TOPICS IN
STEREOCHEMISTRY
VOLUME 8
A WILEY-INTERSCIENCESERIES
ADVISORY BOARD
STEPHEN J. ANGYAL, Universityof New S...
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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 As a result, many of the details found in these texts are already inadequate or out of date, although the student of stereochemistry and conformational analysis may still learn the basic concepts of the subject from them.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 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
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
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
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
G.
M.
KELLIE AND F. G.
233
RIDDELL
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.
G.
M.
KELLIE AND F. G.
RIDDELL
235
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.
KELLIE AND F. G.
237
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
G.
M.
239
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
G.
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
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.
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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