e d ( 4 0 ) . A s e r i e s of fundamental and e x c i t e d s t a t e t r a n s i t i o n s of t h e ring-puckering v i b r a t i o n s were observed i n t h e f a r i n f r a r e d . The series could be f i t t e d e q u a l l y well t o two d i f f e r e n t double-minima p o t e n t i a l f u n c t i o n s . These d i f f e r with r e s p e c t t o t h e ma n i t u d e of t h e p o t e n t i a l energy b a r r i e r . One i s high (803 an-') and t h e o t h e r i s low (485 cm-l). Durig e t a l . (40) b e l i e v e t h a t t h e higher one appears more reasonable when taken t o g e t h e r with microwave r e s u l t s . The nonsymmetric p o t e n t i a l energy curve i s given i n Figure 10. The energy d i f f e r e n c e between t h e equat o r i a l and nearplanar form i s c a l c u l a t e d t o be 722 an-', a l though t h e r e was no experimental evidence f o r t h i s form. The b a r r i e r of 803 an-1 f o r fluorocyclobutane seems high. The b a r r i e r f o r r i n g i n v e r s i o n of cyclobutane found by Stone The t o r s i o n a l b a r r i e r i n f l u o r o and M i l l s (18) was 503 cm-l. ethane ( 4 1 ) of 3370 cal/mole was l a r g e r than t h e b a r r i e r i n ethane of 2947 cal/mole ( 4 2 ) . The b a r r i e r f o r r i n g i n v e r s i o n i n 1,l-difluorocyclobutane was determined by microwave spectroscopy t o be 2 4 1 an-1 (43a) ( s e e Sect. V-A). This remarkably lower b a r r i e r a c t u a l l y p a r a l l e l s t h e behavior due t o i n c r e a s i n g f l u o r i n e s u b s t i t u t i o n f o r hydrogen i n ethane. 1 , 1 , l - T r i f l u o r o e t h a n e has a lower b a r r i e r than 1 , l - d i f l u o r o e t h a n e o r 1-fluoroethane and i s , i n f a c t , c l o s e t o t h a t of ethane i t s e l f (43b). The p r e s e n t author would tend t o favor a b a r r i e r of 485 an-' f o r fluorocyclobutane. (See a l s o t h e d i s c u s s i o n of t h e b a r r i e r h e i g h t f o r 1,1',2,2'-tetrafluorocyclobutane, Sect. VI-E.) An e l e c t r o n d i f f r a c t i o n study on cyclobutanecarboxylic

i;y

3

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

294

-0.2

-0.1 X

0.0

0.1

0.2

Fig. 10. Fluorocyclobutane potential energy curve. Nonsymmetric double-minimum potential energy function V ( X ) = (2.74 x 106)x4- (0.695 x l O 5 ) Z 2 $ (0.307 x 1 0 5 ) X 3 where X is the ring-puckering coordinate in A . [From Durig et al. (401, with permission of the editor.] acid chloride revealed that the ring was puckered by 21 ? 5O, Nith the COCl group oriented in an equatorial gauche conformation. In this sense the conformation resembles an unstrained alkylcarboxaldehyde rather than a cyclopropylcarboxaldehyde in which the C-C=O bond prefers to be eclipsed ( 4 4 ) . In principle, it should be possible to identify v(C-X)eq for the axial and equatorial forms in halocyclobutanes by solvent-induced frequency shifts if indeed the two forms exist. This method has been applied successfully to chloro- and bromocyclohexane ( 4 5 ) . Hallam and Ray have shown that the frequency shift of axial and equatorial chloro and bromo groups in chlorocyclohexane and bromocyclohexane are affected differently by dilution ( 4 5 ) . In this method a linear relationship is

POBERT M. MORI4TITY

295

when t h e r e l a t i v e s h i f t s obtained between LJ!C-X),~ and v(C-X),, [1g3Av/v (C-X) 1 upon d i l u t i o n with q a r i o u s s o l v e n t s a r e p l o t t e d s g a i n s t the corresponzin - ; h i € t f o r the r e f e r e n c e compound %+dichloroethylone, L3 A d / !v ( C - C l ) ( c i s - d i c h l o r o e t h y l e n e j I t x a s found t h a t the zarbon-halogen bands of the a x i a l conFormers a r e l e s s s e n s i t i v o t o t h e s o l v e n t environment than a r e those of t h e e c p a t o r i a l conformer. This i s a m a n i f e s t a t i o n of the general. prcJperty t h a t =he e q u a t o r i a l r ~ r o u pi s less s h i e l d e d {or n i x l o r e d ) r e l a t i v o t o ;he a x i a l p o s i t i o n . A s i m i l a r 3 tudy a p p l i z d t o chloro- and bromocyclobu tane has been c a r r i " d gu2 ( 4 5 , 47). The two bands assigned by at iothscliild to u:C-Cl) 3 t 532.5 aad 531 cm-l and v:C-Br) dere skudi5d ill v a r i o u s s o l v e n t s and p l o t t e d 337.5 and 531 s g a i i i s t =he zorrosponding s h i f t s of cis-dichloroethylene. The s h i f t s a r e compared with ;he cyclohexyl d e r i v a t i v e s i n Table 2 .

3

.

TabLe 2. R e l a t i v e Solvent , S h i f t s € o r Axial snd E q u a t o r i a l S u b s t i t u e n t s (46, 47)

Higher (eq. j a

Compound Cyclohexyl Cyclobutyl Cyclohexyl Cyclobutyl

chloride zhloride oromide bromide

1.04 '3.75 1.9 0.7

Lower ( a x . ) a 1.5 1.36 2.7 1.52

"Dimensionless s l o p e s of p l o t of IO3Av/v (C-X) (CDE) vorsus 103Av/v (c-X) , xhere CDE = c i s - d i c h l o r o e t h y l e n e . Ekejiuba and Ballam (47) noted an important discrepancy Setween the t r e n d s observed i n t h e d a t a i n Table 2 and the sssignments of t h e bands by liothschild. On the b a s i s of the -;lopes f o r each p a i r , t h e higher €requency i n each compound should De reassigned to the q u a t o r i a l conformer, t h e r e v e r s e of H o t h s c h i l d ' s assignments. This r e v e r s a l would l e a d t o the inore reasonable o r d e r i n g gf d a t a as shown i n Table 3 o r , zonversely, i t could be ;hat i n t h e c y c l o b u t y l s e r i e s the o r d e r o€ s h i f t s i s reversed, ilamely, t h e e q u a t o r i a l i s s h i f t e d l e s s than a near-planar form.

296

CYCLOBUTANE AND HETEROCYCLIC ANAMGS

Table 3. S t r e t c h i n g Frequencies f o r Axial and E q u a t o r i a l S u b s t i t u e n t s

Equatorial ' n a

Compound Cyclohexyl Cyclobutyl Cyclohexyl Cyclobutyl

chloride chloride bromide bromide

730.5 618 686 538

Axial, an-1 683 529 ( l i q . ) 657.5 485 ( l i q . )

A. D e Meijere (48) has s t u d i e d t h e e l e c t r o n d i f f r a c t i o n H e was a b l e t o analyze h i s r e s u l t s s p e c t r a of bicyclobutyl. i n terms of a conformation i n which both r i n g s were joined using e q u a t o r i a l bonds and one i n which t h e r i n g s are j o i n e d by means of an e q u a t o r i a l bond and an a x i a l one. This i s t h e f i r s t i n d i c a t i o n of an a x i a l form i n a monosubstituted cyclobutane. While The angle of pucker i n a l l r i n g s i s 147' (4 = 33'). d e f i n i t e evidence was found f o r t h e a x i a l form, r e f e r e n c e t o t h e conformational drawings r e v e a l s r e l a t i v e l y l i t t l e d i f f e r e n c e i n s t e r i c requirement between t h e a x i a l and e q u a t o r i a l forms.

B

= 147"(1$ = 33')

equatorial-equatorial form (w = 1800)

equatorial-axial form (w = 180O)

ROBERT M. MORIARTY

V. A.

297

DISUBSTITUTED CYCLOBUTANES

1,l-Disubstituted Cyclobutanes

The two possible conformations of a symmetrically 1,l-disubstituted cyclobutane are a puckered form with one substituent axial and the other equatorial or a planar form in which each substituent is symmetrically disposed with respect to the basal plane of the ring. The microwave spectrum of 1,l-difluorocyclobutane has been determined for the ground and first six excited states ( 4 3 ) . The energy level transition spacings could be fitted to a quartic-quadratic expression where Q is a reduced harmonicV = 6.184Q4

-

77.30Q2 an-’

oscillator coordinate. Plotting this function in terms of Q and the associated energy levels gives a symmetrical doubleminimum curve with a barrier at 6) = 0 of 2 4 1 ? 5 an-l and minga at Q = f2.5. Figure 11 shows this curve in terms of Q, q (A), and dihedral angle. The distance q of the minima is k0.14 f l , which is the displacement of ,C-BC-,C above the plane The dihedral angle is 25O. This agrees defined by &-CF2-,C. with a dynamic equilibrium between the two nonplanar forms and a planar form as the potential energy maximum. F

F I

CYCLOBUTANE ANE HETEROCYCLIC ANALOGS

298

Energy (cm-' 1

c

I

1

-4

1 -2

-3

I

I

-0.2

-1 I

I 0

I I

-0.1 I

-30

I

I

-20 -10

c

I

I

I

I 0

I 10

0

I 2

1

1 0 I

3

I 14 0.1 Angle ('1

I

20

4

(4

0.2

I

30

Fig. 11. Comparison of the experimentally determined potential functions with that calculated from the molecular model for 1,l-difluorocyclobutane. The curve represents the experimental potential energy while the circles represent points on the calculated potential energy. Q is the reduced harmonicoscillator coordinate, q is the average out-of-plane distance in angstroms, and the dihedral angle is defined as the angle between the aC-BC-aC plane and the aC-CF2-aC plane. [From Luntz (43), with permission of the editor.]

The X-ray structure of cyclobutane-1,l-dicarboxylic acid (49a) agrees with a large ring-puckering vibration or a disordered structure with static molecules having different conformations or different orientations. Later Soltzberg and Margulis (49b) elaborated on the unusual electron density

299

ROBERT M. MORIARTY

distribution fox one of the carbon atoms in the cyclobutane ring and they suggest that this indicates a dynamic inversion of the ring conformation. I?.

1,2-DisubstStuted Cyclobutanes

One consequence of a puckered cyclobutane ring is that a trans lI2-disubstituted compound may exist in two conformational forms, namely, diequatorial and diaxial, while the cis form would be in the axial-equatorial conformation. H

H

cis

trans

=A+

H

X

Base-induced equilibration of the methyl esters of the cisand -brans-l,2-dicarboxylic acids agrees with this description (50). Results for the cyclobutane derivatives compared with the three-, five-, and six-membered rings are given in Table 4. Table 4. Equilibrium Mixture Composition at 65'

Compound (dimethyl ester) 1,2-Cyclopropanedicarboxylic acid 1,2-Cyclobutanedicarboxylic acid 1,2-Cyclopentanedicarboxylic acid 1,2-Cyclohexanedicarboxylic acid

(50)

trans isomer

% cis isomer

99 90 90 93

1 10 10 7

%

300

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

The equilibrium clearly favors the trans form, although the authors do not comment on the conformational structure in terms of whether it is diaxial, diequatorial, or planar. If the principal force in this system is a dipolar destabilization, then the diaxial form might be the most stable since it has the best arrangement of dipoles. The ratios of the first and second dissociation constants for the 1,2-dicarboxylic acid compared with the three-, five-, and six-membered systems are given in Table 5. Table 5. Ratios of First and Second Dissociation Constants of Dicarboxylic Acids (50)

Cycloalkane-dicarboxylic Acid

Cyclopropane-1,2Cyclobutane-1,2Cyclopentane-1,2Cyclohexane-1,2-

Kx/K2 (cis) 1210 200

138 267

K1/K2 (trans) 19.4 72 104 56

The cyclopropyl system serves as a model for the planar arrangement. The ratios in the cyclobutyl case are more similar to those for cyclohexane-l,2-dicarboxylic acid, suggesting a cis-a,e and trans-e,e arrangement in cyclobutane-1,2-dicarboxylic acid (51). The molecular structure of trans-l,2-cyclobutanedicarboxylic acid has been determined by X-ray diffraction (52). It has a nonplanar ring with a dihedral angle of 149 ? 2O (4 = 31 ? 2O) and the two carboxyl groups are diequatorial. This is completely analogous to the geometry found by the same worker for trans-1,2-cyclohexanedicarboxylic acid (53). Figure 12 shows the structure and molecular parameters. A perspective drawing of the trans diacid is shown in Figure 13. Each molecule is hydrogen bonded to two side-byside nearest neiyhbors in order to form rows. The C1-C1* bond length of 1.553 A is in the normal range for cyclobutane but is unusually short. the C2-C2* bond of 1.517

ROBERT M. MORIARTY

3 01

Fig. 1 2 . Molecular s t r u c t u r e of trans-l,2-cyclobutaned~c a r b o x y l i c a c i d . The average standard d e v i a t i o n s a r e 0.004 A and 0.2'. [From Benedetti e t a l . (521, with permission of t h e editor. I

Fig. 13. P e r s p e c t i v e drawing of trans-l,2-cyclobutanecarboxylic acid.

3 ci

CYCLOBUTANE

C.

ANC

HETEROCYCLIC ANALOGS

? ,3-CfsubstS tuted Systems

For a syrmnetrically 1,3-disubstituted cyclobutane der' iVative cis and trens diantereomeric forms may exist. The cis f o m caL pcssesz the diequatorial or diaxial conformation, while the trans forn may possess the axial-equatorial conformatioc. Depen6inq on the nature of the substituents, the d i hedrai angles may be expected to vary cver a considerable range. H

cis

Excellent structural parameters have been obtained for trans-1,3-chlorobromocyclobutane, cis-l,3-dibromocyclobutane, trans-1,3-chlorobromocyclobutane, and c~s-l,3-chlorobromocyclobutane using electron diffraction ( 5 4 ) . Figure 14 shows the stereochemistry of the diequatorial form of cis-lI3-dibromocyclobutane. The experimental radial distribution (RD) curve for this molecule showed it to exist 100% in the diequatorial form with no indication of the diaxial conformation. This example illustrates nicely the use of electron diffraction to show the absence of a conformer. In the calculated curve in Figure 15, the Br-Br distance for the diaxial form should be approximately 3 . 5 A. The experimental RD goes to a minimum at this distance, indicating the absence of this conformer The dihedral angle of ring puckering was calculated to be 33' and "1 (Fig. 14) was calculated to be 51O; all = 5 5 0 ; "2 = 53', and "2' = 5 8 O .

.

3 c3

Fig. 1 4 . S t e r e o s t r u c t u r e of d i e q u a t o r i a l c?k-1,3-dibromocyclobutane ( 5 4 ) .

trans-!,3-Dibromocyclobutane was shown t o e x i s t i n t h e a x i a l - e q u a t o r i a l conformation with a d i h e d r a l a n g l e of pucker equal t o 32O, and a1 = 55'' "3 = 56'. An improved f i t could be obtained by t i l t i n g t h e HCH p l a n e s about 10' around t h e This has t h e e f f e c t of i n c r e a s i n g t h e BrlH2', C z C 4 diagonal. B r l H h ' , Br3H;, and B r 3 H 4 d i s t a n c e s .

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

304

Experimental

-

fa)

Equatorial-equatorial

-

Axial-axial I

1.0

I 1.5

I

2.0

I 2.5

I 3.0

I 3.5

I 4.0

I 4.5

I 5.0

I 5.5

A

fc)

Fig. 15. Radial distribution curves for cis-1,3-dibrmocyclobutane ( 5 4 ) : (a) experimental RD curve; (b) theoretical RD curve calculated from a model with the two Br a t m s in e positions; (c) theoretical RD curve calculated from a model with the two Br atoms in a positions. trans-l,3-Chlorobromocyclobutane is definitely nonplanar, with a dihedral angle of 3 3 O , and is a mixture of chlorine (equatorial)-bromine (axial) and chlorine (axial)-bromine (equatorial). ~~~-1,3-Chlorobromocyclobutane has almost the same molecular shape as c~s-l,3-dibromocyclobutane with a diThe relative constancy for $, al, a3, hedral angle of 33'.

ROBERT M. MORIARTY

305

“‘1, a ’ 2 , and “2 is revealed by the data collected in Table 6. These are definite results which confirm beyond any doubt that axial and equatorial substituents occur in cyclobutane in precisely the same sense that they exist in cyclohexane.

Table 6. a and $I Angles in trans-l,3-Dibrcanocyclobutaner trans-l,3-Chlorobromocyclobutane, cis-l,3-Dibromocyclobutane, ciS-1,3-Chlorobromocyclobutane (54)

Compound trans-Br-Br trans-C1-Br cis-Br-Br cis-C1-Br

$I

“1

“3

32’ 330 33O 330

55O 55O 51O 51°

56O 56’

all

550 550 550 55O

--

530

“I2

“2

--

--53O --

-58 --

O

Wiberg and Lampman (29) carried out equilibration studies on the chloro-, dibramo-, and diiodocyclobutanes. The cistrans equilibrium data are given in Table 7. Table 7 , Equilibration Data for 1,3-Dihalocyclobutanes Dihalocyclobutane Dichloro-a Dibromo-b Diiodo-c

cis-trans

-AGO

(kcal/mole) (124.4OC) 0.29 t 0.01 0.58 k 0.02 0.62 2 0.01

1.44 f 0.01 2.07 t 0.05 2.18 t 0.03 .

-~ - ._ -_-

-_

aEquilibrium constant was estimated by treating both cisand trans-1-bromo-3-chlorocyclobutane with chloride ion in acetone at 124.4O. bEquilibrium constant was obtained by treatment of cis and trans isomers with bromide ion in acetone at 124.4O. CEquilibrium constant was obtained by treatment of two different mixtures of the cis and trans forms with iodide anion at 124.4O.

3 36

ZYCLOBUTANE AND 32TZROCYCL I C 3YATDGS

r h s s e r e s u l t s a r e i n t e r p r e t a b l e i n t e v . 5 3 E 3xial-squa? m i 3 1 €oms €or the t r s n s isomer and a f l i q u a t o r i a l € 3 9 €or t h o z i s =ompound. I n s l l c a s e s the c i s € o m i s the ?rodominant fliasters3mer 2t s q u i l i b r i s r n , and the ?eraentags oE t r a n s 2 a r a l l d s the z i z e 3 E the h s l s g e n , t h a t i s , c h l o r i n e being s m a l l s s t can b e 1zzamnoflated i n t h s a x i a l p o s i t i o n oE the t r s n s more easily ; h m bramine 3r iodine. diberg and LamAman (29) a l s o c a l c u l a t e d tha ang?a 3 f r i 9 9 ?uckering 3 E 29:s- and t r a n s - l , 3 - d i ~ r o m o c y ~ l o b a t a n eE r 3 m d i ? o l ? noments using the same approach a s Lautensahlasgor snd d r i g h t ,-,, ~ a )[sea page 337). The flipole d a t a i n d i z a t e L i t t l e LL" sny 3 E the ziS-a,a zonEonner. The v a r i a t i o n 3 f angle 3 € Ticker ~ p p e x sto i s d i - a t e the o p e r a t i o n of Lwo Eorzss. F a r t h e x s n s s e r i e s , which s u s t have 3rre subatituusnt stom u t i a l , inzr?-asir?g t h e s t e r i a s i z e o € the s u b s t i k u e n t causes 3 E l a t t z n ing 3 E the r i n g . l"his i s most s a s i l y clnderstood i n terms 3f

the r e l i e € oE 3 1 . 3 nonbonded i n t e r a c t i o n . ?he v a r i a t i o n CIE the angle of pucker €or the t r a n s is probab:? d ~ to ~ e3 r s l i e f 3 E a t o r s i o n a l i n t e r a c t i o n ivhich i3 Largest i n :he c m c ai iod i n e The anglo o € pucker and d i p o l e Anoment :rom #hi& i t #as z a l c u l a t e d qre given i n Table 3.

.

ROBERT

Y.

WORIAXTY

307

Table 3. D i p o l e Moments 2nd Calzulated Angle oE Pucker !$)

u, Bromocyclobu tane 2is-l,3-3ibromocyclobutane trans- 1,3-Dibromocyclobutane

c?is-1,3-3ichlorocyclo!xtane

~rans-l,3-Diehlorocy~l~butane c?~s-1,3-i)iiodocyclobutane trans-l,3-Diiodocyclobutane brans-1,3-Dibromo-l,3-di me thyleyclobutane

D

2.03 2.32 1.13 1.33 1.40 1.73

3.34 3.68

+:deg.ja 33 39 32

37

32 13 24

14

~ : d e g .b )

--

33 32

---

aSee Lampman and Niberg :29, 5 5 ) . bSee Almenningen et 31. ( 5 4 ) . T h e last entry in Table 3 , namely, trans-1,3-diSromo-L,3zlimekhylcyclobutane, zupports particularly strongly the idea that the 1,3 interaction causes flattening oE the ring. This nolecule cannot escape the 1,3-diaxial methyl-bromine interac tion.

CH3 9 particularly incisive study of the relationship between

dipole noment and structure o€ 1,3-disubstitu ted cyclobutanes has been carried out by Lautenschlaegcr and Nright ( 5 5 ) . Those nrorkers have developed in analytical form a correlation between the observed dipole moment and the sngle of pucker 3 (0 in this review) o€ the ring €or a series a€ n i s - and trans-1,3-dicyanoand -diisocyano-2,2,4,4-tetr~ethylcyclobutanes. The angles c1 snd 8 sre important in the authors vectorial

308

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

analysis. From various spectrographic measurements 0 averages about 110'. This is rather critical since a choice of 105O would increase Cp by loo, while a may range between 125 and 130O. The vectorial analysis for the trans isomer does not

involve ci (Fig. 16) since the deformation from planarity of the ring is symmetric.

Fig. 16. Vectorial analysis for trans-1,3 derivative. The analytical expression for the relationship between Cp and ?.I based on the congruent triangles using angles 2a - a, 2.rr - Cp, and 2a - 6, y, and a leads to the conclusion that 6 = Cp, and that where m is the group moment of the 1,3 substituent,

in this case cyanide or isocyanide. The results are summarized in Table 9. The observed dipole moments for both the trans-dicyano and trans-diisocyano compounds indicate incursion of a planar form A in which p = 0.

309

ROBERT M. MORIARTY Table 9. Dipole Moments and Dihedral Angle of Ring Pucker in 1,3-Disubstituted 2,2',4,4'-Tetramethylcyclobutanes (56)

lI3-Distributed tetramethylcyclobutane cis-1,3-Dicyanotrans-lI3-DicyanoCiS-1,3-Diisocyanotrans-1,3-Diisocyano1,3-Dione

A

PI

D

Dihedral angle ( $ I l deg. 39 2e 35 28 24

4.26 1.23 3.68 1.22 0.82

B

If A and B contribute equally (nA = n B ) , then p 2 = nAp2

A

+

nBi.li (p

= actual dipole moment)

nA = nB = 1/2

but p 2 = 0 A

thence p

B

=

2p2

Therefore, if p for trans-l,3-dicyano-2,2',4,4'-tetramethylcyclobutane is 1.24 D, then the dipole moment p~ of the rigid a l e conformer B would be 1.76 D. The angle a which the cyano or isocyano group makes with the ring is important in the calculation for the cis compounds. The authors chose ci = 125O and considered three conformers, namely C, D, and E, which correspond to a puckered diaxial

310

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

form, a planar form, and a puckered diequatorial form, respectively.

The angle of vector interaction in D is obviously y = 70°, while for C 2

+

55'

+

(180

4 =y

- i)= 180

- lloo

and for E

y. + 2 + 550 2

= 180

The observed dipole moments for the cis isomers indicate an overwhelming predominance for E , the diequatorial conformer. The configuration and conformation of cis- and trans-1,3dimethylcyclobutane have been the subject of much research. Allinger and Tushaus (57) prepared these two compounds by means of a stereospecific synthesis. The original configurational assignments (58), based on the Auwers-Skita rules, namely that the diastereomer with the lower constants (specific gravity, boiling point, index of refraction) had the trans configuration while the diastereomer with the higher constants had the cis configuration, had to be reversed (57). Apparently a suggestion that these assignments ought to be reversed was made as early as 1952 by A. L. Liberman as mentioned by Aleksanyan (59).

ROBERT M.

311

MORIARTY

The dimethylcyclobutanes could not be e q u i l i b r a t e d under conditions of r e v e r s i b l e c a t a l y t i c dehydrogenation because of r i n g cleavage. Aleksanyan e t a l . (59) have s t u d i e d t h e i n f r a r e d and Raman s p e c t r a of t h e s e two compounds over t h e temperature range +20 t o -looo. The symmetry of t h e p l a n a r 1 , 3 - t r a n s isomer i s C,h and i t s v i b r a t i o n a l spectrum must obey a l t e r n a t i v e p r o h i b i t i o n ; i . e . , frequencies allowed i n t h e i n f r a r e d should be forbidden i n t h e Raman, and v i c e versa. A c t u a l l y , coincidences of a r e l a t i v e l y l a r g e number of bands were observed, t h u s i n d i c a t i n g a nonplanar s t r u c t u r e f o r 1,3-transdimethylcyclobutane. The temperature v a r i a t i o n of t h e i n f r a r e d s p e c t r a of cisand trans-1,3-dimethylcyclobutane i s q u i t e i n t e r e s t i n g . The c i s shows no change over t h e range 20 t o -100'. In the trans isomer, however, new coincidence bands between t h e i n f r a r e d and Raman s p e c t r a appeared a t low temperatures. Absence of change i n t h e spectrum of t h e c i s compound i n d i c a t e s t h a t t h i s compound i s i n t h e 1 , 3 - d i e q u a t o r i a l form with no d e t e c t a b l e c o n t r i b u t i o n from t h e d i a x i a l form. Since t h e b a r r i e r h e i g h t f o r r i n g i n v e r s i o n i n t h i s system ought t o be around 1.5 kcal/mole a t room temperature, a number of molec u l e s could e x i s t i n t h e p l a n a r form. However, i n t h e case of t h e c i s isomer t h e s e l e c t i o n r u l e s a r e unchanged i n going from a nonplanar t o a planar form. A s mentioned above, t h e p l a n a r t r a n s form belongs t o t h e c,h p o i n t group, f o r which f u l l y symmetric v i b r a t i o n s i n t h e i n f r a r e d a r e forbidden. Bending of t h e r i n g removes t h i s r e s t r i c t i o n . A s t h e temperature i s lowered, t h e more s t a b l e nonplanar conformation i s more populated and t h e s e l e c t i o n r u l e s governing t h e planar form no longer apply. The t r a n s isomer should, t h e r e f o r e , be represented by an equilibrium between a nonplanar and a p l a n a r form i n which t h e l a t t e r may be considered t o be a r o t a t i o n a l l y e x c i t e d form e x i s t i n g ( i n B o l t n a n n d i s t r i b u t i o n ) a t higher temperatures.

Cs nonplanar form

Excited C2h p l a n a r form

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

312

The gross appearance of the nmr spectra of the two isomers also bears out this interpretation. The cis form shows more structure and is more complex due to the single conformation. The trans isomer shows three clear sets of nonequivalent protons in the ratio 3 : 2 : 1, indicating a fast averaging process due to ring flipping. Aleksanyan et al. (59) suggest that the configurational assignments for cis- and trans-1-methyl-3-ethyl and l-methyl3-n-propylcyclobutanes ought also to be reversed (60). Allinger et al. (31) have carried out calculations on the 1,3-dimethylcyclobutane system. They consider the cyclobutane ring to exist in a puckered diamond shape with two diagonal ring angles enlarged at the expense of the others. Accordingly a substituent may be located at the carbon subtended by the Table 10 smaller angle (case A ) or the larger angle (case B ) gives the results for methylcyclobutane and 1,3-dimethylcyclobutane. There is little preference for the case A or case B location of a substituent. Furthermore, there is only about a 0.5 kcal/mole preference for the equatorial position. As one would expect, the cis 1,3-diequatorial arrangement of the two methyl groups is favored but by a small amount, namely, 1.87 kcal/mole X-Ray diffraction studies on trans-1,3-cyclobutanedicarboxylic acid reveal that the ring is planar. Figure 17 summarizes the structural parameters.

.

H

I

0

\,I \

0

Fig. 17. acid (61).

Structure of trans-1,3-cyclobutanedicarboxylic

W

P

W

B

A

B

A

B

A

B

A

B

A

c-c

1.518-1.523 1.515-1.527 1.519-1.522 1.516-1.527 1.518-1.520 1.520-1.521 1.520-1.522 1.519-1.523 1.516-1.522 1.518-1.524

length, A 84.8-119.9 84.2-118.2 85.2-114.0 85.2-114.1 85.2-120.1 83.9-118.0 85.4-115.5 84.5-114.7 84.3-119.9 83.3-118.0

c-c-c

angle, deg. 22.43 22.27 22.83 23.21 22.87 22.40 24.20 24.27 22.98 22.98

Total E, kcal/mole

%onformational energy above that of the conformation of lowest energy.

cis-l,3-DhIethylcyclobutane (diequatorial) cis-l,3-DhIethylcyclobutane (diaxial) trans-l,3-Dimethylcyclobutane

Equatorial methylcyclobutane Axial methylcyclobutane

Compound

Table 10. Calculated Structures and Energies of Cyclobutanes (31)

0 1.80 1.87 0 0

0.47

0.16 0 0.56 0.94

Con€." E, kcal/mole

314

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

The disodium salt of cyclobutane-1,3-dicarboxylic acid crystallizes with two neutral acid molecules of crystallization (62). Remarkably, the neutral acid exists in a puckered form and the dianion is planar. This, of course, contrasts with the fact that the free acid is planar when crystallized alone. Since the barrier height for ring inversion is of the order of 1 kcal/mole, clearly crystal forces play the dominant role in determining the shape of these molecules. Allinqer and Tushaus (57) synthesized, stereospecifically, methyl cis- and trans-3-methylcyclobutanecarboxylate. These compounds were equilibrated with base and the equilibrium constant was found to be 1.6. Thus the cis diequatorial form has a lower free energy than the trans form by a factor of AGO330 = 0.3 kcal/mole. According to these workers, the conformational enthalpy difference (Hoax- Hoeq)should be smaller in cyclobutane compared to cyclohexane because of the greater distances. Use of a t-butyl substituent on the four-membered ring should lead to conformationally homogeneous axial and equatorial forms in ethyl C i s - and trans-3-t-butylcyclobutanecarboxylate. These compounds have been synthesized and equilibrated (63, 64). The results are shown below:

AHo ASo

AGalOO

= -0.8 k 0.2 kcal/mole = -0.7 f 0.5 cal/(deg.-mole) = -0.58 f 0.02 kcal/mole

These thermodynamic data show that the cis isomer is favored by enthalpy, but entropically the trans isomer is favored. The analogous parameters for the cis-trans isomerization of ethyl 4-t-butylcyclohexanecarboxylate (65) are AHo = -1.09 kcal/mole and ASo = 0.4 cal/deg.-mole. Enthalpic preference for the cis form may be understood on the basis of a diequatorial form relative to the less stable axial-equatorial conformation required in the trans isomer. Thus the analogy with the behavior of cyclohexane is consistent; however, the entropy change appears t o be reversed in comparing the two systems. The numbers are small compared to the experimental errors involved, however.

ROBERT M. MORIARTY

315

3-t-Butylcyclobutanecarboxylic acid has been synthesized, and upon equilibration the cis isomer predominates to the extent of 68% over the trans form (32%) (66). The base-catalyzed equilibration of the cis and trans forms of methyl 3-isopropylcyclobutanecarboxylate reveals an equilibrium constant Keq3380Kcis/trans = 2.2 0.05 (67). Comparison of this value with the one obtained for the cis and trans isomers of methyl 3-methylcyclobutanecarboxylate of 1.6 agrees with expectation based on the steric demand of isopropyl relative to methyl, AGi-pr - A & H ~ = 0.21 kcal/mole. The methyl- and isopropyl-substituted cyclobutane esters, with Keq338 ratio of 1.6/2.2 = 0.73 ,may be compared with the 4methyl- and isopropyl-substituted cyclohexanecarboxylates, Keq338 ratio of 4.8/5.3 = 0.91. This is somewhat different than would be expected on the basis of nonplanar forms A and B for the two cyclobutane derivatives.

*

C

A H

H

B

u

H

H C02CH3

H

E

F

The axial group in A and B should be less stable than an axial group in the cyclohexyl system because it not only experiences two gauche-butane-type interactions, but also a potentially severe 1,3-type interaction with the transannular

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

316

carbon atom. Of course t h i s can be r e l i e v e d by a modest f l a t t e n i n g of t h e r i n g . Several l i n e s of d a t a i n d i c a t e t h a t such a f l a t t e n i n g may occur. As mentioned e a r l i e r , f i r s t Rothschild and Dailey (33) f a i l e d t o f i n d an a x i a l bromocyclobutane conformation, i n s t e a d a p l a n a r a x i a l form was d e t e c t e d . Second, Wiberg and Lampman (29) showed t h a t f o r t h e 1,3-transdihalocyclobutanes t h e c a l c u l a t e d a n g l e of pucker based on dipole data indicates t h a t the ring f l a t t e n s progressively i n going from c h l o r i n e t o bromine t o iodine. Furthermore, L i l l i e n (68) who s t u d i e d t h e temperature dependence of t h e i n f r a r e d s p e c t r a of methyl C i s - and trans-3isopropylcyclobutanecarboxylate assigned a band a t 1243 cm-' i n t h e vapor a s being due t o both a l e s s s t a b l e c i s form and a l s o t h e only a v a i l a b l e conformer f o r t h e t r a n s . R e l a t i v e i n t e n s i t y v a r i a t i o n s were observed over t h e temperature range 25 t o 150° f o r t h e c i s isomer. N o change was observed i n t h e t r a n s over t h i s temperature range. This behavior was i n t e r p r e t e d i n terms of a cis-e,e i n equilibrium with a c i s p l a n a r form which i s of higher energy than t h e t r a n s - e , a . E q u i l i b r a t i o n of cis- and trans-3-t-butylcyclobutanol with aluminum isopropoxide i n isopropyl alcohol l e a d s t o AHo ( t r a n s t o c i s ) = -1.6 kcal/mole, ASo = 1.1 cal/deg.-mole, and AG;oo = -1.15 kcal/mole (63) The analogous thermodynamic parameters f o r 4-t-butylcyclohexano1 a r e ( a x i a l t o e q u a t o r i a l ) : AHo = -1.09 kcal/mole and A S o = -0.46 cal/deg.-mole (65b). The enthalpy v a l u e s r e f l e c t t h e r e l a t i v e i n s t a b i l i t y of an a x i a l s u b s t i t u e n t i n e i t h e r t h e four- o r six-membered r i n g . The entropy d i f f e r e n c e between an a x i a l and e q u a t o r i a l hydroxyl group i s probably a f f e c t e d by t h e degree of s o l v a t i o n . The e q u a t o r i a l hydroxyl conformation l e a d s t o a lower entropy because of t h e higher degree of s o l v a t i o n r e l a t i v e t o t h e a x i a l conformation. This i s t r u e of both cyclobutanol and cyclohexanol E q u i l i b r a t i o n of dimethyl cis- and trans-1,3-cyclobutaned carboxylate l e a d s t o a predcaninance of t h e t r a n s - a l e isomer by AG&8 of 0.1 kcal/mole ( 5 7 ) . This may be due t o e l e c t r o s t a t i c d e s t a b i l i z a t i o n , and i n f a c t , t h i s w a s v e r i f i e d (57) using t h e coulombic-type i n t e r a c t i o n equation of Jeans.* The carbcnnethoxy d i p o l e s i n the a , e conformer were c a l c u l a t e d t o be more favorably o r i e n t e d by 1 . 4 4 kcal/mole over t h e e , e form; see Table 11.

.

.

*Using t h e expression (J. H. J e a n s , Mathematical Theory of E l e c t r i c i t y a???Magnetism, 5th ed., Cambridge U n i v e r s i t y Press, London, 1933, p. 377). lI11-12(cosx 3 cos "1, cos E =

-

R3E

"2)

was taken a s 1.8 D, t h e d i h e d r a l angle of pucker aso29.50, t h e H-Ca-CO angle a s l l O o , t h e C-C d i s t a n c e s a s 1.52 A , and t h e d i e l e c t r i c c o n s t a n t E a s 2.

ia

5.3

4.1 5.3

R,

151

41 99

x,deg.b 69.5 40.5 42.5

crl,deg.c

13.5

10.5

,deg.

139.5

"2

+0.49 -0.95

+0.76

Ea

(vacuum) kcal/mole

aR is the distance between the midpoints of the two dipoles. b~ is the angle between the two dipoles. and a2 are the angles of the dipole vectors with vector joining their centers.

Conformation

(57)

Table 11. Geometric and Energy Data for Dimethyl

cis- and trans-l,3-Cyclobutanedicarboxylates

318

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

Lillien and Doughty (69) have obtained very good evidence for the existence of axial and equatorial substituents in an examination of the nuclear magnetic resonance spectra of the pairs of cis- and trans-3-isopropylcyclobutanols and -3-isopropylcyclobutylamines. The isopropyl group is considered to function as a conformational anchor. The relevant conformations are as follows:

cis

trans

cis

trans

A marked distinction in the ring methylene protons was observed for the cis and trans isomers. In the trans compounds with axial hydroxyl and amino groups the methylene protons overlap in relatively narrow bands. This is due to two opposing effects; the axial substituents shield the cis equatorial and deshield the trans axial protons. These effects, coupled with the general phenomenon of equatorial protons resonating at a lower field because of C-C bond anisotropy, result in a compression of the methylene resonances. In the cis case the effects are unopposed: The equatorial isopropyl group shields the cis axial proton.

VI.

A.

TETRASUBSTITUTED CYCLOBUTANES

Substituted Ethylene Dimers

Photodimers of substituted ethylenes comprise a large

ROBERT M. MORIARTY

319

class of cyclobutane derivatives. Several reviews on this subject exist (70-75). The truxillic acids and the truxinic acids played a role in the development of the classical stereochemistry of cyclobutane ( 7 6 ) . These compounds, which are related as isomeric dimers of cinnamic acid, are found in nature in the cocoa leaf. The truxillic acids correspond to head-to-tail dimers, and the truxinic acids derive from head-to-head dimerization.

H02C

C6H5

C6H5

Truxillic acid

C02H

Truxinic acid

There are five theoretically possible diastereomeric forms for the truxillic acids, called a, y, peri, epi, and as shown in the formulas: H02C

\

C02H

C6H5

C6H5

C6H5

C02H

Y

Q

per1

[

H02)

epi

E

E,

3 20

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

The structure of these compounds have been proved by chemical degradative methods (76). All five possess a plane or center of symmetry that renders each incapable of resolution. The trwtinic acids may exist in the six diastereomeric forms shown:

The 6 and w diacids are meso compounds, whereas the others are chiral and can be resolved. The photodimerization of an olefin is an allowed concerted reaction in the excited state. Thus retention of relative configuration of the olefins would be predicted. The photodimerization of cis- and trans-2-butene proceeds stereospecificallY (77).

hv

hv

ROBERT M.

3 21

MORIARTY

However, one n o t i c e s a l a r g e number of t r a n s r i n g j u n c t u r e s i n p h o t o c y c l i z a t i o n of cycloalkenes. T h i s may i n d i c a t e t h a t t h e r e a c t i o n a c t u a l l y i n v o l v e s e x c i t e d ground s t a t e molecules. Following t h e Dewar-Zimmerman r e p r e s e n t a t i o n a 472 e l e c t r o n c y c l o a d d i t i o n i s allowed i n t h e ground s t a t e i f t h e Mbbius topology of i n t e r a c t i o n of atomic o r b i t a l s can be achieved, namely, an a r r a y with an odd number of s i g n i n v e r s i o n s (78). This t y p e of nonequilibrium geometry would be expected i n

% /sign

inversion

e x c i t e d ground-state s t r u c t u r e s . Some o l e f i n s i n t h e ground s t a t e a r e such t h a t they c a n r e a d i l y adopt t h e r e q u i s i t e M8bius topology. The spontaneous d i m e r i z a t i o n about t h e s t r a i n e d t r a n s double bond i n cis,trans-cycloocta-lI5-diene i s a c a s e i n p o i n t (79, 8 0 ) . The s t e r e o c h e m i s t r y i s p r e d i c t a b l e a s t h e c i s , t r a n s - f u s e d cyclobutane. Ketene has a b u i l t - i n f a c i l i t y f o r a Mabius-like t r a n s i t i o n s t a t e , and t h u s r e t e n t i o n of c o n f i g u r a t i o n i n t h e o l e f i n p a r t n e r may be observed i n t h e thermal codimerization. One of t h e f i r s t X-ray d i f f r a c t i o n s t u d i e s on a cyclobutane compound was t h a t by Dunitz on t h e (centrosymmetric) r-1 ,cis-2 ,trans-3,trans-4- t e t r a p h e n y l c y c l o b u t a n e (81) This compound, which i s a photodimer of s t i l b e n e , has a p l a n a r cyclobutane r i n g i n t h e c r y s t a l l i n e s t a t e . The bond l e n g t h s i n t h e four-membered r i n g w e r e found t o be 1.585 t 0.02 and 1.555 t 0.02 i. The a n g l e s i n t h e r i n g are 91.1 and 88.9O. A d e t a i l e d d i s c u s s i o n of t h i s s t r u c t u r e has been g i v e n by K i t a i g o r o d s k i (82).

.

322

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

- cN A

*O

H

B.

T r i cyclo[4.2.0. O2 9 5]oc tane

A series of dimers of cyclobutadiene and derivatives is known. One of the earliest is the dimer obtained by decomposition of the silver complex of cyclobutadiene CbH4AgN03 (83, 85).

Nenitzescu et al. (83) favored the trans dimer.

Recent

work on the synthesis of cyclobutadiene and its subsequent

dimerization indicates that the cis dimer is formed (86-89). Similar dimerization has been observed with benzocyclobutadiene (go), tetramethylcyclobutadiene (91), and 1,3-diphenylcyclobutadiene (92). Furasaki (93) determined the X-ray structure of perchloro3,4,7,e-tetramethylene tricyclor4.2.0. O2 ,5 ] octane and found that symmetry demanded a planar central cyclobutane ring. Andersen and Fernholt (94) studied the electron diffraction spectrum of syn- and anti-tricyclo[4.2.0.02~5] octane. The

ROBERT M. MORIARTY

323

structures are shown in Figure 18.

2

I

1\

3'

8'

7

i

4'

Fig. 18.

4' 4

0

syn- and anti-Tricyclor4.2.0. O2 5l octane.

Table 12. Structural Parameters for syn- and antiTricyclo [4.2.0. 02,5 ] octane (94)

anti

Parameter

text)

1.557 k 0.002 1.103 f 0.006 111.9 f 0.5 8.0 f 2.5 9.0 f 1.4

sYn 1.566 1.111 119.0 9.0 110.9 5

f 0.003 f

0.007

?

2.6

f 0.3

k 1.4

The C1C2C3 angle (Table 12) in the syn compound is significantly greater than the analogous angle in the anti compound. This appears to be the result of simple nonbonded steric repulsion, which is also reflected in an increase of 6, the angle of the methylene group and C3CqCg plane. The angle of pucker ( 4 ) for both canpounds is small for the center ring and indeterminate for the outer rings. It is generally believed that centrosymmetric cyclobutanes must be planar. This apparently is not true in the case of the anti compound (nor in the case of cyclobutane itself). Three dimers of benzocyclobutadiene are known (95, 96). The crystal structure of 3,4:7,8-dibenzotricycl0[4.2.0.O~~~l octa-3,7-diene has been determined (9.7). The anti configuration has been proposed earlier for this substance (95). This

324

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

assignment was confirmed; the central cyclobutane ring is planar as are the two benzocyclobutene halves. The two bonds of the central four-memberzd ring which connect the two rings are unusually long, 1.593 A.

The crystal structure of the dimer of acenaphthylene has been found to be a centrosymmetric molecule with $he cyclobutane ring bonds being somewhat longer than 1.5 A (98).

hV

/ 1,4-Epoxy-1,4-dihydronaphthalene yields a photcdimer which was shown by nuclear magnetic resonance to have either the endO-endO or the exo-ex0 configuration (99a). An X-ray study yielded the structure which is the exo-trans-exo centrosymmetric form (99b). The bond lengths and bond distances are given in Figure 19.

VI

W N

Fig. 19. Bond distances and angles for the heavy atoms of the photodimer of 1,4-epoxy-1,4[From Bordner et al. (99b), with permission of the editor.] dihydronaphthalene.

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

326

C.

a,p-Unsaturated Carbonyl Dimers

a,B-Unsaturated cyclic ketones undergo photodimerization and also photoaddition with olefins to yield cyclobutane derivatives (100-105). The photochemistry of p-quinones offers a rich source of four-membered ring dimers upon which structural work has been carried out. The term "topochemistry" is used to describe the study of the correlation between the crystal lattice structure of the p-quinone and the type of dimer which formed upon irradiation of the crystal. For example, depending on the ring substitution pattern in the p-quinone and in turn the crystal lattice structure, cyclobutane, oxetane, or cage c m pounds can be formed (106a). Irradiation of cyclopentenone yields both the cis-cis-mti head-to-head and head-to-tail dimers (106b). The crystal structure of the head-to-tail dimer has been determined. The molecule is centrosymmetric and has a planar cyclobutane ring. The bond lengths and bond angies are given in Figure 20. The cyclobutane C-C bond of 1.59 A is cmparatively long.

Fig. 20. Bond lengths and bond angles in 2-cyclopentenone photodirner. [From Margulis (107), with permission of the editor]. For 2-cyclohexenone and 2-cyclopentenone, head-to-head and head-to-tail dimers have been obtained. Furthermore, the rings may be fused syn or a nti to the cyclobutane ring. The head-to-tail anti dimer possesses a center of symmetry, and techniques such as X-ray and vibrational spectroscopy are sensitive to this element. Ziffer and Levin (108a) have applied this approach to an analysis of the photodimers of 2-cyclopentenoneI 2-cyclohexenone, 3-methyl-2-cyclohexenone, isophorone, and benzindenone.

&*

0

bm H

H

I

A

I

H

H3C

0

8

7

0

6

5

4

H

@ tql H3C

CH3

9

10

22

321

32 8

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

@-+ @ b$$-q% \

H

0

/

I

\

A

H

0

I

A

0

14

13

Table 13. Comparison of t h e Raman and I n f r a r e d Frequency Coincidencesa Head-to-tail photodimer Compound 4 6 8 11

12 13

Head-to-head photodimer

R

ir

C

Compound

R

ir

C

24 24 34 41 33 26

24 46 34 48 41 42

6 10 7 16

5 7 9 10 14

31 33 41 37 24

36 42 46 42 43

26 24 28 23 16

9 10

aR, i r , and C denote number of Raman and i n f r a r e d l i n e s , and coincidences, r e s p e c t i v e l y .

Table 13 l i s t s a comparison of t h e Raman and i n f r a r e d frequency coincidences. Compounds 4, 6, 8, 1 2 , and 1 3 have few such coincidences and a r e t h e r e f o r e considered t o be centrosymmetric. This r e q u i r e s a very n e a r l y p l a n a r cyclobutane r i n g . Compounds 5, 7, 9, 1 0 , 11, and 1 4 have a r e l a t i v e l y l a r g e number of coincidence bands, which i n d i c a t e s absence of a c e n t e r of symmetry. A canparable r e s u l t was a l s o obtained by determining t h e c r y s t a l space group (108b). I n t h e case of 3-methyl-2-cyclohexenone dimer, each u n i t c e l l had e i g h t equal "asymmetric u n i t s " r e l a t e d i n p a i r s by c e n t e r s of symmetry. I t was d e t e r mined t h a t each u n i t c e l l c o n t a i n s f o u r molecules and theref o r e each molecule must have a c e n t e r of inversion. This e s t a b l i s h e s t h e dimer a s c i s fused, h e a d - t o - t a i l , a n t i .

ROBERT M. MORIARTY

329 0

CH3 H

0

A very useful synthetic entry into the [n.2.0]cycloalkyl system is through irradiation of a cyclic a,B-unsaturated ketone in the presence of an olefin (109a). The reaction is characterized by high regiospecificity and frequent formation of trans-fused ring junctures. The reactions of isobutylene and allene with 2-cyclohexenone are typical:

cHi7H3Q L C

+

II

CH2

0

:rQ

(major product)

0

Photoisomerization of 2-cyclooctenone precedes cycloaddition with 1,l-dimethoxyethylene (109a).

Q:

CH3O

H

Base-catalyzed isomerization of the trans-fused compound in the bicyclo[4.2.01 series causes conversion to the cis compound (109a).

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

330

Irrcdiation of cis-dichloroethylene and 2-cyclopentenone yields cis-6,trans 7-dichloro-C~8-bicyclo[3.2.O]heptan-2-one (109b). The four-membered ring is bent with a dihedral angle of 149.3'. In contrast to the "long" C-C bond in the 2-cyclopentenone dimer (Fig. 20) which also possesses a planar cyclobutane, in the [3.2.0lheptanone compound all the C-C bond 0.005 i). lengths are normal (1.537, 1.538, 1.512, and 1.550 Ultraviolet irradiation of carbostyril or N-methylcarbostyril yields trans head-to-head dimers (110-113).

% -w

*

X = NH, NCH3

0

0

0

These compounds are similar to the photodimers of coumarin; however, in the latter case other isomers may be obtained, depending on the reaction conditions (114) (p. 331). The photodimer of 1,4-naphthoquinone is known and it forms a tetrabromo derivative (115) whose X-ray structure has been determined (116). 0

0

0

The bond angles and distances for the four-membered ring are shown in Figure 21. The four-membered ring is significantly distorted from the planar form. One reason for this distortion is probably the relief of torsional strain and van der Waals repulsion between adjacent cis bromine atoms. If the ring were planar, all bonds attached to it would ideally make approximately onehalf the tetrahedral angle with it, namely, 54.5O, and their projection on the plane should lie at 45' to the diagonals. One can see by the following calculation that the cis bromine atoms are uncomfortably close to one another.

3 0

0

331

332

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

Br

Br

1.530 88.1"

1.549

91.8" 1.555

Br

BI

Bond l e n g t h s and bond d i s t a n c e s and a perspec[From Kruger and Boeyens (116) I w i t h p e r m i s s i o n of t h e e d i t o r . ] Fig. 21.

t i v e drawing of t h e tetrabromonaphthoquinone dimer.

t h i s model With r (C-Br) = 1.937 it and r (C-C) = 1.57 c i s = r (C-C) + 2r (C-Br) c o s $ s i n $ = 3.16 i, g i v e s r (Br---Br) y h i c h i s much less t h a n twice t h e van d e r Waals r a d i u s of 1.94 By bending t h e r i n g ($2 = 36O, $ 2 = 28O, and A f o r bromine. $ 3 = 59O1 $ 3 = 36O) a t C2 and C g 1 r e s g e c t i v e l y , t h e nonbonded d i s t a n c e P (Br---Br)cis becomes 3.370 A .

ROBERT M.

333

MORIARTY

D.

Thymine and Urac.11 Photodimers

Photodimerization of t h e pyrimidine p a r t of DNA i s one of t h e prime mechanisms f o r t h e mutagenic e f f e c t s of u l t r a v i o l e t and gamma i r r a d i a t i o n upon organisms. A c o n s i d e r a b l e amount of v e r y f i n e s t r u c t u r a l work h a s been done on t h e photodimers of thymine and u r a c i l . Photodimers of thymine were f i r s t i s o l a t e d and i d e n t i f i e d as products from u l t r a v i o l e t i r r a d i a t i o n of f r o z e n aqueous s o l u t i o n s of thymine and of DNA i t s e l f (117, 118). Weinblum and Johns (119) succeeded i n o b t a i n i n g f o u r d i f f e r e n t isomers from t h e i r r a d i a t i o n of t h e aqueous s o l u t i o n of thymidyl-thymidine o r from f r o z e n s o l u t i o n s of thymidine. The f o u r p o s s i b l e dimers a r e isomer A (meso, CiS-5.5:6.6, headto-head, s y n ) , isomer B (trans-5.5:6.6, head-to-head, Syn), isomer C (cis-5.6:5.6, h e a d - t o - t a i l , anti), and isomer D (meso, trans-5.6:5.6, h e a d - t o - t a i l , anti). 0

A c i s- s yn (meso)

0

334

8

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

N

9

NL

N

C

cis-anti (dZ 1

0

0

H

H

H

0

D

trans-anti (meso)

The X-ray structures of dimers A and C of 1,3-dimethylthymine (120, 125) , and dimer D of thymine have been determined (12lb). The X-ray structure of l13-dimethylthymine dimer c reveals that it possesses the head-to-tail cis-anti configuration (125a). The cyclobutane ring is puckered with a dihedral angle of 154O. Each atom of the ring lies 0 . 5 d out of the plane defined by the other three atoms. The bond lengths and bond angles in the four-membered ring are normal. Table 14 summarizes the structural parameters for several pyrimidine photodimers.

ROBERT M.

MORIARTY

335

Camernan and Camerman (125b) have determined t h e s t r u c t u r e of t h e s t e r e o i s o n e r i c cis-syn photodimer of 1,3-dinethylthymine. I t possesses a puckered four-menbered r i n g with a d i h e d r a l a n g l e of 153'. A remartable f e a t u r e i s an i n t e r p y r i m i d i n e C-C bond d i s t a n c e of 1.66 A! This i s t h e l o n g e s t on record. The s t r u c t u r e of a photodimer of 1-methylthymine has a l s o been determined (126). This d i n e r , from i r r a d i a t i o n of a frozen s o l u t i o n , has t h e t r a n s - a n t i s t r u c t u r e (corresponding t o D ) and it i s centrosymmetric. The cyglobutane r i n y i s p l a n a r with bond l e n g t h s of 1.543 and 1.507 A (ESD 0.004 A ) and a n g l e s of 90.4 and 89.6' (ESD 0.2'). 0

The X-ray s t r u c t u r e (127) of t h e so-called ice d i n e r of u r a c i l confirms t h e e a r l i e r proposed cis-syn c o n f i g u r a t i o n ( 1 2 8 ) . The cyclobutane r i n g i s puckered, w i t h a d i h e d r a l a n g l e of 155', and t h e bond l e n g t h s a r e 1.572 and 1.523 A f o r t h e bonds common t o both r i n g s and 1.540 and 1.533 A f o r t h e o t h e r two. A c i s - a n t i photodimer of u r a c i l has a l s o been analyzed by X-ray d i f f r a c t i o n . I t has a puckered cyclobutane r i n g (150') (129) (Table 1 4 ) . The s t r u c t u r e s of three isomeric tetranethylthymine d i n e r s corresponding t o A , B, and C were d e t e r n i n e d by d i p o l e ncnnent measurements. The c a l c u l a t e d d i p o l e moments f o r A , B, C, and D a r e 6.1 t o 6.8, 3.1 t o 3.5, 5.1 t o 5.6, and 0 D , r e s p e c t i v e l y . The experimentally determined d i p o l e monents f o r t h e t e t r a n e t h y l

W W

cn

1.391

trans-syn ( B ) Methyl o r o t a t e

1.390 1.420 1.402 1.405

1.349

1.320 1.350

6-Methyluracil

cis-syn ( A )

Uracil

c i s u n t i (Cl

Uracil

cis-syn (A)

cis-syn ( A )

1.357

1.364 1.364

1.390 1.360

1.360 1.364

1.41 1.35

1.44 1.42

Dimethylthymine 1.390 1.398

1.378 1.377

c i s u n t i (C) 1.426 1.406

1.370

D i m e t h y l thymine

1.334

1.395

1.357

(D)

1.346

1.502

1.507 1.501

1.500 1.510

1.498 1.497

1.48 1.52

1.509 1.503

1.508

1.507

f o r P y r i m i d i n e Photodimers

1.390

transunti Thymine

t r a n s u n t i (D) Methylthymine

T a b l e 14. Summary of S t r u c t u r a l Parameters

1.544

1.543 1.565

1.540 1.560

1.540 1.533

1.55 1.58

1.533 1.529

1.547

1.543

1.546 1.586

cis-syn (A)

aFor numbering system see s t r u c t u r e A on page 333.

trans-syn ( B ) Methyl o r o t a t e

6-Methy lur ac i1

h e l a t i v e t w i s t of two p y r i m i d i n e r i n g s . CPuckexing of t h e c y c l o b u t a n e r i n g .

$ d i s t a n c e s measured i n t h e t w o r i n g s of t h e dimer.

w

1.590 1.600

c i s - u n t i (C)

Uracil

1.556 1.628

24

1.572 1.563

cis-syn ( A )

170

162

150

155

153

1540

None

None

Pucker

C

134b

134a

129

127

125b

125a

1.21b

126

Ref.

The t w o sets of f i g u r e s r e l a t e t o bond

7

16

21

26

1.60 1.66

cis-syn (A) Dimethyl thymine

uracil

29O

1.571 1.577

None

b Twist

c i s a n t i (C) D i m ethylthymine

1.567

Interp y r imidinea

None

(D)

C ( 6 ) -N ( l ) a

1.587

transanti Thymine

t r a n s a n t i 0) Methylthymine

Structure

T a b l e 14. Continued

338

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

derivatives are A = 6.04, B = 2.79, and C = 5.75 D (130). l,l'-Trimethylenebisthymine, upon photocyclization, cannot yield the anti structure or the trans-syn geometry because of the shortness of the connecting bridge. Therefore it forms the cis-syn structure which has been proven by X-ray diffraction (131). The cyclobutane ring is very close to planar, 0

15 , $ I

= 2O.

16

The crystal structure of a thymine trimer has been determined by Flippen and Karle (132). The scheme on p. 339 accounts for its formation (133) and also for its further photochemical transformation in aqueous medium. The structure of the thymine-thymine adduct obtained by irradiation of frozen aqueous solutions of thymine had been determined by X-ray diffraction earlier. The cyclobutane dimer part of the trimer has the syn-cis structure, and bond lengths and distances are given in Figure 22. This is the same configuration as found in the internal cis-syn photoproduct from 1,l'-trimethylenebisthymine. The cyclobutane ring in the trimer is only slightly puckered with an angle of 173.5'.

n

I

w

t

339

340

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

Fig. 22. Bond l e n g t h s and a n g l e s i n thymine :rimer. The s t a n d a r d d e v i a t i o n s a r e of t h e o r d e r of 0.015 A f o r the bond l e n g t h s and less t h a n 1 ' f o r t h e bond a n g l e s . [From Flippen and Karle (1321, with permission of t h e e d i t o r . ] T h i s i s c o n s i d e r a b l y f l a t t e r t h a n t h e cis-syn ( A ) u r a c i l dimer (155') and t h e 6-methyluracil dimer (162') (134a). The tors i o n a l a n g l e s about Cg-c15 and C g - C l g a r e o n l y 4.8 and 6.8', respectively. The r e l a t i v e l y long cS-c15 bond, 1.583 1, may be due t o nonbonded r e p u l s i o n between t h e two a d j a c e n t methyl groups. The s t r u c t u r e of t h e trans-syn dimer of methyl c r o t a t e i s of considerable i n t e r e s t .

n

' 7 / T I" 3

HN

0

COZCH3

*

CO2CH3 1.628

"

3 4

0

5

1.556

@ I

H

5' 4, 3Nn

H o

The a n g l e of pucker of t h e cyclobutane r i n g i s 170'. Cg-Cg ( i n t e r p y r i m i d i n e bond) is v e r y long a t 1.628 A.

The

ROBERT M. MORIARTY

341

Irradiation of the sulfur analog of uracil, namely, 1thiauracil, yields a cis-syn photodimer. The cyclobutane ring is puckered with a dihedral angle of 153O (134~).

E.

131,2,2-Tetrasubsti tuted Cyclobutanes

Infrared and Raman studies on 1,1,2,2-tetrafluorocyclobutane show that the molecule is puckered (135). The rin puckering vibration is assigned to a broad band at 90 cmThis allows one to set an estimate of the barrier height (the planar form) at 140 2 50 cm-’. This is considerably smaller than that in cyclobutane (503 an-’) or 1,l-difluorocyclobutane (241 an-’). The apparent trend of decreasing barrier height with increasing fluorine substitution reverses itself in going to the fully fluorinated compound. The barrier for octafluorocyclobutane is 640 an-’ (26). A possible rationalization of this trend of vibrational barriers is that the C-F bond is longer and the CH-CF torsional barrier is lower than the CH-CH barrier. However, the CF-CF torsional barrier is higher than that of CH-CH. It is easier for the ring to vibrate when the torsion is about the CH-CF bonds. It is also reasonable that ring vibration would require more energy when torsion is about the CF-CF bond as in octafluorocyclobutane. Anemonin ( 2 8 ) (126) is a naturally occurring dimer of protoanemonin ( 1 7 ) (137), a substance found in plants of the crowfoot family (Ranunculaceae) (136, 137). While the structure of the molecule was fairly well established, the stereochemical relationship of the lactones was not firmly settled. In fact, the originally proposed cis stereochemistry of the two lactone rings (138) proved to be incorrect on the basis of X-ray (139, 140) and nrnr studies (141). Bond lengths and bond angles for anemonin are shown in Figure 23.

9-.

17

18

342

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

F i g . 23. Bond l e n g t h s and a n g l e s i n Anemonin. The standaEd d e v i a t i o n f o r t h e bond l e n g t h s r a n g e s from 0.010 t o 0.017 A and t h e s t a n d a r d d e v i a t i o n f o r t h e a n g l e s i s of t h e o r d e r of 0.8'. [From K a r l e and K a r l e (140) , w i t h p e r m i s s i o n of t h e e d i t o r ] . The molecule i s f o l d e d a l o n g t h e C2-Cq d i a g o n a l t o a n a n g l e of 152O.

0

IH

The nmr spectrum o f t h e A2B2 system gave J A = 10.72, J, = 2.24, J1 = 10.19 and J 2 = -12.15 Hz. JA and J B are

The f a c t coupling c o n s t a n t s between n o n e q u i v a l e n t p r o t o n s . JBrequires t h e t r a n s arrangement of t h e two l a c t o n e the J A

+

ROBERT M.

343

MORIARTY

r i n g s . The angle of t w i s t i n t h e cyclobutane r i n g can be estimated from t h e t o r s i o n a l angle between t h e v i c i n a l protons which, i n t u r n , can be determined from t h e magnitude of t h e v i c i n a l coupling constants. The c a l c u l a t e d angle of t w i s t i s between 9 and 1l0, which agrees well with t h e value of 9.9 2 0.3' found i n t h e X-ray study. The X-ray s t r u c t u r e s of c i s and trans-1,2-dibromo-l,2dicarbomethoxycyclobutane have been determined ( 1 4 2 ) . Both molecules a r e nonplanar i n t h e c r y s t a l l i n e s t a t e with a d i h e d r a l angle of 153' f o r t h e t r a n s compound and 150' f o r t h e c i s molecule. The c i s d e r i v a t i v e i s completely asymmetric, while t h e t r a n s molecule has an approximate twofold a x i s passing through t h e midpoints of C1-C2 and C3-Cq. Figure 24 g i v e s t h e bond l e n g t h s and bond angles.

I

Fig. 24. Bond d i s t a n c e s and angles f o r t h e 1,2-dibromo1,2-dicarbomethoxycycl~butanes. The standard $ e v i a t i o n s axe of t h e order of 0,019 A f o r C-Br bonds, 0.027 A f o r a l l o t h e r bonds, and 1.1' f o r t h e angles. [From K a l e e t a l . (1421, with permission of t h e e d i t o r . ]

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

344

The conformations a v a i l a b l e f o r t h e t r a n s and c i s dibromo diesters are

Br

7d02~~3

The CCOO p l a n e s i n t h e c i s compound are t w i s t e d away from t h e Brl-Cl-C5 and Br2422-127 p l a n e s by a n g l e s of 6 1 and 67O i n t h e t r a n s molecule and 68 and 41° i n t h e c i s molecule. T h i s t w i s t i n g c t u s e s t h e intramolecular Br---0 d i s t a n c e t o be a t l e a s t 3.0 A. The X-ray study complements an nmr i n v e s t i g a t i o n of t h e c i s and t r a n s compounds (143). The 100 mHz proton spectrum of t h e c i s compound shows one peak f o r t h e CH3 protons and an AA'BB' p a t t e r n f o r t h e r i n g protons. This r e q u i r e s t h a t on t h e nmr time s c a l e t h e average symmetry of t h e c i s compound i s p l a n a r C, and t h e average symmetry of t h e t r a n s compound is t w i s t e d Cp. L u s t i g e t al. (143) performed a complete a n a l y s i s of t h e nmr s p e c t r a of t h e t w o compounds using weak double i r r a d i a t i o n ( " t i c k l i n g " ) : f o r t h e c i s d e r i v a t i v e JAB = -12.46 f 0.11, JAB'= 6.73 ? 0.08, JAAI= 9.75 f 0.13, JBB' = 8.55 f 0.18 Hz; f o r t h e t r a n s compound JAB = -13.19 k 0.04, JAB'= 9.00 ? 0.06, J A A I = 10.01 ? 0.06, JBB:' = 3.27 k 0.05 Hz.

VII.

CYCLOBUTANE AS A MEMBER OF A SIMPLE FUSED RING SYSTEM A.

B i c y c l o [ l . l .O]butane

The molecular geometry of bicyclobutane has been s t u d i e d i n d e t a i l . Moments of i n e r t i a have been determined from microwave s p e c t r a and t h e s e i n d i c a t e a d i p o l e moment of p = 0.67 D which i s high f o r a s a t u r a t e d hydrocarbon (144). The r o t a t i o n a l c o n s t a n t s from t h e i n f r a r e d s p e c t y a g r e e w i t h a diagonal C-C bond of approximately 1.49 A and a d i h e d r a l a n g l e of pucker of about 126 f 3O, which is q u i t e l a r g e (145). The h e a t of combustion of bicyclobutane is -633.05 f 0.19 kcal/mole, giving AHf (298OK g a s ) = 51.9 0.2 kcal/mole (146). The s t r a i n energy of bicyclobutane may be estimated from comparison of t h e F r a n k l i n s t r a i n - f r e e v a l u e s (-4.926 kcal/mole/

ROBERT M. MORIARTY

345

CH2 and -1.09 kcal/mole/CH = -12.0 kcal/mole), giving a strain energy of 63.9 kcal/mole. Schleyer (147a) has recently pointed out the inapplicability of Franklin group increments for cyclic compounds. He suggests a value of 66.5 kcal/mole for the strain energy of bicyclobutane. Several substituted bicyclobutanes may be obtained from the photolyses of conjugated dienes as well as by various synthetic routes (147b).

% \

hv

(148, 150)

cu2c12

Microwave studies were carried out on bicyclobutane, 1deuteriobicyclobutane, and 2,2-dideuteriobicyclobutane (153). The structural parameters so obtained are given in Table 15 and Figures 2% and 25b.

Fig. 2% system (153).

H10 Bicyclo[l.l.O]butane

H9

plotted in principal axis

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

346

b

a

Fig. 25b. P r o j e c t i o n of bicyclobutane on molecular ( a ) shows ac p l a n e , (b) shows bd plane (153). symmetry planes: Table 15. S t r u c t u r a l Parameters i n Bicyclobutane (153)

Parameters

c1-c3 c344 C3'H6 C2-H7 C2'H9 C1C3H6 ci ($ i n t h i s review) $1 42


Length,

i,o r

1.497 f 1.498 f 1.071 f 1.093 f 1.093 f 128'22' 122O40' 122O52' 121O34' 115O34' 59058' 130'22'

a n g l e , deg. 0.003 0.004 0.004 0.008 0.008 f 14' f 30' f 47' f 54'

S u r p r i s i n g l y , a l l t h e C-C bond l e n g t h s including t h e diagonal one a r e equal. The C-C bond l e n g t h is c l e a r l y about found i n t h e t y p i c a l cyclobutane 0.04 fl s h o r t e r than t h e 1.54 d e r i v a t i v e . The bridgehead C-H tond i s abnormally s t o r t ( a s expected). The l e n g t h i s 1.071 A compared t o 1.070 A i n ethylene. This agrees with t h e a c i d i t y of t h e s e protons a s observed by Meinwald e t a l . (154a). The a n g l e of pucker i s 122O40' t 30' (quoted as 121O40' i n t h e a b s t r a c t of t h e paper) (153). Bicyclo[l.l.O]butane has been t h e s u b j e c t of molecular o r b i t a l study (SCF c a l c u l a t i o n ) . The most s t r i k i n g f e a t u r e p ~ of t h e e l e c t r o n i c s t r u c t u r e of t h i s molecule i s t h e ~

~

.

ROBERT M. MORIARTY

347

hybridization of the central bond which corresponds to 96%

p character. For comparison, a minimal-basis molecular orbital (MEMO) on cyclopropane results in s p 5 . 6 9 or 86% p character (154b).

B.

Bicyclo[P.l .O]pentane

The first synthesis of this hydrocarbon was reported by Criegee and Rimmelin (155) via the thermal decomposition of the bridged azo compound.

The strain energy in bicyclo[2.1.0lpentane, which may be estimated from the heat of hydrogenation of -55.1 kcal/mole is 53.6 (147b) or 57.3 kcal/mole (147a). This is approximately equal to the sum of the strain energies of cyclopropane (27.5 kcal/mole) and cyclobutane (26.0 kcal/mole), which is 53.5 kcal/mole. It should be noted that the strain energy of bicyclobutane, in contrast, is considerably greater than that of two cyclobutanes, i.e., 63.9 or 66.5 kcal/mole compared to 2 X 27.5 kcal/mole. The strained nature of bicyclo[2.l.O]pentane is reflected in the ease with which cleavage of the central bond occurs in a number of reactions, e.g., with Br2, Tl(OAcl3, Pb(OAc14, H~(OAC)~, H2, and in cycloadditions with unsaturated systems. An electron diffraction study on the molecule reveals some remarkable features (156). The structure and molecular parameters are given in Figure 26. The zero bridge bond length is only 1.439 8 , which is the shorEest C-C single bond known, and the C2C3 bond length of 1.622 A is one of the longest carbon-carbon single bonds yet found. The four-membered ring is planar and the dihedral angle between the three- and fourmembered ring is 109.4'. Nuclear magnetic resonance studies on bicyclo[2.1.0]pentane also led to the conclusion that the cyclobutane ring is planar (157a). The short bond is formed by union of atomic orbitals at C1 and C4 which have a large degree of p character because of the compressed angles. Furthermore the overlapping orbitals composing this bond are bent away from the internuclear axis connecting the two carbons. The greater the bending from this axis, the shorter is the projection of the bond upon the axis. The orbital directionality is also affected by the dihedral angle between the two fused rings. Opening up of the dihedral

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

3 48

Fig. 26. Structure and molecular parameters for [ F r m Bohn and Tai (156), with perbicyclo [ 2.1 .O] pentane mission of the editor.]

.

angle causes the orbitals to be more nearly directed along the internuclear axis. This effect is illustrated in the case of the highly strainedobicyclobutane in which the diagonal bond is longer (1.497 A ) than the corresponding zero bridge bond in bicyclo[2.l.llpentane, but the dihedral angle is considerably larger, namely, 122'. The results from a microwave study on bicyclo[2.l.0lpentane are unfortunately in almost total disagreement with the electrgn diffraction results: C1-C2 = C3-Cq = 16528 A, C2-C3 = 1.565 A, Ci-Cq = 1.536 A, C1<5 = C4-C5 = 1.507 A, and a dihedral angle of 112.74' (157b).

C.

Bicyclo[2.2.O]hexane

This compound has been prepared in low yield by photodecarbonylation of bicyclo[3.2.0]heptan-3-one (158, 159) as well as by photoelimination of nitrogen from the bridged azo

ROBERT M. MORIARTY

349

compound (160, 161). hexadiene.

In both cases the major product is 1,5-

hv

m

An unpublished electron diffraction investigation on bicyclo[2.2.0lhexane has been referred to by Bohn and Tai (162). The salient features are that the rings are nonplanar and the central bond is the shortest in the system. A preliminary electron diffraction result (subject to revision) on perfluorobicyclo[ 2.2.01 hexane has been obtained by Chaing and Bauer (163). The structure is given in Figure 27. The cyclobutane rings are puckered with the Cg atom out of the plane of the C1C2C4 atoms and c6 out of the plane clC4c5 112.0' \

89O

r(c-c)

= 1.566

i

P(C-F) = 1.338

r(c1c3) = 2.196 51

Fig. 27.

Structure of perfluorobicyclo~2.2.0]hexane (163).

D.

Bicycl0[4.2.0]octane

An extremely elegant stereochemical study was carried out by Huisgen et al. (164-167) on the course of halogen addition to cyclooctatetraene. Bromination of cyclooctatetraene at -55' yielded a cis-1, 2-dibromocyclooctatriene which could be ozonized to meso-dibromosuccinic acid. Above -16' the cis dibromide isomerizes to the trans compound. The latter was ozonized to dZ-dibromosuccinic acid. Above - 1 6 O the trans-dibromocyclooctatriene cyclizes to trans-2,3-dibromobicyclo[ 4.2. O11 4l octa-5,7-diene, the final product in this multistep process.

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

3 50

-

H

Br2

-55'

H I I

I

HOOC -C-Br HOOC-C-Br

I

H

I

HOW-C-Br

I I

il The X-ray structure of trans-bicyclo[4.2.0loctyl-l 3,5dinitrobenzoate has been determined (168). Bond distances and bond angles of the four-membered ring shown in Figure 28 are within the normal range. The dihedral angle of ring pucker is 147'. Even though the ring is trans fused this feature apparently does not cause additional strain. Irradiation of a-diazocyclopentanones offers a route to cyclobutanes. A well-known example of this reaction is the irradiation of a-diazocamphor to 1,5,5-trimethylbicyclo[2.1.1] hexane-6-carboxylic acid, discovered by Horner and Spietschka (169).

This procedure has been applied to 16-diazo-17-ketosteroids to yield the D-nor cyclobutane derivative (170). The average angles in the four-membered ring are 87 and 88' in the two c16 epimers, and the dihedral angle of ring pucker is 40' in the c16@ compound (20) and 3 3 O in the c16a compound (192) (171). The ring juncture is, of course, trans. The exocyclic bond angles at c16 are distorted in order to minimize the nonbonded interaction between the C17 methylene and the

ROBERT M. MORIARTY

351

Fig. 28. Structural parameters for trrms-b~cyclo[4.2.01 octyl-1 3,5-dinitrobenzoate. (a)Bond lengths (A). Estimated ( b ) Bond standard deviations lie in the range 0.003 to 0.004 A. angles (deg.). Estimated standard deviations are 0.2’. [From Barnett and Davis (168), with permission of the editor.]

352

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

CH30

C 1 8 meth 1 group.

In the c 1 6 B derivative the c 1 7 " ' c 1 8 distance The exocyclic (17)-(16)-(13)-(18) torsional angles is 2.97 are -39 and -155' in the c 1 6 B C 1 7 a derivatives, respectively. Torsional angles, bond angles, and bond distances are given in Figures 29 and 30.

i.

ROBERT M. MORIARTY

353

I8

I

Fig. 29. Torsional angles for the B, C, and D rings of 19, upper, and 20, lower. [Frm Coggon et al. (1711,with permission of the editor.]

E.

17

Fig. 30. Valence angles (+1.1') at the cyclobutane ring carbon atoms for 19 upper, and 20, lower. +gles not shown above are C (12)C (13)C (16)= 128.3' and C(14)C(13)C(18) = 114.2' on 19. [From Coggon et al. (171), with permission of the editor.]

Bicycl0[7.2.0]undecane

Caryophyllene (211, a naturally occurring sesquiterpene, possesses this basic structure. X-Ray diffraction studies on caryophyllene hydrochloride (22) established the trans fusion of the cyclobutane ring (172). The crystal structure of "caryophyllene chlorohydrin" (23) (from Treibs Epoxyketone) confirmed the trans-fused cyclobutane ring, and also showed that the ring was nonplanar, with a dihedral angle of about 143' (173). The average bond ienfths and bond angles in the four-membered ring were 1.536 A and 87.0°, respectively. Greenwood et al. (174) obtained a tricyclic brcunohydrin (25) from the reaction of humulene ( 2 4 ) with N-bromosuccinimide. The bromohydrin could be converted to caryophyllene (21) or reconverted to humulene ( 2 4 ) .

354

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

21

22

23

NBS

25

24

Me

Me 26

21

X-Ray diffraction study of the bromohydrin revealed the stereochemistry shown in 26 (175, 176). The bond lengths in the four-membered ring tverage 1.562 d, which is close to the average value of 1.556 A in caryophyllene chlorohydrin, and 1.573 A in caryophyllene hydrochloride. The average angle in the four-membered ring is 88,2O, compared to 87.0 and 86.3' in the chlorohydrin and hydrochloride, respectively. Caryophyllene chlorohydrin and caryophyllene hydrochloride are representatives of a large class of compounds resulting from transannular cationic cyclization (177-179). Often more complex changes occur in which the four-membered ring is opened.

ROBERT M. MORIARTY

355

The following transformations reveal this complexity although the basic change which the cyclobutane ring undergoes is the conversion of the cyclobutylcarbinyl ion to the cyclopentyl ion.

Treatment of caryophyllene ( 2 1 ) with aqueous mineral acid gives carophyllene alcohol ( 2 7 ) clovene ( 2 8 ) I and neoclovene ( 2 9 ) (1774.

I

21

27

28

29

Formation of caryophyllene alcohol ( 2 7 ) proceeds via the bridgehead carbocation:

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

3 56

21

H 27

Although it might appear that ring expansion of the fourmembered ring in cation 30 might occur, actually this is impossible because the zero bridge bond is orthogonal to the p orbital of the cationic center. Therefore, the alternative carbocation 31 must be formed. This is an example of the specificity of the reactions of the two possible forms of the cyclobutylcarbinyl ion. Ion 3 0 has the p orbital approximately perpendicular to the cyclobutane ring while ion 31 is a bisected form. The consequences of these two limiting orientations have been more fully developed in the cyclopropylcarbinyl system (see page 373). Furthermore, in contrast to the large preference for the bisected form of the cyclopropylcarbinyl cation, only about 4 kcal/mole separates the bisected and perpendicular forms of the cyclobutylcarbinyl ion. The 4 kcal/ mole is an EHT result (180a). A recent ab i n i t i o result finds the bisected conformation to be 4.08 kcal/mole more stable (180b). However, in the case of 30 and 31 the ring system

dI

Bisected

d

Perpendicular

X

qx

m

X

V

II

X

@

2

V

X

357

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

3 58

constrains the ion in one or the other form. The ring expansion leading to neoclovene is scinewhat more complicated and may involve the following changes:

21

29

ROBERT M. MORIARTY

359

Very recently the structure of another caryophyllene derivative was obtained by means of X-ray diffraction (181). In the early work on caryophyllene, the dihydrochloride ( 3 2 ) was used as a crystalline derivative. Attempts to dehydrochlorinate in order to regenerate caryophyllene led to rearrangement products one of which is 2,6,10,l0-tetramethyltricyclo L7.2.0.0’ 7l undec-5-ene ( 3 4 ) The X-ray on the dibromide

.

HC 1

CH3 ‘Cl

CH2

21

C

H

3

T

W

-2HC1

33

derivative of 34 defines the stereochemistry at the four-membered ring juncture as cis. Product 34 results from a multistep process involving at some stage a double bond exocyclic to the cyclobutane ring. Diene 33 is a possible intermediate. Transannular cyclization of the diene and protonation at the bridgehead yields 34.

360

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

V I I I . lS3-DISUBSTITUTED SYSTEMS I N WHICH THE CYCLOBUTANE IS PART OF A BRIDGED POLYCYCLIC SYSTEM

A.

B i c y c l o [ l . l .l]pentane

Bicyclo[l.l.llpentane was synthesized in about 1% yield by treatment of dibromide (35) with sodium in dioxane (182). CH2Br

I

Br

35 Bicyclo[l.l.l]pentane possesses D3h point group symmetry with a dihedral angle of 120°, which is quite close to that in bicyclobutane. The results of the electron diffraction study are presented in Figure 31 (183a). The C-C bond length of 1.545 f 06006 A is normal for a cyclobutane, but the distance of 1.845 A between the 1,3+arbon a t m s is the shortest nonbonded C-C separation on record. An interesting consequence of this structural feature is the possibility of transannular C1-C3 bonding of the back lobes of the bridgehead C-H bonding orbitals. This may also account for the large long-range spinspin coupling constant of 18 Hz (184). SCF ab initio calculations on bicyclo[l.l.l]pentane indicate that the central carbon-carbon atoms have strongly antibonding overlap populations which agrees with their mutually small separation and the large spin coupling between the bridgehead protons (183b).

Fig. 31. The structure of bicyclo[l.l.llpentane. [From Chiang and Bauer (183a), with permission of the editor.]

ROBERT M. MORIARTY

361

Excellent agreement exists between the results obtained in the above-mentioned electron diffraction study in the vapor phase and an X-ray diffraction investigation of the p-bromo(185). phenylurethan of 2-hydroxy-2-phenylbicyclo[l.l.llpentane This compound was obtained in the irradiation of cyclobutyl phenyl ketone and subsequent reaction with p-bromophenyl isocyanate.

0

The average carbon-carbon bond length was found to be 1.54 The C-C-C angles of 75' at the methylene groups are considerably smaller than the C-C-C angie of 87' at the methine carbons. The C1C3 distance of 1.89 A agrees well with the value determined above for the parent hydrocarbon, bicyclo [l.l.llpentane. The dihedral angle of ring pucker is 60'. The various ring torsional angles of 43 ? 2 ' are greater than those found in cyclobutane. The structure of 1-chlorobicyclo[l.l.llpentane has been studied by microwave spectroscopy (186). The results agree very closely with those obtained for the parentohydrocarbon. The bond distayes are P(C1C2) = 1.536 f 0.007 A, P(C2C3) = 1.566 ? 0.007 A. The 1,3 nonbonded distance is a characteristically short 1.850 &. The principal differences between bicyclo[l.l.l]pentane and bicyclo[2.l.l]hexane is the decrease in the angle of pucker from 60 to 55'. Also, the ring angles at the methylene groups of the cyclobutane are 73.3' in the former and 89.4' in the latter. The relative size of the methine carbon C-C-C angles is reversed, being 87' in bicyclo[l.l.l]pentane and 78.2' in bicyclo[2.l.llhexane.

it.

B.

Bicyclo[2.1 .l]hexane

Bicyclo[2.1.1lhexane has been synthesized by the mercury-

362

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

sensitized irradiation of l15-hexadiene and norbornanone, and also from the decarboxylation of the epimeric bicyclo[2.1.11 hexane-5-carboxylic esters.

(1) NaOH (2) Soclp CO2CH3

(3)

(188)

t-BuOOH

(4) A, cymene

Two independent electron diffraction studies on bicyclo12.l.lIhexane have been reported (189, 190). The motivation for the more recent study (190) was founded upon the contention that the earlier study (189) must be regarded as inconclusive owing to false assumptions in the analysis. Specifically Dallinga and Toneman (189) basedotheir model on the misbelief that the difference of 0.01 A in C-C bond length between cyclobutane and cyclopentane is a wellestablished experimental fact, and a typical value for cyckobutane is quoted as 1.548 b and for cyclopentane as 1.539 A. However, the repgrted C-C distances for the pair are actually 1.548 and 1.546 A (191), respectively. The structure derived by Chiang (190) is given in Figure 32. The struciural 0.015 A, C 1 4 2 = parameters areoas follows: C1<5= 1.544 1.513 f 0.015 b , C-H = 1.112 f 0.003 :.565 ? 0.024 A, C 2 4 3 A, and the dihedral angle of the ring pucker is 125 f . '2

*

363

ROBERT M. MORIARTY

9

Fig. 32 The structure of bicyclo[2.l.l]hexane. Chiang (190)I with permission of the editor.]

C.

[From

Bicyclo[3.1.1 Iheptane

An electron diffraction study of bicyclo[3.l.llheptane has been reported (192), and the structure deduced is shown in Figure 33. The rather large error range in the bond lengths precludes attaching a great deal of significance to their relative magnitudes. The dihedral angle of 137' is about 12' larger than that of bicyclo[2.2.l]hexane, indicating a flatter cyclobutane ring in bicyclo[3.l.l]heptane. The relatively large difference between the methine carbon ring angle and that at the methylene carbon found in the two lower bicyclic analogs is absent in bicyclo[3.1.1]heptanel these angles being 84.9 and 87.1', respectively. The bicyclo[3.l.l]heptane ring occupies an important role in organic chemistry because it is the basic skeleton of the pinane monoterpenes (193). The absolute configurations of (-,)-B-pineneand (-)-cis-pinane, which are precursors of numerous derivatives, are S : 5 S and l5:2R:5SI respectively. These compounds have been degraded to (+)-2-methylsuccinic acid. 10

5

364

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

d Fig. 33. Structure of bicyclo[3.1.1lheptane. [From Dallinga and Toneman (192), with permission of the editor.] Among the conformational possibilities discussed for the pinane system is a bridged chair form or a flattened chair form which is termed a “Y-shaped molecule (194). Furthermore,

the pinane ring containing the gem-dimethyl group may exist in either a boat or chair form. Newnan projections show the manner in which these conformations vary with the torsional angle of the ethane part:

ROBERT M. MORIARTY

365

H

Definite calculations on 6,6-dimethylbicyclo[3.l.llheptane have been carried out recently by Fournier and Waegell (195). These workers used a computer technique to search for an energy minimum in terms of valence angle and dihedral angle defonnation and nonbonded interactions considering bond distances as invariant. In the conformation of minimum energy the C3 carbon is tilted toward the C7 methylene group (Fig. 3 4 ) . This confonnation was proposed earlier (197) and deduced from nmr studies (198, 199). Solvolytic reactions of pinane derivatives reveal their propensity to rearrange to bicyclo[2.2.1lheptane derivatives. These reactions are highly specific. The driving force for the cyclobutylcarbinyl - cyclopentyl rearrangement is probably relief of strain in the four-membered ring. The following examples are illustrative of the stereospecificities (200).

4u OAc

Heating these compounds with acetic anhydride yields isobornyl and isofenchyl acetates along with some a-terpenyl acetate. The selective migration of the methylene or gem-dhethyl

366

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

I

I I

11

I

Me

Fig. 34. Calculated conformation for 6,6-dimethylbicyclo K3.1.11 heptane. [Fournier and Waegell (195): see also Baretta et al. (196).I group of the four-membered ring depends on the relationship of this group with respect to the leaving group. Analogous behavior was observed in the solvolyses of a- and 8-nopinol arenesulfonates (201 202) A rather more subtle conformational effect determines the course of addition of HBr to the 8-pinene derivative (36) (203). Attachment of the six-membered ring causes an increased puckering of the pinane structure and this greatly affects the direction of ring opening of the four-membered ring.

.

ROBERT M.

367

MORIARTY

1

36

RS

38

37

39

Only the fenchyl derivative 38 is formed and none of the bornyl derivatives 39 even though it might appear that the tertiary cationic center in 37 is symmetrically disposed with

368

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

respect to the methylene or gem-dimethyl group of the cyclobutane ring. Examination of a model of the tertiary cation reveals that the six-membered ring fused to the pinane skeleton causes a bending of the Cg carbon toward the gem-dimethyl group. This has the effect of locking the pinane structure in the conformationally rigid form indicated in 37. The molecular changes accanpanying migration of the gem-dimethyl group, namely, movement of the Cg carbon upward or to a more flattened form, is conformationally prohibited (204). Similar stereospecificity has been observed in addition of HX to the adduct of nopadiene and maleic anhydride (205).

D.

Tricycl o[ 3.3.0. O2 r6]octane

Tricyclo[3.3.0.0]octane may be considered to be a tetrasubstituted derivative of cyclobutane; however, because of its structural similarity to the bridged bicyclo[n.l.l] alkanes, it is discussed in this section. An early example of this ring system turned up in the dimerization of hexafluorobutadiene (2061, although the dodecafluorotricyclo [ 3.3.0. O2 6]octane structure was not recognized until an X-ray diffraction study was carried out (207).

The bond lengths are presented in Figurg 35. The C-C distances of 1.488, 1.473, 1.439, and 1.514 A are abnormally short for a cyclobutane derivative. The angle of pucker was determined to be 120'.

ROBERT M. MORIARTY

369

Fig. 35. Bond lengths in CgF12. with permission of the edit0r.J

[From Karle et al. (2071,

The parent hydrocarbon, synthesized by mercury-sensitized photodimerization of cis, cis-1,5-cyclooctadiene (208-210), has been the subject of an electron diffraction study (211). The molecular structure is shown in Figure 36. The bond digtances are normal for the cyclobutane, but the value of 1.516 A is quite short for a cyclopentane bond, and 1.569 fl is very large. The angle of pucker is 126.7'. The variation in angle of pucker for the series of 1,3bridged bicyclic cyclobutane derivatives compared to cyclobutane and bicyclobutane is as follows:

A

33' (ref. 10a)

60' (ref. 153)

60'

(ref. 183)

n

55' (ref. 191)

56.5' (ref. 212)

(ref. 192)

(ref. 211)

370

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

Fig. 36. S t r u c t u r e of tricycl0[3.3.0.0~~~]octane. [From Chiang and Bauer (211), with permission of t h e e d i t o r . ] The apparent trend i s t h a t pinching t o g e t h e r t h e 1,3 p o s i t i o n by a zero-, one-, o r two-carbon bridge causes a s e v e r e puckering of t h e r i n g . However, a three-carbon bridge i s more r e a d i l y accommodated, and t h e degree of puckering i n t h i s c a s e i s cont r o l l e d by minimization of t o r s i o n a l s t r a i n about t h e C-C bonds. Table 16 summarizes t h e s t r u c t u r a l parameters f o r some compounds which a r e of i n t e r e s t i n t h i s series (212b).

w w 4

deg.

A

Ref.

212d

212a

1.33 1.537 2.302 61.8

212a

212c

1.34 1.538 2.292 52.0

1.545

1.580 1.579 1.505 1.345 1.503 2.030 58.2

1.549

1.546

1.34 1.519 2.44 I 26.8

212c

1.559 1.551 1.556 2.317 54.0

211

1.558 1.516 1.569 2.077 63.4b

190

1.544 1.513 1.565 2.172 62.5

191

pseudo-roc (12.5)

1.546 1.546 1.546 2.414

%ram S. H. Bauer e t a l . ( 2 1 2 b ) , with permission of t h e e d i t o r . bQuoted as 126.7O i n r e f . 211.

I) deg.

X

d

C

b

0

Ref.

9

X

L

brf

0 1

183

1.845 60.0

1.544

T a b l e 16. Summary of A n g l e s and Bond Distances for Hydrocarbonsa

2.110 37

1.548

372

CYCMBUTANE AND HETEROCYCLIC ANALOGS

E.

Tricyclo[3.2.1 .O1 r5]octane

A preliminary result subject to revision has been obtained on the electron diffraction spectrum of tricyclo[3.2.1.01 "1 octane (213). Figure 37 gives the determined structure. The cyclobutane ring is planar. This makes it the second known cyclobutane to be planar in the gas phase, the other being bicyclo[2.l.0lpentane. The C-C digtances are normal except for the C2-C5 distance which at 1.518 A is quite short. A low-temperature X-ray study on 8,8-dichlorotricyclo r3.2.1. O1 I 5l octane reveals that theoC-C bond connecting the two bridgehead atoms is only 1.458 A (214).

Q

\

19

17

Fig. 37.

Tricyclo[3.2.1.01

Structural parameters

,5]octane (213).

rij, la

5 o n d distance hstimated standard deviation.

2<jl

ib

ROBERT M. MORIARTY

IX.

373

THE CYCLOBUTYL CARBOCATION

The most characteristic reactions of the cyclobutyl cation are its conversion to the cyclopropylcarbinyl and allylcarbinyl cations.

dNH2 doH +

mo2

D-

CH20H

HNo2

D-

CH2NH2

These ion are related by the following shifts of electrons:

The cyclopropylcarbinyl ion may have two limiting structures, depending on whether the vacant orbital at the exocyclic carbon atom is the perpendicular form b or in the bisected form

a.

374

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

Quantum mechanical c a l c u l a t i o n s i n d i c a t e t h a t t h e b i s e c t e d s t r u c t u r e a i s more s t a b l e by 26 (CNDO) ( 2 2 4 ) , 9 (EHT) ( 1 8 0 ) , 19 (ASMO-SCF) (2181, and 22 kcal/mole ("DO) (216). The b a r r i e r h e i g h t f o r r o t a t i o n measured by nmr i n t h e dimethylcyclopropylcarbinyl c a t i o n i s 13 kcal/mole (215). I n systems i n which s t r u c t u r a l c o n s t r a i n t s f o r c e adoption of t h e perpend i c u l a r gecinetry, r a t e r e t a r d a t i o n of about l o 3 i n c a r b o c a t i o n formation i s observed (216, 217, 219-222). Furthermore, i n t h e b i s e c t e d conformation d i s r o t a t o r y r i n g opening l e a d s d i r e c t l y t o t h e c o r r e c t p a r a l l e l o r i e n t a t i o n of t h e p o r b i t a l s a t C 1 and C 2 .

H H

D i s r o t a t o r y cleavage of t h e C3-Cq bond could, i n p r i n c i p l e , y i e l d an i n t e r m e d i a t e of C3v synnnetry which could t h e n c y c l i z e i n three ways t o y i e l d three cyclopropylcarbinyl c a t i o n s .

H

The question of t h e a c t u a l s t r u c t u r e of t h e c a t i o n , a t p r e s e n t , i s n o t s e t t l e d . These d i s r o t a t o r y ring-opening and -closing r e a c t i o n s r i g o r o u s l y fix t h e stereochemistry of groups on t h e four-membered r i n g .

ROBERT M. MORIARTY

375

The stereochemical changes may be traced by reference to the relationship of to C2-Cq. It remains trans throughout the cyclobutylcyclopropylcarbinyl interconversion. This is the central stereochemical feature in the many diverse examples of this process. Before discussing in detail the stereochemical course of cyclobutyl cation rearrangements, it is appropriate to focus on the structure of the cyclobutyl cation. Quantum mechanical calculation ( E m ) gives results which are conflicting (223, 225). Davis and ohno (223) calculate the overlap population as a function of dihedral angle of pucker. The C1-C3 population becomes negative at 30°. However, they calculate that the most stable form of the ion has all four bond angles equal to 90' and therefore the ring ought to be planar. Since a '0 dihedral

376

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

angle corresponds to a negative 1,3 population, they conclude that no 1,3 stabilization of the carbonium ion occurs. Baldwin and Foglesong (225) conclude on the basis of EHT that the most stable form of the cyclobutyl cation is puckered, in agreement with CNDO calculations by Wiberg (224) which indicate that considerable 1,3 stabilizing interaction occurs. More recently Wiberg (226) calculated using CNDO that the cyclobutyl cation has structure 40 with a pucker angle of 80°.

40

Some of the most penetrating studies on the stereochemical course of carbonium ion reactions of cyclobutane have been carried out by Wiberg et al. (227). Fused ring and bridged bicyclic model compounds were used in which the leaving group was held in a fixed position with respect to neighboring bonds. The impressively large k,do/k,, ratio for 41 and 4 2 , and 43 (228) and 44 illustrates the powerful influence of the stereochemical relationship of interacting bonds in these systems.

H

H 43

/k = 108 kendo ex0

DNBO

44

ROBERT M.

377

MORIARTY

These r e s u l t s may be explained i n terms of a d i s r o t a t o r y r i n g opening of t h e cyclobutane i n one stereochemical sense, namely, t r a n s f e r of e l e c t r o n d e n s i t y from t h e opening sigma bond t o t h e back s i d e of t h e leaving group.

One might p r e d i c t t h a t a s n i s increased t h e inwardly d i s r o t a t o r y change might become s t e r i c a l l y accommodable. This has been b e a u t i f u l l y demonstrated: H H H

TsO

O T s ( r e f . 229)

H

%?do

/k

ex0

= 500

T SO

H

kendo/kexo

=

OTs ( r e f . 230)

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

378

A confonnational effect also operates in this series. Electron diffraction studies show that the cyclobutane ring in bicyclo[2.1.0]pentane is planar and that in bicyclo[2.2.01 hexane is very nearly planar. No goad structural data are available for bicyclo[3.2.0lheptane, but X-ray diffraction studies on bicyclo[4.2.0loctane show that the cyclobutane ring is puckered. Therefore, the torsional angles at the bridgehead are improved and ring opening to the ion 45 is facilitated.

45

Solvolytic reactions in the bridged bicyclic series may be understood on similar stereochemical grounds (231-233).

102

103

10-5

46

47

48

lo3

10-3

1

49

50

51

ROBERT M. MORIARTY

379

The pattern is that the endo isomers (tosyloxy equatorial with respect to the cyclobutane ring) react faster. This is due to disrotatory opening of the ring. The enhanced rate of 46, 47, and 49 over cyclobutyl tosylate itself is probably a result of release of ring strain.

The m o isomers in which the tosyloxy group is axial with respect to the cyclobutane ring cannot undergo a disrotatory opening in the above-mentioned sense.

Schleyer et al. (234) measured the rates of solvolysis of In the bicyclic series the compounds with equatorial leaving groups were accelerated and the ones with axial groups decelerated. In the 3-t-butylcyclobutyl p-toluenesulfonate series the opposite occurs. This, however, is to be expected on the basis of disrotatory opening of the ring. In the equatorial example disrotatory opening is inward in order to bring charge density to the back side of the leaving group. This causes the equatorial t-butyl group to move toward the C 2 methylene group. The stereochemical relationships outlined above also adequately explain the formation of products in the solvolyses of the two t-butylcyclobutyl tosylates as well as their cyclopropylcarbinyl analogs. Cis- and ~an~-3-t-butylcyclobutyl tosylates.

380

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

1

0.008

krel,

60% acetone

a t 50°

0.14 Cyclization of t h e ion i n t h e c i s series t o form o r regenerate t h e cyclopropylcarbinyl system is rendered u n l i k e l y because of t h e t-butyl-methylene i n t e r a c t i o n . Accordingly, an a l t e r n a t i v e pathway is followed i n which t h e open-chain olef i n i c alcohol p r e d m i n a t e s . In t h e t r a n s case d i s r o t a t o r y r i n g c l o s u r e i s s t e r i c a l l y unencumbered and t h e trans-cyclopropylcarbinyl product predominates. U s e of t h e t - b u t y l group as a "conformational anchor" i n t h i s system obviously does not apply i n t h e same sense a s i n t h e cyclohexyl series. This i s because t h e s u b s t i t u e n t a t t h e Cg p o s i t i o n i s very much engaged i n determining t h e s t r u c t u r e and energy of t h e t r a n s i t i o n s t a t e f o r i o n i z a t i o n . The sum of r e s u l t s on solvolyses of secondary cyclobutyl systems f o r c e s t h e conclusion t h a t they y i e l d t h e cyclopropylcarbinyl ion d i r e c t l y . This g e n e r a l i z a t i o n a p p l i e s a l s o t o

and other products

n

60% and other products

381

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

382

work on deamination of secondary cyclobutylamines (235-237). The following results by Lillien and Doughty (238) are interpretable on t h e basis outlined above. Reaction of trUnS3-isopropylcyclobutylamine with nitrous acid yields predcminantly the trans-cyclopropylcarbinyl alcohol, while ciS-3isopropylcyclobutylamine yields a product derived from hydride shift

.

cis

cis 9.3 trans 6.0

NH2-

68.1 28.6

2.2 55.0

11.1

8.8 3.1

7.3

NH2

trans

ROBERT M.

383

MORIARTY

Ring opening a l s o predominates i n o x i d a t i o n r e a c t i o n s of cyclobutanol and i t s d e r i v a t i v e s . Vanadium(V) o x i d a t i o n y i e l d s y-hydroxycarbonyl compounds. The following r e s u l t s by Racek (239) a r e i n t e r p r e t e d on t h e b a s i s of carbon-carbon cleavage i n t h e rate-determining s t e p between t h e c a r b i n o l carbon and t h e more h i g h l y a l k y l a t e d a d j a c e n t one.

( a ) R1 = (b) R1 = (C) R1 = (d) R1 =

R2 = R3 = H1 CH3; R1 R2 = H i R2 = H; R3 Et H I ; Rg = R3 = CH3

94 76 74 71

12.6 116 84.3 1890

Both chromic a c i d and cerium (IV) ammonium n i t r a t e oxidat i o n of cyclobutanol and i t s d e r i v a t i v e s involve carbon-carbon cleavage i n t h e r a t e - l i m i t i n g s t e p .

X.

HETEROCYCLIC FOUR-MEMBERED R I N G D E R I V A T I V E S A.

Trimethylene Oxide (Oxetane)

Some of t h e most e x a c t s t r u c t u r a l d a t a have been obtained by p h y s i c a l methods applied t o four-membered h e t e r o c y c l i c d e r i v a t i v e s . The microwave s p e c t r a of t r i m e t h y l e n e oxide, 1,1,3,3-tetradeuteriotrhethylene oxide, and t r i m e t h y l e n e oxide-018 have been s t u d i e d (240-243). The microwave spectrum i s a p a r t i c u l a r l y s e n s i t i v e probe f o r ring-puckering v i b r a t i o n because v a r i a t i o n s i n t h e moments of i n e r t i a with v i b r a t i o n a l l e v e l s may be determined. A p o t e n t i a l energy f u n c t i o n f o r t h e ring-puckering mode may be constructed from a determination of t h e mean displacement from a p l a n a r conformation i n v a r i o u s vibrational states. I t was found t h a t trimethylene oxide i s an e s s e n t i a l l y p l a n a r molecule with a small b a r r i e r of 35 f 5 cm-l s e p a r a t i n g t h e two puckered minima. The ground v i b r a t i o n a l l e v e l , howabove t h e b a r r i e r , and t h e r e f o r e t h e e v e r , i s 8 2 4 an’’ v i b r a t i o n s of t h e r i n g a r e t h o s e of a p l a n a r c o n f i g u r a t i o n . The s t r u c t u r a l parameters deduced from t h e r o t a t i o n a l c o n s t a n t s

384

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

t,

are r(C-C) = 1.549 f O.gO3 r ( C - 0 ) = 1.449 f 0.002 i, 0.002 A, r(Cg-Hg) = 1.100 0.003 &, Ca-CB-Ca = 84'33' l', Ca-O-Ca= 91'59' f 7', Cg-C, = 91'44' f 3', &-Ca-& = 110'18' f lo', HB-CB-HB = 110'44' f . 3'. The a-methylene planes are bent slightly toward the oxygen atom. The dipole moment was found to be 1.93 f 0.01. A potential function could be calculated which matched the experimental one very closely if the out-of-plane bending was assumed to follow a curvilinear path without C-C or C-0 bond stretching. The far-infrared spectrum in the region 50 to 400 cm-I has been studied by two groups of workers (244, 245). These workers found a series of progression bands between 200 and 500 cm-l which are second overtones of the ring-puckering motion with the same band envelope as the fundamental. Ueda and Shimanouchi (246) have fitted the progression band data to a potential energy function for ring puckering in the ground and first excited states as shown in Figure 38 where v is in reciprocal centimeters and Z is in angstroms. The barrier height at the planar conformation is 15.3 cm'l. These same workers have compared the far-infrared spectrum of 2,5-dihydrofuran with that of trimethylene oxide (247). Analysis of the spectrum of 2,5-dihydrofuran leads to an expression for the ring-puckering potential (v) as a function of the ring-puckering coordinate (Z) of the form v(Z) = 1.557 X 104Z2 + 1.152 X 106Z4. This molecule as well as other fivemembered ring compounds containing one double bond provide an interesting comparison with four-membered ring molecules. The equation set above for the ring-puckering potential of 2,5dihydrofuran has a predominant quartic term and a positive quadratic term in contrast to the energy function for trimethylene oxide for which the quadratic term is negative:

r(ca-&) 1.091

*

*

*

The latter situation corresponds to that shown in the upper part of Figure 39 (case 1) where cabination of the periodic and quartic parts leads to a double minimum, whereas the former leads to a single-valued minimum as shown in the lower part of the figure (case 2). For the general case of

385

ROBERT M. MORIARTY

Energy (cm-’1

-0.20

-0.10

0

0.10

0.20

z (AI

Fig. 38. Ring puckering of trimethylene oxide. [From Ueda and Shimanouchi (246), with permission of the editor.] a single potential minimum results if b is positive or zero (case 2). If b is negative, a double potential energy minimum occurs (case 1). If b is sufficiently small (either negative or positive), the ring is planar. In 2,5-dihydrofuran b is positive, and hence the potential minimum is single valued. In trimethylene oxide b is negative but small. The ring, therefore

386

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

-W 1

2

L

U

Fig. 39. Schematic representation of the origin of the ring-puckering potential. [From Ueda and Shimanouchi (2471, with permission of the editor.] is very nearly planar. Term a is mainly a measure of the angle strain in the ring which tends to maintain a planar system. Term b results from torsion about the ring atoms which tend to cause a puckering of the ring. Cyclobutane itself, because of its very low barrier to inversion (518 k 5 cm”) (17a), cannot be classified as a rigid molecule of Dzd symmetry; rather, spectroscopically, the inversion levels must be assigned to the D4h space group. Several other quartic oscillators have been studied in the far infrared. Among these are trimethylene sulfide (thietane), trimethylene selenide, silacyclobutane, and trimethylene imine (azetane).

B.

Trimethylene Sulfide (Thietane)

Borgers and Strauss (248) have analyzed the far-infrared spectrum of trimethylene sulfide (thietane) in terms of a quartic-quadratic potential:

v(z)=

-23.5

x

10322

+

5.06

x

10524

with a barrier height at the planar conformation of 274 cm”. In contrast to trimethylene oxide, the first four vibrational levels in trimethylene sulfide fall below this barrier. The higher barrier height for trimethylene sulfide, 274 cm-l, relative to 15.3 cm-l may be due to the smaller C-S-C bond angle relative to the C-0-C bond angle in trimethylene oxide. The longer C-S bond length would also favor a nonplanar

ROBERT M.

387

MORIARTY

conformation. E x c e l l e n t agreement e x i s t s between t h e f a r i n f r a r e d study and a microwave study by Gwinn e t a l . (2491. The b a r r i e r h e i g h t which t h e y determined i s 274.2 2 2 c m' The angle of pucker determined by Gwinn e t a l . (249) i s 28O. Also, they confirmed t h e q u a r t i c - q u a d r a t i c behavior of t h e ring-puckering mode. From t h e v i b r a t i o n a l - r o t a t i o n a l i n t e r a c t i o n and l i n e i n t e n s i t i e s they determined t h e p o t e n t i a l energy f u n c t i o n t o be of t h e form:

.

V ( Q ) = 7.0207Q4

-

87.7581Q2 cm"

The d i p o l e moment f o r trimethylene s u l f i d e has been d e t e r mined from microwave s t u d i e s a s 1.85 D (250). They a l s o found t h e s t r u c t u r a l parameters given i n F i g u r e 40.

Fig. 40. S k e l e t a l c o n f i g u r a t i o n and dimensions of trimethylene s u l f i d e . Bond l e n g t h s and angles: C-S = 1.819 A; C-C = 1.549 8; HCH = 110O18'; C2C3C4 = 84O33'; a n g l e of pucker ($1 = 40'.

C.

Trimethylene Selenide

The i n f r a r e d and Raman s p e c t r a of t r i m e t h y l e n e s e l e n i d e and trimethylene selenide-dk have been s t u d i e d (251, 252). The observed f r e q u e n c i e s could be matched with c a l c u l a t e d ones u s i n g t h e p o t e n t i a l energy f u n c t i o n :

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

388

V (cm'l)

= 22.08(Q4

-

8.280Q2)*

The h e i h t of t h e b a r r i e r obtained from t h i s f u n c t i o n i s 378.1 f 4 a n-' (1.081 0.01 kcal/mole). Using t h e reduced mass of 106.0 a.u. f o r trimethylene s e l e n i d e , t h e dimensionless equat i o n above can be converted t o

*

'L

-

= 4.258(+ 0.02) X l O 5 z 4

2.5391(+ 0.007) X

lot2

where 2x i s t h e s e p a r a t i o n of t h e r i n g d i a g o g a l s i n angstroms. The p o t e n t i a l energy minima occur a t +0.173 A and t h e angle of pucker i s 32.5 2 O f o r bending along t h e Se-BC diagonal (Cs symmetry, see Fig. 4 1 ) . The b a r r i e r h e i g h t f o r t h e d e u t e r a t e d compound i s 375 an-'.

*

800

-

I

93.2

-

I

-9

8

86.4

'7

I

nide.

10

I

99.8

600

11

I

105.7

Fig. 41. P o t e n t i a l energy f u n c t i o n f o r trimethylene sele[From Durig e t a l . (252), w i t h permission of t h e e d i t o r . ]

*This f u n c t i o n , i n t h e a u t h o r s ' paper, ( r e f . 252) i s erroneously given a s = 22.08 (Q4 8.78Q2).

v

-

ROBERT M. MORIARTY

389

D.

S i 1 acycl obu tane

Silacyclobutane is somewhat different from trimethylene oxide, trimethylene sulfide, and trimethylene se1eni.de in that silicon, being quadrivalent, may have two hydrogens attached to it. A nonplanar ring should have axial and equatorial positions at silicon. In their infrared study of silacyclobuH

-Si I

-

/

tane Laane and Lord (253) assumed a double-minimum vibrational potential energy curve with a barrier of 440 cm-l.at the planar form. Six ribrational energy levels occur below this barrier. The dihedral angle determined from the vibrational spectrum was 36'. Aleksanyan et al. (254) have obtained infrared evidence for axial and equatorial Si-H and Si-D groups. Q branches of the V(Si-H) and v(Si-D) are split into two components of approximately equal intensity. The data in Table 17 illustrate this trend. These data may indicate axial and equatorial Si-H and Si-D groups in a nonplanar form of the silacyclobutane. It is, however, somewhat surprising that the intensities of the v(Si-H) doublet are equal for 1-chloro-, 1-bromo-, and l-methylsilacyclobutane since this would indicate that the axial-equatorial ratio is approximately constant and independent of the nature of the substituents. The microwave spectra of silacyclobutane and silacyclobutane-l,l-dq have been determined (255). The results may be interpreted in terms of a nonplanar molecule with a dihedral angle of 29O. An electron diffraction study also indicates a nonplanar structure (256a). Electron diffraction studies on 1-silacyclobutane, 1,ldichloro-1-silacyclobutane, 1,1,3,3-tetrachloro-1,3-disilacyclobutane, and 4-sila-3,3-spiroheptane have been carried out (25633). The structural parameters are collected in Table 18. All four compounds possess puckered four-membered rings (Table 18).

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

390

Table 17. &-Branch S p l i t t i n g for v(Si-H)

and v(Si-D) (254)

Frequency

Compound

oi/D

(V),

Cm-l

1558 1563 2147 2150

(Si-D)

2166 2169

(Si-H) (Si-H)

1545 1548

(Si-D) (Si-D)

2169 2172

(Si-H) (Si-H)

2128 2131

(Si-H) (Si-H)

(Si-D)

(Si-H) (Si-H)

\CH3

0'" 'CH3

E. Trimethylene Imine (Azetane) Trimethylene imine (azetane) i s a complicated system, since the two conformers generated by t h e ring-bending vibrat i o n are of d i f f e r e n t energy.

0

ClSiCl

ccc

CSiC SiCC SiCSi

100'22'

30 ? ' 5

--

f 20

--

80 f ' 2 86 f ' 2

--

1.13 f 0.03 1.897 f 0.01 1.585 f 0.01

SiHg

C 99'4' 105 30

1.13 1.882 1.59 2.050 80 86

f ' 5

? 20 ? 1 '

--

(assumed) f 0.02 ? 0.02 2 0.010 ' 2 ? ' 2

--

104 14

90'6'

f ' 2 ? 3'

--

f lo

--

2.048 f 0.005 89 f ' 1

1.13 (assumed) 1.895 f 0.01

--

---

f 0.5' f 0.5'

30

? 2.5'

104O26' f 0.5'

80'83' 86'17'

1.14 f 0.02 1-90 f 0.01 1.596 f 0.01

Table 18. Molecular Parameters for 1-Silacyclobutane and Derivatives (25633)

392

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

The f a r - i n f r a r e d s p e c t r a of trimethylene imine and trimethylene i m i n e d were i n t e r p r e t e d using a p o t e n t i a l function of the form V ( X ) = ax4 h2+ where x i s t h e r i n g invers i o n coordinate (257). S u b s t i t u t i n g t h e reduced mass of trimethylene - h i n e of 99.3 a.u. t h e equation j u s t mentioned be comes

-

V ( X ) = (0.92205 X 1 0 6 ) X 4

-

(0.37944 X 105)x2 +

(0.15913 X 105)m3

This p o t e n t i a l function f i t t e d t o t h e observed frequencies i s shown i n Figure 42. The b a r r i e r h e i g h t i s 441 cm-l with t h e

900 -

1100

1000

800

-

700 -7 600-

-LE

500-

113.7

I

1102.7

I

300 200 100 400

Fig. 42. P o t e n t i a l function of trimethylene imine with frequencies of observed t r a n s i t i o n s i n r e c i p r o c a l centimeters. [From C a r r e i r a and Lord (257), with permission of t h e e d i t o r . ] d i f f e r e n c e between t h e two p o t e n t i a l w e l l s being 95 cm”. The b a r r i e r heights f o r t h e series of heterocyclobutane derivat i v e s j u s t mentioned are summarized i n Table 19.

ROBERT M.

393

MORIARTY

Table 19. B a r r i e r Heights f o r Heterocyclobutanes Barrier

an-1

kcal/molea

Ref.

15.3 f 0.5

0.04

247

35 f 5

0.1

240

274.2 2 2

0.75

248

373

1.07

252

440

1.26

253

441

1.26

257

448 f 1 8

1.28

19

518 f 5

1.48

17a

Molecule

@ O

c1,

e

SiH2

@NH

0

al kcal/mole = 350 cm-'

The f i r s t t h r e e compounds, trimethylene oxide, t r i m e t h y l e n e s u l f i d e , and trimethylene s e l e n i d e , form a series i n which decreasing bond angle C-X-C may account f o r t h e i n c r e a s i n g b a r r i e r , because a smaller bond angle should d e s t a b i l i z e t h e p l a n a r form. The second s e t of t h r e e has i n common t h a t a l l r i n g atoms bear s u b s t i t u e n t s , i . e . , two hydrogen atoms i n t h e case of s i l a c y c l o b u t a n e and cyclobutane i t s e l f and one hydrogen and a lone p a i r of e l e c t r o n s i n t h e case of t r i m e t h y l e n e imine. Torsional s t r a i n may predominate h e r e i n e q u a l i z i n g t h e magnitude of t h e r e l a t i v e b a r r i e r heights.

F.

Substituted Oxetanes

S u b s t i t u t i o n of two f l u o r i n e atoms f o r hydrogen i n oxetane,

394

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

to yield 3,3-difluoroxetaneI removes the barrier to inversion altogether. McKown and Beaudet (258) studied the microwave spectrum of this compound. The potential function which was found to fit the experimental rotational constants was where both terms are positive and a single-valued minimum occurs. Absence of a barrier in 3,3-difluoroxetane agrees nicely with the effect of substitution of a gem-difluoro group (41) for a methylene in cyclobutane. As was mentioned earlier, in that case the barrier drops from 508 to 241 f 5 an-'. The result of fluorine substitution is even more dramatically exhibited in the case of 1,1,2,2-tetrafluorocyclobutane (135) in which the barrier is only 140 f 50 cm-'. The rnnr spectrum of 2-phenyloxetane has been analyzed in detail (259) trans-2,cl-Dimethyloxetane and F-2 ,Cis-3 ,tP~'nS-4trimethyloxetane have been prepared as pure compounds and their ~ 1 1 spectra : have been analyzed (260).

.

G.

Substituted Azetanes

The X-ray structure determination of the trimethylene imine derivative azetidine-1-carboxylic acid (52d) (page 397), which is a naturally occurring hmolog of proline, has been carried out (261). Ring puckering by 1l0 is such as to bring the HC(4) atom further from the carboxyl group connected at the C(2) atom. The X-ray structure of N-methyl-N-t-butyl-3-hydroxyazetidinium methanesulfonate (52e) has been determined (262). The azetidinium ring is similar to that of azetidine-2-carboxylic acid. The C-N distances are 1.525 f and the C-C bond length is 1.528 1. The angle of pucker is 11 f lo. The hydroxy and N-methyl groups lie on the convex side of the ring while the t-butyl group lies on the concave side. The methanesulfonate group is connected with the hydroxyl group of each molecule

0

395

ROBERT M. MORIARTY

through a "bifurcated" hydrogen bond system. The dihedral angle of the azetidiniumoring is 176O and the average C-C distance of 1.50 f 0.01 A agrees well with the earlier examples. The crystal and molecular structure of 1-benzyl-1,3,3trimethylazetidinium iodide (52b) has been determined as shown in Figure 43 (263). This result may be compared with 52d and

c12

\

I

1.488(22)

1

Angles not shown

CI-N.CII C3.N-C4

C I-C2-CI3 c3-c2.c12

1144(13) 1159(1 2 ) 1143 ( 1 . 3 ) 114 2 ( 1 4 )

1.386 (25)

C8

Fig. 43. Schematic view of l-benzyl-1,3,3-trimethylazetidinium iodide ( 5 2 b ) . Bond distances, bond angles, and ESD values (in parentheses) are shown on the figure. [From Townes and Trefonas (263), with permission of the editor.]

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

396

1.52 1.57

52a

52b

52c

1 1.53 r J I . 5 1 1.54

COOH

1.53 OH

52d

52e

Fig. 44. Structures of known simple azetidines. Distances and angles in the azetidine rings are indicated.

5 2 e , which were discussed above, and with l-benzyl-l12,2-trimethylazetidinium iodide (52a) (264), and l,l-dibenzyl-3,3dimethylazetidinium iodide (52c) (265), both of which have been studied by X-ray diffraction. Bond lengths, bond angles, and dihedral angles are presented in Figure 44.

397

ROBERT M. MORIARTY

1491(15 ,5351171 C, 112.4(10)

a

)&)

$1.475120)

1.475(1 1 1 1.211.11

Fig. 45. Perspective drawing of the 4-azonia[3.5]nonane cation with distances and angles given (ESD in parentheses). [From Zacharis and Trefonas (2661, with permission of the editor.I

The azetidine ring appears to adopt a puckered structure Azetidinium compound with an angle of pucker of around 14'. 52e is apparently an exception. The C-C bond distances in the above-mentioned compounds are all in the normal range. A spiro-type azetidinium compound has also been studied by X-ray crystallography. Figure 45 presents the structure of 4-azoniaspiro[3.5] nonane perchlorate (266)

.

H.

Substituted Thietanes

Considerable work has been done on the conformational properties of substituted thietanes. Dodson et al. (267) studied cis- and trans-2,4-dipheny1thietaner their 1-oxide and 1,l-dioxide. Base equilibration of the oxide favored the cis compound 93 : 7. Similarly in the case of the 1,l-dioxide the cis compound is favored to the extent of 96%.

0

\

3 98

//O

ROBERT M. MORIARTY

399

The preferred conformation for the trans compound, to the extent of 93%, is the equatorial oxygen form.

I

C6H5

Dodson et al. (267) also calculated the angle of pucker from the nmr data using the relationship 3J H - H =~ 9.9 cos'

w

-

0.9 cos w

+

3.12

The following dihedral angles were determined for the oxides. H1CCH3 H1CCH4 H2CCH3 H2CCH4

trans oxide 91.0

Cis

oxide

31.6

36.5 159.1

26.5

154.0

From bond &engths given by Gwinn (249) (S-C = 1.833 and C-C = 1.54 A), the angles given above, and H1C2-C6H5 of 112O, the dihedral angle for the trans oxide was calculated to be 140.3' (angle of pucker 39.7O). The X-ray structure of trans-3-carboxythietane-1-oxide has been determined by Allerunark (268a) and also by Abrahamson and Rehnberg (26813). The structural data are given in Table 20. From these data one can calculate an angle of pucker of 29.7O. The results from ref. 268a and 26813 are in essential agreement. Siege1 and Johnson (269) have investigated the stereochemistry of 3-substituted thietane-1-oxides by means of nmr. For the equilibrium of the trans-3-t-butylthietane-l-oxides, the chemical shift data indicate a preference for the equatorial

P 0 0

Bond

1.52 1.83 1.84 1.57 1.61 1.48 1.32 1.22

f 0.015 f 0.017 f 0.017 f 0.021 f 0.021 f 0.021 f 0.021 f 0.021

BonS length,

-

I Bond angle

109 112 78 90 89 94 113 114 114 122 124

f 0.8 f 0.8 f 0.8 f 0.8 f 0.8 f 1.3 f 1.3 k 1.3 f 1.3 f 1.3 f 1.3

S i z e of bond angle, deg.

Table 20. Bond Lengths and Bond Angles with Their Standard Deviations f o r t h e Heavier A t m s i n ~r~s-l-Thiacyclobutane-3-carboxylicAcid 1-Oxide (268a)

401

ROBERT M. MORIARTY

t-butyl group. conformations.

The structures on the left are the predominant This conformational preference is not affected

H

by the nature of the C g substituent. Equilibrium studies on the sulfoxides of the trans-3-t-butyl-,-3-p-chlorophenyl-, and -3-methylthietanes indicate that sulfinyl oxygen has an axial preference. This has been attributed to 1,3-hydrogen-oxygen attraction.

For the 3,3-dimethylthietane-1-oxide, the preferred conformation has an equatorial oxygen which is consistent with the interpretation above, 53a 53bi

53a

53b

402

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

However, the difference in the two cases could also be attributed to the repulsion between the oxygen and the larger methyl group. The structure of 5-thiabicyclot2.1.11 hexane has been determined by electron diffraction (270).

54

55

The C-S bond length in 54 is 1.865 f 0.004 i,whigh is much longer than the C-S bond length of 1.837 k 0.006 A in 55. The CI-S-C~angle in 54 is 69.7 k 0.5O, compared to 80.1 f 0.8O in 55.

I . Substituted 1,2-0xazetidi nes Evidence for nonplanarity and restricted inversion at nitrogen in perfluoro-4-chloro-2-halo-l,2-oxazetidines has been obtained from variable-temperature nmr studies (271). Compounds 56 through 61 were studied. Over the temperature

:-ry

XCF -CF2

56, X = F; Y = F 59, X = F; Y = C1 57, X = C1; Y = F 60, X = C1; Y = H 58, X = C1; Y C1 61 , X = Cl; Y = CF2CFClOEt

range 85 to -120O the geminal fluorines were nonequivalent due to slow inversion at nitrogen. The fluorine chemical shifts varied as shown in Table 21, and the A G O values are given in Table 22.

ROBERT M. MORIARTY

403

Table 21. Fluorine-Fluorine Chemical Shift Differences (271)

Temperature, OC 24

cis-57

6(CF2N), HZ 362 396 420 443 470 498 518

-13

-33 -60 -80 -105 -125

trrms-57

~(CFZN),Hz

cis-58

6(CF2N), Hz

191 154 127 102 80 55

586 554 534 513 488 465 445

--

Table 22. Conformational Data (271)a Parameter

& a r Hz 6br HZ

AGO,

cal/mole

cis-57 -610 +572 -900 k 100

trans-57

cis-58

+1265 -6 -1000 ? 100

+1374 +382 -800 zk 100

aThe data refer to the equilibria shown in the text. The conformations involved are the following: F

F

cis-57a, Y = F cis-58a, Y = C1

cis-57b, Y = F cis-58b, Y = C1

404

CYCLOBUTANE AND HETEROCYCLIC ANALOGS c1

F

F

trans-57a

trans-57b

It was assumed that the a conformation is the less stable. The fraction of molecules in the b conformation is given by

P/l - p

= K =

8

-AGo/RT

and 6 = 6, + p(6b - 6,) where 6 is the weighted average of the chemical shift differences for the axial and equatorial fluorine atoms, 6, and 6br and p equals the fraction of molecules in conformation b. The conformer population at any temperature shows a predominance of the b form. The barrier to inversion at nitrogen is about 17 kcalhole.

J.

Phosphorane and Phosphetane D e r i v a t i v e s

The crystal and molecular structure of the four-membered cyclic oxyphosphorane with a pentavalent phosphorus atom has been determined as shown in Figure 46 (2721, and the bond angles and bond distances are given in Figure 47. The four-membered oxaphosphetane ring is slightly puckered with the Pi and C3 atoms 0.04 and 0.06 A below the plane, respectively. The plane containing C2-PI-04 and the plane containing C2-C3-04 form a dihedral angle of 11O. The crystal structure of the trans (273) and cis (274) isomers of 2,2,3,4,4-pentamethyl-l-phenplphosphetane-l-oxide have been determined. The angle of pucker for the trans compound is 19.6' while the angle of pucker for the cis compound is 23.8O. In the crystal structure the oxygen on phosphorus is axial in the cis compound and equatorial in the trans compund. The rate of pyramidal inversion of several substituted phosphetanes has recently been reported (275).

ROBERT M.

405

MORIARTY

n

F i g . 46. Molecular s t r u c t u r e of PO2 (C6H5)2 ( C F ~ ) L , C I + H ~ . [From Ramirez e t a l . ( 2 7 2 ) , w i t h p e r m i s s i o n of t h e e d i t o r . ] "

Fig. 47. Bond a n g l e s and bond d i s t a n c e s f o r Po2 ( C ~ H ~ ) ~ ( C F ~ ) L , C I + H ~ . * paper:

*Erroneously c a l l e d P O ~ ( C ~ H ~ ) ~ ( C F ~i n ) Lt h ,C e ~o rHi g~i n a l C N. Caughlan, p e r s o n a l communication t o the e d i t o r .

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

406

trans

cis

E q u i l i b r i u m d a t a for t h e p a i r s of d i a s t e r e m e r s 6 2 a e 6 2 b and 6 3 ~ = 6 3 b are given i n Table 23.

62a ( c i s ) ; R = Ph 63a ( c i s ) ; R = t-C4Hg 64a ( c i s ) ; R = CH3

62b ( t r a n s ) : 63b ( t r a n s ) ; 64b ( t r a n s ) ;

R = Ph R = t-CqHg R = CH3

Table 23. Rates and A c t i v a t i o n Parameters € o r I n v e r s i o n i n S u b s t i t u t e d Phosphetanes (275) compound 63a

compound 62aa

112.0 143.2 165.4 190.2

1.65 41.2 2.66 1.66

k 0.11

f 0.17 X 10’ k 0.15 X lo3 f 0.06

a62a+62b: b63a+63b:

1.51 1.49 1.48 1.40

118.8 131.6 145.0 157.0

b

2.65 f 0.03 9.83 f 0.01 27.6 2 0.22 75.1 0.12

*

AH* = 29.8 f 0.1 kcal/mole, A S * = -8 eu. AH* = 28.2 ? 0.9 kcal/mole, As+= -8 eU.

1.31 1.30 1.29 1.23

ROBERT M.

407

MORIARTY

I n c o n t r a s t t o t h e f a c i l e i n v e r s i o n observed f o r 63, t h e 1-methyl d e r i v a t i v e 64 showed no measurable amount of i n v e r s i o n even a f t e r f o u r days a t 162O. The a u t h o r s a t t r i b u t e t h i s t o t h e o p e r a t i o n of a s t e r i c e f f e c t i n t h e t - b u t y l d e r i v a t i v e due t o nonbonded i n t e r a c t i o n s w i t h t h e a d j a c e n t methyl groups i n the ring.

K.

Ferretane

Recently, t h e f i r s t example of a four-membered iron-cont a i n i n g c a r b o c y c l i c r i n g has been synthesized v i a t h e r e a c t i o n of'dibenzosemibullvalene w i t h d i i r o n nonacarbonyl. F i g u r e s 4 8 ( a ) and 48(b) p r e s e n t t h e s t r u c t u r a l parameters o b t a i n e d by an X-ray d i f f r $ c t i o n study. The f e r r e t a n e r i n g i s p l a n a r w i t h i n 50.013 A ( 2 7 6 ) .

Fig. 48.

( a ) Bond l e n a t h s f o r a f e r r e t a n e d e r i v a t i v e (276) .]

[From Moriarty e t a l .

408

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

roo'

Fig. 48. (b) Bond angles f o r a f e r r e t a n e derivative. [From Moriarty e t a l . (2761.3

ACKNOWLEDGMENTS The author thanks M r . Carl Dettman f o r invaluable help i n searching t h e l i t e r a t u r e and preparing many of the drawings. Professor S. H. Bauer, Department of Chemistry, Cornell University, has generously shared unpublished electron d i f f r a c t i o n data with us. Also we thank Professor Jan Rocek, Dean of the Graduate School, University of I l l i n o i s , Chicago Circle, f o r helpful discussions. Professor Paul v. R. Schleyer, Princeton University, a l s o offered numerous valuable criticisms. Finally the author wishes t o thank Professor C. W. Jefford, University of Geneva (where t h i s manuscript was revised during my tenure of a guest professorship) f o r h i s h o s p i t a l i t y .

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2.

E. L. E l i e l , N. L. Allinger, S. J. Angyal, and G. A. Morrison Confonnationui!AmZy8i8, Interscience, New York, 1965, p. 189. M. Hanack, Conformatiomi! Theory, Academic Press, New York, 1965, p. 72.

ROBERT M. MORIARTY

409

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CYCLOBUTANE AND HETEROCYCLIC ANALOGS

410

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28. 29. 30. 31.

32.

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.

ROBERT M.

38. 39.

40. 41. 42. 43. 44.

45. 46 47. 48. 49.

50. 51.

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MORIARTY

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CYCLOBUTANE AND HETEROCYCLIC ANALOGS P. V. R. Schleyer, W. E. Watts, and C. Cupas, J . h e r . Chem. SOC., 86, 2722 (1964). M. Barth6lhy and Y. Bessisre-Chrgtien, Tetrahedron Lett., 1970, 4265. C. W. Jefford and U. Burger, Chimia, 24, 385 (1970). C. Cupas and W. S. Roach, Chem. Cormnun., 1969, 1486. M. Prober and W. T. Miller, Jr., J . h e r . Chem. Soc., 71, 598 (1949). I. L. Karle, J. Karle, T. B. Owen, and J. L Hoard, Acta CrystaZZogr., 18, 345 (1965). R. Srinivasan, J . h e r . Chem. Soc., 85, 819 (1963). R. Srinivasan, J . h e r . Chem. SOC., 86, 3318 (1964). R. Srinivasan, J . h e r . Chem. SOC., 85, 3048 (1963). J. F. Chiang and S. H. Bauer, !Trans. Faraday Soc., 64, 2247 (1968). (a) J. F. Chiang and S. H. Bauer, Abstract, 160th A.C.S. National Meeting, Chicago, Illinois, September 1970, No. PHYS106; (b) D. L. Zebelman, S. H. Bauer, and J. F. Chiang, Tetrahedron, 28, 2727 (1972); (c) J. F. Chiang, C. F. Wilcox, Jr., and S. H. Bauer, J . h e r . Chem. SOC., 90, 3149 (1968); (d) M. I. Davis and T. w. Muecke, J . Phys. Chem., 74, 1104 (1970); (e) G. Dallinga and L. H. Toneman, Rec. Trw. Chim., 87, 805 (1968). S. H. Bauer, private communication, Cornell University, Ithaca, New York, November 1971. K. B. Wiberg, private communicate, Yale University, New Haven, Connecticut, December 1971. D. S. Kabakoff and E. Namanworth, J . h e r . Chem. SOc., 92, 3234 (1970). P. v. R. Schleyer and V. Buss, J . h e r . Chem. Soc., 91 5880 (1969). J. C. Martin and B. R. Ree, J . h e r . chem. SOC., 91, 5882 (1969). Calculations of barrier: ASMO-SCF: T. Yonezawa, H. Nakatasuji, and H. Kato, Buzz. Chem. soc. Japan, 39, 2788 (1966). For a recent review on the cyclopropylcarbinyl system see H. G. Richey, Jr., in ~arboniW?lIons Vol. 3, G . Olah and P. v. R. Schleyer, Eds., Interscience, New York, 1969. T. Sharpe and J. C. Martin, J . h e r . Chem. Soc., 88, 1815 (1966). B. R. Ree and J. C. Martin, J . h e r . Chem. Soc., 92, 1660 (1970). SOC., 88, H. C. Brown and J. D. Cleveland, J . h e r . 2051 (1966). R. E. Davis and A. Ohno, Tetrahedron, 24, 2063 (1968). K. B. Wiberg, Tetrahedron, 24, 1083 (1968).

ROBERT M.

225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249.

419

MORIARTY

Baldwin and W. D. Foglesong, J . Amer. Chem. Soc., 90, 4311 (1968). K. B. Wiberg, J . h e r . Chem. Soc., 90, 59 (1968). K. B. Wiberg, V. 2. W i l l i a m s , and L. E. F r i e d r i c h , J . Amer. Chem. Soc., 92, 504 (1970). R. N. McDonald and C. E. Reineke, J . h e r . Soc., 87, 3020 (1965). F. F. Nelson, Ph.D. T h e s i s , U n i v e r s i t y of Wisconsin, Madison, Wisconsin, 1960. A. C. Cope, R. W. Gleason, S. Moon, and C. H. Park, J . Org. Chem,, 32, 942 (1967). K. B. Wiberg, R. A . F e n o g l i o , V. Z. W i l l i a m s , Jr., and R. W. Ubersax, J . h e r . Chem. Soc., 92, 568 (1970). K. B. Wiberg and R. A . Fenoglio, Tetrahedron Lett., 1963, 1273. K. B. Wiberg and B. A. H e s s , Jr. , J . h e r . Chem. soc., 89, 3015 (1967). P. R. S c h l e y e r , P. LePerchec, and D. J. Raber, Tetrahedron Lett., 1969, 4389. I. L i l l i e n and L. Handloser, J. Org. Chem., 34, 3058 (1969). I. L i l l i e n and L. Handloser, Tetrahedron Lett., 1969, 1035. I. L i l l i e n , G. F. Reynolds, and L. Handloser, Tetrahedron Lett., 1968, 3475. I. L i l l i e n and R. A. Doughty, J . h g . Chem., 33, 3841 (1968). J. Roeek, p e r s o n a l communication, U n i v e r s i t y of I l l i n o i s , Chicago C i r c l e , I l l i n o i s , November 1971. W. D. Gwinn, J. Zinn, and J. Fernandez, BUZZ. Amer. Phys. Soc., 4, 153 (1959). S . I. Chan, J. Zinn, and W. D. Gwinn, J . Chem. Phys., 33, 295 (1960). S . I. Chan, J. Zinn, J. Fernandez, and W. D. Gwinn, J . Chem. Phys., 33, 1643 (1960). S. I. Chan, J. Zinn, and W. D. Gwinn, J . C h . Phys., 34, 1319 (1969). A . D a n t i , W. J. L a f f e r t y , and R. C. Lord, J. Phys., 33, 294 (1960). S . I. Chan, T. R. Borgers, J. W. R u s s e l l , H. L. S t r a u s s , and W. D. Gwinn, J . Chem. PhyS., 44, 1103 (1966). T. Ueda and T. Shimanouchi, J . Chem. PhyS., 47, 5018 (1967). T. Ueda and T. Shimanouchi, J . Chm. Phys., 47, 4042 (1967). T. R. Borgers and H. L. S t r a u s s , J . Chm. PhyS., 45, 947 (1966). D. 0. Harris, H. W. Harrington, A . C. Luntz, and W. D. Gwinn, J. Chem. Phys., 44, 3467 (1966). J. E.

ch.

ch.

CYCLOBUTANE AND HETEROCYCLIC ANALOGS

420 250. 251. 252. 253. 254. 255. 256.

257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. 268. 269. 270. 271.

,

M. S. White and E. L. Beeson, Jr. J . chem. PhyS., 43, 1838 (1965). A. B. Harvey, R. Durig, and A. C. Morrissey, J . chem. Phys., 47, 4864 (1967). A. B. Harvey, J. R. Durig, and A. C. Morrissey, J. Chem. Phys., 50, 4949 (1969). J. Laane and R. C. Lord, J . Chem. Phys., 48, 1508 (1968). V. T. Aleksanyan, G. M. Kuz'yants, V. M. Vdobin, P. L. Grinberg, and 0. V. Kuz'min, Zh. Strukt. Kh.h., 10, 3, 481 (1969). W. C. P r i n g l e , Jr., J. Chem. Phys., 54, 4979 (1971). (a) L. V. Vilkov, V. S. Mastryukov, Iu. V. Baurova, V. M. Vdovin, P. L. Grinberg, DokZ. Akad. Nauk. SSSR, 177, 1084 (1967); Engl. t r a n s l . p. 1146; (b) L. V. Vilkov, V. S. Mastryukov, V. D. Oppenheim, and N. A. Tarasenko, unpublished work communicated t o t h e author by Professor S. H. Bauer, C o r n e l l U n i v e r s i t y , I t h a c a , New York, December 1971. L. A. C a r r e i r a and R. C. Lord, J . Chem. Phys., 51, 2735 (1969). G. L. McKom and.R. A. Beaudet, J . Chem. P h p . , 55, 3105 (1971). J. J o k i s a a r i , E. Rahkamaa, and P. 0. I. Virtanen, SuOmen KemistiZehti, B, 43, 219 (1970). K. P i h l a j a , K. Polviander, R. Keskinen, and J. Jalonen, Acta Chem. S c d . , 25, 765 (1971). H. M. Berman, E. L. McGandy, J. W. Burgner, 11, and R. L. van E t t e n , J. h e r . Chem. SOC,, 91, 6177 (1969). E. L. McGandy, H. N. Bennan, J. W. Burgnen, 11, and R. L. van E t t e n , J . h e r . Chem. soc., 91, 6173 (1969). R. L. Tomes and L. M. Trefonas, J , h e r . Chem. SOc., 93, 1761 (1971). C. L. Moret and L. M. Trefonas, J . HeterocycZ. them., 5, 149 (1968). R. L. Snyder, E. L. McGandy, J. W. Burgner, 11, and R. L. van E t t e n , J. h e r . Chem. Soc., 91, 6187 (1969). H. M. Zacharis and L. M. Tregonas, J . h e r . Chm. soc., 93, 2935 (1971). R. M. Dodson, E. H. J a n c i s , and G. Klose, J. mg. chem., 35, 2520 (1970). (a) s. Allenmark, Ark. Kemi, 26, 73 (1966); (b) S. Abrahamson and G. Rehnberg, A C b Chm. 26, 494 (1972). w. 0. Siege1 and C. R. Johnson, Tetmhedron, 27, 341 (1971). T. Fukuyama, K. Kuchitsu, Y. T a m a r u , Z. Yoshida, and I. Tabushi, J . h e r . C h . Soc., 93, 2799 (1971). J. D. Readio and R. A. F a l k , J. mg. Chem., 35, 927, 1607 (1970).

J.

scd.,

ROBERT M. MORIARTY 272. 273. 274. 275. 276.

M.

421

U-Haque, C. N. Caughlan, F. Ramirez, J. F. P i l o t , and

c. P. Smith, J . h e r . Chem. Soc., 93, 5229 (1971). M. U-Haque, J . Chem. SOC. ( B ) , 1970, 938. M. U-Haque, J . Chem. Soc. ( B ) , 1971, 117.

S . E. C r e m e r , R. J. Chorvat, C. H. Chang, and D. W. Davis, Tetrahedron L e t t . , 1968, 5799. R. M. Moriarty, K.-N. Chen, C.-L. Yeh, J. L. F l i p p e n , and J. Karle, J . h e r . Chem. Soc., 94, 8944 (1972).

SUBJECT INDEX

Acenapthylene, dimer of, 324 Acetone, rotational barrier in, 136 5-Acetoxynorborn-2ene, I 'C nrnr of, 46 2P-Acetoxytestosterone, 195, 197 Acetylferrocene, 137 Activation parameters in exchange studies, 99 Adamantanes, "C nrnr of, 33 Adenosine 5 '-monophosphate, relaxation time of, 139 Alcohols, I3C nmr of, 28 Aldopyranoses, "C nmr of, 65 Alkaloids, "C nrnr of, 59 Alkanes, "C nmr of, 15 Alkenes, "C nrnr of, 48,51 photodimerization of, 320 Alkyl carbocations, ' 'C shielding of, 3, 126, 127 Alkyl derivatives, "C nmr of, 15 N-Alkyl-N-nitrosoanilines, I 'C nmr of, 24 Alkylpiperidines, I 'C nmr of, 56 Alkynes, ' 'C shielding of, 4 Allenes, 'C shielding of, 4, 329 AUyl alcohols, ' 'C nmr of, 51 Allylcarbinyl cation, 373 Ammonia, structure of, 279 Androstan-3P, 17P-dio1, 'C nmr of, 38 Androstane, 198 Anemonin, nrnr spectrum of, 342 structure of, 341, 342 Aniline, spin-lattice relaxation in, 137 Anilinium ion, spin-lattice relaxation in, 137 [ l o ] Annulenes, conformations of, 116 Anomeric carbon, I 'C nrnr of, 65 Aquocyanocobyric acid, I 'C nmr of, 95 Arabinopyranose, 'C nrnr of, 66 Aromatic systems, I 'C shieldings in, 85 Aryl phosphines, geminal I 'C-'I P couplings in, 87 syn-Axial interactions, see 1,3diaxial interactions 1-Azatwistane, 252

Azetane, see Trimethylene imine Azetidine-2-carboxylic acid, structure of, 394 Azetidines, simple, structures of, 396 4-Azoniaspiro[ 3.51 nonane perchlorate, structure of, 397 Barriers to rotation, about hindered double bonds, 22 from TIvalues, 135 in oximes, 23 see also under compound name Benzene, I 'C spin-lattice relaxation in, 13, 131,144 Benzindenone, photodimers of, 326 Benzocyclobutadiene, dimers of, 323 l-Benzyl-l,2,2-trimethylazetidinium iodide, structure of, 396 l-Benzyl-l,3,3-trimethylazetidinium iodide, structure of, 395 Bicyclo[l.l.O]butane, "Cnmr of,47 derivatives, angle of pucker in, 369 deuterated, structure of, 345 structure of, 344, 345, 346 synthesis of, 345 Bicyclobutyl, structure of, 296 Bicyclo[3.l.l] heptane, structure of, 363, 364 Bicyclo[ 3.2.01 heptane, structure of, 378 Bicyclo [ 3.2.01 heptan-3-one, photolysis of, 348 Bicyclo[2.1.1] hexane, structure of, 361, 363 Bicyclo [ 2.1.1 ] hexane-5-carboxylic acid, 362 Bicyclo[2.2.0] hexane, structure of, 348, 378 Bicyc10[3.3.l]non-lene,~CHvalues in, 8 Bicyclo[2.2.2]octane, 237, 241 Bicyclo[ 3.2.11 octane, 171 Bicyclo[4.2.0]octane, structure of, 350, 37 8 423

Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

424 Bicyclo [4.2.01 octyl-l,3,5-(dinitrobenzoate), 350,351 Bicyclo[ 1.1.1 ] pentane, 360 Bicyclo(2.1.0]pentane, structure of, 347, 348,378 Bicyclo[7.2.0] undecane, 353 Biopolymers, I 'C nmr of, 89 Bisectional substituents, 163, 236 2a-Bromoarborinone, 218 Bromocyclobutane, infrared spectrum of, 291,295, 296 microwave spectrum of, 291 Raman spectrum of, 291 structure of, 290,291,307 Bromocyclohexane, 291,294 2&Brornolanost-8ene-3-one,227 3-(4'-Bromophenyl)-3,5,5-trimethylcyclohexanone, 24 3 1-Bromosilacyclobutane, 389 N-Bromosuccinimide, 35 3 2-Bromo-3,3,5,5-tetramethylcyclohexanone, geometry of, 170 Butane, T-effects in, 5 1-Butanol, spin-lattice relaxation in, 11,138 Butanone oxime, "C nmr of, 24 2-Butene, photodimerization of, 320 4-t-Butyl-6-(l'-adamantyl)-l,3dioxane,255 n-Butylamine, spin-lattice relaxation in, 137 n-Butylammonium ion, spin-lattice relaxation in, 138 t-Butylbenzene, molecular motion in, 132 t-Butyl chloride, rotational barrier in, 136 3-t-Butylcyclobutanecarboxylic acid, 315 3-t-Butylcyclobutanol, isomerization of, 316 3-t-Butylcyclobutyl tosylates, 379 4-t-But ylcyclohexanecarboxylic acid, 314 3-t-Butylcyclohexane derivatives, I 'C nmr of, 28 4-t-Butylcyclohexane derivatives, ' 'C nmr of, 28 4-t-Butylcyclohexanol, isomerization of, 316 2~-Butylcyclohexanone,249 4-t-But ylcyclohexyltrimethylammonium iodide, 246

SUBJECT INDEX

3-t-Butyl-4-hydroxycyclohexanone,249 4-t-Butyl-4-methylcyclohexane-2,5diol, 248 4-r-Butyl4-methyl-l,3dioxane, 25 3 l-t-Butyl-4-phthalimidocyclohexane, 246 3-t-Butylthietane-l-oxide, 399,401

Calciferol-precalciferolequilibrium, 2 14 Camphene, 'C nmr of, 44 Camphor-3,3-d2, 'C nmr of, 46 Camphor-3,9,9,9d1,, I 'C nmr of, 44 Camphor-3ao-dl, "C nmr of, 46 Carbon disulfide, spin-rotation relaxation in, 13 Carbonium ions, 'C nmr of, 3, 126, 127 'Carbon nmr spectra, contact shifts, effects of lone pair orientation on, 60 coupling, and hybridizetion, 8 dihedral angle dependence of, 7 general features of, 7 influence of neighboring lone pairs on, 61 -l 'C, long range, 86 constants, exchange effects on, 109 one-bond, 47 -c-P, 75 -I F,47,48,86 -''Fe, 93 - I H, 7,86 dependence on dihedral angle, 7, 21 Fermi contact term of, 8 geminal, 30,46,47 vicinal, 7,46,53 -'H,9,46 -31P, 75,84 -'O'Rh, 93,122 decoupling of, 8 exchange effects on, 97,98,99,109 Fourier transform mode, 9 lineshape (nmr), analysis, 99, 111, 123 and relaxation time, 13 linewidth (nmr), 124 exchange effects on, 98 in rate studies, 99 long range shielding effects in medium rings, 34 nuclear Overhauser effects in, 9,89, 130, 4~-Butyl-2,5dihydroxy-4-methylcyclohex139 ane, 248 relaxation time, 10 2-t-Butyl-4,6dimethyl-l,3dithiane, 259 and lineshapes. 13 N-t-Butyl-3,5dimethylpiperidone, 252 dipolar, 11,130 n-Butylferrocene, 137 of, see under name of compound

SUBJECT INDEX satellites, 7 scalar, coupling, in methyl bromide, 13 relaxation, 130 shielding, and hybridization, 4 Geffect on, 17 yeffect on, 46 general trends of, 3 of carbinyl carbon, 28 substituent effects on, 4, 5 spin-lattice relaxation, 129, 136 effect of hydrogen bonding on, 137 mechanisms of, 10 spin-lattice relaxation time, T I ,10 spin-rotation relaxation in carbon disulfide, 13 spin-spin relaxation time, T 2 , 10 Carbon tetraiodide, I 'C shielding of, 3 Carbonyl carbons, I 3C shielding of, 4 Carbostyril, 330 3Carboxythietane-1 -oxide, 399 Caryophyllene, 353,355, 359 Caryophyllene alcohol, 355 Caryophyllene bromohydrin, 35 3 Caryophyllene chlorohydrin, 353, 354 Caryophyllene dihydrochloride, 359 Caryophyllene hydrochloride, 354 Chair conformation, deformed, 262 Chemical shift anisotropy, 130 2-Chloroadamantane, I 'C nmr of, 33 I-Chlorobicyclo[ I.l.l]pentane, structure of, 361 1,3-Chlorobromocyclobutane,structure of, 302, 304 Chlorocyclobutane, infrared spectrum of, 291,295,296 puckering of,293 structure of, 290, 292 Chlorocyclohexane, 294 Chloroform, dipolar relaxation of, 131 relaxation time of, 15 3-p-Chlorophenylthietane-1 -oxide, structure of, 401 Chlorophyll, "C nmr of, 103 1-Chlorosilacyclobutane,389 Cholesteryl chloride, relaxation time of, 12 Citral, I 'C nmr of, 50 Clovene, 355 Coenzyme B, 2 , I 3C nmr of, 96 Concanavalin A, I 'C nmr of, 103 Conformation, flexible, 235 physical methods of studying, 240

425 representation by torsion angles, 163 skewed, 235 stretched, 235 twisted, 235 Conformational transmission, at a ring junction, 192, 194 and torsion angles, 205 Corrinoids, I 'C nmr of, 95, 96 Coumarin, photodimer of, 330 Crotonaldehyde oxime, ''C nmr of, 24 2',3'-Cyclic nucleotides, vicinal couplings in, 84 3',5'Cyclic nucleotides, 'C-" P coupling in, 84 Cyclic systems, Geffects of substituents in, 33 Cyclobutadiene, dimerization of, 322 Cyclobutane, bond angle, torsional angle relationship of, 286 dihedral angle of, 274,275,276,279, 280,281,282,284,285,393 electron diffraction of, 277 electronic structure of; 287 entropy of, 278 heat capacity of, 278 infrared spectrum of, 276, 278 inversion barrier, see puckering of monosubstituted, conformers of, 289 nmr spectrum of, 282 puckering of, 274, 275, 276, 279, 280, 281,282,284, 285, 393 Raman spectrum of, 276,278,279 structure of, 187, 188, 274, 283, 286 symmetry of, 275 torsional angle of, 274, 275, 276,279, 280,281,282,284,285,393 X-ray diffraction of, 278 Cyclobutanecarboxylic acid, structure of, 293 1,lCyclobutanedicarboxylic acid, 298 1,2-Cyclobutanedicarboxylicacid, 299, 300, 301 1,3-Cyclobutanedicarboxylicacid, 312, 314, 316,317 Cyclobutanol, oxidation of, 382 Cyclobutylamines, deamination of, 381 Cyclobutylcarbinyl cation, 355, 356 Cyclobutyl cation, 373, 375 Cyclobutyl chloride, see Chlorocyclobutane Cyclobutyl phenyl ketone, 361 Cyclodecane, conformations of, 114

426

SUBJECT INDEX

Cyclododecane, conformations of, 114 dimer of, 326 Cycloheptane, conformations of, 190 Cyclohexyl bromide, infrared spectrum of, derivatives, "C spectra of, 31, 33 295,296 Cyclohexane, 263 Cyclohexyl chloride, infrared spectrum of, syn-axial interactions, 168,207, 262 295,296 barrier to inversion in, 180 Cyclohexyltrimethylsilylether, conformaboat form, 173, 175,200 tional equilibrium of, 108 chair form, deformation of, 165, 166,167, Cyclononane, 113 169,262 Cyclonucleosides, 'C nmr of, 82 energy of deformation of, 168 Cycloocta-l,5diene, dimerization of, 321 conformations of, 29,189,200,228,232, Cyclooctane, conformations of, 190, 191 235,245,262 inversion barriers in, 191 conformations, energy relationships of, Cyclooctatetraene, halogenation of, 349 168,180,231,238,261 2Cyclooctenone, 329 1,3diaxial interactions in, see under 1,3Cyclopentadienylirondicarbonyldimer, 3C Diaxial interactions nmr of, 119 diplanar forms of, 178 Cyclopentane, conformations of, 187, 188, flexible form, 173, 176 189,213 reffects in, 29 methyl substituent effects in, 31 half chair form of, 178 phase angle of, 188 inversion, energetics of, 177, 180 pseudorotation of, 187 transition states for, 177, 178, 179, 181 torsion angles in, 188 monoplanar form of, 178 1,2Cyclopentanedicarboxylicacid, 299, monosubstituted, 'C nmr of, 25, 33 300 puckering in, 207 Cyclopentene, 189 relaxation time of, 13 ZCyclopentenone, dimer of, 326, 330 twist form, 173, 175 Cyclopentyl cation, 355 Cyclohexane-l,2dicarboxylicacid, 299,300 "C nrnr of, 127 Cyclohexane-l,4dione, 238,241,242,243, 1,2Cyclopropanedicarboxylic acid, 299, 262 300 monoketal of, 242 Cyclopropanes, substituted, I 'C nmr of, 29, Cyclohexane-l,rldioxime,238 30 Cyclohexanols, I 'C nmr of, 63 Cyclopropylcarbinyl alcohol, 381 conformational equilibria of, 108 Cyclopropylcarbinyl cation, 356, 373 Cyclohexanone, 262 Cyclotetradecane, 114 chair form of, 166 conformations of, energy relationships, Decalin, 227 248 activation parameters in, 109 flattened chair form of, 167,262 "C nmr of, 34 flexible conformations of, 175, 176 geometry of, 207 inversion of, 182, 183 torsion angles in, 206 Cyclohexene, boat form of, 184, 186 P-Decalone, enolization of, 207, 209 conformations of, 183, 184, 186 1-Decanol, relaxation time of, 11, 138 diplanar forms of, 184, 186 A' -Dehydrotestosterone, 197 half-boat form of, 184 2,5-Dialkylcyclohexane-l,4-dione, 250 half-chair form of, 184, 186,218 1,4-Dialkyl-2,5dihydroxycyclohexanes, 244 inversion barrier of, 185, 186 Diastereomericmixtures, analysis of, 20 monoplanar form of, 184 Diastereotopic nonequivalence, 6, 17 sofa form of, 184, 186 Diastereotopic nuclei, 'C shieldings of, 6, substituted, inversion barriers of, 187 15 2Cyclohexenone, 329 1,3-Diaxialinteractions, 197,262

427

SUBJECT INDEX in 2-bromoarborinone, 218 in cyclohexanes, 168,207,262 in 4,4dimethyl-3-0xo-steroids, 215 in labdanolic acid, 2 17 in substituted dioxanes, 255 1,4-Diazabicyclo[2.2.21 octane, 241 a-Diazocamphor, irradiation of, 350 a-Diazocyclopentanones, irradiation of, 350 a-Diazo-17-ketosteroids, 350 3,4,7,8-Dibenzotricyclo[4.2.0.02 ,5 1octa3,7diene, structure of, 323 1,l-Dibenzylcyclohexane,ring inversion in, 111 l,l-Dibenzyl-3,3dimethylazetidinium iodide, structure of, 396 l,l-Dibenzyl-4,4dimethylcyclohexane, ring inversion in, 111 2,3-Dibromobicyclo [4.2.01 1octa-5,7diene, 349 1,3-Dibromocyclobutane, 302, 303, 304, 305,306, 307 1,2-Dibromocyclooctatriene, 349 1,2-Dibromo-l ,2dicarbomethoxycyclobutane, structure of, 343, 344 1,3-Dibromo-l,3-dirnethylcyclobutane, structure of, 307 22,23-Dibrorno+pergost-kn-3-one, 241 1,2-Di-f-butylcyclohexane, 247 1,3-Di-t-butylcyclohexane, 239,245 1,4-Di-f-butylcyclohexane, 29, 239,242, 245,248 2,5-Di-t-butylcyclohexane-l,4dione, 25 1 2,5-Di-f-butylcyclohexanol, 248 3,5-Di-t-butylcyclohexanol, 24 7 2,4-Di-t-butylcyclohexanone, 249 3,5-Di-t-butylcyclohexanone, 249 1,4-Di-t-butyl-2,5dihydroxycyclohexane, 239,248 2,5-Di-t-butyl-l,3dioxane, 259 4,6-Di-t-butyl-l,3dioxane, 255 2,5-Di-f-butyl-l,3,2dioxaphosphorinan-2one, 260 2,5-Di-t-butyl-l,3dithiane, 259 N,N-Di-n-butylformamide, internal motions of, 138 1,4-Di-t-butyl-2-hydroxycyclohexane, 248 o-Dichlorobenzene, relaxation time of, 15 6,7-Dichlorobicyclo [ 3.2.01 heptan-2-one, 330 2,3-Dichlorobutane, 'C nmr of, 18 1,3-Dichlorocyclobutane,structure 9'

of, 305,307 Dichloroethylene, dimers of, 330 2,4-Dichloropentane, 3Cnmr of, 18, 19 1,l -Dichloro-1-silacyclobutane, 389 Dicyanocobyric acid, 'C nmr of, 96 1,3-Dicyano-2,2,4,4-tetramethylcyclobutane, structure of, 307, 309 Dienes, 'C nmr of, 5 1 Diethylphenylphosphine iron tetracarbonyl, "C nmr of, 93 N,N-Diethylpropionamide, 'C nmr of, 23 1,l-Difluorocyclobutane,inversion barrier in, 293, 341 structure of, 297, 298 1,l-Difluorocyclohexane, 'C-I9 F couplings in, 109 1,l-Difluoroethane, rotational barrier in, 29 3 3,3-Difluoroxetane, structure of, 394 1,3-Dihalocyclobutanes, 305 Dihedral angle, see Torsion angle 2,5-Dihydrofuran, puckering function of, 384 113-Diiodocyclobutane, 305, 307

1,3-Diisocyano-2,2,4,4-tetramethylcyclo-

butane, 307,309 4,6-Diisopropyl-5,5-dimethyltrimethylene sulfite, 259 l-Dimethylamino-3,3,5,5-tetramethylcyclohexane, 247 l-Dimethylamino-3,3,5-trimethylcyclohexane, 247 6,6-Dimethylbicyclo[ 3.1.11 heptane, 365, 366 Dimethyl-f-butyl carbonium ion, 'C nmr of, 127 2,4-Dimethyl-6-f-butyl-l,3dioxane, 258 1,3-Dimethylcyclobutane,nmr spectrum of, 312 Raman spectrum of, 3 11 structure of, 310, 311, 312, 313 Dimethyl 1,3-~yclobutanedicarboxylate, 316, 317 Dimethylcyclohexanes, activation parameters in, 109 3,4-Dimethylcyclohexanols,I 'C nmr of, 28 1,l-Dimethylcyclononane,conformation of, 114 1,2-Dimethylcyclopentane, 'C nmr of, 31 1,3-Dimethylcyclopentae, ''C nmr of, 31 1,3-Dimethylcyclopentanol, 'C nmr of, 31

428

SUBJECT INDEX

Dimethyl-2,5dichloro-7-phenylnorcaradiene-7-phosphonate, 103

relaxation in, 143 1,3-Diphenylcyclobutadiene, dimerization of, 322 2,2-Diphenylcyclopropane,' 'C nmr of, 29 2,4-Diphenylthietane, 397 l,ldioxide, 397 l-oxide, 397 Dipoledipole relaxation, 11, 130 Dipropenerhodium acetylacetonate, I 'C nmr of, 93 Diterpenes, nmr of, 41 1,3-Dithiane, 258, 263 Divinylphenylphosphine, I 'C nmr of, 88 Dodecafluorotricyclo[ 3.3.0.0'P ]octane, structure of, 368 Dodecalysine, relaxation in, 140

5,5-Dimethyldioxaphosphorinan-2-one,82 Dimethyldiphenylmethane, spin-lattice relaxation in, 134 1,4-DimethylenecycIohexane,239 Dimethyl formamide, 22 3,4-Dimethylheptane, ' 'C nmr of, 17 3,5-Dimethylheptane, ''C nmr of, 17 3,4-Dimethylhexane, 'C nmr of, 17 1,3-Dimethyl interaction, see 1,3-Diaxial interaction Dimethylisopropyl carbonium ion, 3Cnmr of, 126 1,2-Dimethylnorbornyl cation, I 'C nmr of, 127 2,4-Dimethyloxetane, 394 4,4-Dimethyl-3-oxo-steroids,geometry of Enantiotopic nonequivalence, 20 ring A in, 215 Enols, of hydrindanones, 21 3 Dimethyl-7-phenylcycloheptatriene-7-phos- of ketosteroids, 209, 21 1 phonate, 102 Episantonin, ''C nmr of, 40 2,5-Dimethyl4-phenyl4-hydroxy-N-methyl-1,4-Epoxy-l,4dihydronaphthalene, dimer piperidine, 252 of, 324, 325 1,2-DimethyCA3-phospholene, 'C nmr of, A'-Estrone, 212, 214 75 Ethyl 3-f-butylcyclobutanecarboxylate,con2,6-Dimethylpiperidine, 'C nmr of, 56 formers of, 314 3,5-Dimethylpiperidine, ''C nmr of, 56 Ethyl 4-t-butylcyclohexanecarboxylate,isoDimethylsulfoxide, rotational barrier in, 136 merization of, 314 3,3-Dimethylthietane-l-oxide, structure of, Ethyldiphenylphosphe iron tetracarbonyl, 401 ''C nmr of, 93 Dimethylthymine, dimer of, 334, 336, 337 Ethylene, nmr of, 53 N-N-Dimethyltrichloroacetamide,hindered Ethylene-p-anisonium ion, I 'C nmr of, 127 rotation in, 104 Ethylenebromonium ion, ''C nmr of, 127 4,6-Dimethyltrimethylene sulfites, 'C nmr 3-Ethylidene-2-methylcyclobutane derivaof, 62 tives, I 'C nmr of, 49 1,l-Dimethyoxyethylene, 329 5-Ethylidenenorbornene, 13Cnmr of, 49 1,2-Dioxane, 252 Ethyl 7-phen ylcycloheptatriene-7-carboxyl1,3-Dioxane, conformations of, 55,233, ate, valence-tautomeric equilibrium 234,235,255,263 in, 102 energy relationships, 234,254 y-gauche effects in, 55 Ferretane, structure of, 407,408 substituted, I ' C nmr of, 54 Ferrocenes, spin-lattice relaxation in, 137 substituted, conformations of, 252,255, Fluorocyclobutane, conformers of, 293 258 infrared spectrum of, 293 substituted, H-H coupling constants of, puckering of, 294 25 6 Raman spectrum of, 293 1,4-Dioxane, 252 structure of, 290,292 1,3,2-Dioxaphosphorinan,260,263 Fluoroethane, torsional barrier in, 293 1,3,2-Dioxaphosphorinan-2-ones,'C nmr Fluoronorbornane, "C nmr spectrum of, 47 of, 81 Fluxional processes, activation energjes in, Dipalmitoyllecithin, spin-lattice 124

SUBJECT 1NDF.X in organometallics, 118 Fourier transform mode, of 'C, 9 0-D-Fructofuranose, I 'C nmr of, 68 D-Fructose, anomeric equilibria in, 101 Germacidin S-A, I 'C n m of, 90 Germanium compounds, ''C nmr of, 124 Glaucarubin p-bromobenzoate, geometry of, 171 Glucobiose, I 'C nmr of, 67 aGlucopyranose, 'C nmr of, 65,70 D-Glucose, ''Cnmr of, 65,70 Glycosides, methyl, "C nmr of, 66 Halocyclohexanes, I 'C nmr of, 26 Helix-coil transition, 92, 140 HemimeUitene, rotational barrier in, 135 Hemoglobins, conformational changes in, 142 Heparin, 68 Hexachlorobicyclo[2.2.1] heptenes, 5endosubstituted, 46 ~-1,2,3,4,5,6-Hexachlorocyclohexane, activation parameters in, 113 1,5-Hexadiene, 362 Hexafluorobutadiene, dimerization of, 368 Hexahydronaphthalene ring systems, 209, 210 1,2,3,4,5,6-Hexamethylcyclohexane, 240

2,2,4,4,6,6-Hexamethylcyclohexane-l,3,5-

trione, 25 1 Hindered rotation, see compound name, and under Barriers to rotation Histidine residues, relaxation of, 141 Humulene, 353 Hybridization and I 'C coupling, 8 Hydrindane ring systems, 212 Hydrindanone, 212 enolsof, 212, 213 Hydrocarbons, yguuche effects in, 28 shielding and hybridization in, 4 Hydrogen bonding, effect on spin-lattice relaxation, 137 2-Hydroxyadamntane, 'C nmr of, 33 I-Hydroxy-3,5di-t-butylcyclohexane,247 4-Hydroxy-9-methyldecalin, 'C nmr of, 34 Hydroxyperezone, tautomeric equilibria in, 101 2-Hydroxy-2-phenylbicyclo( 1.1 . I ] pentane, p-bromophenylurethan, structure of, 36 1

429

2-Hydroxy-2-phenylquinolizidine,252 Inositol, 13C nmr of, 6 3 methylated, ''C nmr of, 65 Inversion barrier, see under compound name Iridium compounds, "C nmr of, 93,95 Iron compounds, 1 3 C nmr of, 93,122 Ironpentacarbonyl, "C nmr of, 9 3 9-Isoandrostane, 199, 202 9-Isoandrost4-en-3-one, geometry of, 202 Isobornyl acetate, 365 Isobutylene, 329 Isoclinal substitution, 163, 236 Isodurene, rotational barrier in, 135 Isofenchyl acetate, 365 Isooctane, spin-lattice relaxation in, 134 Isophorone, photodimers of, 326 Isopropylalkylcarbinols, shielding in, 17 Isopropylcyclobutanol, structure of, 318 3-Isopropylcyclobutylamine, deamination of, 381 structure of, 318 1,2~-Isopropylidene~-D-glucofuranose, 'C nmr of, 71 1,24J-Isopropylidene~!-D-glucofuranurono6,3-lactone, "C nmr of, 71 1,24J-Isopropylidene-p-L-idofuranose,'C nmr of, 71 1,24J-Isopropylidene-~-L-idofuranurono-6,3lactone, ''C nmr of, 71 1-Kestose, 68 Ketene, thermal cyclization of, 321 Labdanolic acid, geometry of, 217 Lanthanide shift reagents, 20, 31 Lecithin vesicles, spin-lattice relaxation in, 143 Levopimaric acid, 198 Lunarine hydrobromide hydrate, 24 1 Magnesium compounds, 'C nmr of, 126 Maltose., I 'C nmr of, 6 8 Manganese compound, 'C nmr of, 9 3 D-Mannose-l,44actone, ''C nmr of, 7 1 Medium rings, conformations of, 189 long range shielding effects in, 34 Mercury compounds, ''C nmr of, 124 Mescaline, 134 Mesitylene, spin-lattice relaxation in, 132 Metal carbonyls, ''C nmr of, 121

430

2-Methoxy-5-t-butyl-1,3,2dioxaphosphorinan, 260 Methoxyl carbon, shieldings in, 66 Methyl acetate, rotational barrier in, 136 9-Methylanthracene, rotational barrier in, 136 Methyl bromide, scalar coupling in, 1 3 2-Methyl-5-t-butyl-l,3dioxane, 3C nmr of, 54 Methyl-5-t-butyl-l,3,2dioxaphosphorinane, 79 N-Methyl-N-t-but yl-3-hydroxyazetidinium

methanesulfonate, structure of, 394 N-Methylcarbostyril, 330 Methylcyclobutane, structure of, 290, 31 3 3-Methylcyclobutanecarboxylicacid, 3 14 Methylcycloheptane, ''C nnu of, 31 Methylcyclohexane, 243 'C nmr of, 26 conformational equilibria of, 107, 108 4-Methylcyclohexanol, conformational equilibria of, 108 3-Methyl-2-cyclohexenone,dimer of, 326, 327,328 Methylcyclopentane, 'C nmr of, 31 Methylcyclopentanol, C nmr of, 3 1 9-Methyldecalin, activation parameters in, 111 l 3 C nmr of, 27 9-Methyl-ldecalol, ''C nmr of, 38,58 9-Methyldecal4p-ol, 'C nmr of, 38 MethyL1,3dioxanes, "C nmr of, 55 4-Methylenecyclohexanone, 239 Methylcarbonium ion, 'C nmr of, 127 Methyl ethyl ketoxime, relaxation of, 138 N-Methylformamide, "C nmr of, 23 Methyl group rotation, barriers from T I , 136 3-Methyl-2-hexene, 'C nrnr of, 48 Methylhydrazines, methyl carbon shieldings in, 6 preferred conformations of, 6 Methyl4-isopropylcyclohexanecarboxylate, isomerization of, 315 Methyl 3-methylcyclobutanecarboxylate, 314,315 Methyl 4methylcyclohexanecarboxylate, 315 1-Methylnaphthalene, rotational barrier in, 136 Methylnorbornanes, 'C nmr of, 44

SUBJECT INDEX Methyl orotate, dimer of, 336,337, 340 4-Methylpiperidine, 'C nmr of, 56 N-Methylpiperidines, 'C nmr of, 56,60 N-Methylpiperidine hydrochloride, 3C nmr of, 58 1-Methylsilacyclobutane,389 (+)-2-Methylsuccinic acid, 363 3-Methylthietane-l-oxide, structure of, 401 Methylthiophene, spin-lattice relaxation in, 133 Methylthymine, dimer of, 336, 337 6-Methyluracil, dimer of, 336, 337, 340 Microcalorimetry, 257 Microtacticity, 89 Molecular mechanics, 260 Monodeuteriocyclobutane, 282 Monosaccharides, I3C nmr of, 65,69, 71 1,4-Naphthoquinone, photodimer of, 330 Neoclovene, 355 3-Nitrobipheny1,spin-latticerelaxation in, 132 Nitrogen, inversion by 'C nmr, 117 Nitrosamines, "C nmr of, 22,24 Nmr spectra, see 'Carbon nrnr spectra; name of compound Nonactin, 'C nnu of, 91 P-Nopinol arenesulfonates, 366 Norbornanes, exo reffects in, 42 Norbornanone, 362 Norbornyl cation, 'C nmr of, 127 Norbornyl derivatives, '(2 nmr of, 41 Norcamphors, substituted, 'C nmr of, 43 D-Norsteroids, 213, 352 Nuclear Overhauser effects of I 'C signals, 9,89, 130 Nucleoside conformations, 82 Nucleotides, vicinal, 'C-" P interactions in, 84 Nystose, "C nmr of, 68 Octachlorocyclobutane, structure of, 277,284 Octafluorocyclobutane, electron diffraction of, 277 infrared spectrum of, 277 inversion barrier in, 341 Raman spectrum of, 276 structure of, 276, 282, 284 1,2,3,4,6,7,12,1 2b4lctahydroindolo [ 2,3a] quinolizine, "C nmr of, 59 Octahydronaphthalene, see Octalin Octahydroxycyclobutane, structure of, 284

SUBJECT INDEX

431

I-Phenyl-2-phospholene, I 'C nmr of, 88 4-Phenylpiperidinol, 25 2 1-Phenylpyrazolin-5-one, 99 l-Phenyl-l,3,3-trimethylcyclohexane, 262 3-Phenyl-3,5-5-trimethyIcyclohexanone, 262 Phosdrin, "C nmr of, 50 Phosphetanes, "C nmr of, 73 inversion barriers in, 406 substituted, structure of, 404 Phosphoenol-a-ketobutyrate,I 'C nmr of, 53 Phosphoenolpyruvate, ''C nmr of, 5 3 Phospholenes, "Cnmr of, 75 oxides of, 79 see also under specific compounds Phospholes, aromaticity of, 88. Phosphorane, structure of, 404 Phosphorinanes, conformations of, 80 13C-31P coupling constants in, 80 Phosphorus heterocycles, 'C nmr of, 7 3 Photodimerization of olefins, 320 As(9)-Pimaradienes, I 'C nmr of, 41 Palladium compounds, 'C nmr of, 95 (-)-Pinane, absolute configuration of, 363 Penicillin, 'C nmr of, 61 Pinane derivatives, rearrangements of, 365 2,2,4,5,6-Pentamethyl-l,3dioxane, 25 7 Pinane ring system, conformations of, 363, 1,2,2,6,6-Pentamethyl-4-hydroxy-4-phenyl364 piperidine, 227, 239, 252 (-)Q-Pinene, absolute configuration of, 363 Peptides, "C nmr of, 89 Piperazine-palladium chloride adduct, 238 Perchloro-3,4,7,8-tetramethylenetricyclo- Piperidine, I 'C nmr of, 60 [4.2.0.02 ] octane, structure of, 322 Platinum compound, I3C nmr of, 9 3 Perdeuterocyclobutane, puckering of, 280 Polyacrylic acid, "C nmr of, 89 Perfluorobicyclo[2.2.0] hexane, 349 Poly-(P-benzyl-L-aspartate),I 'C nmr of, 92 Perfluoro-4-chloro-2-halo-l,2axazetidine, Poly-(-y-benzyl-L-glutamate),I 'C nmr of, 92 helix-coil transition of, 141 402 1,4-Polybutadiene, ''C nmr of, 89 Perhydroanthracene, 238,246 Poly-(N-6-carbobenzoxy-L-ornithine),C Phenol, spin-lattice relaxation in, 137 nmr of, 92 Phenylacetylene, relaxation time of, 12 Phenyl benzoate, spin-lattice relaxation time Polyenes, I 'C nmr of, 5 1 in, 133 1,4-Polyisoprene, 'C nmr of, 89 1-Phenyl-3-carboethoxypyrazolin-5-one, Poly-L-lysine, relaxation in, 140 tautomeric equilibria in, 101 Polymer, tacticity of, 89 Phenylcyclopropanes, 1-substituted, 'C Polymethylmethacrylate, 'C nmr of, 89 nmr of, 29 Polypeptides, helix-coil transition in, 92 l-Phenyldimethyl-3-phospholene, 'C nmr Polystyrene, "C nmr of, 51,89 internal motions of, 139 of, 75 l-Phenyl-3-methylpyrazolin-5-one, 101 nuclear Overhauser effect in, 139 2-Phenyloxetane, 394 Polyvinyl chloride, 'C nmr of, 89 N-(l-Phenyl-3-oxobutyl)aziridine, 'C nmr Polyvinyl methyl ether, 'C nmr of, 89 of, 117 Recalciferol-calciferol equilibrium, 2 14 I-Phenylphosphole, ''C nmr of, 88 Regnan-1 lp-01, 'C nmr of, 38 Octalin, stability relationships in, 206, 208 torsion angles in, 205,206 A5 -0ctalone-2, direction of enolization of, 212 Olefins, "C nmr of, 51 photodimerization of, 320 Oligosaccharides, I 'C nmr of, 67 Optical purities, from 'C spectra, 20 Organometallics, C shieldings and coupling constants in, 93 fluxional processes in, 118 Oxacyclooctan-Sane, conformation of, 115 Oxanes, conformations of, 262 Oxaphosphetane ring, 404 1,3-0xathiane, 260 Oxaziridines, I 'C nmr of, 61 Oxetane, see Trimethylene oxide Oximes, hindered rotation in, 23 5-Oxocanone, 115 3-Oxo-steroids, enolization of, 207, 21 1 Oxyphosphorane, structure of, 404 Oxytocin, ''C nmr of, 91

'

9'

432 Rodinol, 13Cnmr of, 58 Progesterone, 203,204 Roline, 90, 394 Romedols, 13Cnmr of, 59 Ropanal oxime O-methyl ether, 13Cnnu of, 21 R0panal-3-'~C,I'C nmr of, 21 Propane, vicinal couplings, JCCCHin, 7 Rotpanemonin, structure of, 341 Pseudocumene, spin-lattice relaxation in, 132 Pseudolibration, 232,263 Pseudorotation, 232,248,261 and torsion angle, 174 Pucker, and torsion angle, 169 Pyridine, spin-latticerelaxation in, 133 Quinuclidine, 13Cnmr of, 59 Rate processes, by I 'C nmr, 96 Reflex effect, 169 Retroprogesterone, 203,204,205 Rhodium compounds, "C nmr of, 93,95, 121 Ribonuclease A, "C nnu of, 90 conformation of, 141 relaxation time of, 12 D-Ribose, 3C nmr of, 66 Ring geometry, flattening, 163 notation, 189 planar representation of, 163 puckering, 163,217 Rotational barriers, see under Barriers to rotation; compound name Ruthenium compounds, I 'C nmr of, 95 "R" value method, 242 Santonin derivatives, I 3C nmr of, 40 Selenetane, barrier height of, see Trimethylene selenide Shielding,see under 'Carbon nmr spectra Shift reagents, lanthanide, 20, 31 Silacyclobutane,barrier height of, 393 derivatives, structure of, 392 structure of, 389, 392 Silacyclohexane, 262 4-Sila-3,3-spiroheptane,389 Silicon compounds, ''C nmr of, 124 Solvolysis, of bicyclic compounds, 378 of 3-t-butylcyclobutyl tosylates, 379 Steric compression and strain,

SUBJECT INDEX effects of, 8 Steroids, I 'C nrnr of, 36 ygouche interactions in, 36 34x0, ketoenol equilibria in, 207 stereochemistry and biological properties of, 203 Sucrose, 'C nnu of, 68 relaxation time of, 139 Sulfoxides, C nmr of, 6 1 y-gauche effect in, 62 rotational barrier of, 136 structures of, 397 Syn-axial interactions, see 1,SDiaxial interactions

'

u-Terpenyl acetate, 365 Testosterone, 195, 197 Tetrabromonaphthoquinone, dimer, 332

1,1,3,3-Tetrachloro-l,3disilacyclobutane, 389

1,1,2,2-Tetrafluorocyclobutane,341, 394

Tetrahydropyran, 252 1,2,3 5-Tetramethylbenzene, rotational barrier in, 135

2,4,4,6-Tetramethyl-2-(4'-brornophenyl)-l,Z dioxane, X-ray structure of, 258

2,4,4,6-Tetramethyl-6-(4'-bromophenyl)-l,3-

dioxane, 262 Tetramethylcyclobutadiene, dimerization of, 322 Tetramethylcyclobutane, isomers of, 320 1,1,3,3-Tetrarnethylcyclohexane,activation parameters in, 111,262 1,1,3,5-Tetramethylcyclohexane,262 3,3,5,5-Tetramethylcyclohexanone,262 2,2,6,6-TetramethyI-lJdifluorocyclohexane, 111 3,3,5,5-Tetramethyl-l ,ldifluorocyclohexane, 111 2,4,4,6-Tetramethyl-l,3dioxane, 55, 255, 257 1,3,3,5-Tetramethyi-l-hydroxy-5-( 1'-naphthyl)cyclohexane, 240 2,2,6,6-Tetramethylpiperidine,I 'C nmr of, 56 2,2,6,6-Tetramethylpiperidin4~l-l-oxyl, geometry of, 170 Tetramethyl-s-tetrathiane,259 Tetramethylthymine, dimers of, 335 2,6,10,1O-Tetramethyltricyclo[7.2.0.02 ] undec-Sene. 359 1,2,3,4-Tetraphenylcyclobutane,32 1 9'

SUBJECT INDEX s-Tetrathianes, 259 5-Thiabicyclo[2.1.1] hexane, structure of, 402 1-Thiacyclobutane-3-carboxylicacid 1-oxide, structure of, 400 Thietane, see Trimethylene sulfide 1-Thiauracil, photodimer of, 341 Thymine, dimer of, 333, 334,336, 337 trimer of, 338, 340 Tin compounds, "C nmr of, 124 Toluene, spin-lattice relaxation in, 134 Torsion angle, 161, 162 and conformational transmission, 205 and geometry, 164 and pseudorotation, 174 and ring pucker, 169 and structure-activity relationship, 203 at a ring junction, 192, 193, 194, 196,206 deformations of, 170, 217 dependence of 'C couplings on, 7,48 in 2a-bromoarborinone, 218 in steroids, 198 relative positions of, 162 sign of, 163,165 values of, 163 Transfer-RNA, conformation of, 142 spin-lattice relaxation times of, 142 1,3,5-Tri-t-butylcyclohexane, 246 Tri-t-butylethylene, JCH values in, 8 1,l,l-Trichloroethane, rotational barrier in, 136 Tricycle[ 3.2.1.0' 15 1octane, 372 Tricycle[ 3.3.0.0' *6 ]octane, 368, 370 Tricycl0[4.2.0.0~~~ 1octane, 322, 323 Triethylphosphine iron tetracarbonyl, I 'C nmr of, 93 1,1,l-Trifluoroethane, rotational barrier in, 293 3,4,5-Trimethoxyphenethylaminehydrochloride, spin-lattice relaxation in, 134 1,2,3=Trimethylbenzene, rotational barrier in, 135 1,2,4-Trimethylbenzene, spin-lattice relaxation in, 132 1,5,5-Trimethylbicycl0[2.1.1]hexane-6carboxytic acid, 350 1,1,2-Trimethylcyclohexane,243 1,2,3-Trimethylcyclohexane, 'C nmr of, 58 1,3,5-Trimethyl-2dichloromethylbenzene, hindered rotation in, 107 1,l '-Trimethylenebisthymine,photodimer of, 338

433 Trimethyleneimine, ring puckering of, 391, 393 structure of, 390, 391 Trimethylene oxide, ring puckering of, 384, 385,393 structure of, 382 substituted, 394 Trimethylene selenide, 393 ring puckering of, 388, 393 structure of, 387, 393 substituted, 393 Trimethylene sulfide, 1-oxides, 3-substituted, 399 ring puckering of, 386, 393 structure of, 386, 387 Trimethylene sulfite, X-ray structure of, 259 Trimethylethylene, JCH values in, 8 1,4,8-Trimethyl-5-fluoro-9,10dihydro-9,10phenanthrenediol, I 'C nmr of, 86 1,4,8-Trimethyl-5-fluoro-9,1 O-phenanthraquinone, I 'C nmr of, 87 1,4,8-Trimethyl-S-fluorophenanthrene,'C nmr of, 86 2,3,4-Trimethyloxetane, 394 1,2,5-Trimethyl-4-phenylpiperidin-4-01,59 1,2,6-TrimethyIpiperidinehydrochloride, "C nmr of, 58 Trimethylstannylindiene, 'C nmr of, 124 1,3,5-Trioxane, 252 J/ -Tropine, 25 2 Truxillic acid, isomers of, 319 Truxinic acid, isomers of, 319, 320 Tryptophan synthetase, 141 D-Turanose, anomeric equilibria in, 101 ''C nmr of, 68 Twistane, 237,241 Ultrasonic relaxation, 257 a&-Unsaturated carbonyl derivatives, I ' C nmr of, 50 Uracil, dimer of, 333, 335, 336, 337,340 Uridine, vicinal couplings in, 82 Uridine-3'-phosphate, 84 Valence angle deformations, 170 Valinomycin, "C nmr of, 91 Vassopressin, 'C nmr of, 91 Vinyl derivatives, C nmr of, 53 Vitamin B,, , ' 'C nmr of, 96 o-Xylene, conformations of methyls in, 5 relaxation of methyls in, 132, 135

CUMULATIVE INDEX. VOLUMES 1-8

VOL .

Absolute Configuration of Planar and Axially Dissymmetric Molecules (Krow) ...................................................................................................... Acetylenes. Stereochemistry of Electrophilic Additions (Fahey) ................. Analogy Model. Stereochemical (Ugiand Ruch) .......................................... Atomic Inversion. Pyramidal (Lambert) ....................................................... Axially and Planar Dissymmetric Molecules. Absolute Configuration of (Krow) ...................................................................................................... Barton. D. H . R., and Hassel. 0 -Fundamental Contributions to Conformational Analysis (Barton. Hassel) ................................................ Carbene Additions to Olefins, Stereochemistry of (Closs) ............................ Carbenes. Structure of (Closs) ...................................................................... sp' -sp3 Carboncarbon Single Bonds. Rotational Isomerism about (Karabatsos and Fenoglio) ........................................................................ Carbonium Ions. Simple. the Electronic Structure and Stereochemistry of (Buss. Schleyer and Allen) .................................................................... Chirality Due to the Presence of Hydrogen Isotopes at Noncyclic Positions (Arigoni and Eliel) ..................................................................... Conformational Analysis-The Fundamental Contributions of D.H.R. Barton and 0. Hassel (Barton. Hassel) ...................................................... Conformational Analysis and Steric Effects in Metal Chebtes (Buckingham and Sargeson) ............................................................................................ Conformational Analysis and Torsion Angles (Bucourt) .............................. Conformational Analysis of Six-membered Rings (KeZlie and Riddell) ......... Conformational Changes. Determination of Associated Energy by Ultrasonic Absorption and Vibrational Spectroscopy (Wyn-Jones and Pethrick) Conformational Changes by Rotation about spa -sp3 Carbon-Carbon Single Bonds (Karabatsos and Fenoglio) .............................................................. Conformational Energies. Table of (Hirsch) ................................................. Conjugated Cyclohexenones. Kinetic 1.2 Addition of Anions to. Steric Course of (Toromanoffl ............................................................................ Cyclobutane and Heterocyclic Analogs. Stereochemistry of (Moriarty) ....... Cyclohexyl Radicals. and Vinylic. The Stereochemistry of (Simamura) ....... Double Bonds. Fast Isomerization about (Kalinowski and Kessler) .............. Electronic Structure and Stereochemistry of Simple Carbonium Ions (Buss. Schleyer and Allen) ........................................................................ Electrophilic Additions to Olefins and Acetylenes. Stereochemistry of (Fahey) ..................................................................................................... Enzymatic Reactions. Stereochemistry of, by Use of Hydrogen Isotopes (Arigoni and EIiel) .................................................................................... 1.2-Epoxides. Stereochemical Aspects of the Synthesis of (Berti) ................ EPR. in Stereochemistry of Nitroxides (Janzen) ..........................................

.

434

Topics in Stereochemistry, Volume8 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1974 by John Wiley & Sons, Inc.

PAGE

5 3 4 6

31 237 99 19

5

31

6 3 3

1 193 193

5

167

7

253

4

127

6

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6 8 8

219 159 225

5

205

5 1

167 199

2 8 4 7

157 271 1 295

7

253

3

237

4 7 6

127 93 177

CUMULATIVE INDEX. VOLUMES 1-8 Geometry and Conformational Properties of Some Five- and SixMembered Heterocyclic Compounds Containing Oxygen or Sulfur (Romers. Altono. Buys. and Havinga) ....................................................... Hassel. 0. and Barton. D . H. R. .Fundamental Contributions to Conformational Analysis (Hassel. Barton) ................................................. Helix Models, of Optical Activity (Brewster) ............................................... Heterocyclic Compounds, Five- and Six-Membered, Containing Oxygen or Sulfur, Geometry and Conformational Properties of (Romers. Altona, Buys. and Havinga) .................................................................................... Heterocyclic Four-membered Rings, Stereochemistry of (Moriarty) ............ Heterotopism (Mislow and Raban) ............................................................... Hydrogen Isotopes at Noncyclic Positions, Chirality Due to the Presence of (Argoni and EIiel) ...................................................................................... Intramolecular Rate Processes (Binsch) ........................................................ Inversion, Atomic, Pyramidal (Lamberr) ...................................................... Isomerization, fast, about Double Bonds (Kalinowski and Kessler) .............. Metal Chelates, Conformational Analysis and Steric Effects in (Buckingham and Sargeson) ...................................................................... Metallocenes, Stereochemistry of (Schlogl) .................................................. Nitroxides, Stereochemistry of (Janzen) ...................................................... Non-Chair Conformations of Six-Membered Rings (Kellie and Riddell) ....... Nuclear Magnetic Resonance, "C, Stereochemical Aspects of (Wilson and Stothers) ................................................................................................... Nuclear Magnetic Resonance, for Study of Intramolecular Rate Processes (Binsch) .................................................................................................... Nuclear Overhauser Effect, some Chemical Applications of (Bell and Saunders) .................................................................................................. Olefms, Stereochemistry of Carbene Additions to (Closs) ............................ Olefms, Stereochemistry of Electrophilic Additions to (Fahey) ................... Optical Activity, Helix Models of (Brewster) ............................................... Optical Circular Dichroism, Recent Applications in Organic Chemistry (Oabbd) ................................................................................................... Optical Purity, Modern Methods for the Determination of (Raban and Mislo w) ..................................................................................................... Optical Rotatory Dispersion, Recent Applications in Organic Chemistry (Crabbd) .................................................................................................... Overhauser Effect, Nuclear, some Chemical Applications of (Bell and Saunders) .................................................................................................. Phosphorus Chemistry, Stereochemical Aspects of (Gallagher and Jenkins) . Piperidines, Quaternization, Stereochemistry of (McKenna) ........................ Planar and Axially Dissymmetric Molecules, Absolute Configuration of (Krow) ...................................................................................................... Polymer Stereochemistry, Concepts of (Goodman) ..................................... Polypeptide Stereochemistry (Goodman, Verdini, Choi and Masuda) .......... Pyramidal Atomic Inversion (Lamberr) ........................................................ Quaternization of Piperidines, Stereochemistry of (McKenna) ..................... Radicals, Cyclohexyl and Vinylic, The Stereochemistry of (Simamura) ....... Resolving Agents and Resulutions in Organic Chemistry (Wilen).................. Rotational Isomerism about sp2-sp2 Carbon-Carbon Single Bonds (Karabatsos and Fenoglio) ........................................................................

435

VOL.

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4

39

6 2

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4 8 1

39 271 1 127 97 19 295 219 39 177 225

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3

97 1 193 237 1

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93

2

199

1

93

7 3 5

1 1 215

31 73 69 19 275 1 107 5

167

436

CUMULATIVE INDEX, VOLUMES 1-8

VOL. Stereochemical Aspects of ' 3C Nmr Spectroscopy (Wilson and Stothers) ... 8 Stereochemistry, Dynamic, A Mathematical Theory of (Ugi und Ruch) ....... 4 Stereochemistry of Cyclobutane and Heterocyclic Analogs (Moriurty) ........ 8 Stereochemistry of Nitroxides (Junzen) ....................................................... 6 Stereoisomeric Relationships, of Groups in Molecules (Mislow und Ruban) . 1 Torsion Angle Concept in Conformational Analysis (Bucourt) .................... 8 Ultrasonic Absorption and Vibrational Spectroscopy, Use of, to Determine the Energies Associated with Conformational Changes (Wyn-Jonesand Pethrick) ................................................................................................... 5 Vibrational Spectroscopy and Ultrasonic Absorption, Use of, to Determine the Energies Associated with Conformational Changes (Wyn-Jonesand Pethrick) ................................................................................................... 5 Vinylic Radicals, and Cyclohexyl, The Stereochemistry of (Simumura) ....... 4 Wittig Reaction, Stereochemistry of (Schlosser) .......................................... 5

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