Topics in Stereochemistry, Volume 11

TOPICS IN

STEREOCHEMISTRY

VOLUME 11

ADVISORY BOARD

STEPHEN J. ANGYAL, University of New South Wales, Sydney, Australia GIANCARLO BERTI, University of Pisa, Pisa, Italy

F. ALBERT COTTON,Texas A & M University, College Station, Texas JOHANNES DALE, University of Oslo, Oslo, Norway DAVID GINSBURG, Technion, Israel Institute of Technology, Haifa, Israel

KURT MISLOW, Princeton University, Princeton, New Jersey SAN-ICHIRO MIZUSHIMA, Japan Academy, Tokyo, Japan GUY OURISSON, University of Strasbourg, Strasbourg, France VLADIMIR PRELOG, Eidgeniissische Technische Hochschule, Zurich, Switzerland

HANS WYNBERG, University of Groningen, Groningen. The Netherlands

TOPICS IN

STEREOCHEMISTRY EDITORS

NORMAN L. ALLINGER Professor of Chemistry University of Georgia Athens, Georgia

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

VOLUME 11

AN INTERSCIENCE

@

PUBLICATION

JOHN WILEY & SONS

New York 8 Chichester Brisbane Toronto 0

An Interscience@ Publication Copyright 0 1979 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons,Inc. Library of Congress Catalog Card Number: 67-13943 ISBN 0-471-05445-3 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

INTRODUCTION TO THE SERIES During t h e l a s t f i f t e e n y e a r s s e v e r a l t e x t s i n t h e a r e a s of s t e r e o c h e m i s t r y and conformational a n a l y s i s have been p u b l i s h e d , i n c l u d i n g Stereochemistry of Carbon Compounds ( E l i e l , McGrawH i l l , 1962) and Conformational Analysis ( E l i e l , A l l i n g e r , Angyal , and Morrison, I n t e r s c i e n c e , 1 9 6 5 ) . While t h e w r i t i n g of t h e s e books w a s s t i m u l a t e d by t h e high l e v e l of r e s e a r c h a c t i v i t y i n t h e a r e a of s t e r e o c h e m i s t r y , it h a s , i n t u r n , s p u r r e d f u r t h e r a c t i v i t y . A s a r e s u l t , many of t h e d e t a i l s found i n t h e s e t e x t s a r e a l r e a d y inadequate o r o u t of d a t e , although t h e s t u d e n t of s t e r e o c h e m i s t r y and conformational a n a l y s i s may s t i l l l e a r n t h e b a s i c concepts of t h e s u b j e c t from them. For both human and economic r e a s o n s , s t a n d a r d textbooks can be r e v i s e d o n l y a t i n f r e q u e n t i n t e r v a l s . Yet t h e s p a t e of p e r i o d i c a l p u b l i c a t i o n s i n t h e f i e l d of s t e r e o c h e m i s t r y i s such t h a t it i s an almost hopeless t a s k f o r anyone t o update himself by reading a l l t h e o r i g i n a l l i t e r a t u r e . The p r e s e n t series i s designed t o b r i d g e t h e r e s u l t i n g gap. I f t h a t were i t s only purpose, t h i s s e r i e s would have been c a l l e d "Advances ( o r "Recent Advances") i n Stereochemistry " I t must be remembered, however, t h a t t h e above-mentioned t e x t s were themselves n o t t r e a t i s e s and d i d n o t aim a t an e x h a u s t i v e t r e a t m e n t of t h e f i e l d . Thus t h e p r e s e n t s e r i e s has a second purpose, namely t o d e a l i n g r e a t e r d e t a i l w i t h some of t h e t o p i c s summarized i n t h e s t a n d a r d t e x t s . I t is f o r t h i s reason t h a t w e have s e l e c t e d t h e t i t l e Topics in Stereochemistry. The s e r i e s i s intended f o r t h e advanced s t u d e n t , t h e t e a c h e r , and t h e a c t i v e r e s e a c h e r . A background f o r t h e b a s i c knowledge i n t h e f i e l d of s t e r e o c h e m i s t r y i s assumed. Each c h a p t e r i s w r i t t e n by an e x p e r t i n t h e f i e l d and, h o p e f u l l y , covers i t s s u b j e c t i n depth. We have t r i e d t o choose t o p i c s of fundamental import aimed p r i m a r i l y a t a n audience of o r g a n i c chemists b u t involved f r e q u e n t l y w i t h fundamental p r i n c i p l e s of p h y s i c a l chemistry and molecular p h y s i c s , and d e a l i n g a l s o with c e r t a i n stereochemical a s p e c t s of i n o r g a n i c chemistry and biochemistry. I t i s our i n t e n t i o n t o b r i n g o u t f u t u r e volumes a t i n t e r v a l s of one t o two y e a r s . The E d i t o r s w i l l welcome s u g g e s t i o n s as t o s u i t a b l e t o p i c s . We a r e f o r t u n a t e i n having been a b l e t o s e c u r e t h e h e l p of an i n t e r n a t i o n a l board of E d i t o r i a l Advisors who have been of g r e a t a s s i s t a n c e by s u g g e s t i n g t o p i c s and a u t h o r s f o r s e v e r a l a r t i c l e s and by h e l p i n g u s avoid d u p l i c a t i o n of t o p i c s appearing i n o t h e r , r e l a t e d monograph s e r i e s . We a r e g r a t e f u l t o t h e

.

V

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INTRODUCTION TO THE SERIES

Editorial Advisors f o r this assistance, but the Editors and Authors alone must as5ume the responsibility for any shortcomings of Topics in Stereochemistry. N. L. Allinger E. L. Eliel April 1979

PREFACE With Volume 11 o f Topics in Sterochemistry w e resume t h e a n n u a l p u b l i c a t i o n s c h e d u l e . There a r e f o u r c h a p t e r s , e a c h o f which examines some s i g n i f i c a n t a s p e c t of s t e r e o c h e m i s t r y . I n t h e f i r s t c h a p t e r H. Aaron d i s c u s s e s i n t r a m o l e c u l a r hydrogen b o n d i n g , as r e v e a l e d i n a d i l u t e s o l u t i o n by i n f r a r e d s p e c t r o s c o p y . I t h a s l o n g b e e n known t h a t hydrogen bonding c a n b e d e t e c t e d and s t u d i e d by t h i s method. The h y d r o x y l g r o u p forms hydrogen bonds t o many e l e c t r o n e g a t i v e atoms, and s i n c e i n t r a m o l e c u l a r hydrogen bonding does n o t s u f f e r from t h e u n f a v o r a b l e e n t r o p y e f f e c t s encountered i n i n t e r m o l e c u l a r bonding, such bonding t e n d s t o be r e l a t i v e l y s t r o n g . The g e o m e t r i c a l cons t r a i n t s r e q u i r e d f o r hydrogen bonding are c r u c i a l and open t o c r i t i c a l e x a m i n a t i o n by t h i s t e c h n i q u e . I n t h e s e c o n d c h a p t e r J. R . Boone and E. C . Ashby r e v i e w t h e w e l l s t u d i e d t o p i c o f t h e r e d u c t i o n o f c y c l i c k e t o n e s by complex metal h y d r i d e s . The v e r s a t i l i t y and u s e f u l n e s s o f t h e s e r e a g e n t s are w e l l known. T h e i r s t e r e o c h e m i c a l b e h a v i o r , o n c e t h o u g h t t o be r e a s o n a b l y s t r a i g h t f o r w a r d , h a s i n f a c t p r o v e d t o b e q u i t e i n t r i c a t e . The c h a p t e r c o n s i d e r s t h e s t e r e o c h e m i s t r y o f r e d u c t i o n o f a s p e c i f i c and i m p o r t a n t c l a s s of compounds, c y c l i c and b i c y c l i c k e t o n e s , t h a t are p a r t i c u l a r l y w e l l s u i t e d t o such i n v e s t i g a t i o n s . The c h e m i s t r y o f s m a l l r i n g compounds h a s been o f wide i n t e r e s t t o chemists s i n c e t h e e a r l y i n v e s t i g a t i o n s o f Perkin. I n Volume 8 o f t h i s s e r i e s c y c l o b u t a n e and i t s h e t e r o c y c l i c d e r i v a t i v e s w e r e d i s c u s s e d i n some d e t a i l . I n t h e t h i r d c h a p t e r of V o l u m e 11 s e v e r a l r i n g s y s t e m s , c o n t a i n i n g as many a s s i x atoms are t a k e n up. The emphasis i s n o t so much on t h e r i n g s y s t e m s t h e m s e l v e s as o n t h e use of v i b r a t i o n a l and microwave s p e c t r o s c o p y f o r t h e i r s t u d y . T. B. Malloy, J r . , L. E . Bauman, and L. A. C a r r e i r a o f f e r a v e r y r e a d a b l e a c c o u n t f o r t h e nons p e c i a l i s t i n t h i s s p e c t r o s c o p i c area of t h e k i n d s o f problems and p o s s i b l e r e s u l t s , I n t h e f o u r t h ' c h a p t e r o f t h i s volume t h e s t e r e o c h e m i c a l a s p e c t s o f six-membered r i n g s c o n t a i n i n g phosphorus a r e examined by B . E. Maryanoff, R. 0. H u t c h i n s , and C . A. Maryanoff. S i n c e t h e phosphorus atom can have as many as f i v e s u b s t i t u e n t s a t t a c h e d t o i t , and s i n c e t h e s e s u b s t i t u e n t s may be v a r i o u s comb i n a t i o n s o f oxygen, n i t r o g e n , s u l f u r , o r o c c a s i o n a l l y o t h e r atoms, i n a d d i t i o n t o hydrogen or a l k y l , t h e r e i s a g r e a t v a r i e t y o f compounds t o be c o n s i d e r e d . The s t r u c t u r e s and conf o r m a t i o n s o f t h e s e compounds, f r e q u e n t l y i n v e s t i g a t e d by NMR s p e c t r o s c o p y , are t h o r o u g h l y d i s c u s s e d . The s t e r e o c h e r i s t r y o f v ii

viii

PFEFACE

s u b s t i t u t i o n r e a c t i o n s a t phosphorus and some of t h e b i o l o g i c a l a s p e c t s o f t h e s e phosphorus compounds are t h e n reviewed. While t h e cyclohexane r i n g may b e t a k e n as t h e s t a n d a r d , s i m p l e , and i d e a l model f o r c o n f o r m a t i o n a l a n a l y s i s , phosphorusc o n t a i n i n g six-membered r i n g s are e s s e n t i a l l y a t t h e other end of t h e spectrum. The d i f f e r e n t i n t e r a c t i o n s ( d i p o l a r , van der Waals, r e s o n a n c e ) t h a t o c c u r are s u b s t a n t i a l l y more complicated t h a n i n t h e hydrocarbon case, and w h i l e much o f t h e o b s e r v e d b e h a v i o r can be r a t i o n a l i z e d , i f n o t n e c e s s a r i l y p r e d i c t e d , o u r b a s i c u n d e r s t a n d i n g of such s y s t e m s i s by f a r l e s s advanced t h a n t h a t of c y c l o a l k a n e s . Norman L. A l l i n g e r E r n e s t L. E l i e l A t h e n s , Georgia C h a p e l hill, North C a r o l i n a A p r i l 1979

CONTENTS CONFORMATIONAL ANALYSIS OF INTRAMOLECULAR-HYDROGEN-BONDED COMPOUNDS IN DILUTE SOLUTION BY INFRARED SPECTROSCOPY by Herbert S . Aaron, ChemicaZ Systems Laboratory, Research Division, Aberdeen Proving Ground, Maryland . . . . . . . . . . . . . . . . . . . . .

..

1

REDUCTION OF CYCLIC AND BICYCLIC KETONES BY COMPLEX METAL HYDRIDES

by James R. Boone, Department of Chemistry, David Lipscomb College, N a s h v i l l e , Tennessee, and E . C. Ashby, School of Chemistry, Georgia I n s t i t u t e o f Technology, A t l a n t a , Georgia

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

53

CONFORMATIONAL BARRIERS AND INTERCONVERSION PATHWAYS IN SOME SMALL-RING MOLECULES

by Tnomas B . MaZZoy, J r . , Department of P h y s i c s , M i s s i s s i p p i S t a t e U n i v e r s i t y , Mississippi S t a t e , M i s s i s s i p p i , L e s l i e E. Bauman, Department of Chemistry, M i s s i s s i p p i S t a t e U n i v e r s i t y , M i s s i s s i p p i S t a t e , M i s s i s s i p p i , and L . A . Carreira, Department of Chemistry, U n i v e r s i t y of Georgia, Athens, Georgia . . . . . . . . . . . . . . . . . .

.

97

STEREOCHEMICAL ASPECTS OF PHOSPHORUS-CONTAINING CYCLOHEXANES

by Bruce E . Maryanoff, Chemical Research Department, MeNeil Laboratories, Fort Washington, Pennsylvania, Robert 0. Hutchins, Department of Chemistry, Drexel u n i v e r s i t y , Phi lade l p h i a , Pennsy Zvania, and Cynthia A . Maryanoff, Department o f Chemistry, Princeton U n i v e r s i t y , Princeton, New J e r s e y

. . . . . . . . . . . 187

Subject Index Cumulative

....................... Index, Volumes 1 . 1 1 . . . . . . . . . . . . . .

327 339

ix

TOPICS IN

STEREOCHEMISTRY

VOLUME 11

Topics in Stereochemisty, Volume11 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1979 by John Wiley & Sons, Inc.

Conformational Analysis of IntramolecularHydrogen-Bonded Compounds in Dilute Solution by Infrared Spectroscopy HERBERT S . AARON Chemical Systems Laboratory. Research Division. Aberdeen Proving Ground. Maryland I

I1

.

.

Introduction

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

2

Spectral Characteristics of the Intramolecular

................... I11 . The Experimental Method . . . . . . . . . . . . . . IV . Spectroscopic Analysis of the Free OH Band . . . . . V

VI

Hydrogen Bond

.

.

2 3 5

Configurational Assignments of Hydrogen-Bonded Compounds

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

Summary of Intramolecular Hydrogen-Bonding .. Studies

7

.

......... B . The O H * * * nHydrogen Bond . . . . . . . . . . . . C . The OH***O=CHydrogen Bond . . . . . . . . . . . 1. Hydroxyketones . . . . . . . . . . . . . . . 2 . Hydroxyesters . . . . . . . . . . . . . . . D . The OH***OHand OH***ORHydrogen Bonds . . . . . E . The OH**" Hydrogen Bond . . . . . . . . . . . . F . The O H * * * SHydrogen Bond . . . . . . . . . . . . G . Miscellaneous Hydrogen Bonds . . . . . . . . . . VII . Quantitative Applications . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . A . The OH.**Halogen Hydrogen Bond

9

9

10

12 12

16 20

22 31 33 37 42

1

INTRAMOLECULAR HYDROGEN BONDS

2

I. INTRODUCTION Dilute-solution infrared (IR) spectroscopy is commonly used to prove the presence of an intramolecular hydrogen bond for configurational and conformational assignments. Properly applied, the method may also be used for more quantitative conformational analysis, because it can often define, simply and uniquely, the equilibrium position between intramolecular bonded and nonbonded conformations. An excellent review of intramolecular hydrogen bonding by IR spectroscopy and its applications in stereochemistry through 1964 has been published (1). Accordingly, this chapter focuses mainly on pertinent literature that has been published since 1964.

11.

SPECTRAL CHARACTERISTICS OF THE INTRAMOLECULAR HYDROGEN BOND

To briefly summarize the aspects of the phenomenon which are most important to the stereochemist, intramolecular hydrogen bond formation occurs when a proton donor (usually OH, but also COOH, NH, and SH) is oriented toward and falls within the proximity [less than about 3.3 d ( 2 ) or, perhaps, 3.4 A (3), but variable] of an electron-rich proton-acceptor function, such as halogen, -NRz, -0-,C=C, and C=O. Hydrogen bonding has usually been reported with OH as the proton donor, because the bonds formed by this common substituent are the most easily recognized and the most conveniently studied in the IR spectrum. Thus, in the vapor phase or in a dilute nonpolar solution in which intermolecular hydrogen bonding has been eliminated, the formation of an intramolecular hydrogen bond is seen (Fig. 1) as a broadening and a shift of woHl the donor OH fundamental band, to a lower frequency compared to that of the corresponding nonbonded or so-called free OH species. The overtone OH band in the near IR is similarly affected (4a), although it may not be as useful as the one in the fundamental region, especially for quantitative applications (4b). The fundamental free OH band, which actually is still weakly associated with solvent even in a nonpolar medium (5), almost always falls above 3600 cm-’ in carbon tetrachloride solution, although certain exceptions are noted here. Hydrogen-bonded OH bands, on the other hand, almost always fall below 3600 cm-l, except for some weak OH***n interactions. When an equilibrium exists between free OH and bonded OH species, the OH band of each is observed, as seen in Fig. 1. It should be noted, however, that due to the broadening of the bonded OH band, roughly in proportion to the magnitude of the WOH shift for any given compound, its size may appear misleadingly large relative to the actual molar concentration of bonded OH species in the equilibrium mixture.

HERBERT S. AARON

Fig. 1. cell path.

3

38-Granatanol (3) at 2.9 X 1 O m 3 M in CCl4, 2-cm

The magnitude of shift of the OH absorption (AvOH) between the free and bonded maxima is customarily taken as a measure of the strength of the hydrogen bond. The AvOH value depends on a number of factors, and is apparently favored by the acidity of the donor OH, the basicity of the acceptor function, the proximity of the OH to the acceptor site, and the approach to linearity of the three-atom bridge (e.g., O-H***N)that forms the hydrogen bond (1). Comparisons of AvOH values between systems with different donor and/or acceptor functions are generally difficult, if not impossible, to assess. However, the AVOH value is useful for correlating molecular geometries and for drawing comparisons between hydrogen bonded structures containing the same donor and acceptor function, as indicated below, for example, for OH***Nbonded systems. Of course, the strength of a hydrogen bond is not necessarily related to the concentration of hydrogen-bonded species in an equilibrium mixture, since the latter may be significantly affected by entropy factors, as indicated in various examples mentioned here and by other conformational interactions that may be present.

111.

THE EXPERIMENTAL METHOD

For these spectral studies a dual-beam IR spectrophotometer that gives good resolution in the OH region must be used. Thus, earlier studies were made with instruments equipped with lithium fluoride optics, whereas more recent work has almost invariably

4

INTRAMOLECULAR HYDROGEN BOND

been carried out on grating IR spectrophotometers, now commonly found in most laboratories. A nonpolar solvent that is essentially transparent in the OH region of the spectrum is required. Carbon tetrachloride, dried and kept dry by storage over 3 A molecular sieves, is the preferred solvent, although carbon disulfide and tetrachloroethylene may also be used. The latter is especially useful (6) for compounds (e.g., some amino alcohols) that react with carbon tetrachloride or carbon disulfide, but must be passed over alumina and distilled to remove its ethanol stabilizer immediately before use. Chloroform (with the ethanol stabilizer removed) has also been used (7), but is not generally recmended, because weak intramolecular hydrogen bonding may not be revealed. In some cases, however, chloroform was reported to be the preferred solvent, because it eliminates residual weak dimeric association without affecting the intramolecular hydrogen bond ( 8 ) . To eliminate intermolecular hydrogen bonding between the solute species, the spectral solution should be diluted until the extinction coefficient of the OH band (or the ratio of bonded to free OH absorbance maxima) does not change on further dilution. A 2.5 to 5.0 X 1 0 - 3 M solution is generally suitable, and may be conveniently examined in a 1 or 2 cm quartz (IR grade or near-IR grade) cell, with a matched cell for the reference solvent blank (9). Commonly available cells of this type are essentially transparent down to about 2500 cm'l. A mini-slide holder such as those available from the Wilks Scientific Corp. can be adapted to serve as an inexpensive cell holder if one does not care to purchase a more expensive type. For very insoluble compounds, or for detection of very small concentrations of an OH species, longer path cells ( 5 or 10 cm-') may be used, at least with carbon tetrachloride (10). Often the spectrum shows the presence of a little water, as a small band at 3702 cm-l (11). This band can readily be balanced out by introducing a trace of water into the reference cell, most simply from water vapor present in the atmosphere, by removing some of the reference solvent with an eyedropper and then squirting it back into its cell. The process is repeated, if necessary, until a compensating amount of water has been absorbed in the reference solvent cell. It may be necessary to distinguish the band of an intramolecular hydrogen bond from that of a carbonyl overtone, which falls in the same spectral region. For this purpose the most reliable method is to simply add a drop of D20 to the solution and to the blank (12, 1 3 ) . On standing, the OH is converted to an OD group, and both its free and bonded absorptions shift to lower frequencies by a factor of ca. 0.73 (14a). The position of the carbonyl overtone or of any other band that does not contain an exchangeable proton remains unaffected by this treatment. For qualitative comparisons of intramolecular hydrogenbonded systems, the ratio of the extinction coefficients (E) of the bonded OH and free OH species is often taken, with each calculated as (14b)

HERBERT S. AARON

5

E

1 L1

= - log

3 2 T

where C is the concentration ( M ) , 1 is the cell thickness (cm), and T O and T are the intensities of the incident and transmitted light. For more quantitative applications, however, the integrated intensity ( B ) or area of the OH band is required, which is equal to (14b) B = 2.303

E

dv

[21

Thus, for a given band E is plotted against v on linear graph paper, and the area is obtained in any one of several ways: by using a planimeter, by simple addition of the graph squares, or by cutting and weighing a photocopy of the curve. On more sophisticated spectrophotometers the area of a band may be integrated directly. Overlapping bands may be separated graphically. More recently, however, a commercial curve resolver (15) or a computer method (16) has been used for this purpose. These methods can be used to determine the presence (or absence) of free and bonded OH absorption bands, the exact position and spectral characteristics of the bands, and the relative molar percentage of each species, if both are present, for use in structural and conformational assignments.

IV.

SPECTROSCOPIC ANALYSIS OF THE FREE OH BAND

The dilute-solution IR data most useful for stereochemical assignments are provided by compounds that contain an intramolecular hydrogen bond. However, the presence of only a free OH band in the spectrum may also be important. Thus, the diaxial diol configuration of p-menthane-trans-2,3-diol ( I ) was assigned based on the presence of a single free OH band in dilute CCl4

r p i % e M

OH

1

H

+I

H OH

2

solution (17), and the stereochemistry of 8-boswellic acid ( 2 ) was confirmed on similar grounds (18). Also, the area of the free OH band may be used to determine the number of OH groups in an unknown structure, through comparison to that of a suitable model compound (19). The position, shape, and extinction coefficient of the free OH band may be useful for structural or conformational assignments. For example, the free OH band usually lies above 3600 crn-l. However, if attached to a strong electronegative atom, as in hydroperoxides (ROOH) (20) or oximes (RzNOH) (21), the free OH band usually falls below 3600 an-’, if not lower. Conversely, the opposite effect is observed in silanol systems (R3SiOH), where unusually high-frequency OH absorptions are observed

6

INTRAMOLECULAR HYDROGEN BOND

(3674 t o 3686 cm-l) (22). Cole and co-workers s t u d i e d a series of t r i t e r p e n o i d a l c o h o l s , and found t h a t primary hydroxyls absorb a t ca. 3640, secondary a t ca. 3630, and t e r t i a r y a t c a . 3615 cm-l i n CC14 s o l u t i o n (7). These p o s i t i o n s vary somewhat according t o s t r u c t u r e and stereochemistry (23), however, and a l k y l s u b s t i t u e n t s a t t h e a d j a c e n t carbon w i l l cause an i n c r e a s e i n vOH (24). For example, some secondary a l c o h o l s with v i c i n a l s u b s t i t u e n t s absorb a t 3642 t o 3654 cm(25). I n carbon d i s u l f i d e (5) o r chloroform (7), however, t h e f r e q u e n c i e s a r e lower by ca. 10 t o 15 cm-l. Phenolic OH, which u s u a l l y absorbs i n t h e same region a s t e r t i a r y a l c o h o l s , is g e n e r a l l y d i s t i n g u i s h e d by i t s sharper band and l a r g e r e x t i n c t i o n c o e f f i c i e n t (26). A s p e c t r a l examination of t h e f r e e OH band may d i s t i n g u i s h an a x i a l from an e q u a t o r i a l OH group, e s p e c i a l l y i f both epimers a r e a v a i l a b l e f o r a d i r e c t comparison. Here an a x i a l a l c o h o l g e n e r a l l y has a s l i g h t l y higher (5 t o 1 0 cm-l) a b s o r p t i o n f r e quency (7, 23, 271, l a r g e r e x t i n c t i o n c o e f f i c i e n t , and g r e a t e r band symmetry than i t s e q u a t o r i a l epimer ( 9 ) . The band symmetry has been c h a r a c t e r i z e d by t h e a/@ r a t i o , corresponding t o t h e half-band widths on t h e high (a) and low ( 8 ) frequency s i d e of t h e OH band m a x i m u m (9, 15). A c t u a l l y , t h e corresponding r a t i o a t t h e one-quarter-band p o s i t i o n , o r t h e r a t i o of t h e band a r e a s on each s i d e of t h e vmax p o s i t i o n , can probably be more u s e f u l i n c h a r a c t e r i z i n g t h e band symmetry, s i n c e t h e presence of a small asymmetrical component may n o t a f f e c t t h e a/B r a t i o , i f taken a t t h e half-band p o s i t i o n . The d i s t i n c t i o n s between t h e a x i a l and e q u a t o r i a l a l c o h o l s a r e apparently caused by a d i f f e r e n c e i n t h e rotamer composition of each isomer (28, 29). Thus, based on a study of sane simple a l i p h a t i c a l c o h o l s , t h e d i f f e r e n t conformers t h a t a r e formed by r o t a t i o n of t h e OH group about t h e C-0 bond have been d e f i n e d , and t h e vOH of each has been assigned a s c a . 3640 cm-l f o r t y p e I , 3628 cm-l f o r type 11, and 3617 cm-l f o r type I11 rotamer forms (28). For example, a s d e f i n e d , e t h a n o l should e x i s t a s a

H

Type 1 Type I1 Type I11 mixture of type I and type I1 rotamers; i s o p r o p y l a l c o h o l , a s a mixture of type I1 and type I11 forms. The apparent vmax of t h e composite band, t h e r e f o r e , d i f f e r s from t h a t of t h e i n d i v i d u a l components, depending on t h e p a t t e r n of t h e i r o v e r l a p . Two exp l a n a t i o n s have been o f f e r e d t o account f o r t h e symmetry observed f o r t h e a x i a l OH band. On t h e one hand t h e r e s u l t has been a t t r i b u t e d t o a conformational homogeneity of t h e a x i a l a l c o h o l s , a s a r e s u l t of a low c o n c e n t r a t i o n of t h e type I11 rotamer, because of s t e r i c i n t e r a c t i o n s of t h e syn-axial hydrogens with t h e hydroxyl hydrogen ( 9 ) . On t h e o t h e r hand Schleyer and co-workers

7

HERBERT S. AARON

Type I11

Type I1

Type I1

(15a) distinguished additional types of OH rotamers according to the substitution pattern at the 8 carbon atom, and suggested that two rotamer types are actually present in the axial alcohols, but that both have equal values of VOH. The results of a recent intermolecular-hydrogen-bonding study of cis- and trans4-t-butylcyclohexano1 (30) have been reported in support of the former explanation. An opposite effect has been noted for some epheric tertiary aryl carbinols, however. Here, the axial-OH epimers gave the unsymmetrical band (31).

V.

CONFIGURATIONAL ASSIGNMENTS OF HYDROGEN-BONDED COMPOUNDS

Probably the simplest useful application of dilute-solution IR spectroscopy has been configurational assignment, based on the presence in one isomer of an intramolecular hydrogen bond that is sterically impossible in the other. If available, however, both isomers should be examined to rule out any possible error arising from persistent intermolecular hydrogen bonding. In two of the earliest applications of this method intramolecular hydrogen bonding was reported for 8-granatanol ( 3 ) (32) and Ytropine ( 4 ) (33). For '4'-tropine, however, the result was shown (34) to result from intermolecular hydrogen bonding in an insufficiently dilute solution. Nevertheless, Y-tropine is still CH

7H3 N

OH 3a

3b

4

occasionally cited as an example of intramolecular hydrogen bonding (35). Reexamination of 8-granatanol [suggested (1) as desirable in view of the I-tropine error] has confirmed (9,36) the original report. This result establishes the configuration of both the a- and B-granatanol isomers, because hydrogen bonding is possible only inthe 8-isomer ( 3 b ) . The equilibrium mixture of this compound has been assigned (9) as 15% boat ( 3 b ) and

INTRAMOLECULAR HYDROGEN BOND

8

85% chair (3a) on the basis of IR data (Fig. 1). Examples of other stereochemical assignments that have been made in this way are given in succeeding sections. For two epimers, each containing an intramolecular hydrogen bond, the assignment of configuration can often be made by conformational analysis, by comparing the relative amounts of hydrogen bonding in each. For this purpose the ratio of bonded OH and free OH species is usually taken simply as the ratio of the extinction coefficients ( E b / E f , respectively). The method has been applied to open-chain vicinal (i.e., 1,2-) diols and amino alcohols, as summarized in ref. 1. Here the threo (or d , l ) isomer invariably shows more bonding (higher Eb/Ef ratio) than the erythro (or meso) isomer. This correlation is consistent with the assumption that the two bulkiest groups are relatively more favored in an anti-trans conformation, when the free OH (or bonded OH) rotamers of the two isomers are compared, as illustrated for the following RCHOHCHOHR diols:

t -

threo HO

c-

erythro

R

OH

Hqx R

OH

In addition, for 1,2-diols and amino alcohols the AVOH value is usually smaller in the erythro isomer, consistent with a longer hydrogen bridging distance arising from repulsion of the bulky groups that are gauche in the bonded conformation. Recently the method has been used for the configurational assignment of the isomers of 5 (37), 6 (38), 7 (39), and 8 ( 8 ) . For 6 no difference in AVOH was observed for the two isomers. Compound 9 has also been studied, but interpretation of the spectral data is complicated because three different types of intramolecular hydrogen bond can be formed ( 4 0 ) . Ph-CH-CH-Ph I 1 OH NR2

5

n CH3 OH 6

OH

H 7

HERBERT S. AARON

9

8

9

V I . SUMMARY OF INTRAMOLECULAR HYDROGEN-BONDING S T U D I E S A.

The OH**-Halogen Hydrogen Bond

The splitting (or asymmetrical shape) of the OH band in 2haloalkanols (41-43) is attributed to intramolecular OH***halogen hydrogen bonding (42,43). Higher w-haloalkanols, however, apparently do not form an intramolecular hydrogen bond(44). For a series of 2-chloroalkanols AVOH decreased in the order of tertiary > secondary > primary chlorine, and primary > secondary > tertiary hydroxyl (45). When the halogen is varied, the AvOH values stand in the order I > Br > C1 > F for 2-haloethanols (45,46), and I > Br > C1 for 2-halocyclohexanols (47). This is the same order that had previously been observed for 2-halophenols (48). This order is consistent with a shortening of the hydrogen bridging distance with increasing size of the halogen atom. For the 2-halophenols it is generally agreed (48) that the relative strengths of the hydrogen bonds stand in the order C1 > Br > I, corresponding to a decreasing concentration of bonded (cis) species in the equilibrium mixtures (48a). Thus these relative bond strengths are exactly opposite to those suggested by their relative AVOH values, based on the relationship between enthalpy (AH) and AvOH postulated by Badger and Bauer for intermolecular bonded systems (49). It should be noted, however, that this criterion is customarily used to compare systems that contain the same donor and acceptor functions, respectively. The 2-fluorophenol analog shows a singlet OH bond at 3591 cm-l (48b), which, if attributable to a bonded OH, would have the smallest AvoH value and be consistent with this series. The relative bond strength of the fluoro analog is uncertain, however, because there is disagreement over whether this band actually results from a bonded or free OH species, or even a mixture of the two (48). For the 2-haloethanols the relative strengths of the hydrogen bonds were assigned as F > C1 > Br > I, based on the enthalpy difference (AH) calculated for the equilibrium between gauche (bonded) and trans (nonbonded) rotamer forms (46). In this case the fluoro analog also gave a singlet OH band, but this unsymmetrical band was graphically separated into two symmetrical bands, and the free OH species was assigned to the high-frequency component. The enthalpy values thus obtained were linearly related to a decrease in AvOH, and the assignments

10

INTRAMOLECULAR HYDROGEN BOND

correspond to those noted above for the 2-halophenol series. The trans-2-halocyclohexanols, on the other hand, have an inverse order of relative bond strengths (I > Br > Cl), based on the energy difference between diequatorial (bonded) and diaxial (nonbonded) conformers, in equilibrium in carbon disulfide solution (47). It should be noted, however, that when criteria defining the relative strengths of intramolecular hydrogen bonds are based simply on relative conformer populations in aliphatic systems, they are not necessarily valid, because the equilibrium position also depends on.electrostatic and nonbonded steric (e.g., syn-axial) interactions of the substituent groups. A spectral study of the mobile equilibrium of trans-2-bromoand trans-2-iodocyclohexanols has shown that the diequatorial forms are largely but not completely hydrogen bonded (501, while only the chloro analogs of some anancomeric (51) (confonnationally biased) 2-chloro, 2-bromo-, and 2-fluorocyclohexanols (10) contained no free OH (rotamer) (52). These results suggest that the O H * * * C lspecies forms the strongest hydrogen bond in these compounds. A theoretical treatment of OH***halogenbonding based on the Schroeder-Lippincott potential function model has recently been presented (53), including an extensive tabulation of the earlier literature.

L d : 10

B. The O H * - * n Hydrogen Bond Conformational studies of OH***nbonded substituted benzyl (54-57), 8-phenethyl (581, olefinic (59, 60), acetylenic (61), and unsaturated terpene alcohols (62) have been reported. The position of the free OH/bonded OH equilibrium in 2-hydroxybiphenyl ( 2 1 ) has been assigned as 16 to 17% free OH (63). Conformational studies of substituted 2-hydroxybiphenyl systems have

/

H

lla llb 12 been carried out (641,and the magnitude of the OH***ashift was related to the degree of overlap of the bonding orbitals. These studies were then extended to a series of olefinic alcohols in which the OH***nshift was correlated with the square of an overlap integral, defined as a function of the geometrical parameters of the system (65).

11

HERBERT S. AARON

For anancomeric axial and equatorial allylic alcohols the equatorial OH isomer is generally observed as a doublet corresponding to bonded and free OH species (e.g., uoH 3605 and 3622 cm-l, respectively, for 1 2 ) while the axial OH isomer is generally observed as a singlet (UOH 3618 cm-’) (65). The latter was assigned as a bonded O H * * * ainteraction, based on the favorable orbital overlap and on the fact that the free axial OH groups generally absorb about 10 an-’ higher than their corresponding equatorial OH epimers. Usually, however, OH***nbonded systems exist in equilibrium between bonded and free OH species, corresponding to rotamer forms of the OH group. Thus the syn isomer of 1,5-dimethylbicyclo[3.3.l]non-2-en-9-ol ( 1 3 ) contains both free OH (3640 cm-l) and O H * * * abonded (3584 cm-l) absorptions. The anti isomer shows only a free OH (3640 cm-I). From these results the configurations of both isomers were assigned (66). In some compounds that contain an O H * * * aabsorption, however, no free OH bands are observed [e.g., 1 4 (67) and the axial OH epimer of 1 2 1 . These results have been attributed to the strength of the intramolecular hydrogen bond, as well as to the unfavorable oxygen lone pair/s-electron orbital/orbital repulsion that exists in the free OH rotamer form of these systems (67b). H’

13

OH

14

15

Studies of tetralol, chromanol, thiochromanol, and tetrahydroquinolinol systems (e.g., 1 5 ) have been carried out (681, and OH conformations have been assigned as quasi-axial (singlet, voH 3618 cm-’) and quasi-equatorial (doublet, VOH 3622 and 3600 cm-1) species. Although there has been some question as to whether the quasi-axial species exists in a free or bonded OH form, it is probably best assigned as a bonded OH***nspecies (68b). It has been concluded that 1-tetra101 exists predominantly in the OH axial conformation (68b), to correct an earlier assignment. In 4-hydroxytetrahydroquinoline systems the influence of the nitrogen substituent on the OH-**ninteraction has been studied (68f). Cyclopropylmethanol, which does not contain an olefinic group, also gives an IR doublet. While the explanation of this result has been a point of controversy, it is apparently the result of O H * - * ninteraction (69a), since the 0 electrons of the cyclopropane ring are known to exhibit characteristics of more mobile n electrons (69b).

12

INTRAMOLECULAR HYDROGEN BOND

C. The OH**-O=CHydrogen Bond 1.

Hydroxyketones

A v a r i e t y of s t r u c t u r e s i n t h i s c a t e g o r y have been s t u d i e d (13,18,70-77). Depending on t h e molecular geometry, two d i s t i n c t a c c e p t o r s i t e s of t h e hydrogen bond can b e involved ( 1 3 , 7 2 ) : t h e s t r o n g l y bonding unpaired n e l e c t r o n s of t h e carbonyl oxygen atom, and t h e weakly bonding a - e l e c t r o n p a i r of t h e carbonyl group. Often, b o t h of t h e s e s p e c i e s are p r e s e n t , i n a d d i t i o n t o t h e f r e e OH, t o produce a d o u b l e t o r m u l t i p l e t of bands i n t h e OH region. I n some cases a d o u b l e t i s a l s o observed (18) i n t h e carbonyl r e g i o n , corresponding t o t h e s t r o n g l y bonded and t h e f r e e ( o r weakly bonded) carbonyl s p e c i e s , and t h i s may be helpf u l i n i n t e r p r e t i n g t h e WOH r e s u l t s . When analyzing t h e OH bands i n t h e s e s p e c t r a , however, one must be c a r e f u l n o t t o a s s i g n an i n t r a m o l e c u l a r hydrogen bond t o t h e carbonyl overtone a b s o r p t i o n , which f a l l s i n t h e 3400 an-l r e g i o n of t h e spectrum (Fig. 2 ) . Some l i t e r a t u r e e r r o r s of t h i s type have been c i t e d (12b,13). Although t h e p o s i t i o n , band width, and i n t e n s i t y may s e r v e t o d i s t i n g u i s h t h e carbonyl overtone from an i n t r a m o l e c u l a r hydrogen bond ( 1 3 ) , t h e most reliable method i s t o simply add a d r o p of D 2 0 t o t h e s p e c t r a l solu t i o n , t o c o n v e r t t h e OH i n t o an OD group, s h i f t i n g i t s absorpt i o n t o lower f r e q u e n c i e s ( 1 2 , 1 3 ) , as d e s c r i b e d i n Sect. 111. For a c y c l i c hydroxyketones, such as CH3CO(CH2)nOH, t h e AvOH v a l u e s d e c r e a s e i n t h e o r d e r l-hydroxy-2-propanone (135 c m - l ) , 4-hydroxy-2-butanone ( 4 8 an-l) , and 5-hydroxy-2pentanone (31 c m - l ) , corresponding t o t h e i n c r e a s i n g s i z e of t h e hydrogen-bonded r i n g f o r n = 1, 2 , and 3 , r e s p e c t i v e l y ( 7 2 ) . This t r e n d i s o p p o s i t e t o t h a t which i s s e e n i n d i o l s , methoxy a l k a n o l s , and amino a l c o h o l s , where t h e v a l u e of AWOH i n c r e a s e s i n going from a f i v e - t o a six-atom bonding r i n g . For t h e hydroxyketones t h e s e r e s u l t s are a p p a r e n t l y caused by a s h i f t of t h e bonding s i t e from t h e n - e l e c t r o n s t o t h e n - e l e c t r o n s , due t o t h e g e o m e t r i c a l c o n s t r a i n t s of t h e system ( 1 3 , 7 2 ) . The AVOH v a l u e s of t h e s e two t y p e s of hydrogen bonds correspond t o t h o s e which a r e observed f o r OH**.O ( e t h e r ) and O H * * * r (C=C) systems, based on s t u d i e s of model compounds of f i x e d geometry. Thus a c y c l i c a-hydroxyketones t e n d t o give symmetrical bands (Fig. 2 ) (131, as a r e s u l t of OH..-O a b s o r p t i o n (AwoH % 130 c m - l ) , w h i l e a c y c l i c 8-hydroxyketones g e n e r a l l y g i v e unsymmetrical (bonded) OH a b s o r p t i o n bands. J o r i s and Schleyer c o n s i d e r t h e l a t t e r t o be a composite of A ~ O H% 30 t o 45 cn-l (OH.**T) and a minor component of AWOH % 90 c m - I ( O H * * * O,) p l u s f r e e OH ( 1 3 ) . That t h e O H * * * O i n t e r a c t i o n i n t h e a-hydroxyketones i s l a r g e r than t h a t of the 8-analogs i s b e l i e v e d t o be caused i n p a r t , by t h e g r e a t e r a c i d i t y of t h e hydroxyl a d j a c e n t ( a ) t o t h e carbony1 group, and i n p a r t , t o a more f a v o r a b l e geometry which

HERBERT S. AARON

13

-

R, R ' = H

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

: : j i. .. .' .. .. .

*

.....

Bonded OH

3600

Fig. 2 . ketones.

3500

3400

Frequency (cm-' )

Hydroxyl-region I R spectra of acyclic a-hydroxy-

permits a better overlap of the a-OH group with the unpaired n-electrons of the carbonyl oxygen. A cyclic a-hydroxyketone may form a strong or weak intramolecular hydrogen bond, depending on its conformation. Thus an equatorial OH group ( 1 6 ) provides the correct geometry for strong intramolecular O H * * - Ohydrogen bond formation, and for systems that are fixed in this conformation, all the molecules (within the detectable limits of the method) are intramolecularly hydrogen bonded and no free OH species is observed (72,73). For cyclic axial a-hydroxy ( 1 7 ) and B-hydroxyketones ( 1 8 ) , however, only weak OH*.*a bond formation should be possible. Accordingly, most systems that are fixed in these conformations exist in an equilibrium between bonded and free OH rotamer forms (72,74), and give an unsymmetrical OH band, which may be separated into two symmetrical components corresponding to each conformer (e.g., 24a, 2 4 b ) . Cyclic equatorial 8-hydroxyketones ( 1 9 ) , of course,

14

INTRAMOLECULAR HYDROGEN BOND

Frequency (cm-'

1

Fig. 3. Experimental OH absorption of 4-hydroxy-2, component bands calculated by computer * * * * .I sum butanone, of the calculated components bands,

-

----.

cannot form an intramolecular hydrogen bond, and only a free OH is observed. H

16

17

18

19

Conformational assignments that have been given on the basis of the spectral results include the l-hydroxyisocarvomenthone (20) system, where only the bonded species (20~2, VOH 3504 cm-l) was observed, and no OH absorption corresponding either to a free OH rotamer form of 2 0 or ~ to conformer 2Ob could be detected (73). A l s o , 1-hydroxycarvomenthone ( 2 1 ) , which shows a

HERBERT S. AARON

-k3y k";" 'H

15

=

2 Oa

20b

doublet at 3610 and 3502 an-', was assigned as an equilibrium between 21a and 2 1 b , respectively. However, the report (75) that

21b

21a

4-hydroxymenthone shows only a 3495 cm-l band, assigned as 2 2 b , is inconsistent with the results for 2 1 .

cH3T++ f+o\H

22a

OH

CH3

0.'

22b

In the steroid series 5$-cholestane-5B-ol-6-one (23) gives only a strongly bonded OH band (AvQ 135 cm-l), whereas 5acholestane-5a-01-4-one ( 2 4 ) and the corresponding 6-one isomer ( 2 5 ) show both free OH (3614 cm-l) and weakly bonded OH (Av 11 to 12 cm-l) bands. In view of these results the fact that 58cholestan-5$-01-4-one ( 2 6 ) shows only an OH***O=Cabsorption at 3480 cm-I (72) (and a significant vc=o shift) is not consistent with that expected for an axial a-hydroxyketone ( 2 6 a ) . To account for these results a shift of ring A into a boat form ( 2 6 b ) has been suggested (78). Here the boat or, better, skew-boat (794 would both be favored by the strong intramolecular hydrogen bond and also be formed in a cyclohexanone ring, in which the chair/boat energy difference is smaller than that in a cyclohexane ring (79b). It is not altogether clear, however, why 24 does not also form a similar species. Possibly the difference between a bowsprit-flagpole (79a) H/CH interaction in a 26 skewboat vs. H/CH3 in a 24 skew-boat may account for this difference, since the latter apparently results in a loss of rotational entropy of the CH3 group. In the epimeric 2-hydro~ypregn-4-ene-3~2O-dionesboth the 2a (27) and 2$ (28) epimers show only O H * - * Obonding at 3497 k

16

p

INTRAMOLECULAR HYDROGEN BOND

*+ H . . . . .0 .

+==HO ’

24a

23

OH

OH.’

24b

2.5

1 cm-l, from which the 28 isomer was assigned the half-boat conformation ( 2 8 b ) ( 7 4 ) . In this case the energy difference between a boat and chair species in a cyclohexene ring is not large (79c), and the formation of the hydrogen bond in 28b plus the syn-axial Me/OH repulsion in 28a combine to produce the observed result.

27

28a

H

2.

28b

Hydroxyesters

The assignment of the OH bands in hydrogen-bonded hydroxyesters (80-87) is also complicated by the presence of multiple bonding sites, corresponding to a strong interaction with the carbonyl oxygen ( 2 9 1 , and a weaker interaction with the alkyl oxygen atom.

17

HERBERT S. AARON

I I

I OH' 'O=C-OR

OH' .O-C=O

29

30

In addition the spectrum may contain bands resulting from the carbonyl overtone and from rotamer forms of the free OH ( 8 6 ) . Although the presence of both n-electron and n-electron sites at the carbonyl group has also been recognized (82) (analogous to that in hydroxyketone systems described above), specific assignments of weak n-electron bonding in hydroxyesters do not appear to have been given. Conformational assignments of bonded OH absorptions in these compoinds may be aided by examination of the C=O absorption. Thus, when the carbonyl oxygen is the proton acceptor ( 2 9 ) , the C=O bond is lowered by 10 to QO cm-l, whereas with alkyl oxygen bonding ( 3 0 ) VC=O is raised by about 19 cm-l over the usual value. When both types of bonds are present, a wc=o doublet (or unsymmetrical vc=o band caused by an unresolved doublet) is obtained (82-84). In a-hydroxyesters (e.g., 3 1 ) hydrogen bonds of both the 29 and 30 type are formed, but that with the carbonyl oxygen predominates and no free OH is observed (82,84,85). Higher R

- P7

-

OH

'f

d

- OEt

61

acyclic w-hydroxy esters show decreasing amounts of bonded OH species through ethyl c-hydroxycaproate. The latter shows only a small OH***O=Cbond, which disappears completely for higher members of this series (82,85). In acyclic 8-hydroxyesters (e.g., HOCH2CH2COOEt) hydrogen bonding to the carbonyl group also predominates, accompanied by a small proportion of free OH (82), and in some cases by the alkyl oxygen-bonded species ( 3 0 ) (85,86). For 8-hydroxyester groups on a cyclohexane ring (32 and 3 3 ) , the bonding pattern depends on their respective conformations (18,85,87). Thus diequatorial trans-hydroxyesters ( 3 2 ) contain both types of hydrogen bonds, but the OH**-O-C=Otype (32b) is preferred. cis-Hydroxyesters ( 3 3 1 , on the other hand, mainly (if not exclusively) form the OH-**O=Cspecies, undoubtR

H

3 2a

+Hi H

0-H 33a

7-

z

OH

33b

*

C-OR

INTRAMOLECULAR HYDROGEN BOND

18

edly as an equilibrium mixture of 33a and 33b. In both 32 and 33 some free OH is also observed (85). A trans-8-hydroxester system that is fixed in a diaxial configuration ( 3 4 ) cannot form an intramolecular hydrogen bond (18).

H 34 In the y-hydroxycyclohexanecarboxylic acid esters (cis or trans) intramolecular hydrogen bonding does not normally occur (85). If the two substituents are fixed in a syn-axial configuration ( 3 5 ) , however, both carbonyl- and alkyl oxygen-bonded species are observed, with only a trace of free OH (80). The OH equatorial epimer of this system also forms an intramolecular hydrogen bond, but almost entirely of the OH***O=Cspecies, and in equilibrium with an appreciable amount of the free OH form.

3 5a

35b

Hydroxyesters of the diol monoacetate type have also been studied (81,83). In the cyclopentane- and cyclohexane-1,2-diol monoacetate series, both the cis and trans isomers form intramolecular hydrogen bonds. For the trans-cyclopentane isomer intramolecular hydrogen bonding is sterically possible only between the OH and carbonyl oxygen ( 3 6 ) , and this conformation is observed in equilibrium with free OH. In the cis isomer ( 3 7 ) ,

36

37

however, only a weak hydrogen bond to the ether oxygen is observed (3610 cm-l) , with no free OH (81). Earlier workers had

HERBERT S. AARON

19

also reported (88) a weak absorption at 3542 cm-l which though not observed in the more recent work, was interpreted to result from a trace of the OH***O=Cspecies (81). In the cyclohexane series both the cis and trans isomers are reported to axist in equilibrium between OH***O-C=O (mainly) and OH**-O=Cforms, with no free OH in either isomer. In the case of the trans isomer, however, this result is not unequivocal, because it is based on w e assignment of the strong 3627 cm-l band as a bonded OH*.*OC=O rather than a free OH form (81). Simple cyclohexane-1,3-diol monoacetates (38,39) show no intramolecular hydrogen bonding. If the cis isomer is forced into a diaxial conformation, however, an OH***O-C=Ointeraction ( 4 0 b ) is observed (83). In a diaxial configuration ( 4 1 ) no free OH rotamer forms are observed (83). Therefore it should be possible to assign the position of the 40 equilibrium from the area

HH

o=Y-oflOH

0

\

8

CH3

H

p;p

C-CH

3

39

38

H3C

0-C-CH I1

0

3

2 'CH3

4 Oa

4 Ob

of the free OH. In these systems the six-membered hydrogenbonded OH**-O-C=Oring is preferred to an eight-membered O H - * * O=C ring, although for the same ring size the OH***O=Cbond is presumably preferred.

H

++=

C H 3 y II 0

......

41

INTRAMOLECULAR HYDROGEN BOND

20

D.

The O H * - * O H and O H * - * O R Hydrogen Bonds

An early classic study of intramolecular hydrogen bonding by IR methods was carried out by Kuhn (2) on cyclohexane- and cyclopentane-1,2-diols. Shortly thereafter Cole and Jefferies (89) studied donor-acceptor relationships in cyclohexane-1,2diol systems, and concluded that a secondary equatorial OH forms hydrogen bonds in preference to a tertiary equatorial OH, but an axial OH forms hydrogen bonds in preference to an equatorial OH, whether secondary or tertiary. Spectral studies of additional cyclohexane-1,2-diols have since been reported (52,901. Thus in 4 2 , for example, the presence of an intramolecular OH***OHbond established that the diaxial conformation 42b is present in the equilibrium mixture (90). It is of interest to note, however, that in 4 3 no hydrogen-bond formation was detected (89). Conformational differences in the isomers of the 1-, 2-, and 3-hydroxymethylcyclohexanols have been described (91). Only the 3-hydroxy isomers (cis and trans) are internally unbonded. The cis isomer must exist as 4 4 b , therefore, because ) show some hydrogen bonding, the diaxial conformer ( 4 4 ~ should as has been observed in a steroid system (92). Transannular hydrogen-bond formation has been observed in some l,4-dialkyland 4-phenyIcycloheptane-l,4-diols (93). OH ‘

k

.OH’’O

H3C 4 2a

42b

H

qip OH

43

In the equilibrium between free OH and bonded OH***OH species in a series of u,w-diols [HO-(CH2),-OH] , values of AHo , ASo, and AGO were reported for n = 2 to 5. Here the enthalpy value (AHo) increased linearly with increasing strength of the and was largest, that is, most favorable hydrogen bond (Avo,), for bonding, for butanediol (n = 4 , AvOH 160 cm-l). However, the contribution of the entropy factor was such that the largest percentage of bonded species (AGO) was observed for ethanediol (ca. 92% at 25OC). Although the general conclusions of this study are undoubtedly qualitatively correct, the quantitative assignments should be reconfirmed, because the conformer concentrations were assigned on the assumption that the absorbances resulting from free and bonded OH groups are equal. While this assumption may yield a reasonably good approximation for small values of AvOH (e.g., 1,2-ethanediolI AVOH 35 cm’l) , it is less valid for larger values. Thus for 1,3-propanediol (AvOH 78 cm-l) the equilibrium constant was assigned in favor of the bonded OH form, by 1.8 kJ/mol (ca. 67%). In an earlier study (95), however, the equilibrium had been assigned in favor of the free OH

21

HERBERT S. AARON

4 4a

44b

form, by 0.4 kJ/mol (ca. 5 4 % ) , based on the extinction coefficient (but not the more reliable band area) of the free OH relative to that of propanol. Enthalpy values calculated in a related study on hydrogen bonding in butanediols (96)were faulted (94) for ignoring the corresponding mole equivalent of free OH that is present in all the bonded species. Spectral studies of terpene (71), triterpene (971, and steroid diols (72, 98-100) have been carried out. Unsuccessful attempts were made to correlate the AvoH values with deformations of the chair conformation in the sterol series (98). In the triterpene systems the presence of boat species was observed. In recent studies of certain diol systems with small dihedral angles, the unexpected absence of intramolecular hydrogen bonding or the presence of an abnormally weak hydrogen bond has been recorded (101). In the case of a piperidine ( 4 5 ) and the corresponding tetrahydrothiopyran diol, however, the reported (102) absence of any intramolecular hydrogen bonding is inconsistent with the assigned structures.

45 Intramolecular O H * * * Ohydrogen bonding has been studied for dioxane (103-107), dioxolan (104), tetrahydropyran (104, 108) , tetrahydrofuran (log), and oxirane (110) systems. The unexpected absence (in 4 6 ) or very minor presence ( 4 7 0 ) of intramolecular hydrogen bonding in 5-hydroxymethyl-1,3-dioxane systems (103, 105, 111) has been attributed either to OH/O dipole/dipole repulsion (103) or to the anomeric effect (112), caused by interaction of the unpaired electron clouds. Accordingly, the predominant conformational species in 47 has been assigned as either 4 7 b or 4 7 c , with 4 7 b being preferred (103). However, 47a should be favored over 4 7 b because it not only has an (attractive) intramolecular hydrogen bond, but also contains one less (repulsive) anomeric interaction. Therefore, in the absence of intramolecular hydrogen bonding conformer 4 7 c appears to be a more likely assignment.

INTRAMOLECULAR HYDROGEN BOND

22

iPr

H I

H

4 7b

4 7c

In both the trans-2-methyl- and trans-2-t-butyl-dioxan-5-01 isomers ( 4 8 ) , the presence of an OH doublet (3629 and 3601 cm-’) was attributed to a mixture of free and bonded OH species, assigned as a 48a-48b chair-chair equilibrium for the 2-methyl compound, and a 48a-48c chair-boat equilibrium for the 2-butyl analog (104). However, the 4 8 b and 4 8 c assignments are questR

R

%

. HO

L ~ o H = & - -A =d = R0 r

‘.HO

48a

48b

48c

b

49

ionable on conformational grounds, in view of the -AGO values of a 2-alkyl (24 kcal/mol) (113) and a 5-hydroxy (ca. 0.9 kcal/ moll (111) substituent on a dioxane ring in a nonpolar solvent. Since the corresponding cis isomers ( 4 9 ) show only a bonded OH at a somewhat lower frequency (3588 cm-l), the 48 doublet is best assigned to the presence of two free OH rotamer forms, as discussed in Sect. IV.

E. The

O H * * - N Hydrogen Bond

Configurations of epimeric amino alcohols that have been assigned on the basis of an OH***Nhydrogen bond include 28tropanol (50) (114), 68-tropanol (51) (115), 3-methyl 3-azabicycl0[3.3.l]nonan-98-01 (52) (34b), endo 2-benzyl 2-azabicyclo [2.2.1]heptan-6-01 ( 5 3 ) (116), 6-epimesambinol and its corresponding 9-phenyl analog ( 5 4 ) (117), and the cis isomers of 5( 5 5 ) and 6-hydroxy-2-methyl-2-azabicyclo L2.2.21 octane (118) Bridgehead nitrogen compounds related to quinolizidine, indoli-

.

23

HERBERT S. AARON

50

WH

51

52

N . . . . . . . . .HO \

CH3

54

53

zidine, and pyrolizidine systems that have been assigned in this way have been reviewed (119). More recently, the configurations of the four 4-phenylquinolizidin-1-01 isomers were assigned on the basis of their dilute-solution spectra (120). This system is further discussed below. A l s o , hydrogen bonding in hydroxymethyl derivatives of quinolizidine (e.g., 56) (121) and indolizidine systems (e.g., 57) (122) have been used for conformational assignments. The stereochemistry of two dibenzotropanol analogs

55

57

56

was assigned on the basis of the OH*-" bond (voH 3560 cm-l) present in the syn-OH epher (58) (123). The anti-OH epimer appears to exist in an OH***Tconformation (vOH 3595 cm-l). In the l-t-butyl-2-methylazetidin-3-ol system the cis isomer ( 5 9 ) was assigned on the basis of a weak intramolecular hydrogen bond (uOH 3580 cm-l), which is absent in the spectrum of the trans isomer (124).

58

59

24

INTRAMOLECULAR HYDROGEN BOND

The r e l a t i o n s h i p between t h e s t r e n g t h of t h e i n t r a m o l e c u l a r hydrogen bond, expressed a s AvOH, and t h e molecular geometry and/or i n t r a m o l e c u l a r hydrogen b r i d g i n g d i s t a n c e (see Sect. 11) may be i l l u s t r a t e d by comparison of a series of O H * * " bonded compounds. Thus, i n h y d r o x y l - s u b s t i t u t e d 5-membered-ring n i t r o gen systems 60-64 an i n t r p o l e c u l a r hydrogen t o n i t r o g e n ( O H - * * N) d i s t a n c e of 3.0 2 0.2 A i s o b t a i n e d from Dreiding models, and t h i s i s about t h e l i m i t i n g d i s t a n c e through which hydrogen b r i d g i n g can o p e r a t e i n t h e s e systems. Accordingly, weak i n t r a molecular hydrogen bonding (AvOH 30 t o 45 c m - l ) i s s e e n ( 6 0 - 6 2 ) h e r e , i f a t a l l (63, 6 4 ) (125). Moreover, f o r weakly bonded systems some f r e e OH s p e c i e s i s almost always observed, c o r r e s ponding t o rotamer forms of t h e OH group (e.g., 6 0 a ) , a l t h o u g h i n some cases (e.g., 60 and 6 1 ) , t h e e q u i l i b r i u m may g r e a t l y f a v o r the bonded form.

6-H

po Nvt '.. ' . H / 0

6 Oa

60b

T

H

N..

' '

H

62

61 OH

I

CH3

63

64

I n 3-hydroxypiperidine ( 6 5 ~ )and r e l a t e d r i n g systems ( e . g . , 66) t h e O H * * " b r i d g e i s more l i n e a r and s h o r t e r (about 2.4 fo , and h e r e moderately s t r o n g i n t r a m o l e c u l a r hydro en bonds a r e formed, which g i v e AvOH v a l u e s i n t h e 85 t o 110 cm-' range ( 9 , 1 2 6 ) . In compounds t h a t c o n t a i n t h e amino a l c o h o l s u b s t i t u e n t s i n e i t h e r a gauche (56) o r syn-axial r e l a t i o n s h i p (54, 6 7 ,

a

RON&

q

"HO

65a

H

OH

65b

'

66

-HO

25

HERBERT S . AARON

6 8 ) , a near l i n e a r O H * * " b r i d g e w i t h a hydrogen t o n i t r o g e n d i s t a n c e of ca. 1 . 9 A i s o b t a i n e d from t h e models, and AvoH v a l u e s from ca. 240 t o 340 cm-l have been recorded (117,126). Some of t h e l a r g e s t AvOH v a l u e s , however, a r e seen i n substit u t e d 4-piperidin01 b o a t s p e c i e s (e.g., 3 and 6 9 ) , where b r i d g i n g d i s t a n c e s as s h o r t a s 1.6 A may be measured from t h e mode l s , and AvOH v a l u e s ranging from 240 cm-l f o r 3 (9) t o ca. 400 cm-l f o r 69 (35d) and o t h e r s (127) have been observed. F i n a l l y , compound 70 has been prepared, i n which an a p p a r e n t hydrogen t o amino n i t r o g e n d i s t a n c e of c a . 0 . 4 f( i s found from t h e model. S p e c t r a l d a t a were r e p o r t e d only f o r a chloroform (128). s o l u t i o n , however, as a broad band a t 3100 t o 3450 cm"

69

H

67

68

70

Such c o r r e l a t i o n s have been used t o show t h a t an e a r l i e r assignment of a band of AvOH 40 c m - l i n a s u b s t i t u t e d 4-piperi d i n o l t o a hydrogen-bonded b o a t conformation a c t u a l l y r e s u l t s from a low-frequency rotamer form of t h e f r e e OH group ( 2 5 ) . By t h e same token t h e claim (129) of an i n t r a m o l e c u l a r O H * * " bonded b o a t conformation i n t h e spectrum of cis-4-aminocyclohexanol (voH 3450 cm-1) should be r e i n v e s t i g a t e d , as suggested

(1).

For O H * - " bonded systems, t h e presence o r absence of f r e e OH rotamer forms may be r e l a t e d t o t h e Avo v a l u e of t h e hydro-

gen bond. Thus, a s noted above f o r weakly Eonded compounds (AVOH <45 cm-l) , some f r e e OH s p e c i e s ( e . g . , 60u) i s i n v a r i a b l y p r e s e n t . However, f o r t h e more Strong1 bonded 1- and 3-quino100 cm-y), no f r e e OH rotamer l i z i d i n o l (66) systems (AvoH forms a r e observed (130). T h e r e f o r e , i n t h e conformational a n a l y s i s of amino a l c o h o l s t h a t c o n t a i n an O H * - * N bonded spec i e s with AvOH 2 100 cm-l, any f r e e OH corresponding t o a s i m p l e OH rotamer form of t h e bonded s p e c i e s i s presumably small enough t o be ignored. Any f r e e OH observed i n such s p e c t r a , t h e r e f o r e , i s presumably caused by o t h e r molecular conformat i o n s ( e . g . , 6th).

INTRAMOLECULAR HYDROGEN BOND

26

A number of I R studies of hydrogen bonding in substituted 3-piperidinol systems have been reported, and conformational assignments have been given (131-135). For the unsubstituted parent 3-hydroxypiperidine ( 6 5 , R = H), the population of the four possible conformers in dilute carbon tetrachloride solution has been assigned (135). Conformational analyses of hydrogenbonded hydroxyalkylpyridine (136) and hydroxyalkylpiperidine (39, 126, 136) systems have been presented. Hydrogen bonding has been reported in decahydroquinoline (68, 71-73) and in tetra- and decahydroisoquinoline (67, 74-77) systems, and the conformational equilibria (e.g., 7 5 ) have been assigned (126,135,137-143). The cis-decahydroisoquinolin-4a(76) and 46-01 ( 7 7 ) epimers each form an intramolecular hydrogen bond. Their respective configurations, however, can be assigned on the basis of the smaller relative proportion of bonded O H * * * Nspecies observed in 7 6 , mainly caused by the unfavorable syn-axial CH2/0H interactions that are present in this species (126,142). Intramolecular hydrogen bonding also has been

--& "

c

N

H

H

71a

H

71b

72a

72b

OH I /

d 0-H

H :

73

74

OH.

7 5a

75b

H

27

HERBERT S . AARON

reported for isomers of a decahydroquinoline-9,lO-diol system (144). Only in the case of the two 9,lO-cis isomers, UOH 3434 and 3490 cm-l , respectively, were the configurations not assigned. However, the fact that the former isomer also contains a free OH band (Au 3614 cm-l), which is not observed in the latter, suggests that the configurations should be assigned as 78 and 7 9 , respectively.

‘Me

0

Ar

Ar 78a

78b

80

79

Intramolecular OH***Nbonding studies of vicinal amino alcohols in substituted cyclohexane and cyclopentane derivatives have also been studied, and AUOH values for the cis and trans isomers were reported (145). In the trans-substituted t-butylcyclopentane isomers (e.g., 80) an intramolecular hydrogen bond is observed ( 1 4 5 ~ ) which ~ is not seen in trans-cyclopentane-l,2diol ( 2 ) . Boat conformers in substituted 4-piperidinol and related systems have been observed in the form of the intramolecular bonded species, as indicated for 3 , 52, and 69. Although hydrogen bonding does aid the formation of the boat conformation, these

28

INTRAMOLECULAR HYDROGEN BOND

systems generally require, in addition, a destabilizing interaction in the free OH form, if a detectable concentration of the boat species is to be observed. Thus OH**" bonding is not observed in N-methyl 4-phenyl-4-piperidinolIbut is observed in pentamethyl-4-phenyl-4-piperidinol ( 8 1 ) (146). The NH analo 81 also exists in equilibrium between a chair (uOH 3604 an- ,Of carbon tetrachloride) and boat (UOH 3388 cm-l) form (147), whose position (26% boat) is similar to that of the N-methyl analog (34% boat). Boat formation is also seen in 8-granatanol ( 3 ) and 52 (but not in 4 or 8 2 ) , undoubtedly because of steric interaction of the 3,7 position of the double-chair form (e.g., 3 a ) . The related bispidinol systems 69 (35d) and 83 (148) also form intramolecular hydrogen bonds (147). For 8 3 the bonded conforma) a majority (75%) of the molecular species, tion ( 8 3 ~ 'constitutes presumably due to anomeric or steric effects in the double-chair forms (83a and 8 3 b , respectively). Intramolecular hydrogen bonding caused by boat formation has been reported for the a - ( 8 4 ) and

s

N' 'CH3

81 b

81a

8 3a

82

83c

83b

B-(85) , but not the y- (86), isomers of promedol (149), a result that is consistent with their configurational assignments, The formation of the boat conformation by 84 and 85 is somewhat analo-

O H

H3C

N-CH H3

H

3HC*OH

N-cH~ CH3

84

85

P

H3C

h

vN-CH 3

H

86

29

HERBERT S. AARON

87a

87b

gous t o t h a t observed f o r t h e 2-phenyLquinolizidin-2-ol isomer 87 (31, 1 5 0 ) . I n t h e l a t t e r 7% of t h e b o a t s p e c i e s ( 8 7 b ) h a s been a s s i g n e d (150b).

NMe2

OH

k

H

8 8a

88b

A b o a t conformation h a s been suggested f o r t h e s u b s t i t u t e d d e c a l i n 8 8 , based on a s t u d y of hydrogen bonding i n cis-2-dimethylaminocyclohexanol (151). Firmer evidence of b o a t f o r m a t i o n , however, has been given f o r t h e trans-amino a l c o h o l isomer 8 9 ,

&+-" =WH NMe

8 9a

OH

.;\

-t

.:' N M e

89b

Y

9 0 : X = N M e 2 , Y = OH 9 1 : X = OH, Y = NMe2

and a l s o f o r the perhydroindane analogs 90 and 91 (152,153). Here t h e b o a t s p e c i e s was formed more r e a d i l y i n t h e perhydroindane than i n t h e d e c a l i n s e r i e s , and a s i g n i f i c a n t amount (26%) (152) of bonded b o a t conformer w a s even observed when t h e bridgehead methyl of 91 was r e p l a c e d by hydrogen. The t r e n d c a r r i e s over i n t o t h e corresponding t r a n s - f u s e d cyclobutane WH=,-&

NMe

92a

Me N

92b

'.+"

INTRAMOLECULAR HYDROGEN BOND

30

analog ( 9 2 ) , where the majority of the molecular species apparently exists in the O H - * * Nbonded form (153). On the other hand the correctness of the assignment (154) of an exclusive boat conformation to 93 (R = H, Me, or phenyl) is questionable on conformational grounds, especially since spectra of the corresponding'N-methyl analogs in Ccl4 reveal no such species. The cause of the anomalous spectra of the 93 series is uncertain, therefore, but might result from solvent (CHC13) reaction or formation of a persistent dimer. R \ HC- OH,

e

AR' 'fH2 -OH

R

93b

94

alkaloid configurations Assignments of some -piperidin-3-01 have been made (155), in part, on the basis of their confonnational analysis, as earlier applied to the carpaine alkaloids (156). Configurational assignments in solanum alkaloids have been based on their intramolecular hydrogen bonds (157). Dilute solution spectral study of some a- (hydroxymethyl-) aziridines (94)) - _ has been reported (158). Ph\ ,Ph

A\ ,Et CH- CH I

Me2

95

Intramolecular hydrogen bonding has been studied in acyclic amino alcohols of the type RzN-(CH2).-0H (159), and also in various C-substituted analogs (159a,d). In the series Et2-N(CHz),-OH (n = 2 to 6) the largest value of AvOH was recorded for n = 4 (159b,c). However, the percentage of bonded species decreased in the order of increasing value of n (corresponding to the increasing entropy loss of the bonded species), and was absent entirely for n = 6 (159b). Very strong hydrogen bonding with little or no free OH was recorded (159d) for the isomeric methadols (95), possibly due to the contribution of a gemdialkyl (160) or Thorpe-Ziegler (79d) effect. The isomethadol isomers were also studied with similar results (159e).

31

HERBERT S. AARON

I n t r a m o l e c u l a r OH**" hydrogen bonding w a s s t u d i e d i n a series of N-(2-hydroxyethyl)propynylamines ( 9 6 ) , and t h e v a l u e s of AVOH were c o r r e l a t e d w i t h t h e b a s i c i t i e s (pKb) and w i t h certain substituent constants related t o nitrogen substitution ( 1 5 9 f ) . For a s e r i e s of amino a l c o h o l s of t h e t y p e 97 and t h e corresponding ( R S ) analog, b o t h O H * - - N and O H o * * Oo r O H * * * S bonding were observed (159g). Attempt5 t o c o r r e l a t e AVOH w i t h t h e b a s i c i t y of t h e m i n e s ( p K b ) , however, were u n s u c c e s s f u l . A s e r i e s of compounds of t h e t y p e 98 were examined, and a l i n e a r c o r r e l a t i o n between an i n c r e a s e i n t h e s t r e n g t h of t h e hydrogen bond (AVOH) and a d e c r e a s e i n b a s i c i t y o f t h e amino a l c o h o l w a s o b t a i n e d , which s u g g e s t s t h a t t h e formation of t h e intramolec u l a r hydrogen bond causes t h e d e c r e a s e i n t h e b a s i c i t y of t h e

R'

R HCEC-CH

I

-N-CH

2 : 1 2 HOP2

RO-CH

I

Ar-C-(CH2)n

-CH-CH2

2 1 I OH...NR'

I

2

97

96

\

OH..,NR2

98

amine (159h). I n f l e x i b l e a c y c l i c systems corresponding t o s t r u c t u r e s such as 98, however, it i s u n l i k e l y t h a t t h e i n t r a molecular hydrogen bond i s r e s p o n s i b l e f o r t h e observed b a s i c i t i e s of t h e s e compounds. Thus, although AvOH i n c r e a s e s w i t h t h e v a l u e of n i n t h e s e systems, t h e p e r c e n t a g e of molec u l a r s p e c i e s i n t h e bonded form becomes correspondingly s m a l l e r (due t o t h e entropy e f f e c t ) even i n nonaqueous media. I n t r a molecular hydrogen bond f o r m a t i o n , t h e r e f o r e , would have a v a n i s h i n g l y s m a l l e f f e c t on t h e b a s i c i t y of t h e system. I n a n aqueous medium, moreover, t h e very s t r o n g i n t e r m o l e c u l a r O H * - " bonding w i t h s o l v e n t most probably t a k e s over a l m o s t e x c l u s i v e l y , e s p e c i a l l y f o r v a l u e s of n > 2. F i n a l l y , f o r e p i m e r i c amino a l c o h o l s t h a t a r e conformationally f i x e d , t h e o p p o s i t e c o r r e l a t i o n i s i n v a r i a b l y observed. That i s , t h e epimer which i s hydrogen bonded i n nonaqueous s o l u t i o n i s i n v a r i a b l y t h e s t r o n g e r base i n aqueous s o l u t i o n (115,125,130,161).

F.

The O H - * * S Hydrogen Bond

I n t r a m o l e c u l a r O H * * * S hydrogen bonding i n t h e w-ethylmercaptoalkanol [Et-S-(CH*),-OH] s e r i e s h a s been s t u d i e d , and t h e e q u i l i b r i u m p o s i t i o n f o r the f r e e and bonded OH s p e c i e s w a s compared t o those of corresponding compounds c o n t a i n i n g an oxygen o r n i t r o g e n i n s t e a d of s u l f u r as t h e proton-acceptor s i t e ( 1 6 2 ) . Although t h e AVOH v a l u e s i n c r e a s e i n t h e o r d e r 0 < S < N , t h e

32

INTRAMOLECULAR HYDROGEN BOND

e q u i l i b r i u m p o s i t i o n s t a n d s i n t h e o r d e r S < 0 < N , and i s much lower i n t h e s u l f u r analogs t h a n i n \ t h e o t h e r two. I n a d d i t i o n , bonding is observed i n t h e s u l f u r series o n l y f o r n = 2 o r 3 , cornpared t o n = 2 t o 5 f o r t h e oxygen and n i t r o g e n analogs. On t h i s b a s i s i t was concluded t h a t t h e s u l f u r atom i s much lower i n i n t r a m o l e c u l a r hydrogen bonding a b i l i t y t h a n t h e oxygen and n i t r o g e n atoms, and t h a t t h e AuOH v a l u e cannot be used f o r comparing s t r e n g t h s of i n t r a m o l e c u l a r hydrogen bonds when d i f f e r e n t proton-acceptor atoms are involved. A similar r e l a t i o n s h i p w a s r e p o r t e d i n Sect. VI-A f o r comparisons of intramolec u l a r bonded OH***halogensystems. A p o s s i b l e e x p l a n a t i o n of t h e s e r e s u l t s might be o b t a i n e d from a reexamination of t h e d a t a r e p o r t e d f o r tetrahydropyran3-01 (163) and i t s corresponding t h i o (99) analog ( 1 6 4 ) . Although

n

99a

99b

e x a c t e q u i l i b r i u m c o n c e n t r a t i o n s were n o t a s s i g n e d f o r t h e former (and should be reconfirmed u s i n g band areas i n t h e l a t t e r ) , a comparison of t h e i r p u b l i s h e d s p e c t r a i n d i c a t e s t h a t t h e percentage o f bonded O H * * * O (AUOH 16 c m - l ) s p e c i e s i s appare n t l y g r e a t e r t h a n t h a t of t h e bonded O H * * * S (AUOH 93 c m - l ) s p e c i e s i n these two compounds. The e q u i l i b r i u m p o s i t i o n of e a c h , however, r e f l e c t s t h e summation of a l l t h e i r conformational i n t e r a c t i o n s . These i n c l u d e t h e r e l a t i v e s t r e n g t h s of t h e i r hydrogen bonds ( a t t r a c t i v e ) , t h e i r s y n - a x i a l H/OH i n t e r a c t i o n s ( r e p u l s i v e , b u t probably comparable i n each s y s t e m ) , and t h e i r syn-axial C-H/O-electron p a i r and C-H/S-electron p a i r i n t e r a c t i o n s ( a t t r a c t i v e , i f a p p l i c a b l e i n t h i s argument), r e s p e c t i v e l y . Thus d i f f e r e n c e s i n e q u i l i b r i u m p o s i t i o n s of e i t h e r c y c l i c o r a c y c l i c c a r b i n o l s c o n t a i n i n g d i f f e r e n t heteroatoms might depend more on t h e i r r e l a t i v e H/electron p a i r i n t e r a c t i o n s t h a n on t h e r e l a t i v e s t r e n g t h s of t h e i r i n t r a m o l e c u l a r hydrogen bonds suggested on t h e b a s i s of t h e i r AUOH v a l u e s , assuming t h a t t h e l a t t e r is s t i l l a v a l i d c r i t e r i o n , even when d i f f e r e n t p r o t o n a c c e p t o r s a r e involved. Transannular hydrogen-bond formation h a s been observed i n e q u i l i b r i u m w i t h f r e e OH i n t h e 4-hydroxythiacycloheptane series ( 1 6 5 ) . For 100 t h e e q u i l i b r i u m p o s i t i o n t e n d s t o s h i f t i n t h e d i r e c t i o n of t h e bonded s p e c i e s a s R changes i n t h e o r d e r H < M e < Ph (165a). C o n f i g u r a t i o n a l and conformational assignments of some 3hydroxytetrahydrothiopyran-4-ones ( 1 0 1 ) had been g i v e n on t h e basis of t h e i r I R s p e c t r a l d a t a ( 1 6 6 ) , and hydrogen-bonding

HERBERT S . AARON

8

33

s t u d i e s i n some d i t h i a n e systems have been r e p o r t e d ( 1 6 7 ) , a s d i s c u s s e d i n Sect. V I I .

H

I

o+.

;

0

2

c

N

Me QH

100

H

101

102

The c o n f i g u r a t i o n s of t h r e o ( 1 0 2 ) and e r y t h r o e p i s u l f i d e isomers of 8 have been a s s i g n e d , a s n o t e d above ( 8 ) . I n t h e s u l f e n y l - s u b s t i t u t e d i n d a n o l ( 2 0 3 ) (168) and n o r b o r n e o l ( 2 0 4 ) (169) systems, only t h e c i s isomers form a n i n t r a m o l e c u l a r hydrogen bond. I n t h e l a t t e r system t h e c o r r e s p o n d i n g OH-**O+S% I bonded compounds were a l s o r e p o r t e d .

,

‘Ar

103

104

I n t r a m o l e c u l a r hydrogen bonding i n a r o m a t i c s u l f i d e s , s u l f o x i d e s , and s u l f o n e s h a s been r e p o r t e d (170,171). For a series of o r t h o - s u b s t i t u t e d t h i o p h e n o l s and o r t h o - s u b s t i t u t e d p h e n o l s , (1.145 c m t h e o r d e r s of frequency s h i f t s were found t o b e O H - - + c m - l ) > O H - * * O ?- SH***O (Q45 cm-l) > S H * * * S(Q19 an-’). The r e l a t i v e bond s t r e n g t h s , c a l c u l a t e d from t h e SchroederL i p p i n c o t t p o t e n t i a l f u n c t i o n model of t h e hydrogen bond, were g i v e n a s OH”-S > O H * * * O > S H * - * O’L S H * * * S( 1 7 2 ) . I t i s n o t cert a i n t h a t t h e s e c a l c u l a t e d assignments, which p e r t a i n o n l y t o a r o m a t i c s y s t e m s , are a c t u a l l y i n c o n f l i c t w i t h t h e r e s u l t s d e s c r i b e d above f o r O H * * + v s . O H * * * O bonded e q u i l i b r i a i n a l i p h a t i c systems. A b e t t e r u n d e r s t a n d i n g and a more p r a c t i c a l a p p l i c a t i o n of t h e s e r e s u l t s would b e o b t a i n e d , however, i f a c t u a l e q u i l i b r i u m p o s i t i o n s between f r e e and bonded s p e c i e s w e r e compared i n t h e a r o m a t i c compounds.

G. Miscellaneous Hydrogen Bonds I n t r a m o l e c u l a r hydrogen bonding by (donor) S H groups h a s been reviewed ( 1 7 3 ) . I n g e n e r a l , a l i p h a t i c SH groups form weak hydrogen bonds, which may b e d i f f i c u l t t o d e t e c t by I R methods. Thus, a l t h o u g h bonding i n o r t h o - s u b s t i t u t e d t h i o p h e n o l s h a s been

34

INTRAMOLECULAR HYDROGEN BOND

reported (174), no evidence of bonding in sane substituted allphatic thiols could be detected (175). Intramolecular NH***Ohydrogen bonding in ethyl a- ( 1 0 5 ) and 8-aminoalkanoates ( 1 0 6 ) has been investigated (176) through measurement of t h e NH and C=O stretching absorptions, and compared to that in the corresponding mercapto analogs, (175b) R-N-CH2-C-OE t

I

H

I1

0

2 05

R-N-CHz-CH2-C-OEt

I

H

11

0

106

(which show no evidence of any hydrogen bonding) and the hydroxy analogs (82,86), which form an intramolecular hydrogen bond exclusively between the OH and C=O group. In the NH system the a-esters ( 1 0 5 ) gave no evidence of hydrogen-bond formation; in the 8-esters ( I 06), however , hydrogen bonding occurs , predominantly between the NH and C=O groups. Intramolecular NH***nhydrogen bonding has been studied in N-benzylanilines, ArCH2NHPh (177), and in N-(w-phenylalky1)aniline, Ar (CH2)nNHAr (178), and compared to the corresponding OH' *TI and NH***Ointeractions in Ar(CH2)nOH and N-(w-phenoxyalkyl)anilines, ArO (CH2),NH$ (179), respectively. Here, the NH.-.O and NH*-*nhydrogen bonding was observed for n = 1 to 5, with the OH***abonding only for n = 1 to 3. For compounds of the type EtO(CH2)nCONHCH3 the percentage of intramolecular NH*-*OEtbonding decreases in the order n = 1 > 2 > 3 (due to the entropy effect), while AwOH increases in the reverse order (180). Thus for a-ethoxy N-methylacetamide (n = 1) a single band was observed, assigned as NH"'OEt, whereas for 8-ethoxyN-methylpropionamide an NH doublet at 3468 and 3409 cm-l was observed, assigned as tree NH and NH**-OEt,respectively. The 2-chloro-substituted N-methylacetamides, such as ClCH2CONHCH3, exist exclusively in an intramolecular NH***Clbonded form (Q~3450 cm-l) (181). Intramolecular hydrogen bonding in some diacyldiphenylamines has been assigned (182) (based on the carbony1 absorption) as a bifurcated hydrogen-bonded species ( 1 0 7 ) in equilibrium with a singly bonded conformer.

107

108

Intramolecular hydrogen bonding in hydroxy acids has been studied, but conformational assignments are often complicated by the presence of a multitude of bands. Thus in 2-hydroxy acids bands at ca. 3615, 3560, 3525, and 3440 cm-l were assigned, respectively, to the unassociated alcoholic OH, the alcoholic

HERBERT

S.

35

AARON

OH bonded to the acid group in a dimer, the free OH of the carboxylic acid group, and the OH of the latter intramolecularly bonded to the alcoholic OH group (183). In a-hydroxyisobutyric acid, however, the corresponding bands were all assigned to monomeric species, with the strong band at 3575 cm-l being assigned to the alcoholic OH intramolecularly bonded to the acid carbonyl group (184). Studies on y-hydroxy acids have also been reported, but conformer percentages were not given, due to uncertainties in the band assignments (80). In salicylic ( 1 0 9 ) and mandelic (110) acids, on the other hand, the compounds exist exclusively as bonded species, apparently with the phenolic and alcoholic hydroxyls, respectively, bonded to the carbonyl oxygen of the carboxylic acid (184).

109

110

Dilute-solution spectra of a-, 8-, and y-alkoxy-substituted carboxylic acids have been recorded (185). For the a-substituted acids, intramolecular hydrogen bonding by the OH of the carboxylic acid group was observed as an equilibrium between free (ca. 3530 cm-l) and COOH***Obonded species. In the B- and y-substituted acids, however, no intramolecular hydrogen bonding was observed. In the a-hydroxy acids the presence of the intramolecularly bonded five-membered chelate ring may be confirmed by an unusually high-frequency exocyclic band (ca. 1782 cm-l) (185b). Intramolecular hydrogen bonding by the carboxylic acid OH group has been studied (186) in substituted o-methoxybenzoic acids. In general, an equilibrium between bonded and free carboxylic acid OH species was observed, and the frequency shift was correlated with the position and alectronegativity of the substituent. However, when the carboxy group was flanked by the second substituent, intramolecular hydrogen bonding was completely suppressed. 0-Methoxy-substituted phenoxyacetic ( 1 1 1 ) and phenylthioscetic acids ( 1 1 2 ) have been investigated (187). The former was found to exist as an equilibrium mixture, with free OH (ca. 3530 cm), OH,bonded to the a-phenoxy oxygen, and OH bonded to the methoxyl oxygen atom. In the latter, however, only a free OH and an OH***OMespecies was observed. Intramolecular OH*.*O=C ( T I ) bonding has been noted in phenylglyoxylic acid ( 1 1 3 ) (188). Conformational equilibria have been observed (189a) between free OH and OH***Fespecies in a-hydroxyalkylferrocene ( 1 1 4 , n = l), and also with an O H - * * Tspecies in the B-hydroxyalkyl homolog (n = 2). These assignments are in agreement

36

INTRAMOLECUAR HYDROGEN BOND

112, 112,

x=0 x=s

113

with those of another study (1901, in disagreement with some earlier work. Intramolecular OH***OHand OH***O=Cbonding in 1,l'-substituted ferrocene systems has also been described (189b). Spectral studies of intramolecular hydrogen bonding also have been reported, and conformational species assigned in nitro alkanols (e.g., 2 1 5 ) (191) and 1- ( 2 1 6 ) and 2-cyano alcohols (192). MeCH-CH2 -OH I N02

R -C

/CN

H O '

116

115

114 Conformational equilibria for a- and B-hydroxyphosphoryl compounds (117) have been reported (193). In this series a stronger intramolecular bond was observed for the @ (six-membered chelate ring) than f o r the CL (five-membered chelate ring) isomers in both the OH***O=P(127b) (3490 vs. 3590 cm-l) and OH-**OR( 1 1 7 ~ )(3600 vs. 3615 cm-') conformers (193a). This 0 II

(EtO)2-P-(CH2)n-OH 117a

0... . .HO

II \

(EtO) -P 2

/

(CH21

tl 117b

117c

37

HERBERT S. AARON

r e s u l t c o r r e c t s t h e e a r l i e r o p p o s i t e assignment of r e l a t i v e bond s t r e n g t h s i n a r e l a t e d system which occurred because t h e s t u d y was n o t c a r r i e d o u t a t s u f f i c i e n t d i l u t i o n t o e l i m i n a t e a l l i n t e r m o l e c u l a r bonded species (193b). I n a n o t h e r s e r i e s p e r s i s t e n t i n t e r m o l e c u l a r bonded dimers were noted even i n very d i l u t e C C l 4 s o l u t i o n s ( 1 9 3 c ) . I n t h e s u b s t i t u t e d oxaphospholan-3-01 r i n g system a c i s OH/P=O isomer (e.g., 118) could be d i s t i n g u i s h e d from i t s corresponding t r a n s isomer on t h e b a s i s of i t s i n t r a m o l e c u l a r O H * * * O = P hydrogen bond (193d).

HO

118

VII.

QUANTITATIVE APPLICATIONS

The r e l a t i v e i n t e n s i t i e s of s p e c t r a l bands of i n d i v i d u a l conformers and/or of model compounds have been used t o calcul a t e t h e p o s i t i o n s and thermodynamic parameters of conformat i o n a l e q u i l i b r i a , a s i n d i c a t e d i n numerous examples c i t e d above. The method i s a g e n e r a l one t h a t i s n o t limited t o dil u t e - s o l u t i o n s p e c t r a l r e s u l t s i b u t assumes t h a t a p a r t i c u l a r s p e c t r a l band can be a s s i g n e d t o a s p e c i f i c conformation. Thus f o r a n e q u i l i b r i u m between conformations C1 and C2 t h e i n t e g r a t e d i n t e n s i t y o r a r e a ( A ) of a band t h a t i s s p e c i f i c f o r a p a r t i c u l a r conformer i s g i v e n by A = aC1, where a i s t h e i n t e g r a t e d a b s o r p t i o n c o e f f i c i e n t , C i s t h e c o n c e n t r a t i o n , and 1 i s the c e l l l e n g t h (194). The e q u i l i b r i u m c o n s t a n t ( K ) i s t h e n g i v e n by

I f one assumes t h a t a1 = a2 (461, then K i s o b t a i n e d d i r e c t l y from t h e r a t i o of t h e band areas. The s t a n d a r d f r e e energy change i s t h e n g i v e n by AGO

= -RT I n

K

[41

38

INTRAMOLECULAR HYDROGEN BOND

In some cases the equilibrium position has been extimated simply from the ratio of the extinction coefficients of the band maxima (195). It is usually assumed, however, that a l # " 2 . In this case the equilibrium constant cannot be determined unless an a l / a ratio is assigned. However, if one assumes that a 1 / a 2 (also AS8 and AHo) remains constant over a given temperature range (196), then, by substituting for K (eq. 131) into the van't Hoff equation RT In K = -AHO

+

TASO

[SI

the standard enthalpy (AHo)may be obtained as the slope (-AHo/R) of the plot of In A2/A1 vs. 1/T:

Recently, Hartman et al. (194) have shown that the assumtion of the temperature independence of a l / a , if correct, may be verified in a simple way. Taking the total concentration CT = C 1 + C 2 and substituting A = acl for each conformer, one obtains

or

If a l / u 2 is indeed temperature independent, then a plot of A 1 for a series of temperatures will generate a straight line with slope - a l / a 2 . The free energy and entropy change can then be calculated from eqs. [31 , [41,and [61. An alternative method of determining ASo (hence, AHo and AGO) has been suggested by Mizushha and co-workers (197), based on the assignment of a third spectral band that is common to both conformers, and measurement of its intensity over the temperature range studied relative to that of each conformer band. It is assumed that the absorption coefficients of the common band and the specific conformer bands all change with temperature in the same way (198). Some free OH-bonded OH**" equilibria have been studied (153) by the method of Hartman and, surprisingly, the a 1 / a 2 ratio was found to be constant between 30 and 8 0 ° , even though the absorbance of each band maximum was used instead of the area in eq. [81. The results thus obtained differed, generally markedly, from those determined for the same systems when a 1 was taken equal to a 2 , or when the extinction coefficient of the free OH band was compared to that of a model compound containing only free OH. VS. A2

HERBERT S. AARON

39

For t h e s i m p l e s t a p p l i c a t i o n of t h e d i l u t e - s o l u t i o n method, however, t h e p o s i t i o n of t h e f r e e OH-bonded OH e q u i l ibrium i s probably b e s t a s s i g n e d from t h e i n t e g r a t e d i n t e n s i t y ( a r e a ) of t h e f r e e OH band, i n comparison t o t h a t of a 100% f r e e OH r e f e r e n c e model ( 9 , 1 2 6 ) , o r , a l t e r n a t i v e l y , from t h a t of t h e bonded OH band, i n comparison t o a f i x e d o r conformat i o n a l l y b i a s e d [ananchomeric ( 5 1 ) ] bonded r e f e r e n c e model ( 1 3 4 , 1 5 2 ) . Thus, a l t h o u g h t h e r e i s g e n e r a l l y a l a r g e v a r i a t i o n i n t h e molar band a r e a s of bonded OH s p e c i e s , a bonded OH ref e r e n c e model a p p e a r s a p p l i c a b l e t o compounds having c l o s e l y r e l a t e d s t r u c t u r e s . Except f o r q u a l i t a t i v e p u r p o s e s , t h e e q u i l i b r i u m p o s i t i o n may n o t b e r e l i a b l e a s s i g n e d from t h e r a t i o of f r e e t o bonded OH band a r e a s , a s h a s been done (761, because t h e a r e a of the bonded OH i s i n v a r i a b l y l a r g e r t h a n t h a t of a n e q u a l p e r c e n t a g e of f r e e OH s p e c i e s . The e q u i l i b r i u m p o s i t i o n a l s o should n o t be a s s i g n e d from t h e r a t i o of t h e bonded t o f r e e OH e x t i n c t i o n c o e f f i c i e n t s , o r from t h e an e x t i n c t i o n c o e f f i c i e n t i n comparison t o t h a t of a r e f e r e n c e OH model, bec a u s e , a s p r e v i o u s l y n o t e d , e x t i n c t i o n c o e f f i c i e n t s may v a r y c o n s i d e r a b l y , even f o r a x i a l and e q u a t o r i a l e p i m e r s , due t o t h e d i f f e r e n c e i n t h e p o s i t i o n of band maxima of t h e v a r i o u s f r e e OH rotamer forms t h a t may be p r e s e n t ( 9 ) . I n c o n t r a s t , f r e e OH band a r e a s a r e e s s e n t i a l l y e q u a l f o r a l i p h a t i c seconda r y a l c o h o l s of s i m i l a r s t r u c t u r e , whether a x i a l or e q u a t o r i a l , hence a r e a p p a r e n t l y independent of t h e OH rotamer c o m p o s i t i o n . Primary and t e r t i a r y a l c o h o l s , however, t e n d t o have l a r g e r and s m a l l e r molar band a r e a s , r e s p e c t i v e l y , hence r e q u i r e t h e i r own a p p r o p r i a t e r e f e r e n c e models, i f s i m i l a r l y s t u d i e d . T o a s s e s s o t h e r c o n f o r m a t i o n a l f a c t o r s i n a hydrogenbonded system, o r t o c a l c u l a t e t h e e q u i l i b r i u m p o s i t i o n f o r t h e corresponding compound w i t h o u t i t s OH s u b s t i t u e n t (hence, w i t h o u t a hydrogen b o n d ) , t h e e f f e c t of t h e hydrogen bond on t h e p o s i t i o n of t h e e q u i l i b r i u m must be t a k e n i n t o a c c o u n t . For example, one e s t i m a t e of t h e e f f e c t of t h e hydrogen bond on t h e rotamer composition of u n s a t u r a t e d a l c o h o l s ( e . g . , b e n z y l and a l l y 1 a l c o h o l ) was g i v e n as a b o u t 0.5 kcal/mol (Ah'),based on a comparison t o t h e e q u i l i b r i u m p o s i t i o n i n t h e c o r r e s p o n d i n g s a t u r a t e d alcohols (56). For more r i g o r o u s a p p l i c a t i o n t o c o n f o r m a t i o n a l a n a l y s i s , however, t h e e f f e c t of t h e i n t r a m o l e c u l a r hydrogen bond c a n p e r h a p s b e s t be t a k e n i n t o a c c o u n t by making a comparative conf o r m a t i o n a l a n a l y s i s of two s i m i l a r systems ( e p i m e r s , i f poss i b l e ) , i n o r d e r t o c a n c e l t h e f r e e energy c o n t r i b u t i o n of t h e i n t r a m o l e c u l a r hydrogen bond, which i s common t o b o t h . A l t e r n a t i v e l y , a v a l u e f o r t h e i n t r a m o l e c u l a r hydrogen bond may be a s s i g n e d from a n a n a l y s i s of t h e same o r a c l o s e l y r e l a t e d system, if a l l o t h e r c o n f o r m a t i o n a l i n t e r a c t i o n s may a l s o be assigned o r canceled. These methods were used t o a s s i g n t h e c o n f o r m a t i o n a l e q u i l i b r i a of t h e 1 , 3 - d i t h i a n e s 119 and 1 2 0 as ca. 1 7 and 80% f r e e OH s p e c i e s , r e s p e c t i v e l y , based on t h e i n t e g r a t e d i n t e n -

40

INTRAMOLECULAR HYDROGEN BOND

120a

120b

120c

s i t y of the'bonded OH i n 121 as a 100% bonded OH r e f e r e n c e ( 1 6 7 ) . Taking t h e conformational f r e e energy of t h e O H * * * S hydrogen

121 bond i n 120b from t h e 119 e q u i l i b r i u m , a -AGO v a l u e of o n l y 1.65 kcal/mol was o b t a i n e d f o r t h e 2-phenyl group i n 1 2 0 . I n t h e same way, b u t on a less r i g o r o u s b a s i s , t h e 2-phenyl group on a 1,3dioxane r i n g was a s s i g n e d a v a l u e o f 1 . 7 kcal/mol. However, t h i s r e s u l t i s i n c o n f l i c t w i t h t h e more r e c e n t v a l u e ( 3 . 1 kcal/mol) determined by NMR (113). The r e a s o n f o r t h i s discrepancy i s u n c e r t a i n , b u t may be caused i n p a r t , by t h e presence of a nonchair s p e c i e s , f o r example, 12Oc, which i s n o t p r e s e n t i n t h e model OH systems. The presence of a t w i s t - b o a t s p e c i e s i n t h e 2-phenyl-l13-dithiane systems has been suggested- by NMR s t u d i e s (199). By t h e d i l u t e - s o l u t i o n s p e c t r a l method t h e conformational e q u i l i b r i a of some trans-2-aminocyclohexanols ( 1 2 2 ) were a s s i g n ed (200). From t h e e q u i l i b r i u m p o s i t i o n t h u s observed and t h e

iPr 4

0

H

=

ipb. R2N .

NR2

122a

122b

'

41

HERBERT S . AARON

l i t e r a t u r e v a l u e s of t h e conformational f r e e e n e r g i e s of t h e individual substituents, t h e i n t e r a c t i o n of t h e v i c i n a l equatoria l R2N/OH groups ( i n 122b) was found t o be a t t r a c t i v e , e q u a l t o ca. 0.9 kcal/mol f o r OH/NH2, and 0.6 kcal/mol f o r OH/NMe2. Thus i n t h i s system t h e conformational c o n t r i b u t i o n of t h e hydrogen bond i s g r e a t e r than t h e v i c i n a l OH/NR2 s t e r i c r e p u l s i o n , t o g i v e , on b a l a n c e , a n e t a t t r a c t i v e i n t e r a c t i o n . By comparison, t h e corresponding OH/CH3 i n t e r a c t i o n h a s been found t o be r e p u l s i v e by 0.4 kcal/mol ( 2 0 1 ) . More r e c e n t l y , t h e conformational e q u i l i b r i u m of t h e t r a n s 8a- (72) and trans-88-decahydroquinolinols ( 7 2 ) have each been compared t o t h a t of t h e p a r e n t decahydroquinoline ( 1 2 3 ) . I n t h i s way a l l t h e conformational i n t e r a c t i o n s were c a n c e l e d , and t h e 123 e q u i l i b r i u m was c a l c u l a t e d t o be simply the average of t h a t of 7 1 and 7 2 , equal t o 0 . 5 kcal/mol i n f a v o r of t h e NH equatori a l form ( 1 2 3 b , 7 0 % ) a t 33’C ( 1 3 6 ) . A s i m i l a r r e s u l t has been

q‘ H

Y = W H

123a

123b

o b t a i n e d from s e v e r a l o t h e r I R s t u d i e s (196,202-205) n o t involvi n g d i l u t e - s o l u t i o n methods, where t h e e q u i l i b r i u m h a s a l s o been assigned from t h e r a t i o s of i n t e g r a t e d i n t e n s i t i e s of v a r i o u s s p e c t r a l bands, each a s s i g n e d t o a s p e c i f i c NH o r N-electron p a i r conformation. I n another example (120) a conformational a n a l y s i s w a s c a r r i e d o u t on t h e two predominantly c i s - f u s e d isomers of 4phenylquinolizidin-1-01 (124 and 1 2 5 ) . Here as i n t h e p r e c e d i n g

&+-qh H

124a

125a

LJ 124b

Y

H

INTRAMOLECULAR HYDROGEN BOND

42

example, t h e t w o e q u i l i b r i a were each d e f i n e d on t h e b a s i s of t h e syn-axial and p e r i i n t e r a c t i o n s i n t h e products ( 1 2 4 b and 1 2 5 b ) and t h e e d u c t s (124a and 1 2 5 a ) , t o g i v e an e q u a t i o n f o r each system. By adding and, respectively,.subtracting t h e t w o equat i o n s t o cancel common t e r m s , two new e q u a t i o n s were obtained from which t h e f r e e energy d i f f e r e n c e between t h e cis- and transq u i n o l i z i d i n e r i n g f u s i o n (defined as A G 4 ) and t h e conformational f r e e energy of t h e i r i n t r a m o l e c u l a r hydrogen bonds ( d e f i n e d a s AG&...N) were independently d e r i v e d . Tichg and co-workers s t u d i e d t h e 3 - p i p e r i d i n o l system ( 6 5 ) and concluded (134) t h a t t h e conformational s t a b i l i z a t i o n arisi n g from i n t r a m o l e c u l a r hydrogen bonding i s s t r o n g e r i n t h e N methyl than i n t h e NH compound, based on a comparison of t o t a l a x i a l OH (bonded p l u s nonbonded) and e q u a t o r i a l OH s p e c i e s i n t h e two systems. Aaron and Ferguson (135), however, considered t h e e q u i l i b r i u m between t h e f o u r p o s s i b l e conformers i n each c a s e , and defined a conformational d i f f e r e n c e between t h e bonded and nonbonded a x i a l hydroxyl s p e c i e s i n terms of t h e i r s y n - a x i a l s u b s t i t u e n t r e l a t i o n s h i p s . On t h i s b a s i s t h e conformational a n a l y s i s of t h e hydrogen-bonded system w a s t r e a t e d i n a manner s i m i l a r t o t h a t used f o r s u b s t i t u t e d cyclohexane systems. When t h e e q u i l i b r i u m p o s i t i o n between any two conformers i n t h e NH system w a s then c a l c u l a t e d , t h e r e s u l t s were c o n s i s t e n t w i t h t h e assumption t h a t t h e conformational f r e e energy of t h e i n t r a molecular hydrogen b o n d o i s e s s e n t i a l l y e q u a l i n b o t h compounds (R = H o r Me), where AGOH ...N 50.55 kcal/mol. This r e s u l t , def i n e d as t h e conformational f r e e energy of a syn-axial OH/Ne l e c t r o n p a i r i n t e r a c t i o n (OH**") r e l a t i v e t o t h a t of t h e syna x i a l H/N-electron p a i r , w a s i n agreement w i t h t h a t c a l c u l a t e d from t h e 124 and 125 e q u i l i b r i a . I t i s presumed t o be a p p l i c a b l e t o t h e conformational a n a l y s i s of O H * * " hydrogen-bonded s stems with s i m i l a r geometry, having AUOH v a l u e s of 90 t o 100 For a group of O H * * " bonded compounds i n which entropy f a c t o r s were assumed t o be s m a l l , a roughly l i n e a r c o r r e l a t i o n of t h e confonna t i o n a l f r e e energy of t h e hydrogen bond w i t h AVOH has been r e p o r t e d a s AG&. .N 20.5 kcal/mol p e r 100 cm-' of A V ~ H (126). This c o r r e l a t i o n was based on t h e s t u d y of a l i m i t e d number of compounds, however, and t h e r e i s a l a r g e probable e r r o r i n some of t h e r e s u l t s . Nevertheless, it may be h e l p f u l f o r e s t i m a t i n g e q u i l i b r i u m p o s i t i o n s i n o t h e r r e l a t e d O H * * - N bonded systems i f v a l u e s cannot be more r i g o r o u s l y a s s i g n e d . t h e AG&...N

.

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Topics in Stereochemisty, Volume11 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1979 by John Wiley & Sons, Inc.

Reduction of Cyclic and Bicyclic Ketones by Complex Metal Hydrides JAMES R. B O N E Department of Chemistry, David Lipscomb College, Nashville, Tennessee

E. C. ASHBY School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia

I. 11.

Introduction

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

Complex Metal Hydrides:

Composition in Solution

and Mechanism of Ketone Reduction 111.

..........

54

Concepts of Stereochemical Control of Ketone Reductions by Complex Metal Hydrides

IV.

54

.........

67

Stereochemistry of Reduction of Model Ketones by

................ A. 4-t-Butylcyclohexanone . . . . . . . . . . . . . . B. 3,3,5-Trimethylcyclohexanone . . . . . . . . . . . C. Camphor . . . . . . . . . . . . . . . . . . . . . D . Nor camphor . . . . . . . . . . . . . . . . . . . . E. 2-#ethylcyclohexanone . . . . . . . . . . . . . . Complex Metal Hydrides

75 76

70 79

a0

81 53

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

54

................. Summary . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

F. V.

Cyclopentanones

85 88

92

I. INTRODUCTION Complex metal h y d r i d e s , have gained widespread use a s reducing a g e n t s f o r carbonyl compounds because of t h e i r a v a i l a b i l i t y and v e r s a t i l i t y . S t u d i e s of t h e s e r e a c t i o n s have g e n e r a l l y c e n t e r e d i n two a r e a s : (1) f u n c t i o n a l group s e l e c t i v i t y , t h a t i s , t h e s e l e c t i v e r e d u c t i o n of one f u n c t i o n a l group i n t h e p r e s ence of one o r more o t h e r f u n c t i o n a l groups; and ( 2 ) s t e r e o s e l e c t i v e r e d u c t i o n of k e t o n e s , i n p a r t i c u l a r , c y c l i c and b i c y c l i c ketones, by complex m e t a l hydrides. Most of t h e d i s c u s s i o n s concerning complex metal hydride r e d u c t i o n of o r g a n i c subs t r a t e s have c e n t e r e d on t h o s e f a c t o r s t h a t a r e thought t o cont r o l t h e course of t h e s t e r e o c h e m i s t r y . The one s i n g l e c a s e t h a t b e s t e x e m p l i f i e s t h e l a c k of understanding a s t o what f a c t o r s c o n t r o l t h e s t e r e o c h e m i s t r y of complex m e t a l h y d r i d e r e d u c t i o n s of ketones i s t h a t of 4-t-butylcyclohexanone. S e v e r a l t h e o r i e s have been p o s t u l a t e d t o e x p l a i n why most complex metal h y d r i d e s a t t a c k predominately t h e more hindered a x i a l s i d e of 4-t-butylcyclohexanone, b u t no one t h e o r y h a s been overwhelmingly s a t i s fying. I t i s t h e i n t e n t of t h i s c h a p t e r t o b r i e f l y review t h e s t e r e o c h e m i s t r y of complex m e t a l h y d r i d e r e d u c t i o n of c y c l i c and b i c y c l i c ketones, and t o e v a l u a t e t h o s e t h e o r i e s t h a t t h e aut h o r s b e l i e v e are t h e most s i g n i f i c a n t . F i r s t , t h e composition of s e v e r a l complex metal hydrides i n s o l u t i o n and t h e mechanism of t h e i r r e d u c t i o n of ketones a r e d i s c u s s e d . I t i s q u i t e c l e a r t h a t one must know something about t h e n a t u r e of t h e r e a g e n t i n s o l u t i o n b e f o r e using k i n e t i c d a t a and o t h e r i n f o r m a t i o n t o cons t r u c t a v a l i d t r a n s i t i o n s t a t e . If it is n o t p o s s i b l e t o cons t r u c t a v a l i d t r a n s i t i o n s t a t e , it i s impossible t o understand t h e reasons f o r t h e observed s t e r e o c h e m i s t r y of t h e r e a c t i o n s i n q u e s t i o n . Second, some t h e o r i e s of s t e r e o c h e m i c a l c o n t r o l involving t h e s e r e a c t i o n s are p r e s e n t e d and d i s c u s s e d . Then t h e s t e r e o c h e m i s t r y of r e d u c t i o n of s e v e r a l model ketones by d i f f e r e n t complex aluminohydrides i s d i s c u s s e d i n l i g h t of t h o s e t h e o r i e s of s t e r e o c h e m i c a l c o n t r o l t h a t a r e considered t o be most s i g n i f i c a n t .

11. COMPLEX METAL HYDRIDES: COMPOSITION I N SOLUTION AND MECHANISM OF KETONE REDUCTION The composition of L i B H , + , L i A 1 H 4 , and N a A 1 H 4 i n d i e t h y l

JAMES R. BOONE AND E . C . ASHBY

55

e t h e r and t e t r a h y d r o f u r a n (THF) h a s been i n v e s t i g a t e d (1,2) by means of conductance, m o l e c u l a r w e i g h t , I R , and NMR s t u d i e s . Sodium borohydride p r e s e n t s a s p e c i a l problem i n t h a t i t i s o f t e n employed i n a l c o h o l i c s o l v e n t s when used a s a r e d u c i n g a g e n t f o r k e t o n e s . The composition of NaBH4 i n t h e s e s o l v e n t s i s t h e n complicated s i n c e t h e borohydride i s n o t o n l y s t r o n g l y s o l . v a t e d by t h e a l c o h o l b u t a l s o r e a c t s w i t h t h e s o l v e n t t o some e x t e n t t o form alkoxy i n t e r m e d i a t e s , NaB(OR),Hb-n. Lithium borohydride a p p e a r s t o e x i s t as c o n t a c t i o n p a i r s ( L i + BH4-) o r t r i p l e i o n s ( L i + BH4- L i + and BHC L i + BHS;) i n THF. I n d i e t h y l e t h e r aggregates l a r g e r t h a n t r i p l e i o n s appear t o e x i s t . The e q u i v a l e n t conductance of LiBH4 i s dependent on conc e n t r a t i o n i n THF, b u t independent of c o n c e n t r a t i o n i n d i e t h y l e t h e r . These o b s e r v a t i o n s i n d i c a t e t h a t L i B H q a s s o c i a t i o n may b e more c o v a l e n t i n n a t u r e i n d i e t h y l e t h e r t h a n i n THF. These s t u d i e s (1, 2 ) a l s o i n d i c a t e t h a t t h e L i B H 4 c o n t a c t i o n p a i r ( I ) contains a disolvated lithium ion. S;i/H\B/H S/

H'

H' 1

On t h e o t h e r hand, l i t h i u m aluminum h y d r i d e i n THF c o n s i s t s mainly of s o l v e n t - s e p a r a t e d i o n p a i r s . The s o l v a t e d l i t h i u m i o n a p p e a r s t o b e f o u r - c o o r d i n a t e , a s determined by NMR, I R , and conductance s t u d i e s . The f a c t t h a t L i B H 4 i s a c o n t a c t i o n p a i r i n THF may b e e x p l a i n e d on the b a s i s t h a t t h e L i + and BH; a s s o c i a t i o n i s more c o v a l e n t i n c h a r a c t e r t h a n t h a t o f L i + and A l H q - , t h u s compensating f o r any loss of s o l v a t i o n energy inv o l v i n g t h e l i t h i u m i o n . I n d i e t h y l e t h e r L i A l H 4 c o n s i s t s mainly of c o n t a c t i o n p a i r s i n e q u i l i b r i u m w i t h smaller amounts of h i g h e r a g g r e g a t e s . The a d d i t i o n of s t o i c h i o m e t r i c amounts of THF t o a d i e t h y l ether s o l u t i o n o f L i A l H 4 r e s u l t s i n an i n c r e a s e i n t h e c o n d u c t i v i t y , i n d i c a t i n g t h a t s o l v a t i o n of L i + by THF i s s p e c i f i c ( 1 - 3 ) i n t h e mixed s o l v e n t a t a molar r a t i o of THF' t o L i A l H 4 of 4:1. S o l u t i o n s of N a A l H 4 i n THF c o n s i s t of a n e q u i l i b r i u m mixt u r e of c o n t a c t i o n p a i r s and s o l v e n t - s e p a r a t e d i o n p a i r s . T h i s c o n c l u s i o n i s based on thermodynamic d a t a o b t a i n e d through conductance measurements a s w e l l a s on a c a l c u l a t i o n of t h e c e n t e r t o - c e n t e r d i s t a n c e of t h e i o n p a i r . The c a l c u l a t e d d i s t a n c e i s a b o u t midway between t h a t found from c r y s t a l l o g r a p h i c d a t a f o r t h e s o l i d and t h a t o b t a i n e d from a D r e i d i n g model of t h e solv a t e d i o n p a i r . The i n d i c a t i o n i s that t h e r e a r e a b o u t e q u a l amounts of each t y p e of i o n p a i r . T e t r a h y d r o f u r a n s o l u t i o n s of L i A l H 4 and N a A l H 4 i n t h e t o 10-lM c o n s i s t of more t h a n 80% c o n c e n t r a t i o n range of i o n p a i r s . Below 10-51Y t h e f r a c t i o n o f f r e e i o n i s 20% o r more. Above 10-lM t h e f r a c t i o n of t r i p l e i o n s i s 20% o r more.

56

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

Studies (4-6) indicate that LiAl(ORlnH4-n (n = 1 to 3 ) compounds are more stable to disproportionation in solution when the OR group is not a secondary alkoxy group. Ebulloscopic molecular weight studies (1, 2) of LiAlHn(OCH3)k-n show that the degree of association increases as the number of methoxy groups increases. This association occurs because of the ability of the methoxy group to form bridge bonds between the lithium and aluminum atoms. Association increases with increasing concentration of these compounds. When the methoxy group is replaced by the t-butoxy group, association is much less, presumably because of the increase in steric hindrance caused by the larger size of the t-butoxy group. The association of alkoxy derivatives of LiBH4 in THF (1, 2 ) is similar to that of the alkoxy derivatives of LiAlH4 already mentioned. The secondary and tertiary alkoxy derivatives of NaBH4 , NaB (OR),Hb-n . (n = 1 to 3 ) , are more stable to disproportionation than primary ones in THF (7) and isopropyl alcohol (8-10). This may be explained on the basis that NaB(0R)q is not easily formed because of steric crowding about the boron atom when OR is secondary or tertiary. Steric hindrance of the secondary and tertiary OR groups about boron also reduces the possibility of an associated mixed-bridge intermediate necessary €or disproportionation to take place. In the reduction of ketones by LiBH4 and NaBH4, the presence of alkoxy intermediates is seemingly more significant than the presence of LiAl(0R)nHq-n in LiAlH4 reductions. The reason for this is that the alkoxy derivatives of the borohydrides are more reactive (7, 11) than the parent hydrides, LiBH4 or NaBH4, while LiAlH4 is more reactive (12, 1 3 ) than its alkoxy intermediates. Since most borohydride reductions of ketones are carried out in alcoholic solvents, the possibility arises of exchange of the alkoxy groups of NaB(OR), HI+-nwith the solvent. However, recent studies (14) show that no significant exchange occurs between NaB(OR)4 and R'OH when R and R' are secondary, though it does occur when R and R' are primary. The significance of this discovery is discussed later. Until recently little more than the reaction order for the mechanism of reduction of ketones by NaBH4 was known, and not even that for LiAlH4 reductions. A thorough knowledge of the mechanisms of these reactions should provide a better understanding of what factors may or may not influence stereochemical control in these reactions. Perhaps the single most intriguing question is what role, if any, the cation plays in these mechanisms. Several kinetics studies have been conducted on the reduction of ketones by NaBH4 in isopropyl alcohol (8,10, 11, 14-26), These show the reaction to be second order: first order in ketone and first order in NaBH4. The transfer.of the first hydrogen is the rate-controlling step, and the transfers of the other three hydrogens from the alkoxy intermediates are faster steps (7, 11):

JAMES R. BOONE AND E. C. ASHBY

NaBH4 NaB(ORIH3

+ +

C=O C=Q

NaB(OR)2H2 +

C=O

+

C=O

NaB(OR)3H

57

a fast

fast fast

NaB(OR)H3

[ll

NaB(OR)2H2

[21

NaB(OR)3H

[31

NaB(OR)4

[41

S e v e r a l H a m m e t t s t u d i e s have shown t h a t r e a c t i o n of NaBH4 w i t h s u b s t i t u t e d f l u o r e n o n e s (18, 19) and acetophenones (20) g i v e s l a r g e p o s i t i v e p v a l u e s : 2.65 and 3.06, r e s p e c t i v e l y . T h i s supp o r t s t h e concept of n u c l e o p h i l i c a t t a c k by BHC a t the c a r b o n y l carbon. C o r r e l a t i o n of t h e r a t e s of r e a c t i o n of s e v e r a l a l i p h a t i c k e t o n e s by T a f t ' s e q u a t i o n shows t h a t s t e r i c e f f e c t s e x h i b i t a s i g n i f i c a n t r o l e i n t h e r e a c t i o n ( 2 0 ) . The k i n e t i c s of t h e r e a c t i o n of t h e ketone and NaBH4 does n o t d i s t i n g u i s h among t h e f o l l o w i n g p o s s i b i l i t i e s : (1) d i r e c t b i m o l e c u l a r r e a c t i o n i n v o l v i n g t h e ketone and borohydride i o n , ( 2 ) complex f o r m a t i o n f o l lowed by i n t e r n a l h y d r i d e t r a n s f e r , ( 3 ) synchronous complex f o r mation and h y d r i d e t r a n s f e r . The r a t e s of r e d u c t i o n of k e t o n e s by NaBH4 show a s m a l l i n v e r s e i s o t o p e e f f e c t (kH/kD = 0.7) ( 2 1 , 24, 2 7 ) . T h i s r e s u l t may be i n t e r p r e t e d t o s u p p o r t e i t h e r an e a r l y o r a l a t e t r a n s i t i o n s t a t e . The p o s i t i o n of t h e t r a n s i t i o n s t a t e a l o n g t h e r e a c t i o n c o o r d i n a t e and i t s e f f e c t on s t e r e o c h e m i s t r y are d i s c u s s e d later. The n a t u r e of t h e s o l v e n t and t h e c a t i o n have been shown t o a f f e c t t h e r a t e of ketone r e d u c t i o n by b o r o h y d r i d e i o n . The r e d u c t i o n of k e t o n e s by borohydride i o n has been r e p o r t e d by Brown t o r e q u i r e t h e p r e s e n c e of an e l e c t r o p h i l i c a g e n t , s u c h as a p r o t i c s o l v e n t , o r l i t h i u m o r magnesium i o n ( 1 7 , 28-33). I t has been r e p o r t e d t h a t sodium borohydride does n o t r e d u c e acet o n e i n a p r o t i c s o l v e n t s such a s a c e t o n i t r i l e , p y r i d i n e , d i methylformamide, and diglyme. Brown s u g g e s t e d t h a t r e p o r t e d ketone r e d u c t i o n s by NaBH4 i n t h e s e s o l v e n t s a c t u a l l y o c c u r r e d d u r i n g t h e workup of t h e r e a c t i o n m i x t u r e u s i n g aqueous hydrol y s i s . However, t h e r e s t i l l a p p e a r s t o be some c o n f u s i o n on t h i s p o i n t . Although Brown p u b l i s h e d (17) i n 1961 t h a t NaBH4 does n o t reduce a c e t o n e i n a p r o t i c - s o l v e n t s , t h e r e c o n t i n u e t o be occas i o n a l r e p o r t s (31, 32, 34-36) of r e a c t i o n s under s u c h condit i o n s . Presumably t h e s e r e a c t i o n s a r e a r e s u l t of trace amounts of water o r a l c o h o l s p r e s e n t i n t h e s o l v e n t , o r water i n t r o d u c e d d u r i n g workup of t h e r e a c t i o n m i x t u r e . Disappearance of t h e c a r b o n y l group b e f o r e quenching of t h e r e a c t i o n mixture has been observed s p e c t r o p h o t o m e t r i c a l l y f o r t h e r e d u c t i o n of ketones by NaBH4 (31, 32) and LiBH4 (31, 32) i n a p r o t i c s o l v e n t s . The i n a c t i v i t y of NaBH4 i n a p r o t i c s o l v e n t s observed by t h e s e workers may b e a m a t t e r of d e g r e e , and w i t h t h e p r o p e r t e m p e r a t u r e (361, s o l v e n t (36) , and k e t o n e (31, 32) t h e r e a c t i o n may occur more e a s i l y . The r e d u c i n g s t r e n g t h of NaBH4 i n r e f l u x i n g t o l u e n e r e p o r t e d l y h a s been enhanced by t h e a d d i t i o n of crown e t h e r s t o complex t h e sodium i o n ( 3 6 ) .

58

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

Three types of mechanisms o r t r a n s i t i o n states have been proposed by workers i n t h i s a r e a ( 1 4 ) . A l l t h e t r a n s i t i o n s t a t e s l e a d t o an alkoxyborohydride product, b u t n o t t h e same alkoxyborohydride. The i n s i g h t of Wigfield l e d t o experiments t h a t r e c e n t l y e l i m i n a t e d two of t h e t h r e e mechanisms. The a c y c l i c t r a n s i t i o n s t a t e 2 was o r i g i n a l l y suggested by Brown (11, 20, 3 0 ) . The product B(OR)H3 has been p r e s e n t e d a s having t h e OR group d e r i v e d from e i t h e r t h e a l c o h o l i c s o l v e n t (30) o r t h e ketone (11, 2 0 ) .

[

*

0

)<e H--BH3

Na+]

2 S i m i l a r t o 2 i n some r e s p e c t s i s t h e c y c l i c t r a n s i t i o n s t a t e 3 proposed by House ( 3 3 ) . The r o l e of t h e s o l v e n t i s more e x p l i c i t l y shown. From 3 , i f c o r r e c t , one might e a s i l y e x p e c t t h e r e a c t i o n t o be f i r s t o r d e r i n ketone, BH;, and s o l v e n t . The product B ( O R ) H 3 , however, would d e r i v e i t s OR groups s o l e l y from t h e a l c o h o l i c s o l v e n t , and a f r e e a l c o h o l would be produced as a r e s u l t of r e d u c t i o n of t h e ketone.

3 The t h i r d suggested (20, 2 1 , 34) t r a n s i t i o n s t a t e i s repr e s e n t e d by t h e four-centered t r a n s i t i o n s t a t e 4 . The produce B ( O R ) H S would d e r i v e t h e OR group only from t h e ketone.

4 Recent s t u d i e s ( 1 4 , 26) by Wigfield show t h a t NaBH4 reduct i o n of ketones i s 1 . 5 o r d e r (26) i n a l c o h o l s o l v e n t and t h a t t h e products of r e d u c t i o n are t h e f r e e a l c o h o l d e r i v e d from t h e ketone and B ( O R ) H 3 , i n which t h e OR group i s d e r i v e d from t h e a l c o h o l s o l v e n t ( 1 4 ) . T h i s , of c o u r s e , e l i m i n a t e s t h e fourc e n t e r e d t r a n s i t i o n s t a t e 4 , i n which t h e OR group i s d e r i v e d from t h e ketone. A d d i t i o n a l l y , t h e c y c l i c t r a n s i t i o n s t a t e 3 a s drawn would only be f i r s t o r d e r i n s o l v e n t . Wigfield s u g g e s t s t h e l i n e a r t r a n s i t i o n s t a t e 5 ( 2 6 ) . The t r a n s i t i o n s t a t e 5 shows no p a r t i c i p a t i o n by t h e N a + i o n , s i n c e p r e v i o u s l y it had been shown

JAMES R. BOONE AND E . C. ASHBY

59

( 1 7 , 3 0 ) t h a t L i ' and Mg2+, b u t n o t Na', p a r t i c i p a t e i n t h e red u c t i o n . More r e c e n t evidence concerning t h e r o l e of Na+ i n NaBH4 r e d u c t i o n s shows t h a t removal of t h e Na' i o n by t h e u s e of c r y p t a t e s does n o t p r e v e n t r e d u c t i o n of ketones by NaBH4 i n methanol ( 2 8 ) . Wigfield has used t h e l i n e a r a c y c l i c t r a n s i t i o n s t a t e 5 t o s u g g e s t a new concept i n s t e r e o s e l e c t i v e r e d u c t i o n s of cyclohexanones. Equations [ 5 ] through [8] show how a 1.5-order r e a c t i o n i n a l c o h o l s o l v e n t may be explained by assuming t h a t RO- a r i s e s from i o n i z a t i o n of t h e s o l v e n t : r a t e = k l k e t o n e ] [BHq-] [ROW] [RO-I ROH

& RO- +

=

RO-

H+

K 1 1 2 [ROH]'/*

r a t e = kK112 [ketone] [BHq-I [ROH] 3/2 Although t h e c a t i o n i n t h e NaBH4 r e d u c t i o n of k e t o n e s i n i s o p r o p y l a l c o h o l does n o t p a r t i c i p a t e i n t h e r e a c t i o n , i n t e r e s t i n t h i s p o i n t remains high because t h e c a t i o n may p a r t i c i p a t e i n o t h e r systems such a s L i B H 4 i n THF and L i A l H 4 i n THF'. K i n e t i c s t u d i e s of t h e r e d u c t i o n of a ketone by l i t h i u m aluminum hydride ( 3 7 ) o r l i t h i u m tri-t-butoxyaluminohydride [LiAl(O-t-Bu)gH] (15, 23) i n THF show t h e r e a c t i o n t o be f i r s t o r d e r i n ketone and f i r s t o r d e r i n hydride. The r e a c t i o n of L i A l H 4 w i t h ketones i n d i e t h y l e t h e r h a s been r e p o r t e d ( 3 8 ) t o be more complex, and it does n o t e x h i b i t simple f i r s t - o r d e r k i n e t i c s i n each r e a c t a n t . I n d i c a t i o n s are t h a t b o t h monomeric and dimeric L i A l H t , p a r t i c i p a t e i n t h e r e a c t i o n . The d e g r e e t o which t h e mechanistic information known a b o u t t h e m e t a l borohydride (MBH4) r e d u c t i o n of ketones can be a p p l i e d t o t h e m e t a l aluminohydride ( M A l H 4 ) r e d u c t i o n i s c l e a r l y u n c e r t a i n . The t r a n s f e r of t h e second, t h i r d , and f o u r t h hydrogens from aluminohydride i o n t o t h e ketone is slower ( 4 , 1 2 , 3 8 ) t h a n t h e f i r s t s t e p , although t h e o p p o s i t e i s t r u e i n t h e case of borohydride r e d u c t i o n . A d d i t i o n a l l y , i t i s known t h a t many secondary alkoxyaluminohydrides (products from ketone r e d u c t i o n ) d i s p r o p o r t i o n a t e r a p i d l y t o r e g e n e r a t e A 1 H c ( 4 , 5 , 12) : LiAl(OR),Hb-,

-+

n

-4

LiAl(OR)4

- n + 44

LiAlH,,

60

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

The stereochemical r e s u l t s of ketone r e d u c t i o n by NaBH4 and

L i B H 4 a r e a f f e c t e d by r e a c t a n t r a t i o , and t h u s it has been con-

cluded (10) t h a t t h e s t e r e o s e l e c t i v i t y v a r i e s w i t h r e a c t a n t r a t i o . Such a conclusion seems reasonable, s i n c e under c e r t a i n c o n d i t i o n s a s i g n i f i c a n t amount of r e a c t i o n i s o c c u r r i n g by t h e f a s t e r r e a c t i n g alkoxyborohydride i n t e r m e d i a t e s . On t h e o t h e r hand, because t h e stereochemical r e s u l t s of ketone r e d u c t i o n s by ~ i A l H 4a r e not s i g n i f i c a n t l y a f f e c t e d by r e a c t a n t r a t i o , it has been suggested ( 4 ) t h a t L i A l H 4 is t h e only s i g n i f i c a n t reducing agent. However, t o conclude, on t h e b a s i s of stereochemical res u l t s a l o n e , t h a t no s i g n i f i c a n t r e a c t i o n of L i A l H 4 w i t h ketones proceeds through alkoxyaluminohydride i n t e r m e d i a t e s may be a g r o s s presumption. The major problem is t h a t t h e s t e r e o s e l e c t i v i t y of t h e alkoxyaluminohydride i n t e r m e d i a t e s i s no b e t t e r understood than t h a t of L i A l ~ 4 . For reasons t h a t become apparent l a t e r i n t h i s d i s c u s s i o n , it seems t h a t s i g n i f i c a n t r e a c t i o n can occur by alkoxyaluminohydride i n t e r m e d i a t e s during t h e r e d u c t i o n of ketones by L i A l ~ 4 ,and t h a t it i s simply n o t observable i n t h e stereochemistry of t h e products. I t should a l s o be pointed o u t t h a t LiAl(CCH3)3H and L i A 1 (O-t-Bu)3HI where t h e OR groups a r e primary and t e r t i a r y , res p e c t i v e l y , a r e s t a b l e t o d i s p r o p o r t i o n a t i o n (4-6, 1 2 ) . The percentage of t h e r e d u c t i o n occurring through LiAl(OR),H4_, s p e c i e s may be s i g n i f i c a n t , e s p e c i a l l y when t h e ketone/LiAlHq r a t i o exceeds 1. I n r e c e n t s t u d i e s ( 3 8 ) , i n which a r e a g e n t w a s prepared from 1.5 t o 1.7 mole t - b u t y l a l c o h o l per m o l L i A l H b , it was found t h a t approximately 50% of t h e r e d u c t i o n of c e r t a i n aromatic ketones occurs by r e a c t i o n of LiAl(O-t-Bu)H3. Mesityl phenyl ketone i s reduced about 10 times f a s t e r by L i A l H 4 i n THF than by N a A l H 4 i n t h e same s o l v e n t (37). A l l i n d i c a t i o n s a r e t h a t r e a c t i o n of MAlH4 w i t h ketones i s n o t independ e n t of t h e c a t i o n ; i f it were, equal r a t e s of r e a c t i o n of L i A l H 4 and N a A l H 4 would be expected. However, it is n o t e n t i r e l y c l e a r how t h e c a t i o n p a r t i c i p a t e s . The c a t i o n could p o s s i b l y a f f e c t t h e r e a c t i v i t y of t h e ketone o r t h e aluminohydride i o n , o r both. Under t h e conditions of t h e s e k i n e c i c s t u d i e s L i A l H 4 i n THF (1 X to 4 x 25") e x i s t s predominantly a s solventseparated ion p a i r s (1, 2) ( 6 ) , whereas N a A l H 4 appears t o be an approximately equal mixture of solvent-separated (8) and c o n t a c t i o n p a i r s ( 7 ) (eg. [ l o ] ) . Under t h e r e a c t i o n c o n d i t i o n s a small f r a c t i o n of each hydride i s p r e s e n t a s f r e e i o n s and t r i p l e ions.

6

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7

8

Because t h e r e a c t i o n r a t e of t h e ketone w i t h MAlH4 depends on t h e n a t u r e of t h e c a t i o n M', it i s r e a s o n a b l e t o assume t h a t t h e t r a n s i t i o n s t a t e i n v o l v e s t h e p r e s e n c e of t h e c a t i o n and n o t j u s t t h e f r e e aluminohydride i o n (33, 37, 4 0 ) . The f a c t t h a t t h e s t e r e o s e l e c t i v i t y of MAlH4 r e d u c t i o n s is a l s o dependent (37, 40) on c a t i o n i s f u r t h e r s u p p o r t f o r t h e p r e s e n c e of t h e c a t i o n i n t h e t r a n s i t i o n s t a t e . Two p o s s i b l e mechanistic pathways f o r t h e r e d u c t i o n of m e s i t y l phenyl ketone by m1~4should be c o n s i d e r e d (37): (1) t h e c a t i o n does n o t complex t h e carbonyl oxygen; ( 2 ) t h e c a t i o n does complex t h e carbonyl oxygen. S i n c e N a A l H 4 consists of both c o n t a c t and s o l v e n t - s e p a r a t e d i o n p a i r s i n THF t o a b o u t t h e same d e g r e e , r e a c t i o n through both t y p e s of i o n p a i r s is p o s s i b l e . LiAlH4 may be assumed t o r e a c t through t h e s o l v e n t s e p a r a t e d i o n p a i r , s i n c e this i s by f a r t h e most abundant s p e c i e s p r e s e n t i n THF s o l u t i o n a t ambient temperature. The f i r s t mechanism s u g g e s t s a t r a n s i t i o n s t a t e 9 which i n v o l v e s n u c l e o p h i l i c a t t a c k by t h e M'AlH; i o n p a i r on t h e c a r bony1 carbon w i t h o u t the c a t i o n complexing the carbonyl oxygen. I f one compares t h e s o l v e n t - s e p a r a t e d i o n p a i r of N a A l H 4 (8) t o t h e c o n t a c t i o n p a i r ( 7 ) , it might be expected t h a t 8 i s t h e

*

9 b e t t e r n u c l e o p h i l e , because t h e A l H G i s more i n s u l a t e d by i n t e r vening s o l v e n t molecules and f u r t h e r from t h e c a t i o n , hence i t should be e a s i e r f o r A l H G t o r e l e a s e t h e n e g a t i v e h y d r i d e i o n (H-) t o t h e carbonyl carbon atom. On t h e b a s e s t h a t 8 should react f a s t e r t h a n 7 , and t h a t 8 and 7 are p r e s e n t i n about e q u a l amount, i t appears l i k e l y t h a t 8 i s t h e major r e a c t i v e s p e c i e s . I f t h e r e a c t i v e s p e c i e s are t h e s o l v e n t - s e p a r a t e d i o n p a i r s of L i A l H 4 (6) and N a A l H 4 (a), t h e n N a A l H 4 and L i A l H 4 would be exp e c t e d t o have similar r e a c t i o n r a t e s according t o t r a n s i t i o n s t a t e 9 , s i n c e t h e expected d i f f e r e n c e between completely s o l -

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

62

vated lithium and sodium ions should be small. However, LiA1H4 (nearly all solvent-separated ion pairs) is ca. 11 times more reactive toward mesityl phenyl ketone than NaA1H4 (about half solvent-separated ion pairs). It is also interesting to note that NR4A1H4 [NRf is tri (n-octyl)-n-propylammonium ion] reacts more slowly (39) with camphor than LiAlH4 or NaA1H4. Although NR4A1H4 [when NRt is tetra (a-butyl) ammonium ion] is a contact ion pair (1,2) in solution, its experimentally observed centerto-center distance is greater than that of LiA1H4 or NaA1H4. Therefore reaction rates (LiA1H4 > NaA1H4 > NR A1H ) cannot be 4 correlated with the observed center-to-center xistances of ion pairs (NR A1H4 > LiA1H4 > NaAlH ) . Reaction rates in THF (LiA4H4 > NaA1H4 > NR4A1H4) may be correlated with the concentration of solvent-separated ion pairs (or free ions) in solution (LiA1H4 > NaAlH,, > NR4A1H4) , assuming that solvent-separated ion pairs or free ions are more reactive than contact ion pairs. However, this explanation of the rate differences based on transition state 9 meets with difficulty when the rates in THF are compared to those in diethyl ether. Lithium aluminum hydride in diethyl ether exists predominately as contact ion pairs, but it reacts ca. 30 times faster ( 3 8 ) with mesityl phenyl ketone than LiA1H4 in THF (predominately solvent-separated ion pairs). This rate difference with solvent change is discussed below. A second possible mechanism ( 1 0 ) involves attack by the M'AlHG ion pair on the carbonyl group, where the cation is bound to the carbonyl oxygen during reduction. This process may simply involve the displacement of one molecule of THF solvent attached

cI I I

H I I

I

6-

A1H

10

to M+ by one molecule of ketone (eq. [11]). S

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, be expected t o react f a s t e r t h a n I n t h i s c a s e L ~ A ~ H ,would s i n c e Li' would a s s o c i a t e more s t r o n g l y t h a n N a + w i t h t h e c a r b o n y l oxygen, hence would more s t r o n g l y p o l a r i z e and a c t i v a t e t h e C=O bond. I t has been shown ( 1 , 2 ) t h a t k e t o n e s a s s o c i a t e w i t h l i t h i u m i o n s i n THF s o l u t i o n s of l i t h i u m s a l t s . I t i s f u r t h e r known (17,30) t h a t LiBH,, i s more r e a c t i v e t h a n NaBH,, toward k e t o n e s i n a p r o t i c s o l v e n t s , and t h i s d i f f e r e n c e i n r e a c t i v i t y h a s been e x p l a i n e d on t h e b a s i s of t h e d i f f e r e n c e i n t h e e l e c t r o p h i l i c n a t u r e of t h e l i t h i u m and sodium i o n s ( 1 7 , 3 1 , 3 2 ) . F u r t h e r e v i d e n c e f o r complex f o r m a t i o n between l i t h i u m i o n s and k e t o n e s i s demonstrated by t h e s u b s t a n t i a l e q u i l i b r i u m c o n s t a n t (1.3 l i t e r s / m o l ) f o r complex f o r m a t i o n between LiClO,, and benzophenone i n d i e t h y l e t h e r , a s determined by W s t u d i e s (37). I R s t u d i e s on a c e t o n e i n THF and i n d i e t h y l e t h e r show t h a t i n c r e a s i n g t h e L i C l O , , c o n c e n t r a t i o n broadens and s h i f t s (1) t h e c a r b o n y l a b s o r p t i o n from 1725 t o 1720 c m - l . NMR s t u d i e s o f cyclohexanone ( 1 . O M ) i n d i e t h y l e t h e r show t h a t a d d i t i o n of L i C 1 0 4 s h i f t s t h e p r o t o n s of cyclohexanone downfield from t h e e t h e r t r i p l e t , by Hz f o r t h e a p r o t o n s , and 2Hz f o r t h e 6 and y ( 3 7 ) . P a r t i c i p a t i o n by t h e c a t i o n i n t h e t r a n s i t i o n s t a t e i s a l s o i n d i c a t e d , n o t o n l y by t h e d i f f e r e n c e i n t h e r e a c t i o n NR4A1H4), b u t r a t e s of M A l H 4 w i t h k e t o n e s (LiAlH,, > N a A l H 4 a l s o by t h e dependence of t h e s t e r e o s e l e c t i v i t y of r e d u c t i o n of a l i c y c l i c k e t o n e s by MA1H4 compounds (39,40). A l l t h e s e s t u d i e s p r o v i d e e v i d e n c e of a s s o c i a t i o n o f ketones with lithium s a l t s i n e t h e r e a l s o l v e n t s , supporting trans i t i o n s t a t e 1 0 which r e p r e s e n t s t h e r e d u c t i o n o f k e t o n e by L i A l H 4 a s proceeding v i a a p r i o r o r synchronous a s s o c i a t i o n of t h e k e t o n e w i t h Li' w i t h r e s p e c t t o t r a n s f e r of t h e h y d r i d e ion. If t h e k e t o n e i s a s s o c i a t e d w i t h t h e l i t h i u m c a t i o n d u r i n g r e d u c t i o n by L i A l H , , i n THF, t h e n c a u s i n g t h e k e t o n e t o compete a g a i n s t a s o l v a t i n g a g e n t s t r o n g e r t h a n THF s h o u l d r e d u c e t h e r a t e of r e a c t i o n . T h i s i s found t o b e t h e case ( 3 7 ) . T h e . r a t e of r e d u c t i o n of m e s i t y l phenyl k e t o n e by excess L i A 1 H 4 i n t h e p r e s e n c e of N,N,N',N",N"',N"'-hexamethyltriethylenetetraamine (complexes l i t h i u m c a t i o n ) (41) i s reduced by c a . one-half when t h e r a t i o of amine t o l i t h i u m i s 2 : l . S i m i l a r l y , i f t h e k e t o n e h a s t o compete w i t h a weaker s o l v a t i n g a g e n t t h a n THF, s u c h a s d i e t h y l e t h e r , t h e r a t e of r e a c t i o n i s e x p e c t e d t o i n c r e a s e . Comparing t h e observed r a t e c o n s t a n t s a t 25O, it i s s e e n t h a t t h e r e d u c t i o n of m e s i t y l phenyl k e t o n e by LiAlH,, (kT - 4.8 x m 3 ,k e t h e r = 0 . 2 6 a t 8.2 X UI-~MY, k T H F , = 11.7 x 1 8 , k e t h e r = 0.40 a t 2 . 0 x 10-2M) i s c a . 30 t o 50 t i m e s f a s t e r i n d i e t h y l e t h e r t h a n i n THF. The r e a c t i o n of L i A 1 H 4 w i t h m e s i t y l phenyl k e t o n e a p p e a r s t o be more complex i n d i e t h y l e t h e r (38) t h a n i n THF ( 3 7 ) . I n e t h e r t h e LiA1H4 monomer i n e q u i l i b r i u m w i t h L i A 1 H 4 dimer i s t h e r e a c t i v e s p e c i e s (eq. [ 1 2 ] ) . No such e q u i l i b r i u m was observed i n THF (eq. [ 1 3 1 ) . For k e t o n e s o t h e r t h a n

NaAlH,,,

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REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

m e s i t y l phenyl ketone t h e LiA1H4 dimer i n d i e t h y l e t h e r i s a l s o a r e a c t i v e s p e c i e s (eq. [141). r a t e i n d i e t h y l e t h e r = k [LiA1H4] i’2[ketone]

[121

r a t e i n TW = k[LiA1H41 [ketone]

[131

rate i n d i e t h y l ether = ( k , [LiA1H4] k2 [ L i A l H 4 ] 2 ) [ketone]

i’2 + ~

4

I t has been r e p o r t e d t h a t t h e c a t i o n i s i n d i s p e n s a b l e (28,29) i n t h e r e a c t i o n of l i t h i u m aluminum hydride w i t h cyclohexanones. No r e a c t i o n w a s r e p o r t e d t o occur when a c r y p t a t e such a s 11 was used t o complex t h e l i t h i u m ion. I n t h e presence of a c r y p t a t e t h e Li’ i o n i s supposedly no longer a v a i l a b l e t o

11 a s s o c i a t e with t h e carbonyl oxygen atom, hence no r e a c t i o n i s observed. On t h e o t h e r hand another study ( 4 2 ) showed t h a t aromatic ketones d i d r e a c t w i t h LiAlH4 i n t h e presence of a c r y p t a t e , although isobutyraldehyde d i d not. However, L i A 1 H 4 alone gave only a 50% y i e l d of i s o b u t y l a l c o h o l on r e a c t i o n w i t h isobutyraldehyde; perhaps e n o l i z a t i o n i s a competing rea c t i o n . I f t h e r a t e of r e d u c t i o n i s slowed down by a d d i t i o n of t h e c r y p t a t e , it i s easy t o s e e how e n o l i z a t i o n could become t h e almost e x c l u s i v e r e a c t i o n . I t is a l s o important t o consider t h a t tetraalkylammonium aluminohydrides have been used s u c c e s s f u l l y t o reduce a l i p h a t i c ketones ( 3 9 ) . I t would appear t h a t t h e tetraalkylammonium i o n and a Li’ i o n complexed w i t h a c r y p t a t e would behave s i m i l a r l y , t h a t i s , as a p o s i t i v e i o n b u r i e d i n t h e c e n t e r of a cushion of o r g a n i c s u b s t r a t e . The r e a c t i v i t y of N R 4 A l H q cannot be a t t r i b u t e d t o any Na’ i o n s remaining from i t s p r e p a r a t i o n from N a A l H 4 because N a A l H 4 and NR4AlH4 e x h i b i t d i f f e r e n t s t e r e o s e l e c t i v i t i e s i n t h e i r r e a c t i o n s w i t h ketones. I t i s a l s o known t h a t crown e t h e r s do n o t i n h i b i t t h e r e d u c t i o n of ketones by aluminohydrides ( 3 9 ) . I n t h i s connection it has a l s o been r e p o r t e d (36) t h a t crown e t h e r s enhance t h e a c t i v i t y of NaBH4 i n t h e r e d u c t i o n of ketones i n r e f l u x i n g t o l u e n e . I t would n o t be s u r p r i s i n g i f c r y p t a t e s slowed t h e r e a c t i o n , b u t i n h i b i t i o n of r e d u c t i o n by AlH; would indeed be v e r y s u r p r i s i n g . These m a t t e r s must be reexamined very c a r e f u l l y . While p o l a r i z a t i o n of t h e C=O bond by M+,gives an unders t a n d a b l e e x p l a n a t i o n of r a t e d i f f e r e n c e s between LiAlH4 and N a A l H 4 , t h e e f f e c t on t h e r e a c t i o n r a t e i s more s p e c u l a t i v e i n

1

JAMES R.

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t h e case of p o l a r i z a t i o n of t h e aluminohydride i o n by M+ o r charge s e p a r a t i o n i n t h e M+AlH; i o n p a i r . I t appears reasonable t h a t t h e f u r t h e r away t h e c a t i o n i s from t h e anion, t h e e a s i e r i t w i l l be f o r A1Hq t o r e l e a s e H- t o t h e carbonyl carbon atom i n t h e r a t e determining s t e p . However, a r a t e enhancement caused by t h e p o l a r i z a t i o n of A1H4- by t h e c a t i o n cannot be r u l e d o u t , based on p r e s e n t evidence. I f t h e carbonyl oxygen atom i s a s s o c i a t e d with t h e aluminum atom i n t h e t r a n s i t i o n s t a t e , t h e p o l a r i z a t i o n of A1H4- by t h e c a t i o n could be of major s i g n i f i c a n c e . Based on t h e evidence a v a i l a b l e t o d a t e , probably t h e most a c c e p t a b l e explanation of t h e c a t i o n e f f e c t on r a t e and s t e r e o s e l e c t i v i t y of A 1 H c i s p o l a r i z a t i o n of t h e carbonyl group by s p e c i f i c complexation of t h e carbonyl oxygen atom, o r simple e l e c t r o s t a t i c i n t e r a c t i o n s between M' and C=O. If t h e mechanism of r e d u c t i o n involved only a n u c l e o p h i l i c a t t a c k by A 1 H q o r M+AlH< a t t h e carbonyl carbon, t h e r a t e and stereochemistry of t h e r e d u c t i o n would l i k e l y show l i t t l e , i f any, dependence on t h e c a t i o n , because it could be o r i e n t e d away from t h e r e a c t i o n c e n t e r . However, r e d u c t i o n s of s e v e r a l ketones by MAlH,, show marked changes i n r a t e and s t e r e o c h e m i s t r y with changes i n the c a t i o n (37,39). I t i s assumed t h a t t h e r e a c t i v e s p e c i e s i s t h e i o n p a i r M'AlH;, because both M+ and M 1 H q a r e p r e s e n t i n t h e t r a n s i t i o n s t a t e ( 3 7 ) . I f t h e ion p a i r i s t h e a t t a c k i n g s p e c i e s , t h e a t t a c k by M+ of t h e i o n p a i r on t h e carbonyl oxygen may be p r i o r t o o r synchronous with a rate-determining hydride t r a n s f e r s t e p . Since complexation of metal i o n s such a s L i t with ketones i s probably extremely r a p i d , it i s reasonable t h a t complex formation t a k e s p l a c e p r i o r t o t h e rate-determining hydride t r a n s f e r s t e p . Howe v e r , it i s a l s o p o s s i b l e t h a t t h e a t t a c k i n g s p e c i e s i s n o t t h e ion p a i r M'AlH; but r a t h e r t h e f r e e i o n s ( 3 7 ) . I n t h i s case t h e carbonyl group a s s o c i a t e s with a f r e e 'M and i s then a t t a c k e d by a f r e e AlH;. S t r u c t u r e s 9 and 1 0 a r e not drawn a s d e t a i l e d t r a n s i t i o n s t a t e s , b u t a r e intended only t o r e f l e c t p o s s i b l e p a r t i c i p a t i o n of t h e c a t i o n ir. t h e t r a n s i t i o n s t a t e . T r a n s i t i o n s t a t e 10 can be represented i n more d e t a i l by s t r u c t u r e s 1 2 and 1 3 , which r e p r e s e n t boat and c h a i r conformations, r e s p e c t i v e l y ( 3 7 ) . A l -

12

13

though t h e boat t r a n s i t i o n s t a t e 1 2 might seem l e s s probable because t h e o r b i t a l on oxygen i s not c o r r e c t l y o r i e n t e d t o overlap t h e back lobe of A1-H o r b i t a l involved i n bond breaking,

66

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

a t l e a s t two f a c t o r s f a v o r t h i s t r a n s i t i o n s t a t e . F i r s t , i n t e r a c t i o n between aluminum and oxygen lowers t h e a c t i v a t i o n energy of the r e a c t i o n and p r o v i d e s a pathway i n which c o l l a p s e of t h e t r a n s i t i o n s t a t e r e s u l t s d i r e c t l y i n formaiton of t h e prod u c t [LiA1(OR)H3] w i t h o u t t h e need of a n i n t e r m e d i a t e s t e p . The second p o i n t i s t h a t such a b o a t t r a n s i t i o n s t a t e can be v a l i d l y suggested i f one assumes p e n t a v a l e n t aluminum i n v o l v i n g pseudor o t a t i o n about t h e aluminum a x i s . The L i - H - A 1 i n t e r a c t i o n shown i n 1 2 and 13 is reasonable a l s o , on t h e basis t h a t M-H-M b r i d g e bond systems a r e w e l l known and i n a d d i t i o n would add s t a b i l i t y t o t h e t r a n s i t i o n s t a t e . Such an i n t e r a c t i o n should lower E, and r e s u l t i n a more n e g a t i v e AS*,.which i s t h e c a s e , a s w e see l a t e r . Although k i n e t i c data do n o t a l l o w f o r the drawing of such d e t a i l e d t r a n s i t i o n s t a t e s , t h e s e s u g g e s t i o n s appear reasonable. The enthalpy of a c t i v a t i o n f o r t h e r e a c t i o n of L i A l H 4 w i t h m e s i t y l phenyl ketone (10.5 k c a l ) i s c o n s i d e r a b l y lower than t h a t f o r t h e r e a c t i o n of N a A l H 4 w i t h m e s i t y l phenyl ketone (18.1 k c a l ) ( 3 7 ) . T h i s may be explained by t h e d i f f e r e n c e i n p o l a r i z a t i o n of the carbonyl group due t o complexation by t h e c a t i o n i n t h e t r a n s i t i o n s t a t e . The l i t h i u m i o n , because o f i t s smaller s i z e , should p o l a r i z e t h e carbonyl group more t h a n does sodium; thus t h e hydride i o n i s more e a s i l y t r a n s f e r r e d from t h e aluminum atom t o t h e carbon atom i n t h e case of l i t h i u m . The much more n e g a t i v e v a l u e f o r t h e entropy of a c t i v a t i o n f o r L i A l H 4 (-26.2 e . u . ) than f o r N a A l H 4 (-5.4 e.u.) r e q u i r e s t h a t t h e t r a n s i t i o n s t a t e f o r L i A l H 4 r e d u c t i o n b e c o n s i d e r a b l y more o r d e r e d than t h a t f o r N a A l H 4 ( 3 7 ) . Again, this o b s e r v a t i o n i s c o n s i s t e n t w i t h c a t i o n a s s o c i a t i o n w i t h t h e oxygen o f t h e carbonyl group i n t h e t r a n s i t i o n s t a t e . The l i t h i u m c a t i o n would o r d e r t o a much g r e a t e r e x t e n t t h e ketone molecule a s w e l l a s b o t h primary and secondary s o l v e n t molecules than would t h e sodium c a t i o n . Such a l a r g e negative v a l u e i s also c o n s i s t e n t w i t h a s i x - c e n t e r e d t r a n s i t i o n s t a t e such as t h o s e shown i n s t r u c t u r e s 1 2 and 13. Since Li-H-A1 b r i d g e bonds should be c o n s i d e r a b l y more s t a b l e t h a n Na-H-A1 b r i d g e bonds, t h e l a r g e n e g a t i v e AS* f o r t h e L i A l H 4 r e a c t i o n compared w i t h t h a t f o r N a A l H 4 can a l s o be a t t r i b u t e d t o some e x t e n t a s t o t h e r e s t r i c t i o n brought about i n t h e t r a n s i t i o n s t a t e by t h i s type of i n t e r a c t i o n . K i n e t i c i s o t o p e s t u d i e s f o r t h e r e d u c t i o n o f m e s i t y l phenyl ketone w i t h L i A l H 4 i n d i e t h y l e t h e r and i n THF show a kH/kD v a l u e of about 1 . 3 (37,38). I n t e r p r e t a t i o n of kH/kD i s n o t s t r a i g h t f o r w a r d because i t r e p r e s e n t s b o t h primary and secondary deuterium k i n e t i c i s o t o p e e f f e c t s (24,27,43,44). The s m a l l v a l u e of kH/kD may be explained by a s m a l l primary i s o t o p e e f f e c t which is n o t completely masked by i n v e r s e secondary e f f e c t s . The small i s o t o p e e f f e c t would t h e n be c o n s i s t e n t w i t h a r a t e - d e t e r mining s t e p i n v o l v i n g t r a n s f e r o f t h e hydride from t h e aluminum t o t h e carbonyl carbon. The s m a l l v a l u e of kH/kD, a s w e l l a s o t h e r o b s e r v a t i o n s , i s c o n s i s t e n t w i t h an e a r l y t r a n s i t i o n s t a t e .

JAMES R. BOONE AND E. C. ASHBY

67

Unfortunately, an exact interpretation of the magnitude of the kinetic isotope effect is not clear, not only because of the secondary isotope effect, but also because of the uncertainty of the A1-H-C angle in the transition state, and other factors. The following mechanism is consistent with known facts about the reduction of ketones by LiAlH4:

+

S

’

111. CONCEPTS OF STEREOCHEMICAL CONTROL OF KETONE REDUCTIONS BY COMPLEX METAL HYDRIDES In recent years the area of stereoselective reduction of ketones by MBH4, MAlH4, and their alkoxy derivatives has been investigated by several workers (33,45). Lithium aluminum hydride reduces 4-butylcyclohexanone predominantly by attacking (90%)the molecule from the more hindered axial side to give (46,47) the more stable equatorial alcohol. The more hindered ketone 3,3,5-trimethylcyclohexanone is attacked predominantly (55 to 75%) (4) from the less hindered equatorial side to give the less stable axial alcohol. These results were first explained by Dauben, who suggested the concept of “product development and steric approach control“ (48). Dauben visualized the formation of an initial complex as the nucleophile approaches the n bond of the carbonyl group, followed by collapse of the complex to products. He further suggested that transfer of the hydride in the complex results in rehybridization of the carbonyl carbon atom from s p 2 to s p 3 . A late transition state in which hybridization is largely s p 3 allows the relative stabilities of the products to be reflected in the transition state. In the case of an unhindered ketone such as 4-butylcyclohexanone, Dauben suggests that the developing s p 3 hybridization is the controlling factor, hence that product development control is observed. On the other hand the C3 axial methyl group of 3,3,5-trimethylcyclohexanone hinders the nucleophile in its axial approach, thus decreasing the ease of formation of this complex. This results in the favoring of equatorial attack, and steric approach control determines the stereochmistry of reduction. These and other results have been generalized (6,48), leading to the conclusion that reduction of unhindered ketones is governed by

60

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

product development control and that reduction of hindered ketones is governed by steric approach control. It is accepted that product development control would require a late transition state resembling the products, whereas steric approach control would require an early transition state resembling the reactants. In 1968 Cherest and Felkin (49-52) suggested that there should be no fundamental difference between the mechanisms of hydride reduction of hindered and unhindered cyclohexanones and that the factors controlling the stereochemical results of these reductions should be the same in each case. They assumed the transition state to be reactantlike in all cases, and introduced the concept of torsional strain to explain the large degree of axial attack by hydrides on 4-t-butylcyclohexanone. As shown by structure 1 4 , equatorial attack on a cyclohexanone introduces torsional strain between the axial C-H bonds (Ha at C2 and c6, and the forming C-R' bond at C1 which partially eclipses them. Axial attack causes steric hindrance between the incoming hydride (R') and the axial substituents (R) at C3 and and C5. When R is hydrogen, as in 4-t-butylcyclohexanone, torsional strain is greater than steric hindrance, so the hydri.de (axial attack)

(equatorial attack)

R'

HaI R'

torsional strain

14

prefers to attack axially. When R is a methyl, as in 3,3,5-trimethylcyclohexanone, steric hindrance to axial attack is increased and equatorial attack is preferred. Other theories of stereochemical control that have been proposed include: torsional strain between the C=O bond and the two equatorial C-H bonds (He in 1 4 ) (53) at Cg and c6 in 4-tbutylcyclohexanone, closeness of approach of the nucleophile to the carbonyl carbon in the transition state (54), and steric hindrance by the axial C2 and Cg hydrogens (55). Most of these theories have gained less acceptance than those of Dauben and Felkin. In light of the fact that LiAl(O-t-Bu)gH attacks the equatorial side of both 2,2-dimethyl-4-t-butylcyclohexanone and 4-t-butylcyclohexanone at the same rate, it may be concluded that steric hindrance to equatorial attack by the axial substituents at Cg and c6 is negligible (14,15). Recently Klein (56-58) Anh (59-61), Liotta (62), and ourselves (39) have presented new theories of stereochemical control f o r complex metal hydride reduction of ketones, based on orbital symmetry and unequal distortion of electron density about the carbonyl group. In these concepts of stereochemical

JAMES R.

BOONE AND E.

C . ASHBY

69

c o n t r o l t h e n u c l e o p h i l e ' s h i g h e s t occupied m o l e c u l a r o r b i t a l (HOMO) i s c o n s i d e r e d t o i n t e r a c t w i t h t h e k e t o n e ' s l o w e s t unoccupied molecular o r b i t a l (LUMO) I n o r b i t a l d i s t o r t i o n t h e o r y t h e r e i s an a t t e m p t t o p r e d i c t , a t l e a s t q u a l i t a t i v e l y , t h e s i z e and shape o f t h e LUMO a b o u t t h e p l a n e of t h e c a r b o n y l group. The f a c e of t h e c a r b o n y l group a t which t h e LUMO i s most e n l a r g e d o r d i s t o r t e d i s r e g a r d e d as t h e favored s i d e of a t t a c k by a n u c l e o p h i l e . The LUMOs f o r a c y c l o hexanone a r i s i n g from symmetrical B u*-n* i n t e r a c t i o n s a r e r e p r e s e n t e d ( 3 9 ) by 1 5 and 1 6 . The LUMO o f 1 5 , r e s u l t i n g from B C-C u*-n* i n t e r a c t i o n s , f a v o r s e q u a t o r i a l a t t a c k , whereas t h e LUMO of 1 6 , r e s u l t i n g from 6 C-H o*-n* i n t e r a c t i o n , f a v o r s a x i a l a t t a c k . The LUMO i n 1 5 i s d i s t o r t e d t o t h e e q u a t o r i a l s i d e bec a u s e t h e n * o r b i t a l o v e r l a p s w i t h t h e l a r g e back l o b e s of t h e

.

15

16

u * o r b i t a l s of t h e B C2-C3 and C 5 - c g bonds of t h e c y c l o hexanonc r i n g . The d i s t o r t i o n of t h e LUMO i n 16 may b e e x p l a i n e d i n a s i m i l a r manner by u s i n g t h e u * o r b i t a l s of t h e a x i a l C - H bonds a t C 2 and C 6 . I f t h e u o r b i t a l s o f t h e B C - C bonds

were used i n 2 5 , t h e LUMO would be d i s t o r t e d t o t h e a x i a l s i d e because t h e 6 C-C u o r b i t a l s would be l a r g e r between t h e c a r b o n atoms (C2-C, and Cs-C6) and n o t l a r g e r o u t s i d e them, a s f o r t h e U * o r b i t a l s ; t h u s n* i s d i s t o r t e d t o t h e a x i a l s i d e and b e t t e r o v e r l a p s t h e B C-C u o r b i t a l s . The u * - n* i n t e r a c t i o n i s cons i d e r e d more s i g n i f i c a n t because u * i s c l o s e r t o 71* i n . e n e r g y t h a n u . The s e l e c t i o n of which u* o r b i t a l i s i n v o l v e d i s a n o t h e r matter. A x i a l a t t a c k by complex metal h y d r i d e s i s u s u a l l y o b s e r v e d f o r unhindered cyclohexanones, and t h e LUMO i n 16 would e x p l a i n t h e e x p e r i m e n t a l r e s u l t s . However, t h e s e l e c t i o n of t h e LUMO i n 16 i s r e a l l y made a f t e r t h e e x p e r i m e n t a l r e s u l t s are known. Although t h e B C-C o r b i t a l s a r e more p o l a r i z a b l e (58), t h e a x i a l C-H o r b i t a l s posses b e t t e r geometry ( 3 9 ) f o r o v e r l a p w i t h t h e C-0 TI* o r b i t a l s . The C=O bond i s a few d e g r e e s ( 3 . 3 t o 12.7) ( 6 3 , 6 4 ) below t h e p l a n e of t h e C-2 and C-6 e q u a t o r i a l C-H bonds, t h u s t h e a x i a l C-H u * o r b i t a l s a r e more c l o s e l y p a r a l l e l

70

REDUCTION O F KETONES BY COMPLEX METAL HYDRIDES

to the C-0 'TI* orbitals (i.e., more closely perpendicular to the plane of the carbonyl group) than to the B C-C orbitals. Using o * orbitals which more closely parallel the C - 0 n* orbital has been more successful than any other method in predicting LUMO distortion in the direction of the experimentally observed direction of attack by complex metal hydrides with several model cyclohexanones, cyclopentanones, and bicyclic ketones (39). This is examined in more detail when each model is discussed. N. T . Anh has suggested (59) that orbital distortion causes the n-electron density to be greater on one face of the carbonyl group than on the other in ketones antisymmetric a b o u t the carbonyl group. Attack on the more positive face by a nucleophile is favored because of coulombic attraction. More recently Anh has pointed out (61) that this orbital distortion may be important only if the transition state is reached early. Even then the stabilization from orbital distortion does not exceed 2 kcal/mol, which is small compared with the 5 to 10 kcal/mol of extra stabilization produced by what Anh calls the "antiperiplanar effect" (61). The antiperiplanar effect arises when the forming C1-H bond and the C2-L (L is large substituent) bond are antiperiplanar (as in 1 7 ) because of good overlap between 1 ~ * and U * C ~ - ~ , leading to stabilization of n*. Although the ~ for synperisame favorable overlap between n* and C J * C ~ -occurs planar attack, antiperiplanar attack is favored because: "(1) while anti attack with respect to L leads to an in-phase overlap between H' and u*C2-L (at C 2 ) , syn attack leads to an outof-phase overlap between H- and u*C2-L " (see 1 8 and 19), and anti

L

"(2) syn attack implies an eclipsing of C1-H and C2-L bonds" (61). For the three substituents at C -R1, R 2 , and R3-the anti-

periplaner effect would increase as tie energy of the

U*

CR

de-

JAMES R. BOONE AND E. C. ASHBY

71

creases, thus the antiperiplanar effect follows the order C1 > CH3 > H.

\

L

L

0

0 0

18

0

19

Anh demonstrated the antiperiplanar effect by a detailed

MO study of the transition state energies describing attack of

on the two faces of the carbonyl group, involving 12 conformations each for 2-chloropropanal and 2-methylbutanal. The most favorable transition state energies leading to the major and minor products were found to agree with the conformations predicted by Felkin ( 4 9 ) , not with those suggested earlier by Cram (65), Cornforth ( 6 6 ) , and Karabatsos (67). Of course, Felkin's models ( 2 0 and 2 2 ) are for asymmetric induction in nucleophilic additions to acyclic ketones, but they can be used to call attention to similar situations involving cyclic ketones H-

(50).

0

R

R

20

21

Anh has quantitatively considered several very important points concerning complex metal hydride reduction of ketones, such as angle of attack and complexation of ketone by Li+, which prior to this time has only been a matter of speculation. Until recently if has always been assumed that the approach of the hydride to the carbonyl carbon occurs perpendicular to the plane of the carbonyl group. Recent MO calculations have shown (68) that the approach of H- to formaldehyde takes place at an

12

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

angle of 126' with the C=O bond at a distance of 2.5 (118" at 1.5 A ) . Anh likewise found approaches of H- to C=O to favor angles greater than 90' (99 to 103' being most favorable). An angle greater than 90' minimized the out-of phase overlap between the nucleophile and the oxygen atom (as in 2 2 ) because the nucleophile is further from the oxygen atom than it is at 90" I

' 0

...:>,..>x.& ,,.Fg;:,,

..... ................. ....:.:.:.:..

.:>,if+.............

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

0

22

90'.

Anh's MO study favors a bond angle of 180' €or C=O.-*Li+

( 2 3 ) , not 120" ( 2 4 ) , as has been suggested (29,39) when a ke-

tone is complexed by L i ' . Additionally, the study suggests stronger interaction between the approaching H- and Li' than

+

+

Li

I I

i

/c\

23

/

/

/

Li

I

7\ 24

the H- and the carbonyl oxygen atom, even though Li' is further from H- than the oxygen atom. This is because the atomic orbital of Li+ is more diffuse. Thus complexation of the ketone by Li' favors nucleophilic attack more closely perpendicular to the carbonyl carbon. Felkin's model of torsional strain for stereoselective reduction of acyclic ketones predicts that 20 is a more favorable transition state than 2 1 . The suggested explanation is that R sterically interacts less with S (small) in 20 than with M (medium) in 21. However, an angle of attack of greater than 90' may allow a better explanation of why 20 is favored over 2 1 . Steric hindrance involving S and the approaching nucleophile is smaller in 25 than the steric hindrance involving M and the approaching nucleophile in 2 6 (61).

JAMES R.

BOONE AND E. C.

73

ASHBY

s.

0 II

R

R

25

26

I f t h e a n g l e of h y d r i d e approach t o t h e c a r b o n y l carbon i s g r e a t e r t h a n go", t h e n s i g n i f i c a n t i m p l i c a t i o n s a r i s e conc e r n i n g p r e s e n t c o n c e p t s of s t e r e o c h e m i c a l c o n t r o l of complex m e t a l h y d r i d e r e d u c t i o n of cyclohexanones. According t o 1 4 , when R' a t t a c k s a x i a l l y it i s pushed more s t r o n g l y a g a i n s t R , and t h u s a x i a l a t t a c k i s more s t e r i c a l l y h i n d e r e d . Additiona l l y , s t r u c t u r e 1 4 shows t h a t , a s t h e a n g l e of approach i n c r e a s e s above go", R ' a t t a c k i n g e q u a t o r i a l l y e c l i p s e s Ha even more, t h u s i n c r e a s i n g t o r s i o n a l s t r a i n . W i g f i e l d h a s s u g g e s t e d a n o t h e r p o s s i b i l i t y ( 2 6 ) . C o n s i d e r i n g b o t h t h e long t r a n s i t i o n s t a t e 5 f o r N a B H 4 r e d u c t i o n s and t h e l a r g e r a n g l e of approach of t h e borohydride i o n , he has s u g g e s t e d t h a t t h e e q u a t o r i a l s i d e of cyclohexanone may be s t e r i c a l l y h i n d e r e d by a C-4 a x i a l s u b s t i t u e n t , a s shown i n 27.

126'

27 Two e m p i r i c a l p r o c e d u r e s (69-71) have appeared f o r c a l c u l a t i n g t h e r a t i o s of a x i a l and e q u a t o r i a l a t t a c k on cyclohexanones. One method c a l c u l a t e s t h e c o n g e s t i o n (70,71), which is based on t h e s u r f a c e a r e a of cones of access, d e f i n e d by each h i n d e r i n g atom, of t h e two f a c e s of t h e c a r b o n y l group. T h i s method s u g g e s t s t h e n e c e s s i t y of i n t r o d u c i n g a c o r r e c t i o n funct i o n f o r t h e t o r s i o n a l s t r a i n proposed by F e l k i n . The o t h e r model i s u s e f u l s p e c i f i c a l l y f o r p r e d i c t i n g p r o d u c t r a t i o s i n t h e r e d u c t i o n of cyclohexanones by sodium b o r o h y d r i d e , and weighs t h e c o n t r i b u t i o g t h a t v a r i o u s s u b s t i t u e n t s on t h e r i n g make toward AH: and AH, ( 6 9 ) . A t h i r d e m p i r i c a l model ( 7 2 ) ,

74

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

which is less definitive regarding the physical significance of the controlling parameters, has been presented for 2-substituted cyclopentanones. Time and space, however, do not allow any detailed discussion of these models for predicting product ratios. Dauben and co-workers (48) suggested that steric approach control and product development control are important in determing the stereochemistry of complex metal hydride reduction of ketones. Steric approach control implies an early, reactantlike transition state in which the entering group approaches the least hindered side of the ketone, whereas product development control implies a late, productlike transition state in which the observed isomer ratio reflects the thermodynamic stability of the products. The concept of steric approach control is generally agreed to be a valid one. However, product development control has not gained this general acceptance, and several alternatives have been introduced to explaining the formation of the more thermodynamically stable product, such as Felkin's (49, 5 0 ) torsional strain, molecular orbital arguments (56-62), steric hindrance (26,55), and the antiperiplanar effect (61). Eliel (15,16)] on the basis of competitive rate studies involving LiAlH,, and 3,3,5-trimethylcyclohexanone, has suggested that product development control is not a major factor in stereoreochemical control. The axial C-3 methyl group retards the rate of axial attack compared with 4-t-butylcyclohexanone, whereas the rate of equatorial attack remains essentially the same. This observation is not consistent with that predicted by product development control, in that an axial methyl group would be expected to retard equatorial attack because of the compression of the forming axial O A ~ H ~against the axial methyl group. Since it is possible that changes in conformation of the transition state can take place in flexible systems such as cyclohexanones, we carried out a similar study, using a rigid system which also eliminated the possible complication of torsional effects (73,74). Studies showing equal rates of anti attack by LiA1H4 on 7-norbornanone and on exo-2-methyl-7-

7-norbornanone

exo-2-methyl-7-norbornanone

norbornanone resulted in the conclusion that the concept of product development control is indeed questionable. It should be pointed out that, although the position of the transition state of complex metal hydride reduction of ketones along the reaction coordinate remains unproven, it is generally conceded that an early transition state is involved in most, if not all, cases.

J W S R. BOONE

AND E. C. ASHBY

75

It is obvious that some chemical property of 4-t-butylcyclohexanone directs the attack of complex metal hydrides to the axial side. Three of the several explanations for this observation involve electronic factors. Felkin's torsional strain (49-52) (single bond repulsions), Klein's orbital distortion (56), and Anh's antiperiplanar effect (61) are electronic in nature, not steric. Perhaps all of these are related. Anh's antiperiplanar effect includes torsional strain, and considers ketone MOs similar to those suggested by orbital distortion theory. Thus we use the term "antiperiplanar factors" to include all three of these concepts, since they do predict the same stereochemical results, and we do not feel that it is necessary to consider each theory separately for every single ketone. In this connection we suggest that it is possible that there is something fundamentally different about a four-centered transition state (28) and a transition state that is not four-centered ( 2 9 ) that causes one side of a ketone to be preferentially favored over another. The profound difference in resulting stereochemistry between a four-centered and sixcentered transition state has been demonstrated (75) for the alkylation of 4-t-butylcyclohexanone by Al(CH3)3. The fourcentered transistion state mechanism results in 20% axial attack, while the six-centered transition state mechanism results in 90% axial attack. 6 i 6I

\

6-

28

*

A1-H

/ \

H

H

29

I V . STEREOCHEMISTRY OF REDUCTION OF MODEL KETONES BY COMPLEX METAL HYDRIDES Table 1 lists results of the reduction of several model ketones by complex metal hydrides and their alkoxy derivatives, in several different solvents. Temperatures are not indicated, but almost all the reductions were carried out in the range 0 to 35'. Although temperature is important in stereochemical control, over the range 0 to 35' the effect is not that pronounced, especially for unhindered cyclohexanones. For example, the percentage of axial attack on 4-t-butylcyclohexanone varies about 1% over this temperature range (47). The variation in percentage of axial attack on 3,3,5-trimethylcyclohexanone is larger: 3 to 6% (47). These variations are well within the range of those caused by changes in other factors (39) such as concentration, ratio of reactants, order of addition of reactants, and method of determination of the ratio of isomers.

76

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

This means that small changes in stereochemical results are not significant, unless reported by the same workers under rigorously controlled conditions. The results reported in Table 1 are for reactions carried out with excess hydride. This table does not by any means include all work reported in the area, but has been obtained from selected papers as representative of general findings. The discussion is centered on the stereochemical results of model ketones by complex aluminohydrides.

A.

4-t-Butylcyclohexanone ( I )

4-t-Butylcyclohexanone (I) should be a good model to represent the (noninverting) chair conformation of cyclohexanone. In this case the t-butyl group is locked in an equatorial position, and removed from any steric influence at the reaction center. In addition its inductive and field effects on the reaction center should be minimal. Therefore the data in Table 1 should represent accurately the ratio of axial and equatorial attack on the chair conformation of cyclohexanone. All the hydrides listed, except LiAl(C€H ) 3H I give similar results in the reduction of I. A trend-name?y, that the smaller the cation, the greater the percent of axial attack-can be suggested for the series LiAlH , NaAlH,,, and NR AlH,, [NR,,' is tri(n-octy)4. n-propylammonium ion]. The small Aifferences found are probably real, since these results are consistently reproducible under the same conditions for each reducing agent (39). In I steric hindrance from the C3 and C 5 axial hydrogens favors equatorial attack and the antiperiplanar factors (we let this term include torsional strain, orbital distortion, and Anh's antiperiplanar effect because they are closely related) favor axial attack. It should be pointed out that steric hindrance and antiperiplanar factors favor different directions of attack in I and many other cyclohexanones; however, this is not always the case. Since axial attack is dominant, the antiperiplanar factors caused by the axial C-H bonds at C2 and C6 are more significant than the steric hindrance by the axial C-H bonds at C3 and C5. The ability of the smaller cation, L i ' , to associate more strongly with the carbonyl oxygen atom than Na' or NR,,' could enhance the antiperiplanar factors and result in a slightly larger percentage of axial attack for Li+. The greater association of the carbonyl oxygen atom with Li+ may possibly reduce the angle of attack (closer to 90') (61), which would eliminate some of the steric hindrance by the C3 and C5 axial hydrogens, allowing slightly more axial attack. That the cation affects the stereochemistry is not that clear in the case of I; however, with other ketones the importance of the cation is clearly established. Lithium trimethyoxyaluminohydride gives greater than 40% equatorial attack on I, whereas Li(O-t-Bu)3H gives only 10%.

77

JAMES R. BOONE AND E . C . ASHBY

The common c o n c e p t s of s t e r e o c h e m i c a l c o n t r o l o f f e r no s a t i s f a c t o r y e x p l a n a t i o n f o r t h i s o b s e r v a t i o n . The d i f f e r e n c e , prob a b l y t h e r e s u l t of some fundamental d i f f e r e n c e s by which t h e s e two alkoxy h y d r i d e s r e a c t , d e m o n s t r a t e s t h e d e s p e r a t e need t o know more d e t a i l s a b o u t t h e mechanism of the r e a c t i o n t o exp l a i n t h e s t e r e o c h e m i s t r y . I t has been s u g g e s t e d ( 7 6 ) t h a t t h e i n c r e a s e d s t e r i c requirement of L i A 1 ( O C H 3 ) 3 H o v e r LiAl(O-t-Bu)3H i s caused by t h e g r e a t e r a s s o c i a t i o n of L1A1(OCH3)3Hcompared w i t h t h a t of L i A l (O-t-Bu)3H i n THF. However, t h e s t e r e o s e c t i v i t y i n t h e r e d u c t i o n of I over a 100-fold change i n concent r a t i o n of h y d r i d e , using L i A l H 4 , L i A l ( O C H 3 ) 3H, and L i A l (O-t-Bu)3H, i n c l u d i n g t h e c o n c e n t r a t i o n f o r which L i A l ( O C H 3 ) 3 H s h o u l d be monomeric, shows no change w i t h c o n c e n t r a t i o n of hyd r i d e ( 3 9 ) . T h i s s u g g e s t s e i t h e r t h a t r e d u c t i o n by L i A l ( O C H 3 ) 3 H o c c u r s through t h e same s p e c i e s a t a l l c o n c e n t r a t i o n s o r t h a t t h e a s s o c i a t e d s p e c i e s have no g r e a t e r s t e r i c r e q u i r e m e n t t h a n t h e monomer. An a l t e r n a t i v e e x p l a n a t i o n i s t h a t r e a c t i o n of LiAl(O-t-Bu)3H proceeds v i a Al(O-t-Bu)zH a s an i n t e r m e d i a t e (6,77) : LiAl(OtBu)3H

$

LiOtBu

+

HA~(O~BU)~

l.161

T h i s does n o t seem l i k e l y , however, s i n c e it h a s been shown t h a t LiAl(0-t-Bu) H and Al(O-t-Bu)zH have s i g n i f i c a n t l y d i f f e r e n t 3 . . s t e r e o s e l e c t i v i t i e s (76) toward t h e same k e t o n e s . The p o s s i b i l i t y t h a t r e a c t i o n of L ~ A ~ ( O - ~ - B U )v ~i aH L i A 1 H 4 produced by d i s p r o p o r t i o n a t i o n ( 4 , 7 8 ) (eq. [ 171 ) does n o t seem l i k e l y e i t h e r , s i n c e L i A 1 H 4 reacts w i t h c e r t a i n s u b s t r a t e s t h a t LiAl(O-t-Bu)3H does n o t r e a c t w i t h (79) : 4LiAl(O-t-Bu) 3H

Z

LiAlH,,

+

3LiAl(O-t-Bu)

1171

The e q u i v a l e n t molar conductance of L i A l ( O C H 3 ) 3 H i n THF (2.32 mhos/cm2 a t 0.1M) i s much g r e a t e r i n THF t h a n t h a t of L i A 1 (0-t-Bu) 3H (0.0124 mhos/cm2 a t 0.1M, i n d i c a t i n g t h a t t h e former i s more s o l v a t e d . The smaller e x t e n t of s o l v a t i o n of t h e l i t h ium i o n i n LiAl(O-t-Bu)3H may p o s s i b l y a c c o u n t f o r l e s s e f f e c t i v e s t e r i c b u l k , hence more a x i a l a t t a c k , t h a n w i t h L i A 1 ( O C H 3 ) 3 H . Of c o u r s e , it i s even p o s s i b l e t h a t a d i f f e r e n t mechanism a l t o g e t h e r i s i n e f f e c t f o r r e d u c t i o n of k e t o n e s by L i A l (OCH3) 3 H compared w i t h LiAl(0-t-Bu) 3 H , a l t h o u g h t h i s i s n o t very l i k e l y . Wigfield h a s s u g g e s t e d (26) t h a t if t h e a n g l e of approach t o t h e carbonyl group i s g r e a t e r t h a n 90' (e.g., 126O), s t e r i c i n t e r a c t i o n i n e q u a t o r i a l a t t a c k from t h e C,, a x i a l s u b s t i t u e n t c o u l d become i m p o r t a n t (26,80) (see 2 7 ) . Such a n a n g l e of a t t a c k , however, would a l s o i n c r e a s e s t e r i c h i n d r a n c e t o a x i a l a t t a c k . I t seems t h a t f o r t h i s e x p l a n a t i o n t o be i m p o r t a n t , a s i g n i f i c a n t amount of r i n g f l a t t i n g (30) would have t o o c c u r about carbon atoms C ~ , C 2 , C 3 , C 5 , and C 6 . The i n t e r a c t i o n of an

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

78

/

126' 30

9'0'

a x i a l C, s u b s t i t u e n t w i t h a n u c l e o p h i l e approaching t h e h a l f c h a i r conformation of cyclohexanone a t 90° h a s been d i s c u s s e d i n some d e t a i l ( 7 5 ) . I n t h i s c o n n e c t i o n w e concluded s o m e t i m e ago t h a t t h e a x i a l C, hydrogen of I i n a h a l f - c h a i r conformat i o n cannot account f o r 90% a x i a l a t t a c k i n t h e r e a c t i o n of A 1 ( C H 3 ) 3 with I. However, the p r o p o s a l by W i g f i e l d i s t h o u g h t provoking, and should be c o n s i d e r e d f u r t h e r .

B.

3,3,5-Trimethylcycl ohexanone (I I )

3,3,5-Trimethylcyclohexanone (11) i n t r o d u c e s a methyl group i n t h e C 3 a x i a l p o s i t i o n , and t h i s s e v e r l y h i n d e r s a x i a l a t t a c k on t h e cyclohexanone r i n g . The l a r g e s t v a r i a b i l i t y i n t h e s e l e c t i v i t y of t h e h y d r i d e s o c c u r s w i t h I1 (see T a b l e 11, and e q u a t o r i a l a t t a c k predominates f o r a l l h y d r i d e s . The importance of t h e c a t i o n i n aluminohydride r e d u c t i o n o f I1 is c l e a r l y shown i n T a b l e 1. A t r e n d - t h e s m a l l e r t h e c a t i o n , t h e g r e a t e r t h e p e r c e n t a g e of e q u a t o r i a l a t t a c k - i s c l e a r l y suggested i n t h e series L i A l H b , NaAlH4, and NR,+A1H4. The t r e n d , i s however, e x a c t l y o p p o s i t e t o t h a t observed i n t h e c a s e of I . I t a p p e a r s t h a t r e g a r d l e s s of what f a c t o r s domi n a t e t h e stereochemistry ( s t e r i c hindrance o r a n t i p e r i p l a n a r f a c t o r s ) , L i A l H , , a p p e a r s t o e x p e r i e n c e t h e s e f a c t o r s more t h a n N a A l H , , o r N R q A l H b , and i s a l m o s t always t h e most s e l e c t i v e (39) ( i . e . , t h e p r o d u c t r a t i o i s f u r t h e s t from 50:50). The b e h a v i o r of L i A l H 4 toward I1 may be e x p l a i n e d on t h e b a s i s t h a t L i A l H , , i s more s o l v a t e d , and t h u s h a s a l a r g e r s t e r i c r e q u i r e m e n t t h a n N a A l H , , and NRqAlH,,. I t might be noted t h a t L i A l H 4 a t t a c k s I1 more from t h e l e a s t h i n d e r e d e q u a t o r i a l s i d e i n THF t h a n i n d i e t h y l e t h e r , a more weakly s o l v a t i n g s o l v e n t . A l s o , i f Li' i s indeed a s s o c i a t i n g w i t h t h e c a r b o n y l oxygen i n t h e t r a n s i t i o n s t a t e , more o r d e r about t h e c a t i o n i n t h e t r a n s i t i o n s t a t e i s l i k e l y t o i n c r e a s e t h e importance of s t e r i c f a c t o r s . Thus L i A l H 4 p r e s e n t s t h e l a r g e s t s t e r i c r e q u i r e m e n t i n h i n d e r e d ket o n e s ; i n unhindered k e t o n e s , however, s t e r i c f a c t o r s s h o u l d be less i m p o r t a n t , and a n t i p e r i p l a n a r f a c t o r s , enhanced from a s s o c i a t i o n of t h e L i t w i t h t h e c a r b o n y l oxygen, s h o u l d become t h e predominant f a c t o r . The h y d r i d e s ClMgAlH4 and Mg ( A l H 4 ) z g i v e r e s u l t s w i t h I1 which a r e i n t e r m e d i a t e between t h o s e of L i A l H 4 and N a A l H 4 . A l though t h e Na' almost always g i v e s r e s u l t s i n t e r m e d i a t e between Li' and NR4+, t h e magnesium i o n f o l l o w s no such p a t t e r n . S i n c e

JAMES R. BOONE AND E. C. ASHBY

79

the magnesium aluminohydrides give more axial attack on I1 than does LiAlH4, it appears that they experience antiperiplanar factors more than does LiAlH4. This is also the case with other ketones in Table 1. The magnesium aluminohydrides, probably more than any other aluminohydride, demonstrate the importance of the cation on stereoselectivity and have produced some very surprising results. The importance of solvation, as suggested for the reactions LiAl(OCH3)3H and LiAl(O-t-Bu)jH with I, is demonstrated with I1 when the solvent is changed from ether to THF. When THF is the solvent, a larger percentage of equatorial attack occurs on I1 than in the same reaction carried out in diethyl ether.

C.

Camphor (111)

All the hydrides listed in Table 1 give predominately endo attack on camphor (111). The syn C7 methyl group severly blocks exo attack, and thus steric approach control is the expected result. LiBH4, ClMgAlH4, and Mg(AlHq)2 give less endo attack than the other hydrides. Lithium borohydride gives results similar to LiAlH4 for I, where antiperiplanar factors are believed to be the controlling elements in determining the direction of attack. When the reduction is controlled by steric hindrance, as in I1 and 111, LiBH4 qives more attack than LiAlH4 from the more hindered side. This is consistent with the smaller size of the borohydride ion (81) compared with the aluminohydride ion and with the fact that LiBHI, is less solvated (1,2) than LiAlH4 in THF, and thus LiBH4 possesses a smaller steric requirement. However, factors other than the size of the anion may be important. NaBH4 in isopropyl alchohol and LiBH4 in THF give similar results with 11, but quite different results with 111. In general the NaBH4 results are more similar to those from NaAlH4 and LiBH4, than to those from any of the other aluminohydrides. Lithium borohydride does not parallel its stereochemical results with any particular aluminohydride. Of course, there is likely to be a pronounced solvent effect in the case of NaBH4 and LiBH4, the former being used in a protic solvent and the latter in an aprotic solvent. It is not necessary to have a smaller anion, such as BHq, to increase the percentage of exo attack relative to LiAlH4, because Mg(AlH4)z gives considerably more exo attack than LiAlH4. Steric hindrance and antiperiplanar factors favor opposite sides of attack in I, 11, and 111. The antiperiplanar factors in I11 arise because of the interactions of the cl-cg bond with the carbonyl 1~ bond and the approaching nucleophile, and thus favor exo attack ( 3 1 ) . Therefore increase in exo attack on I11 by ClMgAlH4 and Mg(A1Hq)z relative to LiAlH4 could be caused by Mg2+ enhancing the antiperiplanar effect by complexing with the carbonyl oxygen. More is said about such

80

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

31

p o s s i b i l i t i e s l a t e r . I t should be p o i n t e d o a t t h a t I11 has a methyl group a t t a c h e d t o a carbon a d j a c e n t t o t h e carbonyl group and l y i n g n e a r l y i n t h e carbonyl p l a n e .

D.

Norcamphor (IV)

The r e s u l t s of t h e r e d u c t i o n of norcamphor ( I V ) , l i s t e d i n Table 1, show a d e f i n i t e t r e n d i n s e l e c t i v i t y : L i A l H 4 > N a A l H 4 > N R q A l H q . S t e r i c hindrance and a n t i p e r i p l a n a r f a c t o r s favor o p p o s i t e s i d e s of a t t a c k i n I , 11, and 111, b u t n o t i n I V , where both favor exo a t t a c k (31). I t i s l i k e l y t h a t both s t e r i c hindrance and a n t i p e r i p l a n a r f a c t o r s a r e important i n t h e s t e r e o chemistry of t h e r e d u c t i o n of I V . The d i f f e r e n c e s i n t h e s t e r e o s e l e c t i v i t i e s of L i A l H 4 , N a A l H 4 , N R q A l H q may be explained by s t e r i c hindrance, a s with I1 ( L i + > N a + > NR$), o r by a n t i p e r i p l a n a r f a c t o r s , a s w i t h I (Li' > N a " > NRG) , or by some combina t i o n t h e r e o f . The s t e r e o c h e m i s t r y of r e d u c t i o n of I V has g e n e r a l l y been explained on t h e b a s i s of s t e r i c hindrance by t h e endo hydrogens. The r e s u l t s i n Table 1 s u g g e s t t h a t o t h e r f a c t o r s m u s t be important, n o t n e c e s s a r i l y because of t h e magn i t u d e of t h e d i f f e r e n c e between L i A l ~ 4and NaAlH4 o r N R q A l H q , o r between L i A l H 4 and Mg ( A l H 4 ) 2 o r ClMgAlH4 , b u t because N a A l H 4 and NRbA1H4 behave s i m i l a r l y t o L i A 1 H 4 toward I11 while ClMgAlH4 and Mg(AlH4)z do n o t , whereas toward I V , ClMgAlH4 and M g ( A l H q ) 2 kehave s i m i l a r l y t o L i A l H 4 while N a A l H 4 and NRGAlH4 do not. The p a i r s N a A l H 4 and N R k A l H b , and ClMgAlH4 and Mg(AlH4)2 have swapped p l a c e s r e l a t i v e t o L i A l H 4 . The magnesium i o n i s indeed causing s i g n i f i c a n t changes i n t h e s t e r e o c h e m i s t r y of t h e r e d u c t i o n of ketones by t h e aluminohydride ion. I f t h e e x a c t r o l e of t h e c a t i o n s i n t h e s e r e d u c t i o n s were b e t t e r known, perhaps t h e r e would be l e s s s p e c u l a t i o n about s t e r e o chemical c o n t r o l . The alkoxyaluminohydrides LiAl (CCH3)3 H and LiAl(0-t-Bu) 3H g i v e 98% and 93% exo a t t a c k on I V , r e s p e c t i v e l y . The r e s u l t s a r e s i m i l a r , b u t LiAl(CCH3)3H appears t o be t h e more s e l e c t i v e reagent. The same t r e n d occurs w i t h 111, e x c e p t t h a t endo a t t a c k i s t h e major pathway. The p a t t e r n i s t h a t L i A l ( O C H 3 ) 3 H always a t t a c k s t h e less hindered s i d e of a ketone t o a g r e a t e r e x t e n t than does LiAl(O-t-Bu)-jH. The borohydrides LiBH4 and NaBH4 g i v e much more s i m i l a r r e s u l t s w i t h I V t h a n with 111.

JAMES R. BOONE AND E. C. ASHBY

81

A frequent observation is that with the more sterically hindered ketones, any change in solvent or cation that increases the solvation of the borohydride or the aluminohydride results in steric factors becoming more dominant in the stereochemical outcome of the reaction. (Compare the results of LiAlH4 in ether and THF with 11, LiAlH4 and NaAlH4 in THF with 11, NaBH4 and LiBH4 with 111, and LiAlH4 and N a A l H 4 in THF with IV.)

E.

2-Methylcyclohexanone ( V )

The flexibility of the ring system in this compound provides a unique case in the study of the stereochemistry of reduction. It is of interest to consider how a methyl group adjacent to the carbonyl group affects the stereochemistry of cyclohexanone reduction by complex metal hydrides. However, before an understanding of this reaction can be realized, one must consider the extent to which each of the two conformations of V(Ve or V,) participate in the reaction. Unlike camphor

(III), which is rigid and cannot change comformation, V can easily flip from Ve to V, and back to Ve. The conformation Va is present to the extent of ca. 5% at ambient temperature ( 8 2 ) . If the methyl group in V is replaced by an ethyl or isopropyl group, the percentage of the least stable conformer (analogous to V,) present in the conformational equilibrium increases (ethyl ca. 12%, isopropyl ca. 30%) because of steric hindrance between the equatorial C p Jlkyl group and the carbonyl oxygen atom. This phenomenon is known as the 2-alkylketone effect ( 8 2 ) . It is likely that 2-t-butylcyclohexanone resides predominately in the flexible (boat) conformation because of such an interaction. It should be pointed out that the flexible (boat) conformation was not considered along with Va and Ve for the sake of simplicity. Of course, if the flexible (boat) conformer is present, reaciton can occur via that conformer. However, in the case of V the two major conformers are Ve and Va, and it is assumed that complex metal hydride reductions involve mainly these two conformers. All the hydrides studied give more equatorial attack on V (see Table 1) than on I, if the reactive conformation is considered to be V,. It has been suggested (83,84) that the hydrogen atoms of the methyl group introduce a third 1,3diaxial interaction with respect to the incoming nucleophile

82

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

(see V,) which, of course, retards axial attack. Reaction of V through the flexible forms (the various boat and twist-boat conformations) has also been suggested (85) to explain the greater degree of equatorial attack on V than on I. This increase in apparent equatorial attack has also been attributed (39,40,48,86,87)to reaction of the chair conformation with the axial methyl group (V,). Axial attack on this conformation gives the same alcohol that results from equatorial attack on the conformer V,, thus accounting for the increase in apparent equatorial attack on V over I. Reduction of cis-2-methyl-4-t-butylcyclohexanone (VI) by LiAlH4 in THF (see Table 1) gives 17 to 19% equatorial attack compared to only 7 to 10% in a similar reaction involving I. This result provides good evidence that the equatorial C-2 methyl group does in fact retard axial attack by LiAlH4 on a cyclohexanone. Reduction of V by LiAlH4 in THF gives 22 to 25% equatorial attack, assuming V, is the reactive conformation. This is slightly more equatorial attack than experienced by VI. The results involving V can be explained by two effects: (1) The equatorial C2 methyl group retards axial attack on V; ( 2 ) V reacts through both conformations, V, and Ve. If both conformations Va (5%) and Ve (95%) had approximately the same rate of reaction, then 17 to 19% equatorial attack on V, by LiAlH4 (since VI gives 17 to 19% equatorial attack) plus nearly exclusive axial attack on Va (only 5% present) would produce ca. 22 to 24% apparent equatorial attack on V, as experimentally observed. The results tabulated in Table 1 for ClMgAlH4 and Mg(A1Hq)z similarly show that a third to a half of the cis-2-methylcyclohexanol produced must arise from the reaction of V,. This result requires ca. 15 to 25% of the reaction to occur via V a l although it is present to the extent of only about 5% in the equilibrium between conformers Va and V . , Thus with ClMgAlH4 and Mg(AlH4)2, V, appears to be more reactive than Ve, or the equilibrium concentration of V, and V e is different when complexed to magnesium compared to lithium. W o questions arise from a consideration of these results: (1) How does the equatorial C2 methyl group of cyclohexanone actually retard axial attack? ( 2 ) Why is conformer V, relatively more reactive than conformer V, with the magnesium aldnohydrides than with LiAlH,? These results, indicating that the equatorial Cp methyl group retards axial attack, may be explained by assuming that the C2 methyl (1) partially blocks the axial approach of the aluminohydride ion from a direction perpendicular (or nearly perpendicular) to the plane of the carbonyl group; (2) blocks the aluminohydride ion from moving into an axial position after or during complexation of the oxygen atom by the cation; and/or (3) causes steric strain as the cation complexes to the oxygen atom, thus causing part of the reduction to occur via the flexible form. The first two reasons may seem to be the same, but

JAMES R. BOONE AND E. C. ASHBY

83

in fact are not. The first explanation is applicable to all approaching nucleophiles. The second suggests that if the mechanism does involve complexation of the carbonyl oxygen by the cation, then the effect of the equatorial C2 methyl group is greater than it would be if no complexation occurred. The third possibility is included because it is felt that the flexible conformer, although a less likely intermediate, cannot be entirely ignored. Conformer V, may be considered more reactive than Vg because the axial methyl of V, pushes against the axial C6 hydrogen atom and the resulting outward thrust of the axial Cg and c6 bonds cause the ring to flatten. The flattening of the ring allows for easier axial attack on V, than on V,, which already has axial attack retarded by the equatorial methyl group. However, such an effect by itself should affect the stereochemistry and reaction rate of all aluminohydrides to about the same degree, since the effect is inherent in the ketone. Thus, if V, is more reactive than V, with one aluminohydride, it should be more reactive with all the aluminohydrides. This, however, is not the case, as pointed out earlier. A larger percentage of the reaction of V appears to occur through conformer Va with the magnesium aluminohydrides than with LiAlH4. It has been shown that the equilibrium constant for the complexation of 2-methylbenzophenone by MgBr2 (88) in diethyl ether has a value of 4.1 liters/mol., and that the equilibrium constant for the complexation of benzophenone by LiC101, (37) in diethyl ether has a value of 1.3 liters/mol. This suggests that Mg2+ is a better complexing agent than Lif, in spite of the fact that 2-methylbenzophenone is a more sterically hindered ketone about the carbonyl group than benzophenone. If it is assumed that cation M+ of MAfH4 complexes with the carbonyl ox gen prior to or con$: being larger than current with reduction, the MgC1' or MgAlH4, L i ' , would interact more with the methyl group of V, (V&) , and thus force more of the reaction to proceed through the conformation V, (VaC).

Actually, the solvated cations should be considered; however, Mg2+ would be expected to be more highly solvated than Li+, and the conclusions would remain the same. If complexation of the carbonyl group occurs during reduction, then the concentration of V,C (and its transition state corresponding to axial attack) should increase relative to that of V,, since the energy difference between V,C and V,C is less than that between V, and V,.

84

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

There is a question that should be asked at this point: Why does complexation not occur at the other side of the carbonyl group away from the methyl group in V,? The answer probably is that if complexation does occur in the manner shown in V,C, it probably occurs predominantly at the side away from the methyl to avoid steric interactions. The net effect, however, would be that V, would have two sites for complexation by M+ and Ve only one; thus on the basis of concentration of active sites V, would be twice as reactive as Ve. Of course, such an effect would be quite dependent on the complexing agent. The complexation of the carbonyl group has been suggested (61) to occur in such a way that the C=O---Liangle is 180°, then the increased effective bulk about the carbonyl oxygen is the same in the direction of both C2 and c6 carbon atoms. Even if the complexation angle is 120°, it may be valid to assume that the increased effective bulk about the carbonyl oxygen (75) is the same on both sides because the equilibrium is quite dynamic, with rapid exchange of solvent and ketone molecules about the complexing ions. The reactivities of conformers Va and V, toward magnesium aluminohydrides may also be explained on the basis of antiperiplanar factors. Examination of conformations V, and Ve suggests that V, should be able to stabilize an induced positive charge at the carbonyl carbon better than V, (58,59), because hyperconjugation should be greater for the more polarizable axial 6,3 C-C bond of V, than for the axial B C-H bond of V,. Thus this increased stabilization in V, allows more of the reaction to proceed via V, when Mg(AIH4)z and CIMgAIH4 are used than when LiAIH4 1.s used (assuming that Mg' polarizes the carbonyl C-0 bond more than Li'). It should be pointed out that the axial methyl group of V, would favor axial attack more than a hydrogen at the same position, because all the antiperiplanar factors (torsional strain, orbital distortion, and the antiperiplanar effect) are more important for the methyl group than for the hydrogen. The reduction of r-2-cis-6-dimethyl-cis-4-t-butylcyclohexanone (VII) reinforces the evidence already present that a C2 equatorial methyl group retards axial attack. Reduction of VII (see Table 1) , by three different complex aluminohydrides gives 48 to 53% axial attack compared with 73 to 83% for VI and 87 to 93% for I. The effect of a C2 axial methyl group is shown in the table for the reduction of trans-2-methyl-4-t-butylcyclohexanone (VIII). The methyl group does retard equatorial attack by complex aluminohydrides ( 4 to 8 % ) as compared to I (7 to 13%). If the amount of equatorial attack on VIII seems suprisingly higher than expected, consider 3 2 , which shows that an axial C2 methyl group may only approximate the steric hindrance of a C3 or C5 axial hydrogen. The reductions of several other 2-alkylcyclohexanones are recorded in Table 1: 2-ethylcyclohexanone (1x1, cis-2-ethyl-4-tbutylcyclohexanone (X), 2-isopropylcyclohexanone (XI), and cis2-isopropyl-4-t-butylcyclohexanone (XII). Results for X and XI1

JAMES R. BOONE AND E. C. ASHBY

85

H

32

show that an equatorial C2 ethyl or isopropyl group does not retard axial attack significantly more than does a methyl group (compare VI and I, X and I, and XI1 and I). This may be explained on the basis that conformers such as 33 participate significantly in the reaction of X and XII, where a methyl seldom interacts in a syn-diaxial fashion with the entering hydride. In the conformation 33 interference of axial approach by the hydride is no greater for ethyl or isopropyl than for methyl. Comparison of the results in Table 1 leads to the same conclusion about IX and XI as about V, namely, that a significant amount of the reaction of IX and XI occurs through a conformer with the alkyl group in an axial position.

33

Wigfield has concluded that both conformers V, and V, are involved in the reduction of V by NaBH4 f87) in isopropyl alcohol, by using 2,2,4-trimethylcyclohexanone (assuming that no syn-diaxial methyl-methyl interaction may occur) instead of VI as a model for a cyclohexanone with an equatorial C2 methyl group. He concluded that about half of the cis-2-methylcyclohexan01 arises from axial attack on V, by NaBH4. Reaction of V through V, probably is significant in accounting for the increase in apparent equatorial attack by LiAl(OCH3)3H and LiAl (0-t-Bu)3H on V over that on I.

F.

Cyclopentanones

The preferred conformation of cyclopentanone, the halfchair model, has a C2 axis of symmetry (63), which allows equal attack from either side ( 3 4 ) . Substitutents distort the symmetry, causing one side to be attacked by hydride more easily than the other. Since 2-methylcyclopentanone (XIII) (see Table 1) is attacked by LiAIH4 to the extent of 74 to 84% from a position cis to a methyl group, any steric hindrance from the

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

86

34 C2 methyl group would seem to be minor. The methyl group is probably in a quasi-equatorial position (35) , and steric hindrance is felt less than the antiperiplanar factors caused by the quasi-axial hydrogen at C2 on the opposite side of the ring (45) cis attack

-

35

3-Methylcyclopentanone (XIV) (see Table 1) is attacked 60 to 73% by LiAlHt, from a position trans to the methyl group. At first glance this may be ascribed to blocking of cis attack by steric hindrance of the C3 methyl group, since the introduction of an axial C3 methyl group on a cyclohexanone ring results in a large decrease in axial attack, from ca. 90% in I-t-butylcyclohexanone to ca. 30% in 3,3,5-trimethylcyclohexanone. This latter observation involving cyclohexanones is clearly the result of steric hindrance. However, it must be remembered that the cyclohexanone chair conformatioa does not allow equal attack on both sides of the ring, while the half-chair conformation of cyclopentanone does. Therefore the C3 methyl group of XIV only changes the preferred direction of attack from 50% to 60 to 73%. This effect is smaller than that observed for the C2 methyl group of XI11 (50% to 74 to 84%), whose stereochemistry of reduction is controlled not by steric hindrance, but probably by antiperiplanar factors. It is also reported that 3-t-butylcyclopentanone is attacked to approximately the same extent as XIV by LiAIH4 [i.e., 60% trans attack ( g o ) ] . These results indicate that factors other than steric hindrance control the stereochemistry of reduction of XIV. The C3 methyl group is probably in a quasi-equatorial position, offering little steric hindrance to cis attack (36). The vicinal methyl groups of cis-3,4-dimethylcyclopentanone (XV) (see Table 1) probably twist in a manner to avoid eclipsing each other. One takes a quasi-axial position and the other a quasi-equatorial position (37). The quasi-axial methyl group can hinder cis attack at the carbonyl group, and thus it is not

87

JAMES R. BOONE AND E. C. ASHBY

H

I

36

surprising that LiAIH4 attacks XV 90% from the trans side. H I

cis attack

CH3

37

The reduction of XIV and XV by ClMgAlH4 and Mg(AlH4)z gives results similar to those for LiAlH4. W i t h XIII, ClMgAlH4 and Mg(AlH4)2 give much more trans attack (35 and 55%, respectively) than does LiAlH4 (16 to 26%). In fact, Mg(AlH4)z gives more trans attack than LiAl(OCH3) 3H (55 vs. 4 4 % ) in THF. It appears that Mg(AlH4)2 experiences steric hindrance of the 2-methyl group more than LiA1(OCH3)3HI which is supposedly very sensitive to steric effects. Probably Mg(AlH4)2 attack on XI11 occurs predominantly trans for reasons other than steric hindrance. In reductions of the cyclopentanones XIV and XV (where the methyl groups are not adjacent to the carbonyl groups) all the complex aluminohydrides behave similarly. Only when the methyl group is adjacent to the carbonyl group, as in XIII, 111, and V, does a difference in stereochemical results occur between LiAlHq and ClMgAlH4 and Mg(AlH4)z. It appears that complexation of the carbony1 group of XIII by Mg2+ pushes the methyl group from its quasi-equatorial position into a quasi-axial position (381, which increases steric hindrance to cis attack.

CH3

cis attack

38

88

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

The possible importance of antiperiplanar factors in the stereochemical control of hydride reduction of XI11 has already been mentioned. Structure 39 shows how orbital distortion or the antiperiplanar effect could arise in compound XIII. Thus the set of antiperiplanar factors can also be applied to XI11 as well as V. In both cases the methyl group becomes quasi-axial and, because it is more polarizable than a C-H bond, it enhances the antiperiplanar factors. If it is assumed that Mg2+ polarizes the carbonyl C=O bond more than L i ' , which causes the antiperiplanar factors to be more significant, relatively more of XI11 reacts through the conformer 39 than through 35 with ClMgAlH4 and Mg(AlH4)z than LiAlH4. It probably is of significance that such an explanation may also be applied to explain the differences in the stereochemical results of the reduction of I11 and V by LiAlH4 and the magnesium aluminohydrides.

39

V.

SUMMARY

The mechanism of LiAlH4 reduction of ketones is not known with a great degree of certainty; however, studies carried out in the past few years have provided much additional information about this reaction. The stereochemical results of complex aluminohydride reduction of ketones are dependent on the nature of the cation ( 3 9 ) , and thus it may be concluded that the cation must be involved in the mechanism of reduction at least to some extent. It has also been demonstrated that solvent, temperature, and concentration are important factors in the stereochemical outcome of these reduction reactions. The stereochemistry of these reductions is probably best explained by steric approach control and antiperiplanar factors which are electronic in nature, although the concept of product development control cannot be completely eliminated as a controlling factor. Reaction of a flexible ketone through minor conformers that may be present in solution must sometimes be considered when explaining the stereochemistry of reduction. If the mechanism of ketone reduction by LiAlH4 were known in more detail and with greater certainty, it might help to explain what factors are involved in the stereochemistry of reduction.

Hydr i d e

Table 1.

THF

90 ( 5 5 ) , 90 (16)

89 (39)

Et20 I

56 ( 3 9 ) , 59 (16)

--

THF

12 ( 4 ) , 12 (55),

27 ( 4 ) 4 (16)

1 (6)

8 (41, 2 (16)

7 (6),

--

--

--

Et20

25 (4)

26 (39)

39 (39)

9 1 (92)

87 (39),

THF

1 2 (39) 1 9 (39)

THF

45 (39)

29 (39)

85 (39) 90 ( 3 9 ) , 93 (92)

TKF

1 2 (39)

5 (55)

9 (391, 8 ( 6 )

4 1 (39)

20 ( 3 9 ) , 23 (47)

--

3 1 (39)

1 4 (93)

87 (39)

90 ( 3 9 ) , 92 (471, 93 (92)

(16)

38 (16,101

i11

THF

THF

45 ( 4 7 ) , 37-42

(16)

48 (251,

92 ( 4 7 ) , 92 (911, 90-91

(39)

Et20

42 (47,10), 47

93 (39)

THF

I1

87 ( 4 7 ) , 83 (16)

I

Ketone ( p e r c e n t a x i a l , exo, o r c i s a t t a c k by t h e hydride on t h e ketone) (Ref:-)

2-propanol

Solvent

Reduction of Model Ketones by Complex Metal Hydrides

W 0

IV

(Cont.)

89 ( 6 )

,

52 ( 3 9 ) , 59 (92)

64 (391, 70 ( 6 ) , 6 3 (55)

--

37 ( 3 9 ) , 31 ( 6 )

--

--

---

79 (39,921 73 (39,921

64 (391, 6 1 (92)

--

--

81 (391, 83

--

---

--

VI

74 (39)

7 1 (39)

76 (39) , 75 ( 6 ) , 78 (95)

82 (481, 64 (94)

7 1 (39)

69 ( 9 3 ) , 75 (161, 60 (10), 70 (25)

V

- o

(Ref.)

VSI VIII

IX

X

'm

2Yz& - -w

Ketone ( p e r c e n t a x i a l , exo, or c i s a t t a c k by t h e h y d r i d e on t h e k e t o n e )

T a b l e 1.

-O

1

1

I

I

o

-

m

O

22. r

J

.

N

1

1

I

a

2.2. m

I

N

o

N

1

I

1

I

1

I

1 I

4J

C 0 V

Y

-- -.

d

N

O

2 2

s,

I

I

I

1 a - J F r n

d

m

Y

I I

I

0

m

I

I I

I

I I

I

0

A

--

rr,

a

0

91

REDUCTION OF KETONES BY COMPLEX METAL HYDRIDES

92

REFERENCES 1. E . C . Ashby, Frank R. Dobbs, and H a r r y P. Hopkins, J. Am. Chem. SOC. , 9 5 , 2823 ( 1 9 7 3 ) . 2 . E . c. Ashby, F. R. Dobbs, and H . P. Hopkins, J r . , J. Am. Chem. SOC. , 97, 3158 ( 1 9 7 5 ) . 3. M. K. Wong, W. F. McKinney, and A. I. Popov, J. Phys. Chem.,

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56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

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Topics in Stereochemisty, Volume11 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1979 by John Wiley & Sons, Inc.

Conformational Barriers and Interconversion Pathways in Some Small Ring Molecules THOMAS B. MALLOY, JR., and LESLIE E. BAUMAN Department of Physics and Department of Chemistry, Mississippi State Universiy , Mississippi State, Mississippi

L. A. CARREIRA Department of Chemistry, University of Georgia, Athens, Georgia

I. 11.

111.

..................... 98 Experimental Considerations. . . . . . . . . . . . . . 105 A. Far-IR Spectroscopy. . . . . . . . . . . . . . . . 105 B. Raman Spectroscopy . . . . . . . . . . . . . . . . 109 C. Mid-IR and Mid-Raman Spectroscopy. . . . . . . . . 111 D. Microwave Spectroscopy . . . . . . . . . . . . . . 115 Examples of Applications . . . . . . . . . . . . . . . 119 A. One-Dimensional Potential Functions. . . . . . . . 119 1. 3-Thietanone . . . . . . . . . . . . . . . . . 121 2. 1,2-Dirnethylenecyclobutane . . . . . . . . . . 124 Introduction

97

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

98

3

.

2. 5.Dihydrofuran

. . . . . . . . . . . . . . . 126

4. Analogues of Bicyclo[3.l.O]hexane.

. 6. 5

Trimethylene Oxide 2. 5.Dihydropyrrole

. . . . . . 128

. . . . . . . . . . . . . . 134 ..............

138

. . . . . . . . . . . . . 141 8. Cyclopentene . . . . . . . . . . . . . . . . . 142 9. Trimethylene Imine . . . . . . . . . . . . . . 145 10. Cyclobutane . . . . . . . . . . . . . . . . . 146 B . Two-Dimensional Potential Functions . . . . . . . 148 1. Cyclopentane . . . . . . . . . . . . . . . . . 152 2. Tetrahydrofuran . . . . . . . . . . . . . . . 152 3 . Cyclopentanone . . . . . . . . . . . . . . . . 153 4. 1 4-Dioxene . . . . . . . . . . . . . . . . . 157 IV . Summary of Investigations of Small-Ring Molecules . . . 161 v . Conclusions . . . . . . . . . . . . . . . . . . . . . 172 172 Appendix 1 . . . . . . . . . . . . . . . . . . . . . . Appendix I1 . . . . . . . . . . . . . . . . . . . . . 174 References . . . . . . . . . . . . . . . . . . . . . . 178 7.

1.3.Disilacyclobutane

.

I

.

INTRODUCTION

Tremendous advances have been made in the last 15 years or so in the determination of conformations and barriers associated with large-amplitude vibrations in molecules Various experimental and theoretical techniques have been applied. including IR. Raman. and microwave spectroscopy as well as electron diffraction. NMR. and a variety of computational techniques We do not address all of these. but rather consider a limited aspect. the advances made in the application of vibrational and rotational spectroscopy to large-amplitude vibrations in ring molecules Omission of references to other techniques is not intended as a slight. but is done to concentrate on the areas mentioned .

.

.

.

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

99

These restrictions sharply limit the problems that are addressed. A further limitation is that we discuss spectra of samples in the gas phase at temperatures ranging from dry ice (185K) to ca. 450K. Despite these limitations useful information on molecular dynamics may be gained for a variety of ring molecules. The examples we give here disproportionately represent work done by the authors, but as much as anything, this represents the availability of the figures. We hope to convey a sense of what is being measured and how the data are then used to extract information about the molecular dynamics. In particular we wish to indicate how these applications differ from some of the applications of vibrational spectroscopy to the determination of normal vibrational modes, and rotational spectroscopy to the determination of structural parameters. The differences mentioned occur because of the large amplitudes of certain vibrational modes of some small-ring molecules. A nonlinear molecule has 3N - 6 molecular vibrations. A four-membered ring molecule has one out-of-plane skeletal mode, usually referred to as the "ring-puckering'' mode (Fig. 1). A five-membered ring has two out-of-plane skeletal vibrations, which may be represented by a ring-puckering and a ringtwisting mode (Fig. 2 ) . In saturated rings these modes are usually the lowest frequency molecular vibrations and have unusually large amplitudes. In the first approximation they may be treated as independent of the remaining 3N - 7 (or 3N 8) small-amplitude vibrations. The large-amplitude coordinates lead to interconversion of different ring conformations (Figs. 1 and 2 ) . The determination of potential energy functions in these coordinates yields barriers to interconversion, energy differences between conformers, and interconversion pathways. For illustrative purposes we compare some one-dimensional examples of potential energy functions appropriate to small-, amplitude molecular vibrations to some one-dimensional potential functions appropriate to large-amplitude modes. The simplest example of a vibrational potential function is that for a diatomic molecule as a function of internuclear separation (1).

Fig. 1. One possible definition of a ring-puckering coordinate x for a four membered ring molecule. The coordinate is half the perpendicular distance between ring diagonals.

100

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

(b)

Fig. 2. Ring-twisting (a) and ring-puckering (b) vibrations for five-membered-ring molecules. The familiar Morse curve (2) is an approximation to this shape which yields a closed form energy expression. The simplest approximation applicable to the lower energy states is the harmonic oscillator approximation, which corresponds to approximating the function by a parabola having the same curvature at the minimum. It may be thought of as expanding the potential energy in a Taylor series and truncating after the second-degree term(1) : V(r)

=

1/2 k (r

-

re)'

= 1/2 kx2

(11

where k = (d2V/dx2) is the Hookes law force constant. Truncation after the quadratic term is a good approximation only if the amplitude of vibration is small, that is, if x is small. The solutions to the Schradinger equation for the harmonic oscillator are the Hermite functions, and the energy levels are given by

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA where v is the temperature IR from the v = 0 transition 0 k in eq. [2]: -+

101

frequency and h is Planck's constant. For room or Raman experiments only transitions originating state are ordinarily observed. The fundamental 1 may be used to calculate the force constant v = 1/2&

[31

where the reduced mass p = mlm2/(ml

+ m2).

On the other hand the first overtone transition 0 2 may be observed, although it is not, strictly speaking, an allowed transition in the harmonic oscillator approximation. Due to anharmonicity the overtone frequency is not exactly twice that of the fundamental, and it may be necessary to carry the Taylor series expansion of the potential function to one more term before truncation: -+

V(X)

=

1/2 k2x2

+ 1/6 k3x3

141

Normally the cubic term in the potential function is small enough that perturbation theory may be used to find an expression for the energy levels (1): E = (V

+ 1/2) hew, -

(V

+ 1/2)2 hcwexe,+ .

..

[51

where we is the harmonic frequency in reciprocal centimeters and wexe is the anharmonicity. The value of the fundamental (0 + 1) frequency and the overtone (0 + 2 ) may be used to determine the two parameters in Eq. [ 4 1 . If more data are available, a least squares fit may be performed. Alternatively, the Morse function may be used. If high-temperature experiments or flourescence experiments are performed, it may be possible to map the excited vibrational states and accurately determine the potential function. For molecules larger than diatomic ones, multidimensional Taylor series expansion in the vibrational coordinates may be used. For a nonlinear molecule of N atoms, the harmonic oscillator approximation to the vibrational potential energy yields 3N-6

3N-6

where x i and xj are vibrational coordinates and kij = (a2V axiax.). In general, even with the use of symmetry ( 3 ) , there 3 are more parameters in Eq. [ 6 ] than there are observed fundamental vibrational frequencies (5 3N - 6). To perform a normal coordinate transformation and simultaneously remove the cross

102

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

terms in the potential energy (Eq. [6]) and the kinetic energy, data from isotopic species and/or assumptions concerning some of the terms are necessary. When this is complete, one has determined the multidimensional eqJivalent of a parabolic approximation. In treating large amplitude molecular vibrations it is usually not possible to make the harmonic approximation. The first approximation neglects cross terms between largeand small-amplitude modes. For a molecule with a single large-amplitude vibration the Taylor series expansion carried through the fourth degree yields V ( x ) = ax4

+

bx2

+

ex3

[71

where x is an out-of-plane ring vibration. In this-equation a = 1/4! (a4V/dx4) , b = 1/2 (8V / d x 2 ) , and c = 1/3: ( d 3 V / d x 3 ) . A linear term may always be excluded by choosing the origin to correspond to a maximum, a minimum, or an inflection point. With the restriction that a 2 0, eq. [7] may represent several different types of molecular potential functions. Figure 3

Fig. 3 . Different types of one-dimensional potential functions are represented by Eq. [7]. These may be symmetric (c=O) or asymmetric (cfO) and single-minimum or double-minimum functions.

.

-0.350 -0250 -0.150 -0.050 0.050

0.150

Q250

X (A)

F i g . 4. Far-IR spectrum and r i n g - p u c k e r i n g p o t e n t i a l funct i o n f o r 3-oxetanone. P r e s s u r e = 2 2 t o r r s , p a t h l e n g t h = 30 c m . The v e r t i c a l l i n e s on t h e spectrum a r e i n t e r n a l f r e q u e n c y markers. Ths spectrum i s d i s p l a y e d w i t h t h e a b s o r p t i o n peaks upward, a l t h o u g h some workers have p r e s e n t e d t h e i r far-IR s p e c t r a w i t h t h e t r a n s m i s s i o n minima downward (see F i g . S ) . (Reproduchd w i t h t h e p e r m i s s i o n of t h e American I n s t i t u t e of P h y s i c s from r e f . 6 ) .

103

0 10

r

I

I I I I I 160 140 120 WAVENUMBER (CM-')

I I

100

I

260

(C)

-4

-2

2 (REOUCEDI

+2

+4

Fig. 5. Far-IR spectrum (a) low-frequency Raman spectrum (b) and ring-puckering potential function for sil.acyclobutane (c). The far-IR spectrum was obtained at a pressure of 60 torrs and a path length of 8 m, the resolution varying from ca. 0.2 to 1 cm-l. The transmission minima are displayed downward in this spectrum. The Raman spectrum was obtained at 400 torrs with ca. 2 W of laser power at 514.5 nm multipassed through the sample. The arrows mark pure rotational transitions of air in the sample. The double-minimum potential function with a barrier of 440 cm - I is based on a least squares fit of 34 far-IR transitions deviation of
-

,

180

0)

a u

I

d

z z

k

W

>

t m z

T

WAVENUMBER IN CM-'

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A . CARREIRA

105

indicates some of the different types of one-dimensional potential functions which may arise. Examples of each type of potential function appear in the literature (4,5). In contrast to small-amplitude vibrations, the excited states of a large-amplitude mode may be appreciably populated at room temperature. For a purely harmonic oscillator the frequency of all the Av = 1 transitions is given by v(eq.[21). Consequently no dramatic effect on the spectrum is observed. The far-IR spectrum of 3-oxetanone shows the effect of quartic anharmonicity (Fig. 4). In this case the Av = 1 transitions increase in frequency with increasing quantum number. The individual Q-branch envelopes corresponding to the fundamental (0 + 1) and "hot bands" (1 + 2, 2 + 3, etc.) are clearly resolved in this spectrum. Figuxe 4 also indicates the potential function and the assignment of some of these transitions. Equation [6] may also represent a symmetric doubleminimum oscillator when a ? 0, b < 0 , and c = 0. Figure 5 shows the far-IR spectrum of silacyclobutane(7), the low-frequency Raman spectrum and the potential function and some of the assigned transitions. The extensive series of Q-branch transitions have been assigned to Av = 1, Av 5 2, and Av = 3 transitions, and used to derive a double-minimum potential function with a barrier of 440 cm-l (1.26 kcal/mol, 5.26kJ/mol). Examples of the other types of potential functions shown in Fig. 3, as applied to the interpretation of low-frequency spectra of ring molecules, are considered in Sect. 111. In addition, extension to the treatment of molecules with two Large-amplitude modes is considered.

11. EXPERIMENTAL CONSIDERATIONS

A. F a r - I R Spectroscopy

In this section we are concerned primarily with the molecular properties that are measured as well as with some of the experimental details. Figures 4 and 5 show the assignment of some of the sharp features apparent in the far-IR spectra. In fact, we are observing an unresolved envelope of a manifold of vibration-rotation transitions. A diagrammatic representation of vibration-rotation transitions for an oblate symmetric-top molecule is shown in Fig. 6. An oblate symmetric-top is one for which the smallest I, and intermediate Ib moments of inertia are equal, with the largest moment I, being unique: [81

Ia = I b < I,

The vibration-rotation energy levels are given by E = EVib

+ BvJ

(J

+ 1) +

(Cv

-

BV) K 2

106

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

4 1

f=T

4k

1

3 2

f=O

P

Q

R

Fig.6. Some vibration-rotation transitions for an oblate symmetric-top molecule. The transitions all involve a change Av = +1 in the vibrational quantum number. The transitions shown are termed P-branch (AJ = -l), Q-branch (AJ = 0), and R-branch (AJ = +1) transitions. In each case AK = 0. These represent appropriate selection rules for a parallel band of a symmetric-top molecule.

. .;

. . .,

. K = -J, -J + 1, J - 1, J; J is where J = 0, 1, 2, the rotational angular momentum quantum number; and Kh is the projection of the angular momentum along the inertial axis corresponding to the largest moment of inertia. The rotational constants BV and CV are defined: and

where v represents the values of all the vibrational quantum numbers and < v Opl v> represents the quantum mechanical average.

I

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

107

For Av = +1 transitions for a vibration whose dipole moment oscillates parallel to the unique, or c, axis, the frequencies are given by

where P, Q, and R represent AJ = -1, 0 , and +1, respectively. If flj B,, than VQ % Vvibf and the position of the Q-branch maximum corresponds to the position of the vibrational band origin. If B , and B,+l are known, corrections for the difference between the band origin and the Q-branch maxima may be made. For ring molecules these corrections are of the order of a few tenths of reciprocal centimeters, except in unfavorable cases. For ring molecules all three moments of inertia may be different, and it is not possible to write a closed expression for the frequencies (eqs. [llal, [llbl, and [llcl). The resolution available is usually not great enough to resolve individual transitions within the P and R branches, much less within the Q-branch. However, three general types of vibration-rotation bands may arise, classified as a - , b-, or c-type bands. Figure 7 indicates an example of each type. The bands are classified as a , b, or c depending on whether the dipole moment oscillates parallel -tothe principal inertial axis corresponding to the smallest, intermediate, or largest amount of inertia. The character of the far-IR spectra shown in Figs. 4 and 5 should now be clearer. The generalized background is the result of overlapped P and R-branch transitions associated with the different vibrational transitions. The sharp features are BV+l

TYPE A

TYPE E

m.l TYPE C

Fig. 7. Examples of a,b,and c type vibration-rotation bands in a IR spectrum. (Courtesy of C. J. Wurrey.)

108

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

the Q-branch transitions of c-type bands. this usually allows us to approximate the position of the band origins within a few tenths of a reciprocal centimeter. For four-membered rings with no out-of-plane atoms except hydrogen atoms, the axis perpendicular to the ring plane is the c axis. This can give rise to c-type bands for ring-puckering transitions. When the b axis is perpendicular to the ring plane or when Ib + I , , the overlapped bands may yield an envelope from which it is difficult or impossible to estimate band origins. 1,l-Difluorocyclobutaneis an example of such a molecule (9). From Fig. I it is seen that overlapped a-type transitions should yield observable Q-branch structure. To our knowledge no ring-puckering spectra have been reported for pure a-type band contours. However, the dipole moment need not oscillate parallel to an inertial axis during a vibration, and vibration-rotation selection rules applicable to more than one band type may be appropriate. This gives rise to "hybrid" bands when the oscillating dipole moment has components along more than one axis. Particularly common in ring-puckering spectra are the occurrence of a-c-hybrid bands. All of this indicates some of the problems that may arise in using far-IR spectra to determine the position of the energy levels for ring-puckering vibrations. The most favorable case arises when the bands are c-type for a near oblate r o t o r (Ic> Ib Id) , in which case prominent Q-branch transitions are expected on less pronounced P and R envelopes. The experimental problems involved with obtaining good far-IR spectra are quite severe. Pioneering work on the application of far-IR spectroscopy to the out-of-plane vibrations of ring molecules was done primarily in two laboratories-that of R. C. Lord at MIT, and that of Herbert L. Strauss at Berkeley-by these men and their co-workers. Sources of radiation are generally quite weak in the far-IR region, simultaneously producing intense shorter wave-length radiation which must be eliminated. The pure rotational spectrum of water vapor is exceptionally intense, and due to the comparatively long optical path length between the source and detector, atmospheric absorption is a serious problem. Secondarily, trace amounts of water can obscure the normally weak absorption by the sample. In addition efficient low-noise far-IR detectors are scarce. Two different approaches have been taken to solve some of these severe problems. Both grating far-IK spectrophotometers and interferometers have been constructed in various laboratories. Both types of instruments have been marketed commercially. In principle the interferometer has significant advantages over the grating spectrometer, but high quality spectra have been obtained with both types of instrument. It has only been in the last few years, with the advent of commercially available, rapid-scanning interferometric spectrometers, that the potential of this technique has begun to be widely exploited.

THOMAS B. MALLOY, L E S L I E E .

BAUMAN, AND L . A. CARREIRA

109

The problem of absorption of the far-IR radiation by atmospheric water vapor has been approached in two ways. The first way is to seal the spectrometer compartment and purge it with a source of dry air or nitrogen. Typically, the boiloff from liquid nitrogen has been used. Readers acquainted with the use of mid-IR spectroscopy are aware of the problems with the vibration-rotation spectra of water and CO2 in the mid-IR. These can cause interference unless removed by purging. The problem in the far-IR is considerably more significant. The pure rotational spectruni of water in the far-IR is many times more intense than the vibration-rotation spectrum in the mid-IR. Consequently, the demands on a purge system are much more severe. A second, and ultimately better, technique is to evacuate the spectrometer. The vacuum attained does not have to be a high vacuum, ca. 100 mtorr being sufficient. The remaining water vapor absorption is such that it may be ratioed out on a doublebeam grating spectrometer or ratioed out by comparison with the background in an interferometric spectrometer. The only remaining problem is removal of water from the sample. For samples with intense far-IR spectra this is less of a problem than for those with weak spectra. For intense spectra, pressures of a few torrs and path lengths of ca. 10 to 30 cm are sufficient. Polyethylene is used as the window material. For samples with weak far-IR absorption full vapor pressure of the sample may be used with path lengths as long as 40 m. The sample cells in this case are multiple-reflection cells with mirrors at each end. The number of traversals of the cell, and thus the pathlength, is determined by adjusting the orientation of the mirrors. For the cyclopentene molecule, 0.05% water in the sample would lead to full-scale water lines at ca. 100 cm-’ under the conditions required to obtain the spectrum (10). Consequently, scrupulous drying of the sample and sample-handling equipment is essential. Finally, the obtainable signal to noise ratio may be severely limited by the detector. Rapid-scanning interferometers with room-temperature detectors rely on extensive signal averaging to obtain reasonable signal to noise ratios. Although expensive to operate, liquid helium-cooled bolometers have given good results. Despite all these difficulties, far-IR spectroscopy is a viable technique in the study of the out-of-plane modes of ring molecules. However, the application requires considerably more effort than do the normal uses of mid-IR spectroscopy.

B.

Raman Spectroscopy

Around 1970, argon ion lasers became available with output powers greater than 1 W at 488.0 nm and 514.5 nm. Coupled with good double monochromators available from several manufacturers, these allow the observation of many ringpuckering spectra at low-frequency shifts from the exciting line. Many of the same considerations concerning band types and

110

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

vibration-rotation selection rules that are a factor in locating the band origins in far-IR spectra are applicable. Figure 8 indicates two drastically different band types in the Raman

T

790

800

FREQUENCY

810

(CM-I)

FREQUENCY

(CM-I)

Fig. 8. Examples of a totally symmetric and nontotally symmetric vibration-rotation band in a Raman spectrum. spectrum of a gaseous sample. The first is a totally symmetric vibrational mode consisting of a highly intense, sharp Q branch (AJ = 0). The accompanying 0 (AJ = -2) and S (AJ = +2) branch envelopes are significantly weaker and are not evident ir, Fig. 8. The second band, however, results from a nontotally symmetric mode and exhibits no sharp features. The sharpness of the Q branches of totally symmetric Raman bands makes them desirable for complex overlspped ringpuckering spectra. However, with the exception of molecules having C, symmetry where the symmetry plane is perpendicular to the ring(e.g., chlorocyclobutane) (11) and the trivial case of C1 symmetry, the ring-puckering vibration is not totally symmetric. If, however, there is substantial electrical anharmonicity, the Av = 2 transistions, which start from and terminate on energy levels of the same symmetry, are allowed. These "overtone" or "double-jump" transitions are totally symmetric, and consequently have sharp Q branches whose maxima occur close to the band origins. The prominent features in the low-frequency Raman spectrum of silacyclobutane (Fig. 5) are the totally symmetric Av = 2 transitions. The sharpness of the Q-branch transitions for Av = 2 transitions and the application of Raman spectroscopy to ring molecules have been most widely utilized by J. R. Durig and co-workers at the University of South Carolina (12).

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

111

The resolution of ring-puckering motions attainable in Raman spectroscopy has typically been 1 to 5 cm-l, less than that for far-IR studies (ca. 0.10 to 1 cm-l). The two techniques have proven to be complementary, and on several occasions Raman data have allowed determination of potential functions when interpretable far-IR spectra proved difficult or impossible to obtain. The primary reason for the lower resolution obtainable from Raman spectroscopy lies in the weakness of the Raman effect and the necessity of using a double monochromator, with consequent lower throughput, to eliminate stray light. One approach is to use high-power lasers. Some spectra have been obtained with laser powers as high as 10 W at the laser head. The liinitation here is the sample. Not all samples can be subjected to powers this high without decomposing, particularly if condensation occurs on the windows. Multipass cavities in which the laser is reflected and refocused a number of times (16 to 20) in the sample have been used to increase the signal. The windows on the cell, usually quartz, are mounted at the Brewster angle to minimize reflection losses, since a number of traversals are made. In additon the Raman signal may be almost doubled by placing a spherical mirror 180' from the monochromator entrance slits on the other side of the sample, and refocusing the scattered light back into the sample and then on the entrance slits of the monochromator. Because of the compact size of the sample cells (ca. 1 cm diamter x 4.0 cm) it has proven convenient to heat liquid samples to obtain a higher vapor pressure and consequently a stronger Raman signal. The most common and most SUCcessful technique has been to blow warm air on the sample cell, which has a reservoir containing excess sample. The main problem is making sure that the windows are heated to avoid condensation and subsequent destruction of the sample. Temperatures used have ranged up to 150OC. Many spectra of gas-phase samples have been obtained in this fashion which would not have ,beenpossible otherwise. Although heated multiple-reflection cells have been used in far-IR spectroscopy (13), this is much less convenient than with Raman spectroscopy. C. Mid-IR and Mid-Raman Spectroscopy Mid-IR and mid-Raman spectroscopy deal with the higher frequency regions (Q300 to 4000 cm-l) corresponding to the fundamentals of the small-amplitude vibrations. In principle these vibrations may have different selection rules depending on the difference in symmetry between the planar and nonplanar ring conformation(s). This may allow determination of the planarity or nonplanarity of the ring molecule. In practice this is a very poor approach if the barriers at the planar conformation are ca. 1 to 2 kcal/mol or less. Even though, in

112

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

principle, selection rules may differ, the "allowed" modes for the lower symmetry may be extremely weak. When mistakes are made in applying these techniques to molecules with large-amplitude modes, it is almost always in incorrectly choosing the higher symmetry. Ueda and Shimanouchi in 1967 pointed out the occurrence of difference-band progressions involving the ring-puckering vibrations and CH stretching modes in the mid-IR spectra of a number of ring molecules (14). The band progressions were compared with the known energy separations for some molecules that had been studied in the far-IR. For others, for which far-IR data

t

W

I

I

0

tt-

I\

z W

21

h

I

1

1

1

Ibl

P. l'

r i

0

a w n

,

3200

f0 )

1

1

3100

3000

I

2900 WAVENUMEER

I

I

2800

2700

Fig. 9. Ring-puckering combination and difference-band progressions in the CH stretching region of the mid-IR (a) and mid-Raman (b) spectra of trimethylene oxide. (Reproduced with the permission of the American Institute of Physics, from ref.29.)

0

7.

3

4

(1

6

0 - 2 -

Y

in

Y

t Y

R

Y AVO

0

R

.l

G

IR

J

R

0

V

A

h

-

Y

R

R -

'a"

&

0-2--7-

In

I)

..

I.

Fig. 10. Assignment of some of the transitions in the mid-IR and mid-Raman spectra of trimethylene oxide. (Reproduced with the permission of the American Institute of Physics, from ref. 29.)

-v

?

0

9

R

1.

114

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

were n o t a v a i l a b l e , t h e ring-puckering p o t e n t i a l f u n c t i o n s were approximately determined from t h e difference-band progress i o n s . S i n c e t h e n numerous band p r o g r e s s i o n s i n v o l v i n g r i n g puckering v i b r a t i o n s have been r e p o r t e d (15-29). S i m i l a r l y , band p r o g r e s s i o n s have been observed i n t h e fundamental r e g i o n o f t h e Raman s p e c t r a o f r i n g molecules (29-33). Extensive s t u d i e s o f t h e far-IR, low-frequency Raman, m i d - I R and mid-Raman s p e c t r a of t r i m e t h y l e n e oxide and s e v e r a l of i t s d e u t e r a t e d analogues have been r e p o r t e d by Wieser and co-workers (27,29-31,34-36). Figure 9 i n d i c a t e s t h e r a t h e r e x t e n s i v e ring-puckering s t r u c t u r e observed n e a r t h e CHs t r e t c h i n g r e g i o n f o r t r i m e t h y l e n e oxide i n t h e mid-IR and mid-Raman s p e c t r a . The assignment of t h e v a r i o u s t r a n s i t i o n s f o r t r i m e t h y l e n e o x i d e is shown i n F i g . 10. Combination and d i f ference-bands p r o g r e s s i o n s i n v o l v i n g ring-puckering and o t h e r small-amplitude modes have been observed. The t r a n s i t i o n s shown i n Fig. 10 a r e t r a n s i t i o n s between v i b r a t i o n a l l e v e l s . Each one of t h e s e t r a n s i t i o n s h a s i t s own a s s o c i a t e d r o t a t i o n a l s t r u c t u r e (e.g. Fig. 6 ) , and t h e d i s c u s s i o n of band t y p e s a p p r o p r i a t e t o f a r - I R and low-frequericy Raman s p e c t r a a p p l i e s . However, t h e band t y p e s now depend on t h e t y p e s corresponding t o t h e d i r e c t product of t h e symmetry s p e c i e s of t h e ring-puckering v i b r a t i o n and t h e p a r t i c u l a r r e f e r e n c e v i b r a t i o n i n q u e s t i o n . I n d e a l i n g w i t h combination- or difference-band progress i o n s , i t is p o s s i b l e t o d e s c r i b e t h e t r a n s i t i o n s by changes i n two quantum numbers. For any s i n g l e p r o g r e s s i o n o n l y t h e change i n a reference-band quantum number vR, t h a t i s , t h e smallamplitude v i b r a t i o n , and a ring-puckering quantum number vp a r e involved. The fundamental t r a n s i t i o n of t h e small-amplitude mode i s d e s c r i b e d by AvR = +1, Avp = 0 , where i t i s understood t h a t t h e quantum numbers corresponding t o t h e o t h e r modes do n o t change. For combination-band p r o g r e s s i o n s i n t h e mid-IR o r Raman s p e c t r a , AvR = +1 and Avp = +l. I n Fig. 1 0 t h e I R t r a n s i t i o n s marked 16 t o 22 are combination bands, and follow t h e above sel e c t i o n r u l e s . Difference-band p r o g r e s s i o n s o r i g i n a t e from exc i t e d s t a t e s of t h e ring-puckering v i b r a t i o n . I n t h i s case AvR = +1 and Avp = -1. I R bands 1 through 8 , among o t h e r s , i n F i g . 1 0 are examples of difference-band p r o g r e s s i o n s . Combination- and/or difference-band p r o g r e s s i o n s may a r i s e from anharmonic c r o s s terms i n t h e p o t e n t i a l f u n c t i o n . The most l i k e l y are t e r m s of t h e form x 2 q $ , where x is t h e ring-puckering and qR i s t h e c o o r d i n a t e corresponding t o t h e r e f e r e n c e v i b r a t i o n A s may be s e e n from F i g . 1 0 , t h e ring-puckering i n t e r v a l s i n t h e e x c i t e d s t a t e of t h e r e f e r e n c e t r a n s i t i o n d i f f e r s l i g h t l y from t h o s e i n t h e ground s t a t e . T h i s is caused by t h e dependence of v i b r a t i o n a l averaging over t h e small-amplitude modes on t h e quantum s t a t e of t h e s e modes. Due t o t h e e f f e c t s mentioned i n t h e preceding paragraph, a s w e l l a s t h e p o s s i b l e occurrence of o t h e r p r o g r e s s i o n s o r weak bands i n t e r l e a f e d w i t h t h e ring-puckering p r o g r e s s i o n s , i t i s sometimes d i f f i c u l t t o a r r i v e a t an unambiguous assignment.

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This is particularly true if the vibrational spacings for the ring-puckering are not known in advance from direct observation in the far-IR or Raman spectrum, or if only one progression, the combination or the difference progression, is observed from a particular reference band. However, combination- and differenceband progressions may yield data when the large-amplitude modes are inactive or are too weak to be observed in the Raman or farIR spectra. The pseudorotational mode in cyclopentane is an example of such a case (22).

D. Microwave Spectroscopy After the end of World War I1 applications of microwave spectroscopy to the study of molecular rotational spectra were possible because of the development of various components for microwave radar. The application of microwave spectroscopy to the analysis of ring-puckering in molecules was first done by Gwinn and co-workers at the University of California at Berkeley in the early 1960s. This group was responsible for many of the theoretical advances that allowed interpretation of the spectra (37-40). With the development of reliable backward-wave-oscillator sources it became possible to scan an entire frequency band in the microwave spectrum of 3-thietanone (4-1)obtained in the R-band region (26.5 to 40.0 GHz) (Fig. 11). For comparison to IR 5-4

6-5

F i g . 11. Microwave spectrum of 3 - t h i e t a n o n e i n t h e R-band r e g i o n ( 2 6 . 5 t o 40.0 GHz). P r e s s u r e = 80 m t o r r , p a t h l e n g t h = 6 f t , S t a r k f i e l d = 2000 V / c m . Zero f i e l d l i n e s are down, S t a r k (Reproduced w i t h t h e p e r m i s s i o n of Academic Press l o b e s a r e up. I n c . N e w York,) ( r e f . 4 1 . )

and far-IR spectra it should be noted that this frequency range corresponds to ca. 0.9 to 1.3 cm-1. For a period in the late 1960s and early 1970s microwave spectrometers were commercially available. Most of these found their way to university research laboratories, and when widespread industrial and government laboratory markets failed to materialize, marketing was discontinued. Yost of the components of these spectrometers are still

116

CONFORMATIONAL BARRIERS I N SMALL RING MOLECULES

a v a i l a b l e , and it i s s t i l l p o s s i b l e t o assemble a microwave system. Usually t r a n s i t i o n s between r o t a t i o n a l l e v e l s a s s o c i a t e d with a p a r t i c u l a r v i b r a t i o n a l s t a t e a r e observed i n a microwave study. I n Fig. 6 t h i s would correspond t o keeping v c o n s t a n t and causing t r a n s i t i o n s between l e v e l s with d i f f e r e n t r o t a t i o n a l quantum numbers. Because of t h e Boltmann population of e x c i t e d s t a t e s of t h e large-amplitude motions, a number of v i b r a t i o n a l s a t e l l i t e s , t h a t i s , r o t a t i o n a l t r a n s i t i o n s from v i b r a t i o n a l l y e x c i t e d s t a t e s , may be observed. These a r e s h i f t e d i n frequency from t h e ground-state l i n e s because of t h e d i f f e r e n c e s i n averaging t h e r o t a t i o n a l c o n s t a n t s over t h e d i f f e r e n t v i b r a t i o n a l s t a t e s (eq. [ l o ] ) . For a small-amplitude v i b r a t i o n t h e v a r i a t i o n of r o t a t i o n a l c o n s t a n t s with v i b r a t i o n a l quantum number i s expected t o be linear:

i=l

where $ i s t h e A , B , o r C r o t a t i o n a l c o n s t a n t . Due t o t h e l a r g e amplitude n a t u r e of ring-puckering v i b r a t i o n s a s w e l l a s t h e anharmonic n a t u r e of t h e p o t e n t i a l f u n c t i o n s , t h e v a r i a t i o n of t h e r o t a t i o n a l c o n s t a n t s with ring-puckering v i b r a t i o n a l s t a t e may d e v i a t e from t h e l i n e a r behavior p r e d i c t e d by eq. [121. The expected r e s u l t s may be c l a s s i f i e d according t o t h e type of p o t e n t i a l f u n c t i o n . For a molecule with a single-minimum p o t e n t i a l f u n c t i o n t h e v i b r a t i o n a l energy spacings a r e , i n g e n e r a l , small (ca. 50 t o 150 cm-'), b u t they a r e s t i l l l a r g e compared with r o t a t i o n a l energy spacings. Consequently, v i b r a t i o n a l and r o t a t i o n a l motions may be s e p a r a t e d , and r i g i d r o t o r s p e c t r a are observed i n t h e microwave with d i f f e r e n t effective rotational constants for the different vibrational s t a t e s . The v a r i a t i o n of t h e A r o t a t i o n a l c o n s t a n t f o r 3thietanone i s shown i n Fig. 1 2 . The v a r i a t i o n , while r e g u l a r , shows a d e f i n i t e curvature a s opposed t o t h e l i n e a r behavior i n d i c a t e d by eq. [ 1 2 ] . For a r i n g molecule with a symmetric double-minimum pot e n t i a l f u n c t i o n , s e v e r a l c a s e s may be d i s t i n g u i s h e d . For a very low b a r r i e r , t h a t i s , one of t h e o r d e r of t h e r i n g puckering zero-point evergy, t h e r e s u l t i n g microwave spectrum is s i m i l a r t o t h a t described f o r t h e single-minimum p o t e n t i a l f u n c t i o n ( 3 8 ) . Rigid r o t o r s p e c t r a a r e observed and, w i t h t h e exception of t h e lowest few l e v e l s , t h e r e i s a r e g u l a r v a r i a t i o n of r o t a t i o n a l c o n s t a n t s with v i b r a t i o n a l s t a t e . The ringpuckering spectrum observed i n t h e far-IR o r Raman spectrum and the v a r i a t i o n of r o t a t i o n a l c o n s t a n t s from t h e microwave spectrum a r e e x c e p t i o n a l l y s e n s i t i v e t o t h e presence of even a small b a r r i e r . For cyclobutanone (42-44) t h e b a r r i e r of 7.6 cm-' (ca. 0.02 kcal/mol) is w e l l below t h e zero-point energy of 16.8 cm-l. Figure 13 i n d i c a t e s t h e v a r i a t i o n of t h e A r o t a t i o n a l c o n s t a n t . The i r r e g u l a r i t y .is i n d i c a t i v e of a small

V

F i g . 1 2 . V a r i a t i o n of t h e A r o t a t i o n a l c o n s t a n t f o r 3t h i e t a n o n e w i t h r i n g - p u c k e r i n g v i b r a t i o n a l s t a t e . (From d a t a i n Ref. 41.)

+ol -l+

-250

0

V

L

F i g . 1 3 V a r i a t i o n of t h e A r o t a t i o n a l c o n s t a n t s w i t h r i n g p u c k e r i n g v i b r a t i o n a l s t a t e f o r c y c l o b u t a n o n e and m e t h y l e n e c y c l o b u t a n e . (From d a t a i n Ref. 44 and 4 5 . ) 117

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CONFORMATIONAL BARRIERS I N SMALL RING MOLECULES

barrier, i l l u s t r a t i n g t h e e x c e p t i o n a l s e n s i t i v i t y t o t h e det a i l s of t h e p o t e n t i a l f u n c t i o n . The presence of t h i s s m a l l b a r r i e r i s a l s o i n d i c a t e d by t h e p a t t e r n of t r a n s i t i o n f r e quencies i n t h e far-IR spectrum(43). I f a b a r r i e r t o p l a n a r i t y i s i n t e r m e d i a t e (ca. 100 t o 500 cm-l) , t h e ring-puckering l e v e l s below t h e b a r r i e r begin t o coalesce i n t o c l o s e l y spaced d o u b l e t s . T h i s can l e a d t o vibrat i o n a l energy spacings t h a t are on t h e o r d e r of r o t a t i o n a l energy spacings. For t h e s e d o u b l e t s , v i b r a t i o n and r o t a t i o n cann o t be t r e a t e d s e p a r a t e l y . Nonrigid r o t o r s p e c t r a arise, and t h e v i b r a t i o n a l dependence of r o t a t i o n a l c o n s t a n t s may be q u i t e i r r e g u l a r . The l a t t e r i s i l l u s t r a t e d f o r methylenecyclobutane i n Fig. 13 ( 4 5 ) . For t h i s molecule t h e 0-1 v i b r a t i o n a l spacing i s ca. 1 cm-', which corresponds t o t y p i c a l r o t a t i o n a l energy spacings. Nonrigid r o t o r s p e c t r a were observed f o r t h e s e two s t a t e s . S i m i l a r l y , €or t r i m e t h y l e n e s u l f i d e t h e 0-1 v i b r a t i o n a l s p l i t t i n g i s c a . 0 . 2 7 cm-', l e a d i n g t o l a r g e v i b r a t i o n v = l

u= 0

1

'01

r

A.E = 8232.5 Mctrec % I

-L

b

Fig. 14. V i b r a t i o n - r o t a t i o n evergy l e v e l s f o r t r i m e t h y l e n e s u l f i d e . The dashed l i n e s i n d i c a t e t h e symmetry-allowed i n t e r - . , a c t i o n s between r o t a t i o n a l s t a t e s i n t h e v = 0 and v = 1 v i b r a t i o n a l states. These i n t e r a c t i o n s cause t h e l e v e l s t o s h i f t from t h e i r unperturbed p o s i t i o n s , and n o n r i g i d r o t o r s p e c t r a r e s u l t . (Reproduced w i t h t h e permission of t h e American I n s t i t u t e of Physics, from r e f . 40.) r o t a t i o n i n t e r a c t i o n s ( 4 0 ) . This i s i l l u s t r a t e d i n Fig. 1 4 . A similar zig-zag dependence of r o t a t i c n a l c o n s t a n t s i s a l s o observed f o r t h i s molecule. When t h e b a r r i e r t o p l a n a r i t y i s very l a r g e f o r a symmet r i c double-minimum p o t e n t i a l f u n c t i o n , t h e l e v e l s are doubly degenerate p a i r s t h a t s p l i t as t h e t o p of t h e b a r r i e r is approached. As long a s t h e r o t a t i o n a l s p e c t r a a r e s t u d i e d i n

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vkbrational levels that are low in energy with respect to the barrier height, rigid rotor spectra and a regular variation of rotational constants with respect to barrier height are to be expected. These cases may be distinguished from the singleminimum results, since the values of the rotational constants are indicative of a nonplanar ring. For molecules with asymmetric potential functions, the single-minimum and low-barrier double-minimum cases are similar to those described for symmetric cases. For intermediate to high barriers the levels are no longer pairs, but correspond, below the barrier, to specific conformations. Rigid rotor spectra are expected in all cases.

111.

A.

EXAMPLES OF APPLICATIONS

One-Dimensi onal P o t e n t i a1 Functions

Several examples of ring molecules with symmetric potential functions have been given in the preceding sections. Several one-dimensidnal potential functions have been used. For single-minimum potential functions the simplest function having positive anharmonicity is

+

V ( x ) = ax4

bx2

~ 3 1

where a > 0, b 2 0. This may also represent a double-minimum oscillator when a > 0 , b < 0. Another double-minimum function is represented by V ( x ) = bx2

+

ce-dx2

[I41

which.is a harmonic oscillator with a Gaussian barrier. Some workers have included a quartic term for shaping the walls at large amplitude, resulting in V ( x ) = ax4

+

bx2

+

By far, eq. [13] has been the most widely used. When it proves adequate, it is the most desirable, since it contains only two adjustable parameters, as opposed to three in eq. [14] and four in eq. [151. The use of eqs. [13] through [15] requires knowledge of the reduced mass of the molecule for the vibrational motion represented by the coordinate x (Fig. 1). This is complicated by the fact that, due to the large amplitude of vibration, this reduced mass may be a function of x . The ramifications of this have been discussed by several authors (Appendix I). For the purpose of determining barrier heights the use of a constant reduced-mass Hamiltonian is quite adequate. In fitting spectroscopic data a Hamiltonian in a reduced or dimensionless

120

CONFORMATIONAL BARRIERS I N SMALL RING MOLECULES

c o o r d i n a t e i s a l l t h a t i s r e q u i r e d . Only i f a d i h e d r a l a n g l e corresponding t o a p o t e n t i a l minimum i s d e s i r e d , is it necess a r y t o know t h e reduced mass. One c o o r d i n a t e t h a t has been used y i e l d s a SchrtMinger e q u a t i o n : A ( d2 - 7 dZ

+

Z4

-+

BZ2 =

[I61

where Z = ( 2 ~ a / h ~ ) l /and ~ x t h e v i b r a t i o n a l energy i s g i v e n by The v a l u e of a i s t h a t a p p e a r i n g i n eq. [ 1 3 ] , p i s t h e reduced mass, and h i s P l a n c k ' s c o n s t a n t d i v i d e d by 2*. The r e l a t i o n between t h i s and t h e o t h e r reduced c o o r d i n a t e s t h a t have been used i s d e s c r i b e d i n Appendix 11. Reduced e q u a t i o n s cor-

AA.

Fig. 15. Eigenvalues of t h e d i m e n s i o n l e s s Schradinger e q u a t i o n (eq. [ 1 6 ] ) . The e i g e n v a l u e s f o r t h e d i m e n s i o n l e s s p o t e n t i a l V = Z 4 +BZ2 are shown f o r B < 0. The b a r r i e r h e i g h t i s (Reproduced shown a s a dashed l i n e ( b a r r i e r = B 2 / 4 f o r B < O ) . w i t h t h e permission of t h e American I n s t i t u t e of P h y s i c s from r e f . 10.)

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responding t o t h e p o t e n t i a l f u n c t i o n s g i v e n i n e q s . [141 and [15] may a l s o be described. Equation [ 1 6 ] , a s it s t a n d s , cannot be solved i n c l o s e d form, b u t must be solved numerically. S e v e r a l d i s c u s s i o n s of t h e l i n e a r v a r i a t i o n method a p p l i e d t o t h e s o l u t i o n appear i n t h e l i t e r a t u r e (38,40,46-50). F i g u r e 1 5 i n d i c a t e s t h e v a r i a t i o n of t h e dimensionless e i g e n v a l u e s h a s a f u n c t i o n of B .

I.

3-Thietanone

3-ThietanoneI mentioned e a r l i e r , is an example of a r i n g molecule having a symmetric, single-minimum p o t e n t i a l f u n c t i o n . The microwave spectrum i n t h e R-band r e g i o n i s shown i n F i g . 11. F i g u r e 16 i n d i c a t e s t h e far-IR spectrum and t h e a s s o c i a t e d p o t e n t i a l f u n c t i o n ( 5 1 ) . I n t h i s case t h e c-type Q-branch t r a n s i t i o n s a r e s e v e r e l y degraded due t o a combination of two f a c t o r s . F i r s t , i n 3-thietanone A > > B 2 C , and c-type bands i n h e r e n t l y do n o t have prominent Q branches i n t h i s l i m i t . Second, t h e r o t a t i o n a l c o n s t a n t s change r a t h e r markedly w i t h v i b r a t i o n a l s t a t e and degrade t h e Q branch f u r t h e r . The band o r i g i n s occur ca. 0.3 t o 0.4 c m - I t o t h e low-frequency s i d e of t h e Q-branch maxima and were s o c o r r e c t e d i n t h e f a r - I R s t u d y . The observed f r e q u e n c i e s were t h e n f i t t e d by a l e a s t s q u a r e s adjustment of t h e two parameters appearing i n eq. [161, A and B , y i e l d i n g a good f i t . The p o t e n t i a l f u n c t i o n , i n t h e dimens i o n l e s s c o o r d i n a t e 2 , i s g i v e n by V(cm-')

= 9.90

(Z4

+ 6,172')

[171

The procedure followed t o f i t t h e v a r i a t i o n of t h e r o t a t i o n a l c o n s t a n t s w i t h v i b r a t i o n a l s t a t e i s t h a t used s u c c e s s f u l l y by Gwinn and co-workers (38-40). The r o t a t i o n a l c o n s t a n t s a r e expanded i n power s e r i e s i n t h e r o t a t i o n a l c o n s t a n t s , and averaged over t h e v i b r a t i o n a l s t a t e :

where B i s t h e A , B , o r C r o t a t i o n a l c o n s t a n t , and B ( O ) , f 3 ( 2 ) , and B a r e e m p i r i c a l parameters determined by f i t t i n g t h e d a t a . The p o t e n t i a l c o n s t a n t B i n eq. [16] depends on t h e microwave d a t a i n t h e s e n s e t h a t t h e e x p e c t a t i o n v a l u e s of 2' and Z 4 depend on t h e v i b r a t i o n a l s t a t e and consequently on t h e v i b r a t i o n a l wave f u n c t i o n s . The r o t a t i o n a l c o n s t a n t s , however, do n o t depend on A , which i s simply a s c a l e f a c t o r , and are b e t t e r determined by r e l a t i n g eigenvalue d i f f e r e n c e s h,+l - A, t o f r e quencies A(A,+1 - A,) measured i n t h e f a r - I R spectrum. The procedure used f o r 3-thietanone w a s t o simultaneously f i t t h e farI R f r e q u e n c i e s and t h e microwave r o t a t i o n a l c o n s t a n t s by a l e a s t

(4y

f

z 0 I-

n

a 0 ln

' 1

k-J

m 4

I

I

1

70

I

60

I

I

50

40

I

30 CM-

lux)-

1400 -

1200

VI.I.0.610

l l O ' X 1 +0.119.10'

x4

p *Il6.lo.n.u. 1000 T

8

8w

600-

E

n.8 800-

400

73.0

-

200 -

Fig. 16. Far-IR spectrum (a) and ring-puckering potential function (b) for 3-thietanone. Pressure ca. 1 torr, path length = 20 m. (Reproduced with the permission of Academic Press, New York, from ref.51.) 122

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123

squares adjustment of A and B, the potential function parameters in eq. [16], and the rotational constant-expansion coefficients in eq. [18]. The potential function compares favorably with that determined by fitting the far-IR data alone (eq. [12]). The ability to fit both microwave and far-IR data with the same potential function is gratifying. The experimental results on 3-thietanone indicate that the out-of-plane mode is anharmonic and large in amplitude. The fact that it was possible to determine the vibrational spacings to such a high vibrational quantum number (v = 10) is a result of the high population of the excited states at room temperature and the increased intensity of high v transitions for molecules having a substantial quartic anharmonicity. Similarly, the high population of the excited states allowed observation of the rotational spectra originating from a number of these states at room temperature. At this stage the interpretation of the experimental data is finished. However, as shown by Gwinn and co-workers for several ring molecules, It is possible to determine something more of the dynamics of the ring vibration by a model calculation ( 3 8 ) . The model error may be quite large, and only qualitative agreement with experimental data is expected. In the model used for the ring-puckering vibration, the methylene groups are assumed to share a common bisector with the adjacent C-C-S angle, and maintain a constant HCH angle. The carbonyl group is assumed to bisect the C-C-C angle. All bond distances were assumed to remain constant. With these restrictions there are two extremes that may describe the ring-puckering vibration. These are shown in Fig. 17. The ring may bend by fixing the C-C-C and C-S-C angles and moving the sulfur atom, or the C-C-S angles may be fixed and the ring bent by moving the methylene groups. These two models lead to the same reduced mass for infinitesimal displacements. However, if we calculate the moments of inertia and then the rotational constants as a function of x , half the perpendicular distance between ring diagonals, it is different for the two models. The predicted variation of the rotational-constant variation as well as those calculated for the two models (Fig. 17) is shown in Fig. 17. The best fit is obtained for a model for which the C-S distance changes ca. 5 times as much as the change in the C-C distance. For this model the two C-C-S angles, which have force constants somewhat greater than the C-S-C angle bending, but considerably less than the C-C-C angle bending (sp2 hydridization), change by greater amounts than those of the other two angles. That the C-C distance changes at all is probably caused by the small C-S -C bending force constant somewhat balancing the effect of the large C-C-C force constant. The model calculation does not yield a perfect fit to the rotational-constant variation, but it does lead to a result that is quite physically reasonable; 0

II

this is, the C-C-C angle, which is the most highly strained,

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

124

150

-300

-

-50

- 0.68 l

5

O

F

; t1

-600 0

5

10

F i g . 17. !Two l i m i t i n g models f o r t h e ring-puckering v i b r a t i o n i n 3-thietanone. Here q = -1 corresponds t o f i x i n g t h e nonbonded C-C d i s t a n c e , and rl = +1corresponds t o f i x i n g t h e nonbonde d C-S d i s t a n c e . For rl = 0 t h e change i n t h e nonbonded C-C and C-S d i s t a n c e s are e q u a l . The observed r o t a t i o n a l - c o n s t a n t v a r i a t i o n with ring-puckering s t a t e i s shown a l o n g w i t h t h a t c a l c u l a t (Reproduced w i t h t h e e d f o r rl = -0.60, which g i v e s t h e b e s t f i t . permission of Academic Press, New York, from r e f . 41.) does n o t d e c r e a s e t o any g r e a t e x t e n t d u r i n g the v i b r a t i o n . For four-membered-ring molecules t h e ring-puckering pot e n t i a l f u n c t i o n s r e p r e s e n t a d e l i c a t e b a l a n c e between two r a t h e r l a r g e e f f e c t s . I n g e n e r a l , r i n g a n g l e s i n t h e s e cases are s m a l l e r t h a n t h e i r u n s t r a i n e d v a l u e s . Since r i n g a n g l e s a r e maximized a t t h e p l a n a r conformation, a n g l e s t r a i n f a v o r s t h i s conformation. On t h e o t h e r hand t o r s i o n a l i n t e r a c t i o n s between a d j a c e n t groups tend t o f a v o r s t a g g e r e d conformations a b o u t t h e r i n g bonds, corresponding t o nonplanar r i n g conformations. 2.

1,Z-Dimot hy ZenecycZobutane

I n t h e molecule 1,2-dimethylenecyclobutane t h e r e is an add i t i o n a l f a c t o r . A p l a n a r carbon s k e l e t o n i s favored by t h e del o c a l i z a t i o n of t h e 'TI e l e c t r o n s . The microwave spectrum w a s

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

125

assigned in the ground state and four excited states of the ringpuckering vibration (52). The rigid rotor fits are found to be quite adequate. The rotational constants A , B, and C in the ringpuckering vibrational states are shown in Fig. 18. The variation, while exhibiting curvature, is smooth, as opposed to that

-

2300 -

,

1

1

4

-

V. 4

409C

B

t

4060 1

4

Fig. 18. Rotational constants (MHz) vs. ring-puckering vibrational state for 1,2-dimethylenecyclobutane. (Reproduced with'the permission of Academic Press, New York, from ref. 52.) shown for cyclobutanone in Fig. 13. Consequently, we may state that the potential function definitely has a single minimum and that all six carbon atoms are coplanar. Figure 13 indicates that even a barrier as small as 0.02 kcal/mol is detectable by this technique.

126

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

3.

2,s-Dihydrofuran

As shown in Fig. 2, a five-membered-ring molecule has two out-of-plane ring vibrations. For a five-membered-ring molecule with an endocyclic double bond, such as 2,5-dihydrofuranI one of these modes, the twisting about the C=C double bond, is higher in frequency. The other mode, the ring-puckering, is low in frequency and large in amplitude. The first approximation is to neglect the coupling of the ring-puckering with all the other modes, including the ring-twisting. Such five-membered-ring molecules have been termed pseudo-four-membered-ring molecules, and the ring-puckering treated as outlined above. The far-IR spectrum of 2,5-dihydrofuran was first reported by Ueda and Shimanouchi in 1967 ( 4 6 ) , and fitted with a single-minimum, onedimensional potential function of the form of eq. [13]. Higher resolution spectra obtained by Carreira and Lord (6) showed the existence of a satellite series of ring-puckering transitions shifted to higher frequency (Fig. 19). These are the ring-puckering transitions originating from the first excited state of the ring-twisting vibration. The fact that they are shifted in frequency from the ground-state transitions indicates the presence of an anharmonic coupling term in the potential function. However, it is possible to derive an effective one-dimensional ring-puckering potential for the two series of transitions separately. The potentials in the reduced coordinate of eq. [16] are given by Ground state of twisting: V(cm-') = 24.6 (2' + 2.93 Z 2 ) Excited state of twisting: V(cm-') = 24.9 (Z4 + 2.99 Z2) The potential function for the ground-state series is also shown in Fig. 19. Later Carreira, Mills, and Person used a two-dimensional Schrtldinger equation with constant effective masses to simultaneously fit both series of ring-puckering transitions and the ring-twisting from the Raman spectrum (53). This two-dimensional equation is given by

where x is the ring-puckering coordinate, y is the ring-twisting coordinate, and pl and p2 are the associated reduced masses. Odd power terms are not present because of symmetry, and the x2y2 cross term is the lowest degree cross term allowed by symmetry. Recently, Malloy and Carreira have shown that effective one-dimensional potential functions for 2,5-dihydrofuranI along with the fundamental frequency of the twisting vibration, may be used to estimate the coefficient of the cross term in eq. [20] (54). For the ground state of the twisting mode the effective potential in dimensioned coordinates is given by

I

1

160

I

I

150

140

CM- I

I 130

I 120

I

I10

I

(4

I000

t

800

700

joot +' y4 = 0

Fig. 19. Far-IR spectrum (a) and ring-puckering potential function (b) for 2,5-dihydrofuran. Pressure = 60 torrs, path length = 30 cm, resolution ca. 0.2 cm-'. The satellite series of ring-puckering transitions originating from the first excited state of the ring-twisting mode is visibly shifted to higher frequencies. The potential function is for the ground-state series. (Reixoduced with the permission of the American Institute of Physics, from ref. 6.) 127

128

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES 1211

and the potential function in the first excited state is given by

V2.x)

= a

-b(1)x2

[221

In these equations the effective potential constants may be related to those in eq. [20] by

and b (i

For 2,5-dihydrofuran and related molecules the wavefunctions required to calculate the matrix elements of y2 may be approximated as a harmonic oscillator with the appropriate twisting frequency and the value of a l 2 , a l , and b l thus determined from the preceding equations. All these refinements on the initial study of 2,s-dihydrofuran have led to a more complete understanding of the out-ofplane ring motions. They have shown that the approximations made still lead to a single-minimum potential function with a substantial anharmonicity. They have also shown that some care must be taken in reaching conclusions on the precise values of potential constants (eq. [19a] and [19b]) subject to interactions with other modes. 4.

Analogues of BicycZo[ 3 . 1 . 0 lhexane

Like unsaturated five-membered-ring molecules, analogues of bicyclo[3.l.0lhexane may be considered to be pseudo-four-membered-ring molecules. A six-membered-ring molecule has three out-of-plane ring vibrations. For bicyclo[3.1.0.]hexane analogues these may be characterized as a rocking motion of the three-membered ring, a twisting vibration of the five-membered ring, and a ring-puckering vibration of the five-membered ring. These are illustrated in Fig. 20. The rocking and twisting modes are essentially harmonic, while the ring puckering is quite anharmonic. The potential function appropriate for the ring-puckering is the given in eq. [7], where the cubic term indicates the lower symmetry of the molecule. In the dimensionless coordinate Z the SchrBdinger equation is given by d2

d ( - T

dZ

+

Z4

+

BZ2

+

CZ3 = A)$

[ 241

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A . CARREIRA

129

Fig. 20. Rocking of the three-membered ring; ring-twisting and ring-puckering vibrations for analogues of bicyclo[3.1.0]hexane. The potential function represents a variety of shapes of potential functions, some of which are indicated in Fig. 3 . For bicyclo[3.1.0]hexane and its 3-oxa, 6-oxa, and 3,6-dioxa analogues, these potential functions have a single minimum (23,55, 56). Figure 21 indicates the far-IR spectrum of 3,6-dioxabicyclo[3.1.0]hexane and the ring-puckering potential function. The nine transitions decrease in frequency, reaching a minimum with the 5 -+ 6 transition, and then begin to increase in frequency. The correspondence between the observed and calculated frequencies is quite good, the phenomenon of the transitions reversing direction after the 5 -f 6 transition being quite well reproduced. The potential function derived from fitting the data is also shown in Fig. 21.

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

130

I

I

\

1500

1000

5 00

l , 130

l , 150

l

, l 170' 180

CM-'

I

I 200

I

I

220

I 1

-40

-30 - 2 0

-10

00

I0

3

V ( C M - ' ) vs Z(REDUCEDI

Fig. 21. Far-IR spectrum and ring-puckering potential function for 3,6-dioxabicyclo[3.1.O]hexane. Pressure ca. 1 torr, path length = 20 m; x marks pure rotional transitions of residual water vapor in the sample. (Reproduced with the permission of Academic Press, New York, from ref. 55.) One major difference between the asymmetric and symmetric potential functions lies in the identification of the conformation corresponding to the origin. For a symmetric function the planar conformation lies at the origin. For symmetric singleminimum functions the planar ring conformation corresponds to the minimum energy. For a symmetric double-minimum potential function the planar ring conformation corresponds to the maximum in the potential function, which occurs at the origin. The two equivalent minima correspond to puckering the ring above and below the plane, respectively. The precise angle corresponding to the minimum may be determined only if the reduced mass is known or if this angle is obtainable from some other experimental technique. For a molecule having an asymmetric potential function, the situation is not as clear-cut. It is always possible to define the puckering coordinate in a fashion similar to that done for four-membered rings, as shown in Fig. 20 for bicyclo[3.1.0]hexane. However, the planar ring conformation does not necessarily correspond to a point on the potential function where the first derivative is zero, and consequently a linear term may be required to describe the potential function as well as quadratic, cubic, or quartic terms. On the other hand we may always elimi-

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

131

nate the linear term by translating the origin to a minimum in the potential energy. This leads to an equation of the form of eq. [ 7 ] and a reduced Schrodinger equation of the form of eq. [ 2 4 ] . However, since we do not know the distance or even the direction of the translation required, we do not know the position of the planar ring conformation on the potential curve, nor do we know the identity of the conformer corresponding to the minimum. Consequently, fitting the low-frequency vibrational data allows us to determine the potential function in the reduced coordinate, but does not allow direct correlation between the reduced coordinate and the conformation. This is a simple matter to rectify in the case of 3,6-dioxabicyclo[3.1.0]hexane. The dipole moment is dominated by the presence of the two oxygen atoms. In the boat comformer the two oxygen atoms are on one side of a plane formed by the four carbon atoms, and a large dipole moment is expected. In the chair conformer a small dipole moment is expected. The dipole moment, measured by a heterodyne-beat method in benzene solution, is 2.50 D ( 5 5 ) . Analysis of the Stark effect in the microwave spectrum yielded a value of 2.48 f 0.04 D ( 5 7 ) . The microwave data, however, also yield additional information indicative of the preference for the boat conformation. Lafferty and Cresswell calculated the moments of inertia and corresponding rotational constants for a number of postulated structures for 3,6-dioxabicyclo[3.1.0]hexane ( 5 7 ) . This was done by transferring structural parameters from dimethyl ether and ethylene oxide (58,59), fixing the angle between the planes defined by C ~ C ~ C L ,and C ~ the oxirane ring at 116O, and then varying the position of the oxygen atom in position 3 for a grid of boat and chair conformers. This admittedly crude procedure yielded quite good agreement between the observed rotational constants and those calculated for a boat conformer, as shown in Fig. 22. Similar agreement was found for bicyclo[3.1.0]hexane and its 6-oxa and 3-oxa analogues ( 6 0 - 6 2 ) . This was of some importance, since total dipole-moment measurements of these three compounds are not indicative of the conformation. For the oxygencontaining analogues, however, the direction of the dipole moment is indicative of the conformation. For 3,6-dioxabicyclo[3.1.0]hexane it was possible to predict the dipole-moment components in the principal inertial axis system by assuming a group dipole of 1.90 D (from ethylene oxide) for the oxirane ring directed along the C1025bisector, and a group moment of 1.30 D (from dimethyl ether) directed along the CzOC4 bisector. Then, as the rotational constants were calculated for a grid of values, it was possible to calculate the components of the dipole-moment vector in the principal axis system. The results are shown in Fig. 22. The agreement, in both the magnitude and the direction of the dipole moment, is good evidence for the preference for a boat conformation. The direction of the dipolemoment vector in the principal axis system for 6-oxa- and 3-oxabicyclo[3.l.0lhexane is also consistent with the boat conformation ( 6 0 , 6 1 ) .

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

132

Chair

Dihedral angle q4 (deg.)

Dihedral angle

Boat

6 (deg.)

Fig. 22. Model calculations for the rotational constants and dipole-moment components for 3,6-dioxabicyclo[3.l.O]hexane. Here # is the angle between the ClC2CqCg plane and the C2O3C4 plane. Values of 6 less than 180' correspond to boat conformations; values of 6 greater than 180' correspond to chair conformations. The solid lines are the model calculations; the dashed horizontal lines are the experimental values. (Reproduced with the permission of Academic Press, New York. from ref. 5 7 . ) Figure 23 shows projection diagrams that indicate the reason for the preference of the boat conformation for these molecules. The boat form leads to a staggering of the bridgehead hydrogens with the adjacent methylene groups, whereas the chair conformation leads to an eclipsed configuration.

THOMAS B. MALLOY, LES LI E E. BAUMAN, AND L. A. CARREIRA

133

6

Fig. 23. Projection diagrams for boat and chair conformations of 3,6-dioxabicyclo[3.1.0]hexane. For the boat conformation the preferred staggered configuration about the C1C2 and C 5 C 4 bonds is obtained. (Reproduced with the permission of Academic Press, New York, from ref. 55). A few more comments should be made about these molecules. Examination of Fig. 21 shows a single minimum in the potential function, corresponding to the boat conformation. Since no chair conformation corresponds to a minimum in the potential energy, it is meaningless to speak of the difference in energy between the boat and chair conformations. The potential energy function given in eq. [29] is quite well characterized. The data extend to levels well above the second inflection point in the curve. The potential functions for the other analogues of bicyclo[3.1.01 hexane are not as well determined but, conservatively speaking, extrapolations of the shapes of the curves should be accurate above the last observed tranto at least 1 kcal/mol (350 cm-') sition. Although there is no indication of a second minimum in these potential functions, if there is one present, (1) the barrier between the two minima is at least 3 to 5 kcal/mol, (2) the second minimum is at least 2 to 3 kcal/mol above the ground state. These statements are conservative.

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

134

5.

Trimethylene Oxide

I t i s n o t p o s s i b l e t o d i s c u s s experimental s t u d i e s of r i n g molecules without mentioning t r i m e t h y l e n e o x i d e , the most t h o r oughly s t u d i e d four-membered-ring molecule, and t h e f i r s t f o r which a q u a n t i t a t i v e p o t e n t i a l f u n c t i o n w a s determined from s p e c t r o s c o p i c d a t a . I n t e r e s t i n g l y enough, t h e p o t e n t i a l f u n c t i o n f o r t h i s molecule i n d i c a t e s t h e extremely d e l i c a t e balance between a n g l e s t r a i n and t o r s i o n a l i n t e r a c t i o n s , the p o t e n t i a l f u n c t i o n having a s m a l l b a r r i e r a t t h e o r i g i n . T h i s i s shown i n F i g . 24, which shows t h a t t h e b a r r i e r i s below t h e lowest energy l e v e l . T h i s s m a l l barrier (ca. 0.04 k c a l / m o l ) , h a s a s i g n i f i c a n t e f f e c t on t h e s p e c t r a of t r i m e t h y l e n e oxide. P a r t i c u l a r l y , t h e 0-1 t r a n s i t i o n i n t h e far-IR spectrum and t h e 0-2 t r a n s i t i o n i n t h e Raman spectrum are unusually low i n frequency compared to t h e o t h e r t r a n s i t i o n s . F i t t i n g t h e s e d a t a w i t h the Sohrtidinger e q u a t i o n given by eq. [16] r e q u i r e s a s m a l l n e g a t i v e c o e f f i c i e n t f o r t h e q u a d r a t i c term i n t h e Hamiltonian. The b a r r i e r t h a t res u l t s a l s o has an e f f e c t on t h e microwave spectrum. The v a r i a t i o n of t h e r o t a t i o n a l c o n s t a n t s w i t h v i b r a t i o n a l s t a t e i s shown

c

"

-2

-1

0

z

1

2

Fig. 24. Ring-puckering p o t e n t i a l f u n c t i o n f o r t r i m e t h y l e n e oxide. The b a r r i e r i s less t h a n t h e ring-puckering zero-point energy. (From d a t a i n r e f . 36.)

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

135

i n F i g . 25. T h i s should be compared t o t h e v a r i a t i o n of t h e rot a t i o n a l c o n s t a n t s f o r 1,2-dimethylenecyclobutane, which h a s a single-minimum p o t e n t i a l f u n c t i o n ( F i g . 1 8 ) . I t s h o u l d b e emphas i z e d t h a t t h e same p o t e n t i a l f u n c t i o n which r e p r o d u c e s t h e obs e r v e d f a r - I R and Raman t r a n s i t i o n s a l s o r e p r o d u c e s t h e r o t a t i o n a l - c o n s t a n t v a r i a t i o n when t h e expansions g i v e n by eq. [18] a r e used ( 3 8 ) .

C

20 -

t

u 5

I

I

5

t

u 5

F i g . 25. V a r i a t i o n of t h e r o t a t i o n a l c o n s t a n t s w i t h v i b r a t i o n a l s t a t e i n t r i m e t h y l e n e o x i d e . The e f f e c t of t h e s m a l l b a r r i e r i s q u i t e e v i d e n t . (Reproduced w i t h t h e p e r m i s s i o n of t h e American I n s t i t u t e of P h y s i c s , from r e f . 37.)

A s mentioned, t r i m e t h y l e n e o x i d e h a s been t h e most t h o r oughly s t u d i e d r i n g molecule. Far-IR, low-frequency Raman, microwave, mid-IR, and mid-Raman s t u d i e s of t r i m e t h y l e n e o x i d e and s e v e r a l i s o t o p i c a l l y s u b s t i t u t e d a n a l o g u e s have been r e p o r t e d (14,16,27,29-31,34-39,63-66). Such e x t e n s i v e d a t a make p o s s i b l e the examination of some of t h e assumptions made i n d e r i v i n g r i n g puckering p o t e n t i a l f u n c t i o n s from s p e c t r o s c o p i c d a t a . A s much a s a n y t h i n g i t g i v e s an i n d i c a t i o n of t h e d e g r e e of r e l i a b i l i t y of t h e p o t e n t i a l f u n c t i o n s f o r o t h e r molecules f o r which such e x t e n s i v e d a t a are n o t a v a i l a b l e . I t s h o u l d be emphasized t h a t it i s t h e a b s o l u t e v a r i a t i o n which i s i m p o r t a n t , n o t t h e p e r c e n t a g e , i n t h i s unusual c a s e . I t has been found t h a t t h e r i n g - p u c k e r i n g p o t e n t i a l funct i o n s a r e n o t p r e c i s e l y i s o t o p i c a l l y i n v a r i a n t . I f t h e dimens i o n e d p o t e n t i a l f u n c t i o n ( e q . [131) i s i n v a r i a n t , t h e r e l a t i o n between t h e p o t e n t i a l c o n s t a n t s i n eq. [161 should be g i v e n by

136

CONFORMATIONAL BARRIERS I N SMALL RING MOLECULES

and

where 1 and 2 r e f e r t o t h e d i f f e r e n t i s o t o p i c s p e c i e s , and P I and p 2 r e f e r t o t h e reduced masses. These e q u a t i o n s do n o t h o l d p r e c i s e l y . E r r o r s may a r i s e i n c a l c u l a t i n g t h e reduced masses, and eqs. [25a] and [25b] may be .combined, y i e l d i n g

which e l i m i n a t e s t h i s p o s s i b l e s o u r c e of e r r o r . However, even t h i s equation does n o t hold. The b a r r i e r h e i g h t s d e r i v e d from f i t t i n g each i s o t o p i c s p e c i e s i n d i v i d u a l l y vary from 1 5 . 1 c m - I f o r normal t r i m e t h y l e n e oxide t o a low of 1 1 . 2 cm-l f o r t r i methylene oxide-dg (36). P o s s i b l e s o u r c e s of t h i s discrepancy i n c l u d e (1) f a i l u r e t o c o r r e c t Q-branch maxima f o r s h i f t s from t h e v i b r a t i o n a l band o r i g i n s , ( 2 ) f a i l u r e t o t a k e i n t o account t h e change i n reduced mass d u r i n g t h e c o u r s e of a ring-puckering v i b r a t i o n , and ( 3 ) f a i l u r e t o i n c l u d e t h e e f f e c t of t h e i n t e r a c t i o n w i t h o t h e r v i b r a t i o n a l modes of t h e molecule. Workers have concerned themselves w i t h t h e f i r s t of t h e s e t h r e e sources o f e r r o r . J o k i s a a r i and Kauppinen o b t a i n e d t h e spectrum of normal t r i m e t h y l e n e o x i d e under h i g h e r r e s o l u t i o n c o n d i t i o n s and used the r o t a t i o n a l c o n s t a n t s from t h e microwave s t u d y t o show t h a t t h e band o r i g i n s w e r e s h i f t e d from 0 . 1 c m - l t o 0 . 4 c m - l from t h e Q-branch maxima ( 6 6 ) . They t h e n f i t t e d t h e d a t a w i t h a c o n s t a n t reduced-mass Hamiltonian i n c l u d i n g an adj u s t a b l e s i x t h power term i n t h e o t e n t i a l f u n c t i o n . The b a r r i e r they d e r i v e d w a s 15.23 f 0.05 cm-', where t h e e s t i m a t e d uncert a i n l y i s o b t a i n e d from t h e l e a s t s q u a r e s t r e a t m e n t of t h e d a t a . This e s t i m a t e d u n c e r t a i n t y , f 0.05 an-', does n o t i n c l u d e t h e e f f e c t of model e r r o r mentioned i n p o i n t s (2) and ( 3 ) . However, it does show t h a t f o r t r i m e t h y l e n e oxide c o r r e c t i o n of t h e f r e quencies f o r s h i f t s from t h e band o r i g i n s does n o t account f o r t h e d i s c r e p a n c i e s on t h e o r d e r of t h e v a r i a t i o n i n t h e b a r r i e r heights,among i s o t o p i c s p e c i e s . Of t h e t w o remaining s o u r c e s o f e r r o r , f a i l u r e t o i n c l u d e t h e i n t e r a c t i o n of the ring-puckering w i t h t h e small-amplitude modes i s t h e m o s t important. The e f f e c t of the v a r i a t i o n of t h e reduced mass is d i s c u s s e d i n Appendix I. There a r e s e v e r a l c a t e g o r i e s o f i n t e r a c t i o n s w i t h small-amplitude modes. I f a s m a l l amplitude v i b r a t i o n is of t h e same symmetry s p e c i e s a s t h e r i n g puckering v i b r a t i o n , harmonic c r o s s terms such a s t h o s e d e s c r i b e d

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A . CARREIRA

137

in eq. [6] may occur. CH2 rocking vibrations are the most likely to fall in this category, because of their symmetry and low frequency. These interaction terms may be removed by a "normal coordinate" transformation, but the result is that the effective one-dimensional ring-puckering coordinate may differ for isotopic species. Particularly, it may involve differing degrees of CH2 or CD2 rocking motions. If this is the case, then at this stage we expect different effective potential functions for isotopic species, since they would describe different motions. Figure 19 shows the effect of the anharmonic interaction of two modes for 2,5-dihydrofuran via a x2y2-type cross term (eq. [20]). The only reason that it is observable in the spectrum is that the thermal population of the ring-twisting mode (y) is high due to the low frequency of this vibration. If the frequency is high, satellite transitions may not be observed in the farIR spectrum, but it may be possible to find combination- and difference-band progressions in the mid-IR or mid-Raman spectra. Figure 9 indicates such band progressions for trimethylene oxide, and these have been discussed in some detail. Some indication that such terms contribute to the effective potential functions may be seen by examining Table 1. It is seen that the quartic terms in the dimensioned potential functions vary only slightly among the isotopic species. On the other hand the variation of

Table 1 Potential Function Constants for Trimethylene Oxidea

n-TMO A

(cm-

Bb

)

(U)

a ( 1 0 5 ~ ~ -i1- 4 ) ~

b (103~m-l8-21

Barrier (cm-l) ~d (cm-1) Separatione ( 8 )

a Ref. 36.

a - d2 TMO

28.12 25.46 -1.465 -1.445 95.7 110.4 7.16 7.07 -6.58 -6.13 15.1 13.3 12.2 11.3 0.135 0.132

B

- d2 TMO

26.10 -1.465 107.3 7.19 -6.34 14.0 11.3 0.133

a,a' - d4 TMO

dg -TMO

22.85 -1.445 129.8 7.07 -5.81 11.9 10.2 0.128

21.54 -1.445 141.8 7.07 -5.64 11.2 9.6 0.126

Eq. [201. Eq. [16]. H is the separation between the top of the barrier and the lowest energy level. Separation between minima.

138

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

the quadratic term is more marked. If we consider interaction terms of the form x2yI and simply average over the 3N - 7 smallamplitude modes, we obtain the effective potential function

In this degree' of approximation (first-order perturbation theory), we would expect the quartic coefficient to be isotopically invariant and the quadratic term to change. That is, since the small-amplitude frequencies change on isotopic substitution, vi> changes, and consequently the averaging of terms like
I~ $ 1

6.

2,s-Dihydropyrrote

2,s-Dihydropyrrole is a pseudo-four-membered ring molecule with an asymmetric potential function having an extremely low

w

W

P

150

Wavenumber cm-'

200 100

100

200

300

400

30 25 20 .I5 .I0 M

0 D5 .I0 .I5 20 25 30

Fig. 2 6 . Low-frequency Raman (a) and f a r - i n f r a r e d ( b ) s p e c t r a and ring-puckering p o t e n t i a l funct i o n € o r 2,5-dihydropyrrole. The Raman spectrum was recorded a t t h e f u l l vapor p r e s s u r e a t 25OC w i t h a s p e c t r a l s l i t width of 3 cm-l, u s i n g a laser power of c a . 2 W a t 514.5 nm. The far-IR s p e c t r a (ca. 0.5-c1n-~ r e s o l u t i o n ) were obtained a t 8 t o r r s , a t p a t h l e n g t h s of 4 m and 8 m , and i n d i c a t e d . (Reproduced w i t h t h e permission of t h e American I n s t i t u t e of Physics, from r e f . 23 and 6 7 . )

fa)

250

2500

I

3

7600

700

800

900

I la,

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

140

b a r r i e r ( 2 3 ) . The far-IR and Raman (67) s p e c t r a are shown i n F i g . 26. Many of t h e f r e q u e n c i e s o f t h e observed Raman t r a n s i t i o n s a r e shown i n Fig. 26. Many of t h e f r e q u e n c i e s of t h e observed Raman t r a n s i t i o n s are t h e sum of t w o f r e q u e n c i e s of t r a n s i t i o n s i n t h e far-IR spectrum, t h u s v e r i f y i n g t h e assignment. F i g u r e 26 i n d i c a t e s t h e p o t e n t i a l f u n c t i o n f o r t h e ring-puckering v i b r a t i o n i n 2,5-dihydropyrrole. T h i s p o t e n t i a l f u n c t i o n , though asymmetric, has only a very s m a l l b a r r i e r , and o n l y one energy

t

ru

,

I

40

(a)

1

I

60

I

1

(CM-)

I

I

I

80

100

.--L

I

-

-

400

H ~ S + n2 160 mm 3.OcmP stit

-

100coun!r/sec

t

?

-

300

-

too -

v (em* I

200

0 -

1 ' 1 ' 1 ' 1 . 1 ' 1

#

-2.0

-3.0

*I* _ _ ZOO la)

-

'71

150

1.5

RAMAN SHIFT km"1

Fig. 27.

100

,

(c,

1

-0 3

'

1 -02

'

-1.0 0 . 0 1.0 2 (REDUCED1

2.0

1

"

-01

'

1

'

0 0

1 01

'

1 0.2

. I

1

3.0

l

0.3

x Ill

Low-frequency Raman spectrum (a) and far-IR spec-

trum (b) and ring-puckering p o t e n t i a l f u n c t i o n ( c ) f o r 1 , 3 - d i s i l acyclobutane. The Raman spectrum w a s o b t a i n e d a t 3-cm-l r e s o l u t i o n a t a vapor p r e s s u r e of 163 t o r r s . The far-IR spectrum a t a r e s o l u t i o n of 0.5cm-1 was o b t a i n e d a t a sample p r e s s u r e of 140 torrs and a p a t h l e n g t h of 1 5 cm. (Reproduced w i t h t h e permiss i o n of t h e American Chemical S o c i e t y , from r e f . 68.)

THOMAS B. MALLOY, LESLIE F. BAUMAN, AND L. A. CARREIRA

141

l e v e l o c c u r s below t h i s b a r r i e r . As f o r t r i m e t h y l e n e o x i d e , t h e e f f e c t of t h e s m a l l b a r r i e r i s h a r d l y n o t i c e a b l e f o r t r a n s i t i o n s between h i g h e r energy l e v e l s .

7.

1,d-Disilacyclobutane

1 , 3 - D i s i l a c y c l o b u t a n e i s an example of a molecule having a b a r r i e r t o p l a n a r i t y t h a t i s low, y e t h i g h enough t o produce a n i n v e r s i o n d o u b l e t below t h e b a r r i e r ( 6 8 ) . F i g u r e 27 shows t h e p o t e n t i a l f u n c t i o n and some of t h e f a r - I R (Av = 1 or 3 ) and Raman (Av = 2 ) t r a n s i t i o n s o f 1 , 3 - d i s i l a c y c l o b u t a n e . Reduced mass c a l c u l a t i o n s and t h e p o t e n t i a l f u n c t i o n d e r i v e d f o r 1,3-disilacyclobutane-l~l,3,3-d1+from t h e f a r - I R spectrum i n d i c a t e t h a t t h e r i n g - p u c k e r i n g c o o r d i n a t e i s a mixt u r e of pure puckering and SiH2 motion. The most l i k e l y candid a t e i s t h e in-phase S i H 2 r o c k i n g mode, which i s r e a s o n a b l y low i n frequency and a l s o of t h e same symmetry as t h e ring-puckeri n g . F i g u r e 28 shows t h e in-phase mixing of ring-puckering and SiH2 r o c k i n g . I t i s n e c e s s a r y t o mix t h e r o c k i n g v i b r a t i o n t o a c c o u n t f o r i s o t o p i c s h i f t of t h e ring-puckering f r e q u e n c i e s from the normal compound t o t h e 1 , 1 , 3 , 3 - d ~ , compound. T h i s s h i f t i s u n d e r e s t i m a t e d by t h e reduced r a t i o c a l c u l a t e d f o r a model i n which t h e SiH2 groups r i g i d l y m a i n t a i n a common b i s e c t o r w i t h the adjacent i n t e r i o r ring angle. E x t e n s i v e c a l c u l a t i o n s have been c a r r i e d o u t which i n c l u d e t h e reduced mass v a r i a t i o n e x p l i c i t l y i n t h e SchrBdinger e q u a t i o n f o r a number of d i f f e r e n t models. S a t e l l i t e ring-puckering t r a n s i t i o n s were a s s i g n e d i n t h e spectrum of 1 , 3 - d i s i l a c y c l o b u t a n e , most l i k e l y o r i g i n a t i n g from

F i g . 28. D e f i n i t i o n of r i n g - p u c k e r i n g ( x ) and r o c k i n g ( 8 ) coordinates f o r 1,3-disilacyclobutane; 8 = R x . For 1 , 3 - d i s i l a c y c l o b u t a n e and i t s 1 , 1 , 3 , 3 - d ~ analogue t h e i s o t o p i c s h i f t i s reproduced f o r R = 0 . 4 . (Reproduced w i t h t h e p e r m i s s i o n of t h e American Chemical S o c i e t y , from r e f . 6 8 . )

142

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

t h e f i r s t e x c i t e d s t a t e of t h e SiH2 in-phase r o c k i n g . T h i s i s most l i k e l y t h e r e s u l t of a p o t e n t i a l energy c r o s s t e r m of t h e form x2B2 (Fig. 2 8 ) . The c r o s s term c a u s i n g t h e mixing of coord i n a t e s (Fig. 28) i s p r o b a b l y a harmonic term of t h e form xB. E x t e n s i v e s t u d i e s a r e i n p r o g r e s s ( 6 9 ) on t h e mid-IR and midRaman s p e c t r a w i t h a view o f examining t h e s e and o t h e r i n t e r actions i n 1,3-disilacyclobutane.

8.

Cyolopentene

Cyclopentene i s a n example of a pseudo-four-membered-ring molecule w i t h a double-minimum p o t e n t i a l f u n c t i o n and a mode r a t e (ca. 232 c m - l , 0.66 kcal/mol) b a r r i e r t o p l a n a r i t y . The b a r r i e r h e i g h t i s such t h a t t h e l o w e s t p a i r of v i b r a t i o n a l l e v e l s are q u i t e c l o s e l y spaced (see F i g . 1 5 ) , t h e s e p a r a t i o n b e i n g of t h e o r d e r of t y p i c a l r o t a t i o n a l energy s p a c i n g s . Cons e q u e n t l y , i t was n e c e s s a r y t o t r e a t t h e r a t h e r l a r g e v i b r a t i o n r o t a t i o n i n t e r a c t i o n t o a c c o u n t f o r t h e t r a n s i t i o n s i n t h e microwave r e g i o n ( 7 0 ) . The far-IR spectrum i s shown i n F i g . 29, a s i s t h e p o t e n t i a l f u n c t i o n d e r i v e d from f i t t i n g t h e f a r - I R d a t a (10)

-

There have been s t u d i e s of r i n g - p u c k e r i n g p r o g r e s s i o n s i n t h e mid-IR (14,16) and mid-Raman (32) s p e c t r a of c y c l o p e n t e n e . I n a d d i t i o n t h e low-frequency Raman spectrum was r e p o r t e d . T h i s was one of t h e f i r s t examples of a gas-phase s t u d y of r i n g puckering i n t h e Raman spectrum ( 3 2 , 7 1 ) . Although n o t a s obv i o u s a s i n t h e spectrum of 2 , 5 - d i h y d r o f u r a n r t h e r e i s a s a t e l l i t e ring-puckering series o r i g i n a t i n g from t h e f i r s t e x c i t e d s t a t e of t h e r i n g - t w i s t i n g mode. T h i s series a l s o was f i t t e d w i t h t h e one-dimensional c o n s t a n t e f f e c t i v e mass S c h r a d i n g e r e q u a t i o n (eq. [ 1 6 ] ) . The p o t e n t i a l f u n c t i o n s a r e g i v e n by Ground s t a t e o f t w i s t i n g :

E x c i t e d s t a t e of t w i s t i n g :

i t w a s p o s s i b l e t o f i t t h e ring-puckeri n g s e r i e s and t h e r i n g - t w i s t i n g frequency w i t h t h e two-dimens i o n a l Hamiltonian g i v e n by eq. [20] ( 5 4 ) . Laane and co-workers have c a r r i e d o u t e x t e n s i v e f a r - I R and low-frequency Raman s t u d i e s on a number of d e u t e r a t e d a n a l o g u e s of cyclopentene ( 7 2 , 7 3 ) . They have c o n s i d e r e d t h e e f f e c t of t h e reduced m a s s dependence on t h e c o o r d i n a t e and t h e e f f e c t of mixing C H z ( C D 2 ) r o c k i n g w i t h t h e r i n g - p u c k e r i n g c o o r d i n a t e . More r e c e n t l y , t h e y have a d d r e s s e d t h e problem of f i t t i n g b o t h r i n g puckering and r i n g - t w i s t i n g t r a n s i t i o n s two-dimensionally f o r the several deuterated species (74).

A s w i t h 2,5-dihydrofurant

I

'

, I

I

0 I

I

-

1

I

-

-

-

0 1

200

400 -

VlCU+

600

no0 -

-

F i g . 29. Far-IR s p e c t r u m (a) and r i n g - p u c k e r i n g p o t e n t i a l funct i o n ( b ) o f c y c l o p e n t e n e . Pressure = 115 t o r r s , p a t h l e n g t h = 4 m , r e s o l u t i o n 0.2 t o 0 . 5 c m - l . (Reproduced w i t h t h e p e r m i s s i o n of t h e American I n s t i t u t e of P h y s i c s , r e f . 10.)

20

40

.,^

1000

I4 4

1 I

I

I

I

220 200 180 160 140

I1

I

(C)

X6,

I

I

I

120 I00 80

I

1

60 40(vl-'

Fig. 3 0 . Low-frequency Raman (a) and far-IR spectra (b) and ring-puckering potential function for trimethylene imine. The Raman spectra were obtained at 3-an-' and 6-cm-l resolution with ca. 2 W of laser power at 514.5 nm. The far-IR spectrum was obtained at 140 torrs with a 30-cm path length. (Reproduced with the permission of the American Institute of Physics, from refs. 23 and 67.)

fL)

33

a

u) 0

e

c

0 .c

THOMAS B. MALLOY, LESLIE F. BAUMAN, AND L. A . CARREIRA

9.

145

Trimethylene Imine

Trimethylene imine i s an example o f a four-membered-ring molecule w i t h a n asymmetric double-minimum p o t e n t i a l f u n c t i o n . F i g u r e 30 i n d i c a t e s t h e f a r - I R spectrum ( 2 3 ) and t h e low-frequency Raman spectrum of t h e normal compound ( 6 7 ) . Below t h e b a r r i e r t h e f r e q u e n c i e s measured i n t h e f a r - I R and Raman are t h e same, whereas above t h e b a r r i e r t h e s t r o n g Raman t r a n s i t i o n f r e q u e n c i e s are t h e sum of two f a r - I R t r a n s i t i o n f r e q u e n c i e s . T h i s s e r v e s t o unambiguously confirm t h e assignment. The p o t e n t i a l f u n c t i o n determined from f i t t i n g t h e d a t a i s asymmetric. One puckered conformation h a s t h e imino p r o t o n a x i a l , whereas t h e o t h e r has t h i s p r o t o n e q u a t o r i a l . The l e v e l s below t h e b a r r i e r have a d e f i n i t e " l e f t - w e l l ," " r i g h t - w e l l ' ' c h a r a c t e r , b u t t h i s d i s t i n c t i o n becomes l e s s c l e a r f o r t h o s e l e v e l s above

-0.300

-0.200

-0.100

-

0.000 X(B,

0100

0.200

0.W

F i g . 31. Ring-puckering p o t e n t i a l f u n c t i o n and p r o b a b i l i t y f o r t r i m e t h y l e n e imine. A s i n d i c a t e d , $2 i s m u l t i d e n s i t y (9') p l i e d by 2 f o r c l a r i t y f o r t h e h i g h e r l e v e l s . The l e v e l s below t h e b a r r i e r have a d e f i n i t e l e f t w e l l - r i g h t w e l l i d e n t i f i c a t i o n . (Reproduced w i t h t h e p e r m i s s i o n of t h e American I n s t i t u t e of P h y s i c s , from r e f . 2 3 . )

146

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

t h e barrier. T h i s i s shown i n F i g . 31, which a l s o i n d i c a t e s t h e probability density f o r the levels. The a v a i l a b i l i t y of d a t a f o r t h e two i s o t o p i c s p e c i e s and the f a c t t h a t t h e y are f i t t e d w i t h two s l i g h t l y d i f f e r e n t potent i a l f u n c t i o n s allow us t o estimate t h e r e l i a b i l i t y of t h e b a r r i e r h e i g h t s and energy d i f f e r e n c e s . T a b l e 2 l i s t s t h e b a r r i e r s and determined AE v a l u e s . Though n o t i d e n t i c a l they a r e q u i t e c l o s e and do n o t r e p r e s e n t an unreasonable s p r e a d i n values. T a b l e 2 Comparison of t h e P o t e n t i a l Functions f o r

Trimethylene Imine and Trimethylene Imine N-d Barrier? (cmN o r m a l species N-d s p e c i e s a

441 442

AE

(cm-1) 95

91

Measured from t h e lowest minimum. 10.

Cyclobutane

Cyclobutane is t h e p a r e n t hydrocarbon of a l l four-membered r i n g molecules, and c o n s i d e r a b l e e f f o r t h a s been expended toward i t s study. S i n c e it has no permanent d i p o l e moment, no microwave d a t a are a v a i l a b l e . The ring-puckering v i b r a t i o n i s i n a c t i v e i n t h e I R r e g i o n , and no d i r e c t o b s e r v a t i o n of t r a n s i t i o n s i n t h e far-IR spectrum h a s been made. The f i r s t e s t i m a t e of t h e ' b a r r i e r t o p l a n a r i t y from ring-puckering d a t a w a s made by Ueda and Shimanouchi, based on o b s e r v a t i o n of a difference-band p r o g r e s s i o n i n t h e CH s t r e t c h i n g r e g i o n ( 2 1 ) . The only r e q u i r e ment f o r t h e o b s e r v a t i o n of t h e s e bands i s t h a t t h e d i r e c t product of t h e symmetry s p e c i e s f o r t h e r e f e r e n c e v i b r a t i o n (CH s t r e t c h i n g ) and t h e ring-puckering be a symmetry species t h a t transforms a s one of t h e dipole-moment component o p e r a t o r s . T h e i r e s t i m a t e , 448 an-', was s l i g h t l y lower t h a n t h e c u r r e n t l y accepted value (500 t o 515 c m - l ) . Several y e a r s a f t e r t h e work of Ueda and Shimanouchi, two groups r e p o r t e d combination- and difference-band p r o g r e s s i o n s i n cyclobutane and cyclobutane-d8 o f f CH2 ( C D 2 ) s c i s s o r i n g modes ( 2 4 , 2 5 ) . I n a d d i t i o n , o v e r t o n e (Av = 2 ) t r a n s i t i o n s were observed i n t h e low-frequency r e g i o n of t h e Raman spectra. Minor d i f f e r e n c e s i n assignments and d i f f e r e n t methods of t r e a t i n g t h e d a t a l e d t o s l i g h t d i f f e r ences i n t h e determined b a r r i e r h e i g h t s . The two sets o f d a t a were l a t e r r e c o n c i l e d by Malloy and L a f f e r t y ( 7 5 ) . Table 3 summarizes t h e p o t e n t i a l c o n s t a n t s f o r t h e ground and e x c i t e d s t a t e s of t h e C H z ( C H 2 ) s c i s s o r i n g mode ( 7 5 ) .

P m

a m

N m

0 0

0 0

W

m

. .

-m

..

rr-? 0 4J

P

w

-.d

am

a, V

N

N

+I

+I

I W

I F

a,

Lc rd

v

a

ac

0 4

rd

m

3: f

V

a, 4J

N 0 Icl

*

.

N W

a

+I +I

2

a

4J ffl

4

. . 3Pi

a 0

.A

o m o m m q

rd

a 0 4J

ffl

4

m

a,

.A

d

4 4

Lc

0

I-!

b

N

rd

!a

..

a

crd

0 0

+I +I

m m P W

ffl

o m o m .o

-s

..

4

m + m m

4J

c

a,

I

V

I

I

a

a,

f

0

+I 00

.

0

2l IJ

4 0

+I

o m

.. . .

P N

m N 0 0 d 4

I

I

d

c rd m

u

4J

P W

m o rrm

rd

0 0

0 0

m

+I +I

+I +I

0

m +

q

ffl

W

..

0 0

c

4J

c

u

m 4

4 4

*

4

rd

.

W W

"

TI

4J

c

.N

..

0 0

m a

d

..

m m m m

?-Id

4J

u a a

0

.ta,a,

[4

m

a,

a,

a,

4J rd

4J

m

v1

rd

u

i

a c7

H

0 m 4

u rl

I1

3

x u >

4

f

u

147

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

148

Several conclusions may be drawn. When treated one-dimensionally, slight differences (in this case 3%) may be obtained in the barrier heights determined for isotopic species. The primary reason is the difference in zero-point averaging over the small-amplitude vibrations for the isotopic species. On the other hand it was found that reduced mass calculations (Appendix I) underestimated the isotopic shift of the ring-puckering vibration for cyclobutane and cyclobutane-d8 for a model in which the CH2 (CD2) groups maintained a common bisector with the adjacent C-C-C angle (24,25,75). Preliminary analysis of electron diffraction data indicates that the CH2 groups in cyclobutane tilt (rock) forward as the ring puckers (76). These data are consistent with the vibrational data, which are not definitive on this point.

B.

Two-Dimensional P o t e n t i a l F u n c t i o n s

Examples of two-dimensional potential functions have been mentioned earlier in connection with 2,5-dihydrofuran and cyclopentene. For these molecules the Schr6dinger equation was approximately separable in Cartesian coordinates, the cross term being treated by perturbation techniques. This is not always the case. Gwinn and co-workers have discussed various cases arising in the treatment of the two out-of-plane skeletal vibrations of five-membered-ring molecules (77). All the possible cases are not considered here, only those appropriate to the molecules used as examples in this section. In 1947 Kilpatrick, Pitzer, and Spitzer introduced the notion of "pseudorotation" to explain the thermodynamic data on cyclopentane (78). Figure 32 indicates a potential energy contour deagram appropriate to pseudorotation in five-membered-ring molecules (77). 21 and 2 2 are dimensionless ring-puckering and ring-twisting coordinates (see Fig. 2 ) , respectively. It i s seen that the minimum energy trackl V = 0, is surrounded by a steep wall on the outside, while there is an energy maximum at the origin, which corresponds to the planar conformation. Pure pseudorotation, as implied by Fig. 32, arises when bent and twisted conformations having the same vibrational amplitudes are equal in energy; interconversion occurs via intermediate benttwisted forms having the same energy. Another way of stating this is to say that the potential energy function, expressed in polar coordinates, is independent of the angular coordinate. In Cartesian coordinates, for a constant mass model, the conditions on eq. [20] are that a1 = a 2 = a 1 2 / 2 , b l = b 2 , and p1 = p 2 . In dimensionless coordinates the Schrbdinger equation is given by a2

-6+-

az:

a2

azi

11,

THOMAS B. MALLOY, LESLIE F. BAUMAN, AND L. A. CARREIRA

149

where

and x and y are the ring-puckering and ring-twisting coordinates,

T

v=o

Fig. 32. Potential energy contour diagrom appropriate to pseudorotation in five-membered-ring molecules. Here Z1 and Z2 are ring-puckering and ring-twisting coordinates. The minimum energy track, V = 0, is surrounded by steep walls on the outside and a high barrier at the origin. (Reproduced with the permission of the American Institute of Physics, from ref. 77.) respectively; the energy levels are given by E = A h , where A is the appropriate scale factor. In polar coordinates with

the Schradinger equation is separable, the angular equation being

150

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

with

I

and a series of radial equations for different 111 :

Figure 33 is a plot of the eigenvalues of eqs. [29] and [321 as a function of B (79). The limit on the left is an isotropic harmonic oscillator, in the center is an istotropic quartic oscillator, and pseudorotation is indicated on the right. When the barrier height is very high, the energy levels may be approximated by E

2

%I2

I

1

where 8 is the pseudorotational constant A . Frequencies of A L = +1 transitions exhibit a linear dependence on quantum number:

vv. -+ R+1 = %(2n. + 1)

[341

with a constant separation of 28 between transitions. The numerical solutions to eqs. [29] and [32] exhibit a negative curvature to the frequency vs. R plots, being more pronounced for lower barriers (79). This has been observed experimentally. Although very few, if any, molecules exhibit pure pseudorotation, it is a good starting point for the treatment of a number of other molecules. For molecules in which the barrier to planarity is much greater than the barriers between nonplanar conformations, hindered pseudorotation may be appropriate. This case is described in some detail by Gwinn and co-workers ( 7 7 ) . In this procedure the SchrBdinger equation, eq. [201, is expressed in mass-weighted coordinates and then transformed to polar coordinates. The resulting equation may be averaged over the radial coordinate, and the following angular equation results:

The formalism from this point on is identical to that used in the treatment of internal rotation. The requirement for using this formalism is that the barrier to planarity be high compared to interconversion harriers and, consequently, the radial coordinate be approximately constant during the vibrational motion

w

L P n

50

J

1

20.0

I

15.0

1

10.0

1

5.0

1

0.0

1

- 5.0

1

-15.0

1

-10.0

EIGENVALUES(DIMENSIONLESS) vs B Fig. 33. Eigenvalues for the two-dimensional potential function ( Z f + Z $ ) 2 + B ( Z f + Z $ ) vs. B . The dashed line gives the barrier height. The limit on the right is appropriate to pseudorotation. (Reproduced with the permission of the American Institute of Physics, from ref. 79.)

0.0

5.0

10.0

I 5.0

2o.c

1

-20.0

1

-25D

152

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

(77). The data for tetrahydrofuran and 1,3-dioxolane were treated in this fashion (80,82,83). In other cases polar coordinates are not a good choice for obtaining even approximately separable equations, and the two-dimensional Hamiltonians are treated directly. I.

CycZopentane

As mentioned, in 1947 Kilpatrick, Pitzer, and Spitzer introduced the notion of pseudorotation to explain th2 thermodynamic data on cyclopentane (78). It was not until 1968 that direct spectroscopic evidence was obtained. As with cyclobutane, no direct observation of the transitions is possible in the farIR. Durig and Wertz, however, observed combination- and difference-band progressions in the mid-IR in combination with a CH2 scissoring mode (22). Later Carreira and co-workers reported the presence of hot bands involving the radial mode in the lowfrequency Raman spectrum (84), and fitted the data two dimensionally, which allowed them to spectroscopically determine the barrier to planarity as 1824 f 50 cm-l, quite close to that estimated by Pitzer and Donath from thermodynamic data (85). Extensive studies have been made on pseudorotation in various deuterated analogs of cyclopentane (86). 2.

Tetra hydro f uran

Prior to the report of pseudorotational combination- and difference-bands in cyclopentane, spectroscopic evidence for pseudorotation had been obtained €or tetrahydrofuran (87). Due to the presence of the oxygen atom, the pseudorotational transitions were allowed in the far-IR spectrum. Although tetrahydrofuran should be termed a hindered pseudorotator, for transitions originating from levels well above the pseudorotational barriers, the pattern of transitions follows those expected for a pure pseudorotator. A microwave study of tetrahydrofuran indicated a complicated energy pattern for the lower levels (80). The rotational constants were determined in several vibrational states in addition to the small energy splittings between the 0-1 and 2 - 3 levels. These small energy splittings and rotational constant variations were used with the pseudorotational constant, 6 = 3.25 crn-l, from the previous far-IR study ( 8 7 ) to determine the potential function V ( 4 ) = -15 cm-l (1

- cos 241) - 20 cm-'

(1 - cos 44I)

[361

from eq. [35]. The potential function is shown in Fig. 3 4 . The potential function represents the minimum energy path for intezconversion on the potential surface in bending and twisting coordinates.

THOMAS B. MALLOY, LESLIE R. BAUMAN, AND L. A. CARREIRA

153

r t t

0

n12

n @

%I2

2n

Fig. 3 4 . Pseudorotational potential function for tetrahydrofuran. Tetrahydrofuran interconverts via bent and twisted conformations, the highest barrier being ca. 0.15 kcal/mol. The barrier to planarity, on the other hand, is several kilocalories per mole. (Reproduced with the permission of the American Institute of Physics, ref. 80.) Concurrently with the microwave study, a high-resolution study of the far-IR spectrum showed it to be quite complex, with a number of pseudorotational bands being split by Coriolis interactions (81). Fitting the observed bands with the Schriidinger equation of eq. [35] led to the potential function V ( @ ) = -13.5 cm-l (1

-

cos 241)

-

20 cm-' (1

-

cos 4 4 )

1371

with 0, the pseudorotational constant, equal to 3.19 cm-l. This is in quite reasonable agreement with the potential function derived from microwave data.

3.

Cyclopentanone

One of the dangers of using one-dimensional approximations for some five-membered-ring molecules came to the fore in the study of cyclopentanone. Although it was possible to fit the far-IR data for cyclopentanone with a one-dimensional periodic potential function (eq [35]) , the "barrier" derived has no meaning ( 6 , 8 8 ) . For this approach to be valid, the barrier to

Fig. 35. Potential energy contour diagram for cyclopentanone. The third and fourth quadrants are mirror images of the first and second quadrants. The minima lie along the y (twisting) axis. Interconversion of the two equivalent Cp conformers takes place via the planar ring conformation. The barrier to interconversion is ca. 750 an-'. (Reproduced with the permission of the American Institute of Physics, from ref. 89.)

4 y (twisting)

CPH 8

2

PEAK

0

a

:: K

Q Y >

-

I-

U

J

L Y

90

I

1

.

85

N U M B E R lcrn.')

-WAVE

I

I

80

75

5

I

I

85

t WAVE

80

NUMBER

I

75

C WAVL

lcm')

NUMBER

lbl

2

0 a

8 U w

?

5 w

80

70

75

t WAVE NUMBER

65

Y)

F i g . 3 6 . Far-IR s p e c t r a of c y c l o p e n t a n o n e , cyclopentanonea,a,a',a'=d4, c y c l o p e n t a n o n e - 8 , ~ , 8 " - d q r and cyclopentanone-dg. S p e c t r a l s l i t w i t h 0.15 t o 0 . 4 cm-l. P r e s s u r e c a . 5 t o r r s , p a t h l e n g t h s 4 t o 1 2 m. (Reproduced w i t h t h e p e r m i s s i o n o f t h e American I n s t i t u t e of P h y s i c s , from r e f . 89.)

155

156

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

planarity must be very high compared to the pseudorotational barriers. A rather thorough study of the far-IR spectra of cyclopentanone and its a - d 4 , P-d4, and d 8 analogs yielded the potential surface shown in Fig. 35 (89). The two equivalent, stable twisted-ring (C2 symmetry) (90) conformers interconvert via the planar conformation, which is ca. 750 cm-’ less stable. There ai-e no minima corresponding to the equivalent bent (C,) conformers. For cyclopentanone full treatment of a two-dimensional Hamiltonian is required. The observed spectra are shown in Fig. 36, the calculated spectra in Fig. 37. To reproduce the isotopic shift it was necessary to mix methylene rocking at the a position with the ring-twisting. However, the isotopic shift was accounted for without mixing rocking at the B positions ( 8 9 ) .

CPD4 - P

I

CPD4-~i

85

I

Ib

r l

.t

90

CPH 8

95

90

-Wave

I

80

I

75

1

70

I

85

80

75

70

85

80

75

70

810

75

70

85

number

Fig. 37. Calculated far-IR transitions for cyclopentanone and its deuterated analogues. (Reproduced with the permission of the American Institute of Physics from ref. 8 8 . )

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

4.

157

I , 4-Dioxene

The preceding examples are molecules for which barrier heights may be derived to an accuracy of a few reciprocal centimeters or, at worst, a few tens of reciprocal centimeters. Gasphase rotational and vibrational spectroscopy has also been applied to the determination of barriers to interconversion in cyclohexene analogs. In these cases the barrier heights involved are 6 to 10 kcal/mol, and their determination represents extrapolation above the point for which data are available. This results in barriers whose uncertainty may be several hundred reciprocal centimeters, or ca. 10 to 15%. On the other hand barriers in this range may be determined by NMR techniques, and this offers an opportunity to compare the results determined from two very different techniques. 1,4-Dioxene may be considered a pseudo-five-membered-ring molecule. The two low-frequency out-of-plane ring vibrations are shown in Fig. 38 (91). The third out-of-plane skeletal vibration

Fig. 38. Ring-twisting (T) and ring-puckering ( 6 ) coordinates for 1,4-dioxene. The third out-of-plane ring mode is a twisting about the double bond. (Reproduced with the permission of the American Institute of Physics, from ref. 92.) is a twisting about the C=C double bond which is somewhat higher in frequency and is treated as a small-amplitude harmonic vibration. The far-IR spectrum of 1,4-dioxeneI which is rather rich in detail, is shown in Fig. 39. The prominent features between 150 and 200 cm-’ are 0-branch transitions of a-c hybrid bands involving primarily Avb = +1 selection rules, where vh is a serial quantum number for the bending ( 6 ) mode. The weak series of ()-branch transitions from 90 to 125 cm-’ represent difference bands, where Avb = -1 and Avt = +1, with vt a serial quantum number for the twisting mode. The weak, featureless adsorption near 300 cm-’ represents overlapped b-type-bands corresponding to Avt = +1 transitions. However, since the equilibrium conformation has C2 symmetry ( 9 2 ) , a twisted conformer, the twisting vibration is totally symmetric and the resulting hotband structure is evident in the Raman spectrum (93) (Fig. 39). The combination of far-IR and Raman data allow unambiguous assignment of the transitions. The sum of a bending 0 branch and

Y

85

I

I

I 90

I

150 160

I

I IeO

I

190

1

XK)

I

PI0

I 95

I 105

I

1

1

I

115

(a)

220 230

I00 110 FREOUENCY (CM-')

I

FREOUENCY (CM- 1

no

120

I

(C)

FREOUENCY (CM-3

(dl

WAVENUMBER CM-'

300

250

Fig. 39. Far-IR (a-d) and low frequency Raman ( e ) s p e c t r a of 1,4-dioxene. ( a ) Survey of t h e bending r e g i o n (230-150 cm-l) (c) d i f f e r e n c e band r e g i o n (130-80 cm-' a t 8 m and 10 t o r r ( d ) t w i s t i n g band r e g i o n (3I5-250 cm-l) a t 4 m and 1 0 t o r r ( e ) Raman spectrum of t w i s t i n g band r e g i o n showing h o t band s t r u c t u r e . (Reproduced w i t h t h e permission of t h e American I n s t i t u t e of P h y s i c s ) (References 91 and 9 3 ) .

I

10.11

8.9 289.

-

6,;

4,E

2,:

9 297.4 -

191.3

0.

0

Fig. 40. Assignment of the far-IR and Raman transitions for 1,4-dioxene. There are numerous checks on the internal consistency of the assignment. (Reproduced with the permission of the American Institute of Physics, from ref. 93.) 159

i

( a ) P o t e n t i a l energy s u r f a c e f o r 1,4-dioxene and a c r o s s s e c t i o n a l o n g t h e minimum energy F i g . 41. p a t h f o r i n t e r c o n v e r s i o n . The dashed l i n e of t h e s u r f a c e i n d i c a t e s t h e minimum energy p a t h t o i n t e r c o n v e r s i o n . ( b ) The energy ( c m - l ) along t h i s p a t h .

4000

THOMAS B. MALLOY, LESSLIE E. BAUMAN, AND L. A. CARREIRA

161

d i f f e r e n c e band i n t h e far-IR spectrum must e q u a l one of t h e Raman Q branches ( t w i s t i n g t r a n s i t i o n s ) . The assignment of t h e t r a n s i t i o n s i s shown i n F i g . 40. The d a t a were f i t t e d by l e a s t s q u a r e s v a r i a t i o n of t h e f i v e p o t e n t i a l c o n s t a n t s i n eq [20]. Figure 41 i n d i c a t e s t h e determined p o t e n t i a l energy s u r f a c e . I t i s s e e n t h a t t h e two e q u i v a l e n t t w i s t e d forms i n t e r c o n v e r t v i a a metastable b e n t (C,) form r a t h e r t h a n v i a t h e p l a n a r conformat i o n . The minimum energy p a t h i s denoted by t h e dashed l i n e . F i g u r e 4 1 a l s o shows a p l o t of t h e energy f o r t h e i n d i c a t e d minimum energy p a t h . The shape of t h e p o t e n t i a l i n t h e second minimum corresponding t o t h e b e n t (C,) conformation i s i n d i c a t e d by a dashed l i n e . I t should be emphasized t h a t no d i r e c t d a t a have been o b t a i n e d i n t h i s w e l l . The s p e c t r o s c o p i c t r a n s i t i o n s were observed f o r t h e t w i s t e d (Cs) conformation. While e x t r a p o l a t i o n of t h e curve t o e s t i m a t e t h e b a r r i e r h e i g h t i s a r e a s o n a b l e approximation, i n no way are t h e d a t a d e f i n i t i v e a s t o t h e energy of t h e second minimum. The v a l u e o f A E , t h e energy d i f f e r ence between t h e two forms, when s u b j e c t e d t o a s t a t i s t i c a l a n a l y s i s of t h e l e a s t s q u a r e s f i t t i n g procedure, i s found t o be u n c e r t a i n by t h e amount of i t s own magnitude. With a l l t h e s e c a u t i o n s it i s s t i l l p o s s i b l e t o e s t i m a t e t h e b a r r i e r t o i n t e r c o n v e r s i o n from t h e p o t e n t i a l s u r f a c e . Subs e q u e n t study of t h e temperature dependence of t h e NMR spectrum y i e l d e d a b a r r i e r w i t h i n 1 kcal/mol o f t h a t determined from t h e v i b r a t i o n a l d a t a (94). Considering t h e d i f f e r e n t approximations involved and t h e f a c t t h e experimental d a t a were o b t a i n e d f o r t h e molecule i n d i f f e r e n t p h a s e s , t h e agreement i s s a t i s f a c t o r y .

IV.

SUMMARY OF I N V E S T I G A T I O N S OF SMALL-RING MOLECULES

This s e c t i o n i s an a t t e m p t a t summarizing t h e r e s u l t s on r i n g molecules s t u d i e d i n t h e g a s phase by low-frequency v i b r a t i o n a l and r o t a t i o n a l spectroscopy. W e have i n c l u d e d o n l y t h o s e molecules s t u d i e d by t h e s e techniques and o n l y t h o s e f o r which some d a t a i n v o l v i n g t h e low-frequency modes were o b t a i n e d . W e have n o t , f o r example, included d e t e r m i n a t i o n o f molecular symmetry based on s e l e c t i o n r u l e s i n t h e mid-IR o r mid-Raman spect r a . When w e r e f e r t o mid-IR o r mid-Raman s t u d i e s i n T a b l e 4 , w e i n c l u d e only t h o s e s t u d i e s i n v o l v i n g ring-puckering band progressions. The following a b b r e v i a t i o n s have been used: FIR far-IR MIR mid-IR R low-frequency Raman MR mid-Raman MW microwave Where a p p l i c a b l e , b a r r i e r s have been g i v e n i n r e c i p r o c a l c e n t i m e t e r s . The following conversion f a c t o r s may prove u s e f u l : 1 kcal/mol = 350 cm-’

=

4.184 kJ/mol

Formula

-

ethylene ozonide

fluoroethylene ozonide

Name

3,3-difluorooxetane

vinylene carbonate

1I 0

CHpOCOCHp

0

-

II

CH2CCH20

6-propiolactone (2-oxetanone) ethylene carbonate

3-oxetanone

I

kH2CF2CH2

0

H

CWHOCO

-

CF2SCF2S

1,1,3,3-tetrafluorodithiethane CHpSiH2CHpSiHp 1,3-disilacyclobutane

OC HpOCH20

-

F

I

kH20CHO

Structure

One-dimensional potential function determined from both MW and FIR. Planar. One-dimensional potential function determined from both FIR and MW data. Planar. Isotopic species in Mw. Planar. Spectrum assigned in excited states. Half-chair. Splitting characteristic of doubleminimum potential function observed in MW spectrum

FIR, Mw

MW

MW

FIR, MW

One-dimensional, doubleminimum potential function barrier 87 cm-’ , deuterated species (see text). Planar, excited states assigned. Isotopic species.

Half-chair ring. Several isotopic species. Planar, harmonic.

Half-chair ring, fluorine axial.

Comments

FIR, MIR, R, MR

FIR

Mw

Mw

Techniques

Table 4 Summary of Investigations of Small-Ring Molecules

115

114

6,112,113

110,111

108,109

68,69

107

104-106

103

References

P (r, w

0

II

dHzCCH23

MW

propylene ozonide

trimethylene sulfoxide

CH3 iHzCH2SdH2

C3H6S

C3H60S

CHzCHzSCH2

0

II

-

I

~CH~OCH~

C3H603

F I R , MW

1,3-dioxolane

trimethylene sulfide

Mwf

R

F I R , MIR,

Mw

F I R , MIR, MW, R , MR

kH20CH20dH2

trimethylene oxide

3H602

!

C

FIR

3H6O

1-pyrazoline

M I R , MW

F I R , MW

dHzN’NCHzdH2

2-oxazoline

3-thietanone

3H6N2

C ~ H ~ N O =CH~

C3H40S

One-dimensional potential function from vibrational and MW data. Barrier 274 cm-1. Isotopic species.

Puckered ring with 0 equatorial. Isotopic species.

28 ,40,42, 43,122-124

121

One-dimensional potential 41,51 function determined from both F I R and MW data. Planar (see text). One-dimensional potential 116 function from M I R band progressions and MW data. Planar. One-dimensional potential 117,118 function. Barrier 113 cm-’. One-dimensional potential 14,16,27 function from F I R and MW 29-31,34data. Several isotopic 39. 63-66 species. Extensive vibration-rotation interaction studies. Barrier 15.3 cm-’ (smaller than zero-point energy) (see text). Pseudorotational barrier 45 81-83 ,119 cm-l C, ca. 10cm-1 lower in energy than C2. Barrier to planarity is much higher. Half-chair, methyl equatorial 120 Isotopic species.

0

w

Structure

kH2CH2CF2dH2

Formula

C4H6F2

FIR, MIR, MW

FIR, R

FIR, MIR, R, M R , MW

trimethylene selenide

trimethylene imine

silacyclobutane

1,l-difluorocyclobutane

MW

FIR, MW

1,1,2,2-tetrafluorocyclo- MW, FIR butane 1,4-dioxadiene FIR

Techniques

Name

Table 4 Continued

One-dimensional, doubleminimum potential function from variation of rotational constants and inversion

One-dimensional, doubleminimum potential function from FIR and MW data. Barrier 373 an-’. One-diminsional, asymmetric, double-minimum potential function. Barrier 441 cm-’, AE=90 cm-’. Assignment confirmed by Raman study. N - D species (see text). One-dimensional, doubleminimum potential function. Barrier 440 cm-l. SiD2 species. Nonplanar based on MW data. No barrier determined. One-dimensional potential function. Planar. Evidence for interaction with ringtwisting mode. Planar, harmonic.

Comments

132

6,131

54,130

128,129

7,8,26,127

23,67

125,126

’References

2,5-dihydrofuran

CH7 kH=CHCH20kH2

C4H60

CqH602

C4H602

qH 6O

3-methyleneoxetane

CHCHCH20CH2

0

II

CH2CH2COCH2

1

-

CH=CH-OCH2CH2

F I R , R , MW

F I R , R , MW

1;4-dioxene

MW

F I R , MIR

MW, R

F I R , MIR, R

MW, F I R

F I R , MW, M IR

MW

3,6-dioxabicyclo[3.1.0] hexane

y-butyrolactone

2,3-dihydrofuran

I

I1

n OCH2CCH2

1 U

CH=CHCH2SiF2kH2 1,l-difluorosilacyclopent-3-ene C B H2 cyclobutanone

CqH60

C4H60

C4HbF2Si

133

One-dimensional, asymmetric single-minimum, potential function from F I R data confirmed by Raman study. Boat conformation determined from MW data (see text). Two-dimensional potential surface determined from F I R and Raman data. The two equivalent C 2 (from MW) con-

91-93

55-57

6,46,53,54, One-dimensional potential 71 ,118 function. Planar. Spectra show evidence for interaction between ring-puckering and ring-twisting modes ( s e e text). One-dimensional, double14,118,137minimum potential function. 139 Barrier 83 cm-’. 140 Nonplanar.

One-dimensional potential 16,42-44, function. Barrier 7.6 cm-’ 134 (less than zero-point energy). Several isotopic species. 135,136 One-dimensional potential function. Planar.

splittings. Barrier 241 cm-’. Planar.

Formula

F

I

CH=CHCH2NHCH2

I

I

CHzCHzCHCHz

m CHzCHzCHCH2 I C1

-

Br

I

dH2CH2CHCH2

CH=CHCH2SCH2

0 CH3

II I

CHzCOCH

7

-

Structure

One-dimensional, asymmetric, 23,67,151 double-minimum potential function with a barrier of the order of the zero-point energy. N - D species studied,

FIR, R, MW

2,5-dihydropyrrole

147,148, 150

Same as bromocyclobutane.

Rt Mw

147-150

144-147

14,138

14,118,143

fluorocyclobutane

One-dimensional potential function. Planar. One-dimensional, doubleminimum potential function from Raman. Barrier 325 cm-l. One-dimensional, asymmetric, single-minimum potential function (FIR, R ) corresponding to a puckered ring with the bromine equatorial (MW) . Same as bromocyclobutane.

FIR, R, MW

MW, FIR, R

bromocyclobutane

References

formers interconvert via metastable C, conformers (see text). Planar. 141,142

Comments

chlorocyclobutane

MIR, R

2,3-dihydrothiophene

FIR

FIR, MR

MW,

Techniques

2,5-dihydrothiophene

6-butyrolactone

Name

Table 4 Continued

C4H80

FIR, MIR FIR, R

silacyclopent-2-ene

cyclobutyl amine

R t MW

FIR, MIR, R

silacyclopent-3-ene

FIR, MIR,

Half-chair conformation.

MW

selenacyclopentane

One-dimensional potential function. Planar. SiD2 species. One-dimensional potential function. Planar. One-dimensional, asymmetric, single-minimum potential function.a ND2 species. Two-dimensional surface determined from FIR and Raman data. The two equivalent half-chair forms (from MW) interconvert via the planar conformationb

Half-chair conformation.

.

MW

MW

FIR, MW

MIR, R

and assignment confirmed by Raman study (see text). One-dimensional, doubleminimum potential function. Barrier 515 cm-l. C4Dg species studied. Evidence for mixing of CH2 motion (see text) Twisted and bent forms interconvert with a small pseudorotational barrier rather than via the planar conformation (see text). Half-chair, methyl equatorial. Isotopic species.

tetrahydrothiophene

kHzCH2GeH2CHzdH2 germacyclopentane

CH3

CH3

butylene ozonide

I

~-cH-o-cH-~

I

tetrahydrofuran

cyclobutane

hH2CH20CH2CH2

I

CH2CH2CH2CH2

m

157-159

156

26,155

8,26 ,118, 154

153

152

120

119

80,81,87,

21,24,25, 75

Formula

Name

0

II

CH=CHCCH2kH2

methylenecyclobutane

cyclopentene

MW, MIR, R

MW, FIR

FIR, MW

2-cyclopenten-1-one

cyanocyclobutane

FIR, MW

FIR, R, MW

Techniques

3-cyclopenten-1-one

kH2CHzSiH2CH2tH2 silacyclopentane

Structure

Table 4 Continued

One-dimensional, asymmetric, single-minimum potential function from FIR. Puckered ring with CN equatorial (MW). One-dimensional, doubleminimum potential function. Barrier 232 cm-’. Isotopic species. Evidence f o r interaction between ring-puckering and ring-twisting (see text). One-dimensional, doubleminimum potential function. Barrier 140 cm-’. Isotopic species (MIR).

(see disucssion of cyclopentanone in text). Barrier 1454 cm-’. Same as germacyclopentane.b Barrier 1414 cm-’. One-dimensional potential function. Planar. Isotopic species in MW. One-dimensional potential function. Planar.

Comments

17,45,124

10,14,16, 32,54,7074,118,172

147,170, 171

167-169

163-167

18,160-162

References

al \D

~

C5H10

C gH 8 0

C5H80

CH3 w

H

2 0 [3

1.01-

3-oxabicyclo[3.1.0]hexane

6-oxabicyc hexane

2-methyl-4 5-d hydrofuran

cyclopentanone

-

kH2CH2CH2CH2dH2 cyclopentane

CH=CHCH2NHCH2CH2 1,2,3,6-tetrahydropyridine

\sI

dHCHCH2CH2dH2

6-thiabicyclo[ 3.1.01 hexane

CH2 &H=CHCH20CH2tH2 3,4-dihydropyran

\I

kHCHCH20dH2

0

7

1

m CH=COCHzCH2

0

kH2CH2CCH2CH2 /I

MIR, R

MW

Mw

FIR, R

MW

R

R , MW

F I R , MW,

FIR,

FIR

F I R , MW

55% half-chair NH equatorial to 45% half-chair NH axial at room temperature. N - D species. Pure pseudorotation. Barrier to planarity 1824 cm-l.

.

Two-dimensional surface for interconversion of halfchair conformation (see 1,4dioxene) Boat conformation.

Half-chair conformation.

Same as 3,6-dioxabicyclo[ 3.1.0 1hexane.

Two-dimensional potential energy surface determined from F I R data. The two equivalent half-chair conformers (from MW) interconvert via the planar conformation. Several deuterated species (see text) . One-dimensional, doubleminimum potential function. Barrier 98 cm-l. Same as 3,6-dioxabicycloL3.1.0Ihexane.

22 ,84,86, 176

175

174

91,93

173

55,56,61

23,55,56 60

6

6,89,90

0

P 4

I

II

I

R

FIR, R, MW

CH2

\/

I

bicyclo [ 3-1-01 hexane

CHCHCH2CHzCHz

C6H10

MW, R

& H = C H C H ~ C H Z C H ~cyclohexene ~H~

C6H1 0

FIR, R

2-oxabicyclo[3.2.Olhept-6-ene

I I CH=CH

&H- CHOCH2&H 2

C6H80

FIR, MW

Mwr

&HCHCH2CH=CHdH2 7-oxabicyclo[4.1.0]hept-3-ene

0

I

CH=CHCCH2CH2CH2 2-cyclohexen-1-one

FIR, R

&H=CHCH2CH=CHdH2 1 ,4-cyclohexadiene

Mw

FIR

Techniques

R, Mw

1,2-dimethylenecyclobutane

3,3-dimethyloxetane

Name

CH7 CH7 eH2CH=CHCH=CHdHz 1,3-cyclohexadiene

CCH2CH2C

3

CH3

7

I

,-C

Structure

CgHg0

CgHEO

CgH8

C6H8

C6H8

C5H100

Formula

Table 4 (Continued)

Half-chair interconverts via half-boat (see 1,4-dioxene). Same as 3,6-dioxabicyclo[3.1.0]hexane (see text).

All ring atoms coplanar except for Cs(MW). Barrier to planarity 935 cm-1 (R). Slightly anharmonic potential function (FIR). Boat conformation ( M w ) . Single-minimum, asymmetric potential function.

.

Half-chair conformation ( M w ) . One-dimensional, doubleminimum potential function (R) Barrier 1099 cm-l. Planar.

One-dimensional, doubleminimum potential function. Barrier 46 cm-l. Planar (see text).

Isotopic species. Twodimensional treatment.

Comments

93,186, 187 55,56,67

185

183,184

181,182

179,180

178,179

52

177

References

BH2SHBH2H

B2H6S IR

p- aminodiborane

One-dimensional, asymmetric, single-minimum potential function. One-dimensional potential function. Planar. Isotopic species. One-dimensional potential function. Planar. Isotopic species. One-dimensional potential function. Isotopic species.

Half-chair conformation.

192

191

189,190

185

188

aThe potential function reported has a second shallow minimum. However, this is determined by extrapolation. Since there is no direct evidence for a second minimum, and because the extrapolated second minimum is quite shallow, we have designated this as a single-minimum function. bThe potential surfaces derived have very shallow minima at puckered conformation. However, the puckering angle is quite small, and the uncertainty in the potential parameters is such that the shallow minima may well not be real. Consequently, we have termed the interconversion as occurring essentially via the planar conformation.

IR

IR, R

FIR, R

MW

p-mercaptodiborane

diborane

BH2HBH2H

B2H6

m

CH-CHCH2CH; I ~2H bicyclo[3.2.0]hept-6I I ene CH=CH

C7H10

methylenecyclopentane

172

CONFORMATIONAL BARRIERS I N SMALL RING MOLECULES

V.

CONCLUSIONS

W e have reviewed a p p l i c a t i o n s of gas-phase, low-frequency v i b r a t i o n a l spectroscopy and r o t a t i o n a l spectroscopy t o t h e determination of conformations, b a r r i e r s , and i n t e r c o n v e r s i o n pathways i n s m a l l - r i n g molecules. W e f e e l t h a t t h e s e t e c h n i q u e s have l e d t o some of t h e most a c c u r a t e l y determined b a r r i e r s i n t h e range of 0 t o 3 kcal/mol. We a r e , q u i t e o b v i o u s l y , propone n t s of t h e s e t e c h n i q u e s , and f e e l q u i t e stro’ngly t h a t , when a p p l i c a b l e , t h e s e should be t h e methods of choice f o r barrier d e t e r m i n a t i o n s i n t h i s range. We have, however, attempted t o be honest about t h e shortcomings o f some of t h e s e t e c h n i q u e s , and have t r i e d t o g i v e r e a s o n a b l e e s t i m a t e s of t h e u n c e r t a i n t i e s and sources of e r r o r . We f e e l t h a t i n most c a s e s we have been q u i t e c o n s e r v a t i v e i n t h e claims w e have made. I n some cases, f o r example, i n t h e d e t e r m i n a t i o n o f t h e puckering angle of a four-membered-ring molecule, e x t e n s i v e d a t a may be r e q u i r e d t o reduce t h e u n c e r t a i n t y . I t may be t h a t o t h e r t e c h n i q u e s , o r a combination of gas-phase s p e c t r o s c o p i c d a t a and d a t a from o t h e r t e c h n i q u e s , might l e a d t o a more c e r t a i n d e t e r mination of t h i s q u a n t i t y . As mentioned i n o u r I n t r o d u c t i o n , w e excluded c o n s i d e r a t i o n of o t h e r t e c h n i q u e s , experimental and c a l c u l a t i o n a l , n o t through v a l u e judgment of t h e i r worth, b u t i n o r d e r t o c o n c e n t r a t e on t h e case a t hand. W e have n o t g i v e n a complete review of gas-phase spectroscopy, nor o f t h e s t e r e o chemistry of s m a l l - r i n g molecules, by any means. We have t r i e d t o c r i t i c a l l y examine t h e a p p l i c a t i o n of gas-phase spectroscopy t o small-ring molecules. Low-frequency spectrsocopy i s n o t l i m i t e d t o t h e s t u d y o f r i n g molecules, and t h e r e have been many a p p l i c a t i o n s t o l a r g e amplitude v i b r a t i o n s i n q u a s i l i n e a r molecules such as carbon suboxide, among o t h e r s , and t o s t u d i e s o f i n t e r n a l r o t a t i o n . It was n o t p o s s i b l e t o c o n s i d e r a l l of t h e s e t o p i c s h e r e .

APPENDIX I The experience of a number of chemists w i t h reduced masses i s l i m i t e d t o t h e reduced mass o f a t w o - p a r t i c l e system:

The v i b r a t i o n a l c o o r d i n a t e , a change i n t h e d i s t a n c e between mi and m2, does n o t appear i n t h e e x p r e s s i o n f o r p. Most s p e c t r o s c o p i s t s a r e aware t h a t t h e G m a t r i x elements corresponding t o , f o r example, t h e angle-bending c o o r d i n a t e f o r a t r i a t o m i c molec u l e depend on t h e v a l u e of t h e a n g l e . However, i n d e a l i n g w i t h small changes from t h e e q u i l i b r i u m v a l u e of t h e a n g l e , t h i s G matrix element i s taken t o be c o n s t a n t and e v a l u a t e d a t t h e e q u i l ibrium value.

173

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

On t h e o t h e r hand, f o r reduced mass depends on t h e s u i t a b l e quantum mechanical problem. The correspondence texts,

a l a r g e - a m p l i t u d e motion where t h e v i b r a t i o n a l coordinate, obtaining a k i n e t i c energy o p e r a t o r p r e s e n t s a i n most elementary quantum mechanics

E2 + - h2 -

d2 21.1 d 7

2u

[A1-2]

i s no l o n g e r v a l i d , s i n c e t h e r e s u l t i n g o p e r a t o r i s n o t Hermitian. However, a s p o i n t e d o u t by H a r r i s and co-workers ( 4 0 ) , one may u s e an o p e r a t o r of t h e form of [ A 1 - 2 ] w i t h t h e f o l l o w i n g j u s t i f i cation. I f

1-I =

-

u

[A1-3]

(XI

a new c o o r d i n a t e x may be d e f i n e d by a n o n l i n e a r c o o r d i n a t e transformation lA1-41 The c o o r d i n a t e ST has an e f f e c t i v e reduced mass t h a t i s c o n s t a n t and e q u a l t o t h e v a l u e of p ( x ) a t x = 0. The k i n e t i c energy o p e r a t o r is then

The c o o r d i n a t e SF i s t h e one r e f e r r e d t o throughout t h e t e x t . The " t r u e " p o t e n t i a l f u n c t i o n i s r e l a t e d t o t h i s by u s i n g a cons t a n t reduced mass Hamiltonian by t h e n o n l i n e a r t r a n s f o r m a t i o n [A1-4]. I n p r a c t i c e t h i s i s n o t a s e r i o u s problem. B a r r i e r h e i g h t d e t e r m i n a t i o n s a r e o n l y v e r y s l i g h t l y a f f e c t e d ( a few r e c i p r o c a l c e n t i m e t e r s ) . The geometry c o r r e s p o n d i n g t o t h e minimum energy i s o n l y s l i g h t l y a f f e c t e d (ca. +lo). Wilson, Decius, and Cross ( 3 ) r e f e r t o a p r o c e d u r e f o r obt a i n i n g a quantum mechanical k i n e t i c energy o p e r a t o r , g i v e n i n a t e x t by Kemble ( 1 9 3 ) . The r e s u l t f o r a molecule w i t h a s i n g l e l a r g e - a m p l i t u d e mode i s

T=*

2

2

d_

d-+

dx 9P(x) dx

V'(x)

[Al-61

where g p ( x ) ( = l / p ( x ) ) i s t h e G m a t r i x element c o r r e s p o n d i n g t o ring-puckering and V ' ( x ) i s a " p s e u d o p o t e n t i a l . " The pseudop o t e n t i a l f o r ring-puckering i s g e n e r a l l y a slowly varying f u n c t i o n of x , and may be n e g l e c t e d o r absorbed i n t o t h e e f f e c t i v e p o t e n t i a l f u n c t i o n . I n g e n e r a l t h e o p e r a t o r i n [A1-5] i s q u i t e a d e q u a t e , and [A1-6] s h o u l d be used o n l y i f t h e r e i s some

174

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

p r e s s i n g need t o t a k e i n t o a c c o u n t s m a l l d i f f e r e n c e s i n p o t e n t i a l functions (118). I n p r a c t i c e t h e p o t e n t i a l f u n c t i o n i n a d i m e n s i o n l e s s coord i n a t e ( s e e Appendix 11) i s t h a t which i s determined from t h e e x p e r i m e n t a l d a t a . Except f o r s m a l l changes a r i s i n g from t h e n o n l i n e a r i t y of [ A l - 4 1 , t h e d e t e r m i n a t i o n of b a r r i e r h e i g h t s i s e n t i r e l y independent of model c a l c u l a t i o n s of a reduced m a s s . The b a r r i e r h e i g h t i s given by b a r r i e r =-

A B ~ 4

IA1-71

i n terms of t h e reduced c o o r d i n a t e Z (eq. [ 1 6 ] ) . The puckering a n g l e , however, does depend on t h e reduced mass. For t h e p o t e n t i a l f u n c t i o n of eq. [ 1 6 ] V = A(Z4

+

[A1-8]

BZ2)

w i t h B < 0. The v a l u e s of Z c o r r e s p o n d i n g t o t h e minima a r e [A1-9] To c a l c u l a t e a puckering a n g l e , w e r e q u i r e t h e d i s t a n c e 1x1 corresponding t o t h e minimum ( a c t u a l l y IF]), [Al-101 which r e q u i r e s knowledge of p a t x = 0. T h i s v a l u e of p depends on t h e model used f o r t h e v i b r a t i o n . P a r t i c u l a r l y i f ring-puckeri n g i n v o l v e s mixing w i t h methylene r o c k i n g modes, 1-1 may change by ca. 20 t o 30% o r more ( 7 5 ) . Consequently, u n l e s s d a t a are a v a i l a b l e i n d i c a t i n g t h e e x t e n t of mixing of CH2 o r o t h e r lowfrequency modes, puckering a n g l e s d e r i v e d i n t h i s f a s h i o n may be somewhat u n c e r t a i n . However, t o r e i t e r a t e , t h i s does not a f f e c t t h e d e t e r m i n a t i o n of b a r r i e r h e i g h t s .

APPENDIX I1 The most widely used p o t e n t i a l f u n c t i o n f o r symmetric r i n g puckering v i b r a t i o n s i s t h e mixed q u a r t i c - q u a d r a t i c , V = ax4 + b x 2 , where a and b a r e t h e dimensioned p o t e n t i a l c o n s t a n t s . The one-dimensional wave e q u a t i o n t h a t must b e s o l v e d f o r t h e energy levels is

-hq-+ 2

2

2p d x

(V

-

E)J, = 0

[A2-21

THOMAS B. MALLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

175

where p is the reduced mass for the vibration, which is assumed to be constant (see Appendix I). For many calculations u is not known, and the dimensioned equation cannot be solved. This problem is circumvented by removing the dependence on the reduced mass by means of a linear transformation to a dimensionless coordinate 2. The dimensionless or reduced potential constants and energy levels can then be calculated without explicit knowledge of the reduced mass. Many different transformations have been used, resulting in a wide variety of potential constants, making it difficult to compare potential functions. The relationships between the various reduced potential constants and the dimensioned potential constants are given below. The transformations have been reviewed by Laane ( 4 9 ) and by Gibson and Harris (112). (Note: Gibson and Harris used the dimensioned potential V = a x 2 + b x 4 . ) The first two transformations are of the type used by Ueda and Shimanouchi (46). The first is the most widely used transformation, where [A2-3] The wave equation in reduced form is now [A2-4] where

v

= A ( Z ~+ B Z ~ )

[A2-5a]

The wave equation is solved for the eigenvalues 1, and these are related to the energy levels by the scale factor A : E = AA

so h =

(3)

2/3

a-'13E

[A2-61

The eigenvalues A have been tabulated by Laane ( 4 9 ) for many values of B . When the potential is nearly harmonic, it is more convenient to use the second transformation, [A2-7]

176

CONFORMATIONAL BARRIERS I N SMALL R I N G MOLECULES

The d i m e n s i o n l e s s wave e q u a t i o n i s

where

[A2-9~] and b

= ($)1/2

-1/2

E

[A2-9d]

These reduced c o n s t a n t s are r e l a t e d t o A , B , and h as f o l l o w s :

S i m i l a r t r a n s f o r m a t i o n s , which d i f f e r by o n l y a f a c t o r o f 2 i n t h e momentum t r a n s f o r m a t i o n , have been used by Chan and coworkers, ( 4 7 ) . I n t h e f i r s t of t h e s e t r a n s f o r m a t i o n s [A2- 11] The wave e q u a t i o n becomes

where

V =

Arl (2:

Arl = (%)-2/3 7&2

rl=

($)113

+

~2:)

a1/3 = 4-2/3 A

.-2/3

b = 41/3 B ,

[A2- 13a ] [A2-13b]

[A2-13~]

THOMAS B. MALLOY, L E S L I E E . BAUMAN, AND L. A. CARREIRA

177

[A2- 13d]

In the second transformation [A2-14]

The wave equation is now 4

3

+

(Ac

-

622

-

= 0

[A2-15]

where [A2- 16al [A2-16b]

IA2-16~1

Chan and co-workers have also used a transformation in which a is a measure of the anharmonicity, varying from 0 for a harmonic oscillator to 1 for a quartic oscillator:

The wave equation reduces to [A2-181

178

CONFORMATIONAL BARRIERS IN SMALL RING MOLECULES

Eigenvalues have been tabulated for many values of ci (47). The dimensioned constants can be found from the reduced constants if p is known. The relations are as follows: I.

b' = ($-)d2L3

[A2-20a]

11. 111. IV

.

[A2-20d] tA2-20eI

V.

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P. S. MjiJberg, W. M. Ralowski, S. 0. Ljunggren, and J. E. BEickvall, J. Mol. S p e c t r o s c . , 6 0 , 1 7 9 ( 1 9 7 6 ) . S. Chao, T. K. Avirah, R. L. Cook, and T. B. Malloy, Jr., J. P h y s . C h e m . , 8 0 , 1 1 4 1 ( 1 9 7 6 ) . T. H. Chao and J. Laane, J. Mol. Spectrosc., 6 7 , 000 (1978).

177.

J. A. Duckett, T. L. Smithson, and H. Wieser, J. Mol. Spectrosc.,

6 9 , 159 (1978).

THOMAS B. MALtLOY, LESLIE E. BAUMAN, AND L. A. CARREIRA

178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188.

189. 190. 19i. 192. 193.

S . S. B u t c h e r , J. C h e m . P h y s . ,

185

4 2 , 1830 ( 1 9 6 5 ) .

L. A . C a r r e i r a , R. 0. C a r t e r , and J. R. D u r i g , J . C h e m . P h y s . , 59, 812 (1973). J. Laane and R. C. L o r d , J. Mol. S p e c t r o s c . , 3 9 , 340,

(1971). Manley and J. K. T y l e r , C h e m . Commun., 6 , 382 (1970). L. A . C a r r e i r a , T. G. Towns, and T. B . Malloy, Jr., 70, 2273 ( 1 9 7 9 ) . T. B. Malloy, J r . , J. C h e m . P h y s . , 6 5 , 2538 ( 1 9 7 6 ) . S . Chao, T. B. Malloy, J r . , and R. L. Cook, J . C h e m . P h y s . , 6 8 , 4027 ( 1 9 7 8 ) . J. R. V i l l a r r e a l and J. Laane, J . C h e m . P h y s . , 6 8 , 3298 (1978) L. H. S c h a r p e n , J. E . W o l l r a b , and D. P. Arnes, J . C h e m . P h y s . , 4 9 , 2368 ( 1 9 6 8 ) . T. Ogata and K. Kozima, B u l l . C h e m . SOC. Jpn., 4 2 , 1263 (1969). J . R . D u r i g , Y . S. L i , and L. A. Carreira, Chem. P h y s . , 5 7 , 1896 ( 1 9 7 2 ) . W. C. P r i n g l e , J r . , a n d A . L. M e i n z e r , J. C h e m . P h y s . , 5 7 , 2920 ( 1 9 7 2 ) . L. A . C a r r e i r a , J. 0. Odom, and R. D u r i g , J . C h e m . P h y s . , 5 9 , 4955 ( 1 9 7 3 ) . W. C . P r i n g l e , C . A p p e l o f , and K. W. J o r d a n , J . Mol. S p e c t r o s c . , 5 5 , 351 ( 1 9 7 5 ) . A . S. Gaylord and W. C. P r i n g l e , J r . , C h e m . P h y s . , 59, 4674 ( 1 9 7 3 ) . E . C. K e m b l e , F u n d a m e n t a l P r i n c i p l e s of Q u a n t u m Mechanics, M c G r a w - H i l l , N e w York, 1937. S. A.

.

J.

J.

J.

Topics in Stereochemisty, Volume11 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1979 by John Wiley & Sons, Inc.

Stereochemical Aspects of Phosphorus-ContainingCyclohexanes BRUCE E. MARYANOFF Chemical Research Department, McNeil Laboratories, Fort Washington, Pennsylvaniu

ROBERT 0. HUTCHINS Department of Chemistry, Drexel University, Philadelphia, Pennsylvania

CYNTHIA A. MARYANOFF Department of Chemistry, Princeton University, Princeton, New Jersey I. 11.

111.

. . . . . . . . . . . . . . . . . . . . . 189 Applications of N M R Spectroscopy . . . . . . . . . . . 194 A. 1,3,2-Dioxaphosphorinanes . . . . . . . . . . . . 195 B. Phosphorinanes . . . . . . . . . . . . . . . . . . 202 C. 1,3,2-Diazaphosphorinanes . . . . . . . . . . . . 203 D. 1,3,2-Dithiaphosphorinanes . . . . . . . . . . . . 204 E. 1,3,2-Oxazaphosphorinanes . . . . . . . . . . . . 205 F. Lanthanide-Induced-Shift ( L I S ) Method . . . . . . 205 G. Conclusion . . . . . . . . . . . . . . . . . . . . 205 Introduction

Structure, Conformation, and Stereochemistry of Cyclohexane Rings Containing Tetracoordinate Phosphorus

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

206

187

188

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES A

.

1

.

..

206

l-Phospha-2,6,7-trioxabicyclo[2.2.2]octane

. . . . . . . 210

l.Phospha.2.8.

3

l-Phospha-2,7,8-trioxabicyclo[3.2.lloctane

5.

.

206

2.

. 4.

B

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

Polycyclic Phosphites

9.trioxaadamantane

l-Phospha-2,5,7-trioxabicyclo[2.2.llheptane

General Comments

..

211

. 212

. . . . . . . . . . . . . . . 213

. . . . . . . . . . . . 214 1. Structure and Conformation . . . . . . . . . . 214

1.3. 2.Dioxaphosphorinanes

2-0x0 Compounds

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

214

. . . . . . . 223 . . . . . . . . . 226

2-Thiono and 2-Seleno Compounds Miscellaneous P-X Compounds

2 . Stereochemistry of Electrophilic and Nucleophilic Substitution Reactions at Phosphorus

. . . . . . . . . . . . . . . . . . 228 2-0x0 Compounds . . . . . . . . . . . . . . . 228 2-Thiono and 2-Seleno Compounds . . . . . . . 250 . . . . . . . . . . . 255 1.2.Oxaphosphorinanes . . . . . . . . . . . . 255 1.3. 2.0xazaphosphorinanes . . . . . . . . . . 257 1.3. 2-Oxathiaphosphorinanes . . . . . . . . . 258 1.3. 2.Dithiaphosphorinanes . . . . . . . . . . 260 1.3. 2.Diazaphosphorinanes . . . . . . . . . . 262 Phosphorinanes . . . . . . . . . . . . . . . . 264

C . Other Phosphorinane Systems

. 2. 3. 4.

1

5. 6. D

.

. . . . . . . . . . . . . . . . 269 1. Cyclic Nucleotides . . . . . . . . . . . . . . 269 2. Cyclophosphamide and Related Compounds . . . . 276

Biological Aspects

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF IV.

Structure, Conformation, and Stereochemistry of Cyclohexane Rings Containing Tricoordinate Phosphorus A.

B. C. D.

E. F. V. VI.

........ 1,3,2-Dioxaphosphorinanes . 1,3,2-Dithiaphosphorinanes . 1,3,2-Diazaphosphorinanes . Phosphorinanes . . . . . . . Introduction

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

189

278

. . . . . . 278 . . . . . . 278 . . . . . . 283 . . . . . . 286 . . . . . . 288

Origin of the Axial Preference for Substituents on Phosphorus

. . . . . . . . . . . . . . . . . . 290

Stereochemistry of Compounds with Cyclohexane Rings Containing Pentacoordinate Phosphorus

. . . . . . . . 294 297 Overview . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . 298 References and Notes Addendum..

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

..................... I.

298 318

INTRODUCTION

Although diverse phosphorus-containing heterocycles had been synthesized as early as the late nineteenth century, work was still sparse in this area as recently as 1950 (1,2). The realization, around 1950, of the importance of phosphorus substances in biological processes resulted in intense activity in preparative organophosphorus chemistry and in an upsurge of research on structural and mechanistic problems (3-6). This post-1950 revolution in organophosphorus chemistry was followed by investigations of varied organophosphorus heterocycles, including probes into reaction mechanisms, stereochemistry, and spectroscopic properties. The accumulation of general organophosphorus stereochemical stJdies and spectral work, documented in some texts (5,6) and in numerous reviews (7-15), laid a foundation for conformational studies. A concern for the conformational analysis of organophosphorus compounds emerged in the late 1960s, succeeding the major surge in conformational research, which occurred between 1950 and 1965 (16-23). Emphasis centered on the six-membered-ring (phosphorinane) (24) system, interest in which was heightened because of its presence in biologically important substances: (1) the cyclic nucleotides

0

W

P

10b

6a 6b 7a 7b 8a 8b 9a 9b 10a

5b

3a 3b 4a 4b 5a

Compound

x R5 H H H H H H H H H H H H H H H H H H H

0

0 0

0

0

0

0

H H H H H H H H H H H

R6

R4

H H H H H H H H H

R3

0 0

R2

H

R1

R7

0

0

0

0

0

0

0

= X'

R6

Table 1 L i s t of C o m p o u n d s a

R7

H H H H H H H

H

H H H H H H H H H H H H

R8

30 30 30 30 30 30 30 30 29a 29a 29a 29a 29a 29a 29a 29a 34 34 34 34

Reference

P

10

P

18b 19a 19b 2 Oa 20b 21a 2Lb 22a 2 2b 23a 2 3b 24 25 26 27 28 29 30 31a 31b

lla 1l b 12.3 12b 13a 13b 14b 15a 15b 16 17 18a

CH.2

CH2 CH2 CHZ

CH2 CH2 CH2

0

0

0

0 0

0

0 0 0 0 0

0

0

0 0

H

H H

H H

H

H H H

CH3 CH3

CH3 H H H H H

H

H H H H H H H H H

H

t-CqHg t-CqHg t-CqHg t-CqHg t-CqHg H CH3 H H

- (CH2 ) 3 0 -

- (CH2) 3 0 -

- (CH2) 30- (CH2 ) 30-

CH3 CH3 CH 3 CH 3 CH3 CH 3 CH3 CH3 CH3 CH3 CH3 CH3 H

H H

H

0 0

H H H

0

0

0

0 0

0

0

0

H H H H H H H H H H H H

H

H H

H

H H H H H H H H

H

H H H H H H H

H H H H H H H H H H CH3 H H H H H OH OH

H

H H CH3 H H

H

H H H

H

H H H

H H H

:i

H H

H

H H H H H H H H H H H H H H H H H

H

H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

40 40 40 42 42 43 43 43 43 43 43 43

PO

38 39 39 39 39

38

34 34 34 34 35 35 35 35 35 36 36 37 37

N

F

47 48a 48b 49a 49b 50a 50b 51a

32a 3% 33a 3% 34 35 36 37 38 39 40 41a 41b 42 43 44 45 46

Compound

s s

S

s

S S S S

S S

S S S

S

S

CH2 CH2 CH2 CH2 NCH 3 NCH 3 NCH 3 NCH 3 NCH 3 See t e x t See t e x t

X = X'

t-CqHg

1P

IP C6H5 CgH5 C6H5

1P 1P 1P

OCgH5 0

R2

t-CqHg

0 OC6H5

R1

H H H CH 3 CH3 CH3 CH3 CH 3

H H H H H

D

D

H H H H H H H H H

R3

H t-CqHg t-CqHg H H H H H

C6H5 C6H5 CH 3 CH3 t-CqHg H H H H H H H

D

D H H CH3 CH3 H H H

CH3 H CH 3 H

H H H H

CH3 H CH3 CH3

OH OH OH OH H

R6

H H H H H

R4

t-C4Hg t-CqHg t-CqHg t-CqHg H

R5

Table 1C o n t i n u e d

CH3 CH3 H H H

H H H

H H H H H H H

R7

H H H H H H H H

H H H H H H H

H H H H H H H H H

Ra

48 49 49 51 51 50 50 50

45 46 46 47 47 47 48 48

45

43 43 43b 43b 45 45 45 45 45

Reference

a

S

c1

1P

f X' 0 , NCH3 0 OCgH5 0, NCH3 S OCgH5 0, NC6H5 0 OCgH5 0, NH 0 N (CH2CHzCl)2. 0 , NH N(CH2CH2C1)2 0

x

lp = lone pair of electrons

52 53 54 55a 5 5b

51b

H H H H H H

CH 3

H H H CH3 CH3 H H H H H

H H H H H H

H H H H H H

H H H H H H

H 53 54 55 55

53

50

194

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'monophosphate (cyclic GMP), mediators of cell metabolism and proposed ubiquitous intracellular "second" messenger substances; (2) the antimetabolic, antitumor agent cyclophosphamide and its congeners; and (3) other pharmacologic agents (25). Certain biological aspects relating to phosphorinanes are discussed in Section 111-D. Over the past 15 to 20 years a voluminous, widely dispersed body of information has accrued on the stereochemical aspects of phosphorus-containing cyclohexane derivatives. This review attempts to draw these widespread data together, with a main concern for critical and historical assessment of relevant studies, rather than, necessarily, and exhaustive survey of the literature (covered up to mid-1977). We are particularly attentive to exposing key, general themes, and to indicating significant conclusions that develop from them. This chapter is divided into major segments treating (1) tricoordinate, (2) tetracoordinate, and (3) pentacoordinate compounds, with further subdivisions along structural and mechanistic lines, as required. A section on the application of nuclear magnetic resonance (NMR) spectroscopy to the study of organophosphorus stereochemistry precedes this, since a background in this subject is essential for dealing with stereochemical and conformational questions. Some stereochemical information on phosphorinanes has been collected in other reviews (5-8,15,26,27). To keep this chapter to an acceptable length, we avoid discussion of areas such as nonsix-membered rings, chiefly inorganic heterocycles, and benzofused or otherwise unsaturated molecules. Since X-ray structural data have already been organized and presented (15), we only refer to X-ray work briefly, in support of structural discussions

11.

APPLICATIONS OF NMR SPECTROSCOPY

Developments in NMR 'spectroscopy and conformational analysis have paralleled each other, and NMR probably provides more information about the shape of complicated molecules in solution than any other physical method (28). Both NMR chemical shifts and spin-spin coupling constants are very sensitive to the spatial arrangement of atans in a molecule, and both may be used effectively to elucidate molecular structure and conformation (28). This section discusses the use of NMR data in the analysis of various phosphorinane systems (see Table 1). Since several recent publications (7b,27,29) have also addressed this subject, this section mainly deals with overviews of empirical trends and generalizations along systemic lines, since each general system type has its own norms.

195

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

A.

1,3,2 ,-Di oxaphosphori nanes

The identification of isomeric cyclic phosphorus compounds can be assisted by proton, carbon-13, and phosphorus-31 chemical shift data. Fbr example, conformationally rigid molecules such as the highly biased chair systems 1-12 (Table 1) may be considered. In the isomers withan axial methoxy group on phosphorus ( l a , 3 a ) , the C4 carbons are shifted upfield relative to those of the isomers with an equatorial methoxy group ( l b , 3b) (cmpd, 613c): (la, 63.8), ( I b , 67.0), ( 3 a , 65.71, ( 3 b , 69.7). The same trend is followed by 31P chemical shifts also (see Table 2), Additionally, by comparing the 31P chemical shifts for two highly biased model compounds epimeric at phosphorus with the values for conformationally nonbiased analogs, the fraction of each conformer in the nonbiased system can be estimated (27). The 31P chemical shift trend is not without exception, even in relatively rigid systems: for example, A3IP 8a, 2.9; 8b;-1.3; 12a, 75.1; 12b, 74.4. The notion that the chemical shifts of axial protons on the carbons 8 to phosphorus are shifted downfield relative to the corresponding equatorial protons, when the (nonchalcogen*) group on phosphorus (phenyl excluded) is axial, is not general: for example, l a : R7, 3.49; Re, 3.94; 2a: R7, 3.91; Re, 3.59. Proton-proton, proton-phosphorus, and carbon-phosphorus coupling constants are more reliable for the study of molecular conformations than are chemical shift data. The angular dependence of JHH, Jpc, and JPH has been extensively studied (7b,13, 27,29), and this section is devoted to empirical interpretations of the available data. A.

Table 2 Chemical Shift Data

'H Chemical Shifts ( 6 , ppm downfield from TMs)

Compound la lb 2a 2b 3a 3b 8a 8b 13a 13b

Solvent R1

R2

CCl4 CCl4 CDCl3 CDCl3 neat neat CDCl3 6.90 CDC13 6.95 CDCl3 3.45 CDCl3 3.46

R3

1.41 1.39 3.87 4.39

R4

4.60 4.60 4.24 3.92

R7

R8

3.49 3.91 4.10 4.14

3.94 3.59 4.05 4.13 4.49 4.18

Reference 30

30 30 30

30 30 33 33 35 35

*Chalcogen refers to group VI of the Periodic Table just as halogen refers to group VII.

196

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

T a b l e 2 Continued B.

13C Chemical S h i f t s ( 6 , ppm d o w n f i e l d from TMS)

Compound

Solvent

OCH3

c4

c5

la lb 3a 3b 19a 19b 22a 22b 23a 23b 50a 50b 51a 51b

CDCl3 CDCl3 CDCl3

49.4 48.7 49.4 48.0

63.8 67.0 65.7 69.7 74.4 74.8 75.5 73.5 75.6 71.8 35.7 33.0 35.4 31.7

43.0 40.9 42.7 40.7 33.7 32.7 33.4 33.1 32.8 34.8 26.7 22.2 28.7 22.8

Compound 26 27 28 29 30

C.

CDCl3 unknown unknown C6H6 CgH6 C6H6 C6H6 C6D6 C6D6 C6D6 C6D6

33.9 37.1 35.9 39.3

c6

Reference

65.7 69.7 65.7 64.6 66.4 65.2 64.8 63.8 25.3 24.7 25.8 25.1

32 32 32 32 38 38 40 40 40 40 50 50 50 50

Solvent

c2,6

C3,5

C4

P-C

P-C-c

Reference

CHC13

27.0 25.2 24.4 21.7 24.9

23.7 24.0 24.2 25.3 23.7

28.6 28.7 28.6 28.7 28.2

11.2 20.4 26.7 23.7

10.0 19.3 27.0

43 43 43 43 43

CHC13 CHC13

CHC13 CHC13

31P Chemical S h i f t s ( 6 , ppm d o w n f i e l d f r o m 85% H3P04)

Compound S o l v e n t la lb 3a 3b 5a 5b 6a 6b 7a 7b

neat neat neat neat C 6H 6 C6H6 C6H6 C6H6 C6H6

C6H6

31P 129.3 132.0 127.2 131.5 -7.06 -4.98 3.49 6.58 19.4 28.0

Ref Compound S o l v e n t 32 32 32 32 29a 29a 29a 29a 29a 29a

8a 0b 9a 9b 10a 10b lla llb 12a 12b

CDCl3 CDCl3 unknown unknown unknown unknown unknown unknown unknown unknown

31P

Reference

3.1 -1.2 55.5 59.0 63.6 67.8 86.5 94.6 75.1 74.4

33 33 34 34 34 34 34 34 34 34

B.

E.

197

MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF T a b l e 2 Continued

Compound S o l v e n t 15a 15b 16 17 18a 18b 19a 19b 20a 20b 21a 21b 2 2a 22b 23a 2 3b 24 25 31a 31b 32a 3 2b 33a 3 3b

C 6D 6 C6D6 CDCl3 CDCl3

C 6H 6 C6H6 C6H6 C6H6 CgH6 C6H6 C6H6 C6H6 C6H6 C6H6 C6H6 c6 H6 C6H6 C6H6 CDC13 CDC13 CDC13 CDC13 CDC13 CDCl3

lP 129.3 137.8 126.0 126.5 57.2 57.6 4.5 -1.0 64.2 61.2 67.7 66.0 19.0 24.5 92.0 96.9 131 123 28.8 31.1 29.4 31.9 64.6 57.7

Ref Compound S o l v e n t 35 35 36 36 37 37 39 39 39 39 39 39 40 40 40 40 42 42 43 43 43 43 43b 43b

34 35 36 37 38 39 40 44 45 46 47 48a 48b 49a 49b 50a 50b 51a 5 lb 55a 55b

C6H6 C6H6 C6H6 C6H6 CgH6 C6H6 CgH6 C6D6 CgD6 CDCl3 C6D6 C6H6 C6H6 C6H6 C6H6 CgD6 C6D6 CgD6 CgD6

unknown unknown

'P

Reference

131.6 122.6 91.9 81.3 85.8 94.3 108.8 28.9 40.0 97.3 125.0 55.1 47.3 37.0 63.5 145.2 154.2 139.5 146.5 11.0 13.4

45 45 45 45 45 45 45 47 48 48 48 49 49 51 51 50 50 50 50 55 55

Coupling c o n s t a n t s c h a r a c t e r i s t i c o f c h a i r c o n f o r m a t i o n s c a n b c g l e a n e d by e x a m i n a t i o n o f s y s t e m s 1 - 3 , which are anancomeric due t o e i t h e r a n a n n e l a t e d r i n g o r 4 , 6 - d i m e t h y l substit u t i o n . T y p i c a l t h r e e - b o n d c o u p l i n g c o n s t a n t s i n c l u d e 3JHaHa, which r a n g e s from 1 1 . 2 t o 1 1 . 8 Hz, ' J H ~ H which ~ , varies from 2.2 t o 5.5 Hz, and 3Jp0CHa, which i s t y p i c a l l y 1 . 7 t o 4.6 Hz, w h e r e a s 3 J p ~ ~i s~ l,a r g e r , r a n g i n g from 8 . 3 t o 25.0 Hz. Note t h a t JPOCH, i s o f t e n l a r g e r ( 2 2 t o 25 Hz) f o r t h e t e t r a c o o r d i n a t e phosphorus compounds t h a n f o r t h e t r i c o o r d i n a t e o n e s (8 t o 1 0 H z ) . F o r t r i c o o r d i n a t e compounds, when t h e group o n p h o s p h o r u s i s e q u a t o r i a l , 3J p w c 5 is r o u t i n e l y g r e a t e r ( 3 J ca. 1 4 H z ) t h a n when t h e group i s a x i a l ( 3 J ca. 4 . 5 t o 5.0 Hz). T h e r e f o r e a n a l y s i s of t h e coupling p a t t e r n can l e a d t o t h e d e t e r m i n a t i o n o f r i n g c o n f o r m a t i o n , and g i v e some i n d i c a t i o n o f t h e stereoc h e m i s t r y a t phosphorus (see T a b l e 3 ) . The magnitude o f c e r t a i n s t e r e o s p e c i f i c t h r e e - b o n d c o u p l i n g s f u r n i s h e s knowledge of t h e c o n f o r m a t i o n o f t h e r i n g o n l y . The 3 J ' s o f compounds 14b and 16 are comparable a n d i n d i c a t e a b i a s t o a c h a i r c o n f o r m a t i o n : 3JHaHa ca. 11, 3 ~ H a H e c a . 3 t o 4 ,

la lb 2a 2b 8a 8b 13a 13b 14a 14b 15b 16 17 18a 18b 20a 20b 21a 21b 19a 19b 22a 22b 23a 23b

Compound 4.2 5.5 4.4 4.5 3.71 4.65 3.84 3.75 4.58 2.7

11.4 11.2 11.8 11.2

11.9 4.9 11.18 10.81 10.24 11.4

JHaH€?

CCl4 CCl4 CDCl3 CDC13 CDC13 CDCl3 CDC13 CDC13 C6D6 oDCB C6D6 CDC13 CDC13 c6 H6 c6116 CgH6 CgH6 C6H6 c61i6 C6H6 C6H6 CDCl3 CDC13 CDcl3 CDCl3

%Ha

3

Solvent

3

Table 3

2.89 8.40 2.50 2.39 2.32 2.9 1.7

2.5 4.6 1.7 4.2

3JPHa

11.0 5.03 19.75 21.56 20.24 21.9 22.5

10.8 8.3 25.0 24.3

JPH,

Coupling Constant Data

909 883

1130 1140 591 639 566 618 667 714

664 719

JPX

1.9 1.9 1.0 1.6

1.7 1.8

JPXCCH3

30 30 30 30 33 33 35 35 35 35 35 36 36 37 37 39 39 39 39 39 39 40 40 40 40

Reference

W W

P

C6D6 C6D6 CgD6 C6H6 C6H6 CgD6

CgD6

C6D6

unknown

53

54

55a

aPOCH c o u p l i n g c o n s t a n t . ~ P N C Hc o u p l i n g c o n s t a n t .

CDCl3

C6D6 C6D6 C6D6 C6D6

CgD6 C6D6 CgD6 CDCl3 CDCl3

CDCl3

34 35 36 37' 41a 4l b 42 43 44 45 46 47 48a 48b 49a 49b 52

10.5 12.3 11.5 12.4 7.2 9.6

8.0

1.7-2.0 2.1 2.0 2.2 6.0 3.5

-

2.9 4.6

10.8

-

2.8

-

3.15

12.4

-

11.8

23 .O 24.5 22.6 21.8 21.8 20.2 2.1 2.4

2.5a 1.7b 5.4a 5. Zb 3.0a 2.4b 12.4a 12. l b

0

0

0.1 16.5 26.0 22.5 19.6

8.7 9.1 5.3 5.5 28.0 24.5 14.5

4.2 4.9 0 0 8.9 17.7 1.5 2.5 1.5-1.8 3.1 1.6 4.0 14.5 11.6 0.4 0.4

55

54

55

45 45 45 45 46 46 47 47 47 48 48 48 49 49 51 51 53

lb 3a 3b 19a 19b 22.3 22b 2 3a 23b 31a 31b 3 2a 32b 3 3a 33b 45 46 47 50a 50b 51a 51b

la

Compound

CDcl3 C6D6 C6D6 C6D6 c6 D6 C6D6

C6D6

CX13 CDCl3 CDC13 CDC13 CDCl3 CDCl3 CDC13 CDCl3

CDCl3

CDC13

neat neat unknown unknown

CCl4 CCl4

Solvent

3.6 0.5 3.8 1.2

13.8 12.1 13.6 12.8

0 8.4 12.1 1.5 1.3 1.7 1.2

14.0 11.3 13.6 1 3 .O

8.9 4.8 6.5 7.4 5.9 10.3

4.7 14.0 4.2 13.5 6.1 9.9 7.4 4.4 8.8 5.9

2.1 2.2 2.7 1.8 5.3 6.8 5.9 7.4 8.8 5.9

1.8 1.7 2.7 1.8 5.9 7.2 5.9 7.4 10.3 5.9

JPXCCH 3

3Jc5P

JC4P

2

Table 3 Continued

50 54 52 55 16 12

JP-c

31 31 31 31 38 38 40 40 40 40 43b 43b 43b 4 3b 43b 43b 48 48 48 50 50 50 50

Reference

26 27 28 29 30

Compound

CHC13

CIICl3 CHCl3 CHCl3 CHCl3

Solvent

3 2 3 2

2

JPC4

2

14

12 18

4

6 7

13

14

1 Jpc2, 6

3 4

%,5

19 14 12 28

Jp-cexo

1 lJP-C

43 43 43 43 43

Reference

202

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

3JHap ca. 3, 3J~,p ca. 22 Hz. Note that in 14b the t-butyl substituent on phosphorus is equatorial, whereas in 16 the phenoxy group is axial. Thus in 1,3 ,2-dioxaphosphorinanes 3 J and ~ 3~ ~ H p reveal little about the disposition of substituents on phosphorus. Consideration of the 3J values for the isomers of 13 leads to the conclusion that 13a is predominantly a chair, and that 7 3 b , given the middling values of ~ J I and I ~ 3J~,~e: ~ ~ is a a mixture of several conformers. Indeed, thorough analysis of these coupling constants can afford an estimate of conformer distribution (see ref. 35). For dioxaphosphorinanes that have 4- and/or 6-methyl substituents, a 4 J p ~ of ~ ~2 to ~ 33 Hz generally indicates an equatorial methyl group, while a lower value (0.5 to 1.5 Hz) indicates a conformational mixture of axial and equatorial methyl groups: compare the values for 22a, 2 2 b , 23b with 23a. The coupling of phosphorus to a 4- and/or 6-equatorial methyl carbon is often larger when the substituent on phosphorus is axial: 3 J p ~ for ~ ~3 a~, 319a, 22a, and 23a are 3.2, 8.9, 6.5, and 5.9 Hz, respectively, while those for 3 b , 19b, 22b, and 23b are 1.6, 4.8, 7.4, and 10.3 Hz. Note that at least one isomer of the variant system ( 2 3 a ) has been judged a mixture of conformers on the basis of 4 J p ~ data. ~ ~ ~ 3 Several systems in which NMR-active nuclei are directly bonded to the phosphorus atom exhibit stereospecific (43) onebond coupling constants (see systems 1 8 , 1 9 , 2 0 , 2 3 , Table 3 ) . Typically 'Jpx for X = 'HI 13C, 19F, and 77Se is larger when the predominant conformer is a chair with an equatorial PX arrangement. Although systems 19-21 do not follow the 6 3 1 P trend, they do follow the 'Jpx (and for 19 the 3Jpocc5) trend. Systems 22 and 23 point out the complexity of making isomer assignments: lJpc is greater for 22b and 23b and lJpse is greater for 23a than that value for their respective isomers; also 22a and 23a each have a 31P chemical shift that is upfield from the corresponding b isomers. All information supports the assignments as made. However, the 13C resonances of C4 and c6 show no y effect, and 3Jpc5 is less for the b isomers with equatorial benzyl groups. An axial methyl group is indicated in isomer 23a by a 4 J p ~ value ~ ~ ~of3 1.0 Hz; all data combined suggest a conformational mixture. X-Ray crystallographic data and chemical reactivity patterns could be used to determine configuration unambiguously.

B.

Phosphorinanes

Most of the information regarding the conformation of phosphacyclohexanes has been gathered through the use of 3C NMR data. Systems 26-30 (Table 1) are conformationally unbiased, but several useful trends in 13C chemical shifts and coupling constants are evident. A y effect is operative on carbon atoms C2, C6, C3, and C5. As methyl groups replace hydrogens on the exocyclic P-C substituent (thus increasing the number of a carbons there), the chemical shifts of C2 and c6

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

203

move to higher field (Table 2). A s the substituent increases in bulk, the chemical shifts of C3 and C5 move to lower field; this is probably caused by a decrease in the normal axial preference of the phosphorus substituent as the steric size of the substituent increases. The two-bond coupling constant 2Jpc3,5 gives an indication of conformational preference, varying in line with the chemical shifts of C 3 and C5(as discussed above): that is, for 33a with an axial methyl group on phosphorus, 2Jpc3,5 = 0 to 1 Hz, whereas for 33b with an equatorial methyl group on phosphorus ' J P c ~ , ~ = 7 Hz. Compound 2 9 must have a high population of the equatorial conformer, as the 2 J p ~ 3 , 5value is the same as for the locked system 33b. For the exocyclic substituent Jpc increases.with an increasing amount of equatorial conformer. Even 'JPH seems stereoselective; for example, 'JPH for 33a is 2.1 Hz contrasted with 2 J p ~of 4.0 Hz for 3 3 b . The 3 1 P chemical shifts of the 4-phosphorinanol sulfides 31 and 3 2 show an upfield shift for the isomers with axial P groups; the opposite is true for 3,7. A l s o for 31 and 3 2 lJpc for the isomer with the axial methyl group is less than that for the isomer with the equatorial methyl group; again, the opposite is true for system 3 3 . The nature of this effect is certainly not well understood ( 4 4 ) .

'

C.

1 ,3,2-Di azaphosphori nanes

A limited amount of NMR analysis has been performed on diazaphosphorinanes, which have an added dimension of complexity because of the other tricoordinate heteroatoms in the system (two additional stereocenters). One series of N,N'-dimethyl systems ( 3 4 - 3 7 ) has been found to have predominantly a single chair conformation (45). The three-bond coupling constants are reminiscent of those in the dioxa systems: values for 34 and 3 6 , respectively, are ' J H ~ H ~ 11.8, , 12.4 HZ; 'JHaHer 3.15, 2.8 Hz. For system 3 9 , with the N-methyl group constrained in an equatorial position, 3 ~ p N c Bis ~ 12 HZ (51),; in these systems 3Jp~C~ are 3 all in the range of 15-18 H Z (ca. 15 HZ for P-phenyl compounds). The three-bond proton-phosphorus coupling shows a large variance with the nature of the substituent on phosphorus; 3 J ~ a pand 3 J ~ e pvary from 4.5 and 9 Hz in 34 and 3 5 to 0 and 5 Hz in 36 and 3 7 . For compounds with 5,5-dimethyl substituents (such as 3 5 and 3 7 ) , the methyl signals in the 'H spectrum are of unequal height; the ~ 1 ,of~ the methyl resonance at lower field is broader, implying an axial methyl group which couples to the axial protons on carbons CI, and Cg through a Id pathway. The 5,5-gem-dimethyl groups seem to cause a 10-ppm upfield shift in the 3 1 P resonance with respect to the corresponding 5,5-unsubstituted compound (compare the 3 1 P chemical shift of 34 and 3 5 , 3 6 , and 3 7 ) . This same effect is noticed in dioxa systems 24 and 25 but not in dioxa systems 16 and 1 7 . A study (45) of the 31P chemical shifts of 1,3,2-diazaphosphorinanes has shown that the 3 1 P atom is most shielded when the N atoms are oriented with tho lone pairs of electrofis axial; thus

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

204

39

40

38, with presumably two axial nitrogen lone pairs, resonates at 85.8, while 39, with one axial lone pair, resonates at 94.3, and 40, with no axial nitrogen lone pairs, resonates at 108.8 ppm. The observed shielding appears to be stepwise in nature. Further study (such as 13CNMR) is needed to elucidate the configurations at phosphorus and at nitrogen in these systems.

D.

1,3,2-Dithiaphosphorinanes

Like the diazaphosphorinanes the dithiaphosphorinanes have not been studied extensively, and thus the observed trends may be reversed when additional data are obtained. Whereas isomers with tetracoordinate phosphorus have been separated and each isomer analyzed by NMR techniques (46,49), complete analyses of both isomers of tricoordinate phosphorus systems have not yet been reported. Experimentally the isomers are not easily separated (51), and the NMR spectral patterns are complex. Analysis of the three-bond coupling constants for the specifically deuterated, tetracoordinate compound 41 showed that both isomers have a chair conformation. The magnitudes of the coupling constants compare well with the diaza and dioxa systems; ~a 3J~a~ 3 e to 5, 3Jp~, 25, and 3Jp& 1 0 to 17 that is, 3 J ~ a 10, Hz. However, a different picture emerges upon examination of the tricoordinate systems 42-47. In 42, 46, and 47 the predominant conformer was assigned an equatorial phosphorus substituent; 3Jpscc5 [shown (48) to give an indication of the configuration at tricoordinate phosphorus] is equal to a characteristic 8 to 12 Hz, indicative of an equatorial substituent. Compounds 43-45 have been assigned an axial group on phosphorus in the predominant conformer; a 3Jpscc5 of zero for 45 and shielded 31P chemical shifts (40 for 45 and 28.9 for 44 vs. 97, 125, and 64 for 46, 47, and 49b, respectively) support the assignment. The conformations of 42-47 are confirmed by 3JpH values: 3JpHe for 42, 46, and 47 (equatorial substitution on P) are 14.5, 16.5, and 26.0 HZ, respectively, while 'JPH, for 43-45 (axial substitution on P) are all nearly zero! This trend is not found in the dioxaand diazaphosphorinanes, and is indicative of the stereochemistry at phosphorus in the dithiaphosphorinanes. An interesting discussion of the possible reasons for the strange P-S-C-H coupling constants is presented in ref. 51. For the tetracoordinate phosphorus systems 48a the averaged values for 3 J and ~ 3~ J p ~ are evidence for a twist-boat/chair conformational equilibrium. Both isomers (52) have a small value (1.5-2 Hz) for 3Jpscc5; as in the dioxa systems, 3 J p s ~ ~ 5

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

205

is not indicative of the stereochemistry of a tetracoordinate phosphorus center. The small values of 3Jpsccg for 5 0 and 5 1 , together with the absence of a y effect for the 13C chemical shifts of C4, lead to the conclusion that both systems are biased toward conformers having an axial phosphorus substituent.

E.

1,3,2-0xazaphosphorinanes

Several of the oxazaphosphorinanes studied (53-55) were found to have predominantly chair conformations. The typical three-bond coupling constants indicative of the chair conformaticn for systems 5 2 and 5 3 are, respectively; 3 ~ p 2.5, m ~ 5.4 ~ HZ; 3Jp,-yH, 23.0, 22.6 HZ; 3 J p ~ ~1.7, ~ , 5.2 HZ; 3 J p ~ 24.5, ~ ~ e 21.8 Hz. Both systems have been assigned equatorial N-methyl groups and axial P-phenoxy groups, but the assignment seems arbitrary. A ~ J ~ N of C H 11.0 ~ and 14.0 H Z , respectively, for 5 2 and 53 may imply an equatorial N-methyl group. Similarly, analysis of the coupling constants for 5 5 , indicates a chair conformation. For system 5 5 , where both isomers were studied, 55a was assigned an equatorial phosphoryl bond, since the 31P chemical shift is upfield (11.0) relative to that for 5 5 b (13.51, and the phosphoryl IR stretching frequency is higher (56); 4Jp C C H ~is lower for 5 5 a (2.9 Hz) than for 55b (1.9 Hz). For 5 5 a a 'JPNCH3 of 7.6 Hz results from a conformational mixture, while a value of 12.1 H z for 5 5 b implies a bias toward one conformation. Work on this type of system is also novel and more data must be compiled before the stereochemistry at nitrogen or phosphorus can be assigned with confidence.

F.

Lanthanide- Induced-Shi f t ( L I S ) Method

The lanthanide-shift technique is useful for determination of the stereochemistry of phosphorus-containing cyclohexanes, and it has been discussed at some length elsewhere (7b,27,29,49, 51). If the original coupling constants remain the same throughout the LIS experiment, the results usually lead to accurate conclusions. However, if the coupling constants vary, the conformational population is changing as a result of complexation of the substrate with the shift reagent, making stereochemical interpretations more complex. Further discussion of the LIS method is contained in Sect. 111-B-1-a (also see ref. 142c).

G.

Conclusion

Throughout this section we have organized NMR information which allows one to characterize chair conformations for phosphorinane rings, to determine whether the conformational equilibrium is biased, and to suggest the disposition of substituents on phosphorus. The power of such analyses has recently been pointed out in the determination of the conformation and configuration of cyclic nucleotides (57-59).

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

206

Critical discussions of NMR and other methods for structural determination of phosphorinanes have been published (13, 27-29). We hope that this section will contribute to an understanding of the scope and limitations of NMR methods for the determination of phosphorinane structure, configuration, and conformation.

III .

STRUCTURE, CONFORMATION AND STEREOCHEMISTRY OF CYCLOHEXANE RINGS CONTAINING TETRACOORDINATE PHOSPHORUS A.

Polycycl i c P h o s p h i t e s

In the early 1960s the chemistry of polycyclic phosphites

57a (60) and 580 (61,62) began to arouse some interest. As is

evident in the succeeding discussion, reactions of these cordpounds served to introduce the problem of stereochemistry in six-membered phosphorus-containing rings.

1.

l-Phospha-2,6,7-trioxabicyclo 12.2. Bloctune

The bicyclo[2.2.2]octane system first attracted the attention of Wadsworth and Emmons (63). Bicyclic phosphite 58a was observed to undergo the Arbuzov reaction (eq. [l]) when heated

Y

'0

57

58

(R = H, CI13, C H )

2 5 with an alkyl halide (64), generating a six-membered-ring phospi-ionata by severance of a bridge. The product with benzyl chloR e ) P

+

R'X

-

xcH2co R

\p40 d'R'

tll

58a 59 ride (59, R = C2H5, R' = CgHsCH2) appeared to be a single isomer, and was presumed to be cis on mechanistic grounds (eq. [21) (64,65). The initially formed boat conformation converted to the chair form cis-60" (path A), since this conformer is presumed (63) to be more stable by analogy to cyclohexane systems. Although pathways B and C (eq. [21) were not considered (63), they must occur as well. Comparison of infrared (IR) spectral data for cis- and t r a n s - 6 0 , the latter derived from 61 (cis/trans mixture) and C6H5CH2ClI led to a proposal that the isomeric phosphonates ( 6 0 ) differed by the orientation of the groups at the 5-position. Thus the trans isomer was assigned the config-

B. E. MARYANOFF, R. 0. HUTCHINS AND C . A. MARYANOFF

,

00

CH2C1

1.

0'

O ~ O B

207

(ref. 6 3 )

b-

-CH

C

-----

C 2 H 5 b o\p,o 0 \

I

cis-60'

C H

2 6 5

cis-60"

C2H5

CH2C6H5

[21

uration and conformation (actually predominant conformation) shown here; this conformational analysis is discussed more fully later on. 0

C2H5 CH2Cl

61

trans-60

Wadsworth and Emmons a l s o observed that 58a ( R = C 2 H 5 ) reacted with chlorine ( 6 3 ) to give a stable crystalline intermediate, assumed to be 62 (66),which rearranged to phosphorochloridate 63 (eq. [ 3 ] ) . Since 63 was also formed from treatment of a moncyclic phosphite, such as 6 1 , with chlorine, these authors concluded (incorrectly) that the synthesis of phosphorohalidates (e.g., 6 3 ) from bicyclic precursors ( 5 8 ~ is ) not stereospecific. The reaction of 58a with halogen has since been 2a ( R = C H ) - c12

-100

c1-

C H 5*:JpLl

/

" Y

62

ClCH2

[31

K O "/ ( 0 ) C l

C2H5

0

63

established to proceed stereospecifically, with retention (eq. [ 4 1 ) (69,70).

cis-63

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

208

Wadsworth explored the reaction of 58a (R = C2H5) with Nchloropiperidine (C~HloNC1)(70). A single product, presumably c i s - 6 4 , was obtained (eq. [5]).

7

.-

(-0'

\

cis-63

t rans-64

[51

cis-64

A single isomeric solid, t r a n s - 6 4 , was also obtained from cis6 3 and piperidine. The configurational relation in t r a n s - 6 4 was later verified by X-ray analysis of 65, prepared in the same manner from 58a (R = CH3) (71). Edmunson and Mitchell reported similar results with 58a (R = CH3) a year later (72a), and suggested that their phosphoramidates (and phosphorochloridate intermediate) possessed chair structures on the basis of 'H NMR spectral data. Values of A 6 for CH3 and CH2C1 were employed (72) to tentatively propose that their homologues of 64 differed in conformation at C5; that is, that their trans and cis isomers were mostly 65 and 6 6 , respectively, in solution (72a); the phosphorochloridate was suggested to be mostly conformer 6 7 . The

CH3

C1CH2

CH2C1

FzP-' c1

I

65

CH3

CH2C1

CH 3

66

67

conformational preferences derived from the qualitative A6 = G(CDC13) - 6(C&) method (72) are parallel to conformations manifested in the solid state in 2-R-2-oxo-1,3,2-dioxaphosphorinanes rather unbiased by substitution at positions 4 , 5, and 6 : axial C1 (69) , Br (73); equatorial piperidine (71). c1 0 y5H10 I CH3

C1CH2 CH2Cl 68

CH2C 1 69

CH3 70

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF

209

The action of C12 and of S02C12 on 58a (R = CH3) was initially thought (74) to produce different isomers ( 6 7 and 68, respectively), which on further reaction with piperidine supposedly led to different isomers of the corresponding phosphoramidates ( 6 5 and 65). Since three isomeric phosphoramidates ( 6 5 , 6 6 , 6 9 ) were thought to have been synthesized and isolated, Wadsworth asserted (74) that 65 and 6 9 , not interconvertable even at 250°, defined conformational isomers that were separated by an exceptionally high barrier to chair-chair interchange. This proposal was similar to a previous, erroneous suggestion (72a) that the two chair forms of 5,5-dimethyl-2-piperidino-2-oxo-1,3,2-dioxaphosphorinane are detectable at ambient teniperature. Later work (71b,76) established that the phosphorochloridate ( 6 7 , 6 8 ) and phosphoramidate ( 6 5 , 6 5 ) pairs are actually the same: the phosphoramidate from the C12/piperidine route is an impure specimen of that obbained in a pure state from the S02C12/piperidine sequence. The conformational equilibria for the 5-methyl analogs of c i s - 6 4 and c i s - 6 3 were realized to be strongly dominated by onechair species (based on 'H NMR 3JpOCH data) : structures 66 and 7 0 , respectively (79). On the contrary, the 5-methyl analogs of ?'gH5 CH 3F

V

p

-0 O

CH-Cl cis-71 72 73 t r a n s - 6 4 and t r a n s - 6 3 appeared to be conformationally heterogeneous, possibly being ca. 80% 65 and ca. 50% 6 7 , respectively (79). Although twist forms were proposed to be the major conformers for the 5-methyl analogues of t r a n s - 6 4 and t r a n s - 6 3 , these forms probably are not important in their conformational equilibria. The topic of twist conformations in 1,3,2-dioxaphosphorinanes is discussed in Sect. 111-B-1-a. Another ring-opening reaction of 58a (R = CH3) occurred with CgHgSCl, affording a single isomer, c i s - 7 1 , which exists mainly in conformation 7 2 (71b). Reaction of c i s - 6 3 (R = CH3) with CgHsSNa, lacking the clean stereospecificity observed with the amine nucleophiles (74,76), produced a mixture of t r a n s and c i s - 7 1 in a 9O:lO ratio. It was proposed that t r a n s - 7 1 exists mainly in the conformation with axial CH3 and axial CgHgS groups (71b). Additional discussion on the stereochemistry of nucleophilic substitution at phosphorus in phosphorinanes is reserved for Sect. 111-B-2-a. Acid-catalyzed hydrolysis of 58a (R = CH3) occurs nonstereospecifically to give cis- and t r a n s - 7 3 , whose dominant conformations in solution are chair forms with axial P-H bonds ( 8 0 ) . The phosphoryl oxygen was shown to arise from the water, rather than a bridging oxygen, by 180-labeling experiments.

'

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

210

Reaction of 58a (R = CH3) with acetone in the presence of acid gave a single crystailine product, whose stereochemistry is uncertain since the mechanism of this process is unknown (78,81); however, a trans structure ( 7 4 ) was postulated.

74

2. l-Phosphu-2,8,9-trinxaadamantane Berlin and co-workers (82) investigated the MichaelisArbuzov reaction of 5 7 a , which underwent a ring-cleavage process with benzyl chloride to afford a single isomer ( 7 5 ) . This molecule ( 7 5 ) may be considered as an equilibrium mixture of four conformations: 75a-75d. The authors felt that chair-boat conformations were favored and, of the two possibilities, they preferred 75b (82b). IR spectral data, dipole moment measurements, and 'H NMR arguments supported 75b as the predominant conformation (82). The solid-state structure was established as 75b by

75a (chair-chair)

H &

7 5b (boat-chair)

o=P\o H&TT

0

C H CH -P 6 5

Lo

II

7 5 c (chair-boat)

75d (boat-boat)

x-ray diffraction (83). The 0-P-0 region of the boat ring is flattened into a "half-chair" conformation, which presumably alleviates serious 1,4 steric interaction between the 3-benzyl and 9-hydrogen groups. A similar half-chair structure for a 1,3,2-dioxaphosphorinane ring was observed in the X-ray analysis of 7 6 . The interested reader is directed to other structural investigations of bicyclo[3.3.l]nonanes (85). Reactions of 57a with other benzylic halides (82b), methyl halides (80) , bromine (80) , and aqueous acid (80,86) have also been reported. Hydrolysis (80,86) of 57a was not stereospecific (cf. the acidic hydrolysis of M a ) , thus two isomeric products

B . E. MARYANOFF, R.

0. HUTCHINS AND C. A.

MARYANOFF

211

77a and 77b, were o b t a i n e d ; s t r u c t u r a l assignments were based on I R and '€5 NMR s p e c t r o s c o p i c d a t a ( 8 6 ) . The s t r u c t u r e o f 77a was s u b s e q u e n t l y confirmed by an X-ray s t r u c t u r a l a n a l y s i s ( 8 7 ) , wnich shows an u n f l a t t e n e d b o a t r i n g . The f a v o r e d conformation f o r t h e 1,3,2-dioxaphosphorinane r i n g o f 77b i s less d e f i n i t e and may be a f l a t t e n e d b o a t ( o r a c h a i r ) , s i n c e t h e phosphoryl oxygen normally p r e f e r s an e q u a t o r i a l p o s i t i o n v s . a hydrogen and r e f . 2 1 ) . s u b s t i t u e n t (see Sect. 111-B-1-a. Both isomers of 77 dehydrated back t o 57a a t 120' i n vacuo, o r t o d e r i v a t i v e s of 57a under t h e i n f l u e n c e of Cu2' o r t r i t y l c a t i o n ( 8 7 ) . Hydrated d i v a l e n t metal i o n s such a s Zn2+ and Fe2+ a c t e d on 57a t o form complexes o f g e n e r a l formula [M(57amH20)t,] ( X ) , ( X = monovalent a n i o n ) , wherein 57a*H20 w a s s u g g e s t e d t o be an " e n o l " form of 77a ( i . e . I a hydroxyphosphine) I bound t o t h e metal v i a phosphorus. Although 77a a l s o formed i d e n t i c a l comp l e x e s , a t t e m p t s t o produce complexes from 77b were u n s u c c e s s f u l . The mode of c o o r d i n a t i o n of t h e phosphorus l i g a n d w i t h t r a n s i t i o n m e t a l s i s u n c e r t a i n s i n c e X-ray d a t a a r e n o t a v a i l a b l e . 3.

l-Phospha-Z,7,8-trioxabicyclo[3.2. lloctane

The Arbuzov r e a c t i o n of 78 (R = H ) (88) w i t h b e n z y l c h l o r i d e y i e l d e d only b e n z y l phosphonate 79 ( R = H ) ; no a l t e r n a t i v e openi n g of t h e six-membered r i n g took p l a c e . The r e a c t i o n o f 78 (R = H ) w i t h B r 2 was a l s o s t e r e o s p e c i f i c , o c c u r r i n g by opening of t h e

k 78

k2 80

79

81

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

212

five-membered ring to give 8 0 (R = H), characterized by its conversion with piperidine to 81 (R = H), presumably with inversion of configuration at phosphorus. Conformational questions regarding 79-81 had been unanswered at that time. More recent work (90) concerning electrophilic cleavage of 78 (R = H or CH3) revealed that the reactions involving alkyl chlorides, alkyl tosylates, and N-chloramines are stereospecific, furnishing single products, formulated as 1,3,2-dioxaphosphorinanes. Edmunson (79) focused on the reaction of 78 (R = CH3) with N-chloropiperidine, and the chlorination of 78 (R = CH3) followed by treatment with piperidine (eq. [ 6 ] ) . Compounds 83 and t r a n s - 8 2 are chiefly one chair form, whereas c i s - 8 2 , displaying

I

cis-82

S02C12

83

trans-82

nearly equivalent 3 ~ p m values H , is conformationally heterogeneous. As discussed in Sect. TII-B-1-a, this conformational outcome derives from favorable axial chloro/equatorial P=O and equatorial dialkylamino/axial P=O arrangements in 8 3 and t r a n s 8 2 , and an unfavorable axial amino/equatorial P=O arrangement in c i s - 8 2 (in a chair form). Edmunson (79) suggested that c i s - 8 2 may possess a skew (twist-boat) conformation, which is compatible with reports of low-energy (1 to 2 kcal/mol) twist conformations for certain 2-oxo-1,3,2-dioxaphosphorinanes (35,91). However, since the twist form is still at least 1 kcal/mol higher in energy than the chair form, the chair forms of c i s - 8 2 probably account for the major portion of the conformer distribution. Little temperature dependence in the 'H NMR spectra was observed for 82 or 83. 4.

I - P h o s p h - 2 , 5,7-trioxabicycZof2.2.1 ]hep*ane

Although attempts by Edmunson and Mitchell to synthesize strained phosphite 84 were abortive ( 8 8 ) , this compound was prepared from glycerine and (CH30)3P by Denney and Varga (92,93). The oxide of 84 (i.e., 8 5 ) , generated using N2O4, was very sensitive to hydrolysis, as was 84 itself (93). Reaction of 85

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF

84

213

86

with methanol occurred readily with formation of a single product, phosphorinane 8 6 , by preferential fission of the fivemembered ring ( 9 4 ) . Although no conformational study has been reported for 8 6 , two diastereomers related to 86 have been described (95) as highly biased chair conformations with equatorial P=O groups (via., 87a and 8 7 b ) . FgH5

CHCHO 6 5 2

YgH5

87a

87b 5.

Genera2 Coments

In Sect. 111-B-1-a we fully discuss the conformational properties of 1,3,2-dioxaphosphorinanes; at that point the preferences for substituents on phosphorus are addressed. In an otherwise unbiased 1,3,2-dioxaphosphorinane ring these preferences control the conformational equilibrium, but in rings (unequally) substituted at positions 4 , 5, or 6 , substituent competition becomes important in describing the conformational distribution. As a case in hand, in 5-halomethyl/5-alkyl derivatives the question of bias, induced by the inequivalent substitution, arises. c1

-

Fo’%I

O---ko

CH3

-

CH2Cl

c1 68 67 Wadsworth and co-workers (71b) obtained equilibrium mixtures of 67 and 68 in a solvent-independent ratio of ca. 2.5:l. Since the axial P-Cl/equatorial P=O arrangement is strongly preferred by at least 3 kcal/mol (see Sect. 111-B-1-a), the compromise of conformational preferences, favoring 6 7 , apparently indicates a strong axial preference for the 5-chloromethyl group over the methyl group. Of course, this bias has to be accounted

214

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

for in any measurement of the free-energy difference between substituents on phosphorus. Likewise, Edmunson (79), using 3 J p ~ ~ values, noted some 5-chloromethyl/5-methyl compounds that were virtually one chair conformer (65 and 6 7 ) , and some that were more or less heterogeneous ( 6 6 , 69, and 6 8 ) . These results are in accord with the axial favoring of the chloromethyl substituent (AGO for CH2C1 vs. CH3 is ca. 1 kcal/mol). The preference of a chloromethyl group over methyl has also been reported for 88 (88b/88a = 2.5) (96) and 89 (42).

P4

OC

H -4-NO2

f=2p-o

C1CH2

-

CH3

CH2Cl t

~ ~ 3 + 3 ~ ~ o

I

GC

88b

88a

H -4-N02 6 5

A similar axial preference of 5-halo- (97), 5-hydroxy- (98), and 5-methoxymethyl (98) groups, and other 5-polar substituents (98), has been observed in 1,3-dioxanes and attributed to dipolecharge attractions (97,98). The magnitude of axial preference for a 5-halomethyl group relative to a 5-methyl group in 1,3dioxanes was estimated to be ca. 1 kcal/mol (97).

89

B.

1,3,2-Dioxaphosphorinanes

1.

Structure and Conformation

%Ox0 Compounds. Early on, Edmunson (99) briefly considered the conformational aspects of 2-oxo-1,3,2-dioxaphosphorinanes. For 90 [e.g., R = OCH3, SCzH5, NHCH(CH3)2] chair forms (9oa and 90b) were suggested instead of boat forms (9Oc and god) on the basis of molecular models (a twist-boat conformation 90e was ignored).

0 II

C H 3 G o , l P I= O

C H 3 e 2 ’ - ” CH3

R 9 Oa

90b

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF cH3%

CH3

,I-0R

cH3<0,/=0 CH3

" 0I 9oc

R 0

9 Od

215

cH300,p/0 CH3

'0'

R'

90e

The first X-ray crystallographic structure determination of a six-membered tetracoordinate phosphorus ring, 91, was reported by Beineke (69a). The conformation of 91 is a distorted chair, somewhat flattened at the phosphorus end of the ring (C-0-P angles ca. 118.5'), with the bromo and bromomethyl groups in axial positions. The ring flattening results in partial l o s s of distinction between axial and equatorial sites on phosphorus. Similar solid-state structural results were found for 1 7 [ g o (R = OCgHg)] (100). X-Ray structures for two other 2-aryloxy derivatives also show axial ArO substituents (101). Eventually, X-ray crystallographic data became available on a number of 2-R-2-oxo-1,3,2-dioxaphosphorinanes in which R = CH3 (102a), OH (103), C6H5 (104), H (105), C1 (73), 5,5-dimethyl-2oxo-~,3,2-dioxaphosphor1nan-2-y1 (106b), piperidino (71), 5,sdimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl-oxy (106a), anilino ( 1 0 6 ~ 5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinan-2-yl-thio )~ (106d), formamido (106e), OCH3 (102b), and trityl (84). The ring shapes are consistent for the related structures except in the case of the trityl derivative 76, which is forced to adopt a distorted "half-chair" conformation to accommodate the bulky axial group (84). In the other compounds the OH; CgH5; 5,S-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-y1, 2-yl-oxy1 and 2-ylthio; anilino; and C1 groups are oriented axially in otherwise unbiased molecules. In compound 92 (102a) the methyl group is axial (107), in 65 the piperidino group is equatorial (71), and

in 19a the hydrogen is axial (105). The X-ray data for six-membered-ring compounds may be compared with those for five-membered-ring cognates in which considerable flattening of the 0-P-0 region is also observed (108). In an early 'H NMR investigation of some 5,5-dimethyl-2-oxo1,3,2-dioxaphosphorinanes (90, R = CH3, H I t-CqHg, trityl, CH2CgH5, cc13, OC2H5, OCH3, 0CgH5, O-i-C3H7, NH-t-CbHg, NH-i-C3H7, Cl), Edmunson and co-workers concluded that most of the compounds studied are biased toward one chair conformation

216

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

(log), and suggested (72) that the axial P=O form is favored. In addition they claimed that stable conformational isomers (93a and 93b) were isolated, but this seems unlikely (eq. [7]) (72).

P(OCH313

\\

*

c H 3 K > CH3

P-CCH3

-

C H NC1 CH3 l1

0

CH3C)Ch'C5H,,

25

'OC13

93a

'"3KX0 CH3

0

'!jH1lNH. c1

90 (R = C1)

[TI

cH3~0>(0 CH3

0

NC5H11

93b

Dipole moment measurements on 90 [R = NH-n-C3H7, NH-t-CbHg, N(C2H5) 2, O-n-C3H7, OCgHg] evoked the suggestion that the conformation with an equatorial P=O bond predominates in solution (110). However, later work showed that a dialkylamino group is actually favored in an equatorial orientation relative to P=O (vide i n f r a ) . The application of vicinal P-0-C-H coupling constants ( 3JpocH) to the stereochemical study of the 2-0x0-1 ,3 ,2-dioxaphosphorinanes rapidly advanced understanding of their conformational behavior, spin-spin coupling data being more reliable for structural description than chemical shift data. Certainly, the marked stereospecificity of 3 J p (Sect. ~ ~ 11-A), along with its Karplus-type variation of magnitude with dihedral angle, has been particularly useful. Kainosho and co-workers (111) reported that 90 (R = C1, Br, and OH) and 94 (R = C1 and O X + ) , conformationally biased by the 4-phenyl group, assume virtually single chair forms in solution, by consideration of vicinal H-H and P-H coupling constants. Hall and Malcolm (36,112) supplied 3J ~ O C Hdata which indicated that 94 (R = OCgH5) is also virtually one chair conformation. Bentrude and Hargis (113) utilized 'H NMR vicinal H-H coupling constants for cis/trans pairs of 2-oxo-5-t-butyl-1,3,2dioxaphosphorinanes of known geometry ( 9 2 , 95-97) to show that the rings are largely single chair conformers, with the 5-tbutyl group equatorial (see Table 4 ) . Whereas 96 and 97 are ananHX

94

95 R = OCH3 97 R = CH3

96 R = OCH 3 92 R = CH 3

B. E . MARYANOFF, R.

0. HUTCHINS AND C. A. MARYANOFF

217

comeric (19), 92 and 95 have a c o n t r i b u t i o n from a n o t h e r conf o r m e r , e i t h e r t h e a l t e r n a t i v e c h a i r form w i t h an a x i a l t - b u t y l group o r a t w i s t - b o a t form. I t w a s l a t e r l e a r n e d t h a t t h e c h a i r -

Table 4 'H NMR V i c i n a l Coupling C o n s t a n t s (113) Compound

JAX Sum

95 96

11.6 10.5 10.1

97

92

JBX =

11.8 H Z 4.4 4.5 4.7

3

3 JBP

JAP

sum 10.1 4.1 6.8

=

23.4 Hz 22.8 20.2 16.9

b o a t energy d i f f e r e n c e f o r t h e 2-0~0-1,3,2-dioxaphosphorinane system nay be as low as ca. 1 . 0 kcal/mol ( 3 5 , 9 1 ) , which c o n t r a s t s w i t h a A G O ( c h a i p b o a t ) f o r 1,3-dioxane o f 8.3 2 0.5 kcal/mol ( 1 1 4 ) . I f i t i s assumed t h a t t h e c o n f o r m a t i o n a l p r e f e r e n c e f o r t h e 5 - t - b u t y l group i s a b o u t 1 . 4 k c a l / m l , as s e e n i n 1,3-dioxa n e s ( l l 5 ) , t h e n c o m p e t i t i o n between a c h a i r form w i t h an a x i a l 5 - t - b u t y l group and a t w i s t form would be f a i r l y b a l a n c e d . The X-ray s t r u c t u r e of 92 d i s p l a y e d t h e six-membered r i n g as a d i s t o r t e d c h a i r , w i t h t h e 5 - t - b u t y l group e q u a t o r i a l and t h e methyl group a x i a l ( 1 0 2 a ) . That 92 i s n o t a s s t r o n g l y b i a s e d toward one c o n f o r m a t i o n , as i s 9 6 , c o u l d be a consequence o f u n f a v o r a b l e s t e r i c i n t e r a c t i o n s i n 92, a r i s i n g from an a x i a l 2methyl group, and/or s t a b i l i z a t i o n o f t h e a x i a l 2-methoxy conf o r m a t i o n by e l e c t r o s t a t i c i n t e r a c t i o n s ( t h e g e n e r a l i z e d anomeric e f f e c t ) . X-Ray a n a l y s i s o f 95, t h e epimer o f 96, showed a f l a t t e n e d c h a i r conformation w i t h a x i a l 2-methoxy and 5-tb u t y l groups ( 1 0 2 b ) . The t e m p e r a t u r e dependence o b s e r v e d f o r 92 p o i n t e d t o d i s placement o f a c o n f o r m a t i o n a l e q u i l i b r i u m . Evidence f o r "conf o r m a t i o n a l m o b i l i t y " i n 2-oxo-1,3,2-dioxaphosphorinanes had a l s o been p r e s e n t e d by o t h e r s (78,116,117) [such as f o r 98a, 98b, cis-60, 90

98a

98b

99

E s t i m a t e s of c o n f o r m a t i o n a l p r e f e r e n c e s f o r 2-oxo-1,3,2dioxaphosphorinanes can be deduced from POCH c o u p l i n g c o n s t a n t s ( s e e S e c t . 1 1 - A ) . K a t r i t z k y a n d co-workers (117) and Edmunson and M i t c h e l l (116b) a r r i v e d a t estimates f o r systems w i t h o u t s t r o n g b i a s i n g s u b s t i t u e n t s on r i n g p o s i t i o n s 4 , 5 , o r 6 . Some

218

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

l o l a : X = OTs b: X = Br

1OOa: X = OTs b: x = Br Table 5

P-H Coupling Values and Conformer D i s t r i b u t i o n (109,117)

Compound 26.7 14 0 14.9 15.9 19 16.3 15.7 11 13.0 14.4 12.1 11.7 11.6 18.9 19.4 14.5

1.0 9.9 7.8 6.0 2 7.8 6.6 11 10.4 9.0 11.5 8.9 10.0 4.6 3.2 8.7

100 60 65 75 100 c a . 75= 75 50 55 65 50 65 55 90 85 70

aMeasured i n chloroform o r benzene. 3 J p o c ~ ( 1 )= n J t + (1 - n ) J g ; 3Jp ~ ( 2 = ) nJg + (1 n ) J t ; Jg = 3. 3 J p 0 ~( a~c y c l i c ) [ 3 J p o c ~ ( 1 )+ J p x ~ ( 2 ) I Jt ; = 2[3Jpx~ (1) ' J p x ~ (2)] - 303Jpoc~(acyclic). CNot r e p o r t e d ; e s t i m a t e d from g i v e n c o u p l i n g c o n s t a n t s .

-

@i

-

3~pOCHv a l u e s and (approximate) % major conformer a r e g i v e n i n T a b l e 5. Although t h e c o n f o r m a t i o n a l q u a n t i t a t i o n had o f f e r e d no

c o n c l u s i v e evidence f o r t h e i d e n t i t i e s o f t h e f a v o r e d conformers, t h i s work s u g g e s t e d t h a t secondary and t e r t i a r y a l k y l groups on phosphorus r e s i d e mainly i n an e q u a t o r i a l o r i e n t a t i o n , whereas primary a l k y l groups p o p u l a t e a x i a l and e q u a t o r i a l p o s i t i o n s about e q u a l l y i n t h e absence of o t h e r b i a s i n g r i n g s u b s t i t u e n t s . Compound 99 was b e l i e v e d t o have t h e s u l f u r group e q u a t o r i a l , which is probably u n l i k e 1 (see pp. 209, 222-223) Verkade and ' NMR d a t a which were c o n s i s t e n t w i t h co-workers (78) g a t h e r e d H t h e p r e v a l e n c e of one c h a i r conformer w i t h an e q u a t o r i a l P=O bond, when t h e P s u b s t i t u e n t s w e r e a l k o x y , bromo, c h l o r o , and hydrogen; and w i t h a r a t h e r heterogeneous e q u i l i b r i u m when t h e P s u b s t i t u e n t s were primary a l k y l , b e n z y l , p h e n y l , and t r i t y l .

B. E . MARYANOFF, R. 0. HUTCHINS AND C. A. MYANOFF

219

Extensive s t u d i e s by Navech and co-workers on 2-0x0-1,3,2dioxaphosphorinanes (118-126) , employing I R (Vmax P=O) and 'H NMR d a t a , provided conformational p r e f e r e n c e s (118-120) and approximate e q u i l i b r i u m free-energy v a l u e s (119,121,124,125). The 'H NMR spectrum f o r 16 (AA'BB'KLX),w a s solved a s an A2B2KLX approximation t o g i v e H-H coupling d a t a . The v a l u e s obt a i n e d were s i m i l a r t o t h o s e found f o r anancomeric 1,3-dioxanes ( 1 2 7 ) , and i n d i c a t i v e of a c h a i r l i k e s t r u c t u r e f o r t h e -OCH CH CH 0- p o r t i o n of t h e r i n g , which i s s t r o n g l y b i a s e d to2 2 2 ward one conformation (AH' 2 2 kcal/mol). The conformational p i c t u r e f o r 90 and 1 0 2 [R = OCgH5, C 1 , N ( C H 3 ) 2 ] is a s t r o n g l y

R

16

102

I03

b i a s e d e q u i l i b r i u m with 80 t o 90% of one c h a i r conformer; an a x i a l p o s i t i o n i s p r e f e r r e d by phenoxy and c h l o r o , whereas an e q u a t o r i a l p o s i t i o n is p r e f e r r e d by dimethylamino. An e q u a t o r i a l p r e f e r e n c e f o r t h e phenyl group w a s suggested f o r 90 (R = C g H 5 ) from a c o r r e l a t i o n of phosphoryl s t r e t c h i n g f r e q u e n c i e s (118) Conformational f r e e e n e r g i e s were estimated (120,121a) f o r 90 ( R = C g H 5 ) and r e l a t e d compounds by 3JpOC~v a l u e s (and I R d a t a ) . I n carbon d i s u l f i d e t h e more s t a b l e conformer of 1 0 3 ( R = H , C H 3 , C 2 H 5 , C g H 5 ) is t h a t with an a x i a l phosphoryl bond: AG2980~1s ca. -600 cal/mol f o r R = H ( I R ) , c a . -600 t o -650 cal/mol f o r R = CH ( I R , 'H N M R ) , c a . -1050 t o -1200 cal/mol f o r R = c g H 5 [ I R , ?H NMR) , and ca. -350 t o -600 cal/mol f o r R = C 2 H 5 ( I R , 'H N M R ) . In p y r i d i n e t h e e q u a t o r i a l P=O conformation i s s l i g h t l y favored f o r 103 (R = C H 3 ) , and (K = C 2 H 5 ) : A G 2 g e 0 ~ i s ca. 100 t o 200 cal/mol; whereas 103 ( R = C g H 5 ) s t i l l had a p r e f e r e n c e f o r an a x i a l P=O conformation; dco c a . -400 cal/mol ( a l l by 'H N M R ) . A more thorough s o l v e n t - e f f e c t study on 1 0 3 (R = C H 3 , C 2 H 5 , C g H 5 ) , 16 and 90 (R = O C g H 5 , OC2H5, C 1 ) i n d i c a t e d t h a t p o l a r s o l v e n t s s t a b i l i z e t h e e q u a t o r i a l P=O conformation, probably by s o l v a t i o n of t h e P=O bond (121b). Conformational free-energy values have been given f o r compounds with a v a r i e t y of P s u b s t i t u e n t s (121b,122-125), and some a r e given i n Table 6. The t r e n d s of conformational p r e f e r e n c e r e p o r t e d by Navech and co-workers, and o t h e r s ( v i d e supra), were r e f l e c t e d i n d i p o l e moment and Kerr c o n s t a n t measurements by Arbuzov and co-workers (128) [P s u b s t i t u e n t = C H 3 , C (CgH5) 3 , C 1 , H I Narech's group ( 1 2 4 ) computed group A G O v a l u e s f o r v a r i o u s P s u b s t i t u e n t s , given t h e f f i o v a l u e f o r hydrogen vs. P=O i n 90 ( R = H I , and found s i m i l a r i t i e s and d i f f e r e n c e s when they compared t h e v a l u e s with those f o r l f 3 - d i o x a n e s . Complexation of 90 [ R = OCgH5, OC2H5, C g H 5 , N ( C H 3 ) 2 ! w i t h B F 3 , a f f o r d i n g 1:l adducts, a l t e r e d t h e conformational d i s t r i -

-

.

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

220

Table 6 Conformational Free Energies

Compound 90 90 90 90 90

(R (R (R [R

= = = =

(R =

xgH5) OC2Hg) CgH5) N(CH3)2] H)

cs2

-

1.4 (1.5) -0.6

-

-

CgDg

CgDgN

1.6

4.3 2.4-3.0 0.1 -1.0 1.1

-

-1.1 1.2

CH3CN >5

-

0.2

-0.8 0.8

CHC13 2.0

-

-0.1

-

bution (126). Thus 90 (R = OCgH5, OC2H5) , with an axial P substituent strongly preferred in the uncomplexed form, showed increased conformational heterogeneity when complexed. On the other hand 90 (R = CgH5), which normally is mixture of conformers, showed a strong preference for a.single form when complexed. The dimethylamino derivative, normally having a strong predilection for an equatorial amino conformation, showed little change in conformational distribution in the complex. It appears that the P=O bond is predisposed to an axial position in the BF3 adducts. Changes in conformational proportions have also been noted in the complexation of certain 2-oxo-1,3,2-dioxaphosphorinanes with europium(II1) chelates ( v i d e i n f r a ; see Sect. 11-F) (91br129-131). The shift of conformational equilibria for a number of unbiased derivatives of 9 0 , on complexation with Eu(fod) 3 , was toward the axial P=O bond conformer (131), in analogy to the BF3 complexation. Hall and Malcolm also studied 1 6 and 90 (R = OCgH5, C1, OH, CgH5) as well as 104 and 1 0 5 . Their analysis of the 2H-decoupled 'H NMR spectrum of 205u showed a marked bias (ca. 100%) toward a chair conformer with equatorial 5-phenyl and P=O groups (46). D

-

104

However, because of the strong predilection of the 2-phenoxy group for an axial orientation (vs. P=o), 105b favors (80 to 90%) a conformation with the 5-phenyl group in the less stable axial arrangement (46). The use of europium(II1) shift reagents to facilitate assignment of configuration and conformation of 2-oxo-1,3,2-dioxa-

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

221

phosphorinanes was first reported by Bentrude and co-workers (129,132,133). ’H NMR parameters for 97 and 106 were consistent

II

k‘p-c 0

106

107a

‘6H5

6H 5

0

107b

with chair conformations having equatorial 5-t-butyl and phenyl or methyl groups. In contradistinction the cis isomers 92 and 107 were found to be conformationally heterogeneous. Addition of Eu chelate displaced the conformational equilibria of 9 2 and 1 0 7 , but did not do so with 97 and 1 0 6 , For 107 the ratio of 107a to 107b was ca. 85:15 with 0.0 mol Eu/mol of compound, ca. 60:40 at 0.51 mol Eu/mol of compound, and ca. 47:53 at 0.95 mol Eu/mol of compound. Thus, the formation of the Eu.107 (or 9 2 ) complex shifts to the equilibrium in the direction of the axial P=O bond conformer. Di-t-butyl compound 108 was found to exist completely in the diequatorial conformation (shown) ( $ l a ) , and 3 J p ~ ~ values H for 108 were almost identical to those for 90 (R = t-CqHg) , the latter lacking the biasing 5-substituent (109,117). In comparison the identical 3 J p 0 C ~values (10 Hz) for 109 indicated either boat conformations (109b-109e) or a mixture of boat forms and chair conformers (109a and l o g e ) , with 1 0 9 c present to a minor extent (from ’H-lH vicinal coupling constants) (91a) Evidently severe syn-axial nonbonded interactions in 109a and 1 0 9 c cause an escape to the boat structures. The nonaveraged ’H-’H vicinal ~~

.

108

109d

109e

coupling constants observed are more in accord with a rigid boat form ( 1 0 9 d ) as the predominant conformation, since more average values should be seen with flexible, pseudorotating forms ( 1 0 9 b and 1 0 9 e ) (91b).

yo\ Jo<”..’ k t o--p=o

109a

0 ’

109b

*

bp+ I

0

109c

The A G O for chair-boat interconversion in 1 0 9 was estimated to be ca. 1 kcal/mol, which is low compared to ca. 8.3 5 0.5

222

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

kcal/mol in 1,3-dioxane (114). Likewise, for the 2-dimethylamino derivatives 110 and 111, trans isomer 110 showed essentially one chair conformation, while the cis isomer (111) is a conformational mixture (91b). Furthermore, whereas 110 was conformationally stable to added Eu(dpm)3, 111 experienced alteration of its

110 111 conformational equilibrium (the effect was less dramatic than that observed for 1 0 7 ) (91b,130). The conformational equilibrium for 111 was composed of ca. 90% chair conformers, which had the axial 5-t-butyl form favored over the equatorial 5-t-butyl form by 2:l. An analogous situation was observed for the 2-isopropyl congener (91b). Given the tendency for participation of a nonchair conformation in the conformational profile for cis isomers 209 and 111, [ A G O (chair-boat) = 0.7 to 1.0 kcal/mol], caution should be exercised in considering conformational equilibria for other (expecially closely related) 2-oxo-1,3,2-dioxaphosphorinanes. It is possible that 92 and 107 also have a twist form that is significantly involved in their conformational equilibria, a point which was not brought out in the preceding discussion. A number of reports dealing with biased, diastereomeric systems have furnished data on the preferred disposition of groups on phosphorus in the 2-0~0-1,3,2-dioxaphosphorinane s y s tem. A strong axial preference has been observed for hydrogen (33,105,134-136) [AG0400C = -1.6 f. 1 kcal/mol (33)], alkoxy (136b), chloro (71b,136b,137,138), isothiocyanato (139), cyano (140), aryloxy (71bI138b), and fluoro (138b,141) vs. the phosphoryl bond. To summarize, in the 2-oxo-1,3,2-dioxaphosphorinanes P substituents such-as fluoro, chloro, bromo, alkoxy, aryloxy, cyano, isothiocyanato, methylthio (131), and hydrogen strongly favor an axial orientation in nonpolar media. Conversely, the t-butyl and dialkylamino moieties are strongly favored in an equatorial orientation. Other substituents such as primary and secondary alkyl, benzyl, trityl, aryl, and primary amino tend to exist in an equatorial orientation to an extent between 50 and 05%, in nonpolar media. It should always be kept in mind that the conformational distribution of 2-oxo-1,3,2dioxaphosphorinanes may be highly sensitive to solvent, as shown especially in the work of Navech and co-workers. Estimates of conformational preferences for various groups on phosphorus vs. P=O in nonpolar media are displayed in Table 7. General explanations of the conformational preference in 2-oxo-1,3,2-dioxaphosphorinanes, based on the interactions of the lone pairs on the 1,3 oxygen atoms with the adjacent groups on phosphorus, have been advanced (142). A theoretical discus-

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

223

Table 7 Conformational Preferences of Groups on Phosphorus vs. P=O Substituent methyl benzyl trityl phenyl t-butyl amino dimethylamino phenoxy methoxy hydrogen chloro fluoro methylthio

Approximate

%

Equatorial

50-60

55-65 65-75 60-70 95-100 75-85 85-95 5-15 5-10 10-20 0-5 0-5 0-10

sion of factors involved in conformational selection appears in Sect. IV. 2-Thiono and 2-SeZeno Compounds. X-Ray structure determinations on 2-thiono- and 2-seleno-1,3,2-dioxaphosphorinanes 112, 113a, 113b, and 114 revealed chair conformations in each case (143). The P=S and P=Se bonds in 123a and 114 are equatorial, while the P=S bond in 112 and 113b is axial. The cis diastereomers 11 5 (144a) and 11 6a (102b) assumed chair conformations ,

CH3

112

113a: R = OC H 5 b: R =

OCH3 114

~ ( 6 ~ ~ 1 ~

the former having the 4-methyl group equatorial and P=Se bond axial, and the latter having the 5-t-butyl group and P=S bond axial. Ring-puckering at the phosphorus end was unusually large for 116a, which in addition was flattened at the other end of the ring (102b). Interestingly, 116a has an axial 5-t-butyl moiety rather than a twist-boat structure, which occurs in the solid-state structures of related 1,3,2-dithiaphosphorinanes (Sect. 111-C-4). Conversely, the related cis compound 116b has a chair structure with equatorial 5-t-butyl and axial 2-phenyl groups in the solid state (1025). Early 'H NMR investigations of some 5,5-dimethyl-2-thiono derivatives (72b,109) suggested strongly biased chair conformations in solution for 113 [R = N(CH3)2, NH-i-C3HyI O C H ~ ,Cl]. Kainosho and co-workers (111) reported that 113 (R = Cl), by comparison with 1 1 7 , exists virtually in one chair conformation.

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

224

t-C H \I 49

0

H'

CH; 115

116

b/ r O\

P (SIC1

c6H5 117

Katritzky's group (117) estimated the amount of major conformer for 118a, 118b, and 118c to be 95%, 95%, and 80%, respectively, using 3Jp~CHvalues. Majoral and Navech reported 'H NMR data for 113 (R = C1, OCgH5) and the 5,5-diphenyl analogs (119a). The ' J ~ O C values ~ for 113 (R = ~ 6 ~ were 5 ) employed to estimate a conformational free energy in carbon disulfide of 650 cal/mol; the direction of preference was ambiguous (121a). It is possible that the conformational tendency for 113 (R = CgH5) was opposite in CSg and pyridine. Free-energy differences of 300 to 900 cal/ mol have also been estimated for 1 1 3 (R = OH) in various solvents (124).

= 0; Z = S = Z = S; Y = SeSe c : X = Z = Se; Y = SS

118a: X = Y

b: x

119a: X/Y = OCH3/S b : X/Y = S/OCH~

Investigation (lH NMR) of 119 indicated a chair structure with equatorial t-butyl and P=S groups for the trans isomer (119a), but a heterogeneous conformational equilibrium for I19b (113). Since the vicinal proton-proton coupling constants for 119b did not vary nearly as much as the 3Jp0~Hvalues, the tbutyl end of the ring is substantially fixed, leading to a proposal that the other conformer present in 119b is a boat (or "chaise-longue") structure (eq. [ a ] ) . Thus competition between P=S and P-OCH3 favors the axial P-OCH3 conformer.

S

I

OCH3

'H NMR data for 120 were supportative of virtually a single cha,ir conformation with equatorial t-butyl and methylamino groups (91b), reflecting the stable arrangement of substituents

B. E. MARYANOFF, R.

0. HUTCHINS AND C. A. MARYANOFF

225

a t phosphorus. The p r e f e r e n c e of t h e alkylamino group f o r an e q u a t o r i a l p o s i t i o n i s similar t o o b s e r v a t i o n s f o r t h e 2-0x0and t r i v a l e n t r i n g analogs. The t r a n s isomer of 115 ( i . e . , 1 2 1 ) , based on NMR d a t a and comparison with t h e c i s isomer 1 1 5 , i s a mixture of c o n s i d e r a b l e amounts of both c h a i r conformers (ca. 60% 121a and 40% 121b) (144b). X-Ray a n a l y s i s of 121 showed a c h a i r conformer with t h e me'thyl and s e l e n o s u b s t i t u e n t s equatorial ( 1 4 4 ~ ) .

-%p-NHcH3

II S

CH3 S

L

I

e

NH-t-C

120

y>-NH-t-C4Hg H

4 9

121a

Se

CH3

121b

Diastereomers of 122 [X = S , R = C H 3 (146,147) , C2H5 (145) I were obtained through s t e r e o s p e c i f i c r e a c t i o n of t h e correspondi n g phosphites with s u l f u r ; t h e methyl d e r i v a t i v e s were conv e r t e d t o s a l t s of t h e same t h i o a c i d s , which were produced by t h e s t e r e o s p e c i f i c r e a c t i o n of d i a s t e r e o m e r i c hydrogen phosp h i t e s 1 9 with s u l f u r and a secondary amine ( s e e S e c t . I I I - B 2-a) (146,147). Comparable work was p u b l i s h e d f o r t h e analogous selenium compounds (146,147), and s e l e n o e s t e r s 122 ( R = C H 3 , X = Se) were discovered t o t h e r m a l l y r e a r r a n g e t o i s o m e r i c s e l e n o e s t e r s 123 (R = C H 3 , X = Se) w i t h complete r e t e n t i o n of c o n f i g u r a t i o n a t phosphorus. Acid-catalyzed rearrangements of t h i s kind f o r s u l f u r and selenium compounds have been d i s c u s s e d (148). For

x

=

s,

R = CH,

123b Dipole moment measurements w e r e used t o a s s i g n a x i a l alkoxy o r i e n t a t i o n s f o r a s e r i e s of thiophosphates 1 2 2 ( R = C H 3 , C2H5, i - C 3 H 7 ; X = S ) d e r i v e d from t h e more s t a b l e p h o s p h i t e s ; equat o r i a l alkoxy p o s i t i o n s were assigned f o r s u l f i d e s from t h e l e s s s t a b l e phosphites (eq. [ 9 ] ) (149). Russian workers l a t e r r e -

226

GI,

CH3

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

y.OR

1

'8

A '8

- GLs CH3

-

I

OR

CH3G'P-OR

I1

S

ported similar results for 1 2 2 (R = CH3, X = S ) (150a) on the basis of dipole moment data and molecular Kerr constants. The preferred conformations of 124 (R = C1, CH3) were suggested to be those with chloro axial and methyl equatorial (151a); conclusions of an earlier paper of these workers are of uncertain validity (151b). Raevskii and co-workers (152) applied IR data to a conformational study of thiono compounds, but conclusions from this type of work are probably ambiguous. Robert's group (153) has used 3jp0CH values to estimate conformational preferences for nonanancomeric 2-thiono-1,3,2-dioxaphosphorinanes ( 1 1 3 ) in a polar and a nonpolar medium (Table 8 ) . Table 8 Percentage of Axial P=S 113

R=CH 3 R=CgHg R=OC6 H 5 R=C1

CCl4 95 100 10 0

CD3CN I0

70 15 0

Miscellaneous P-X Compounds. Little work on 2-imino-1,3,2dioxaphosphorinanes has appeared in print, though a few isolated papers concerned with chemical aspects exist (39,167,183). Borane adducts of 1,3,2-dioxaphosphorinanes have been studied (154aI155).The methoxy groups in both isomers of 125 are axially disposed, based on dipole moment data (154a). X-Ray analysis of adduct 1 2 6 a (155) showed a chair conformation with equatorial 4,6-dimethyl and BH3 substituents (154b). The equatorial positioning of the BH3 group is thermodynamically more stable (vs. that of the methoxy group). B-H stretching frequencies for the isomers of 1 2 6 suggest that an equatorial lone pair is less basic than an axial lone pair (155). Molybdenum

B. E. MARYANOFF, R. 0. HUTCHINS AND C.

A.

MARYANOFF

227

carbonyl complexes elicited a similar conclusion regarding phosphite basicity (156), as did low-temperature 'H NMR l J p ~ values on protonated derivatives of 3 (157). Denney (187) has mentioned this same trend (axial lone pair more nucleophilic than equatorial lone pair) with phosphites analogous to 3. Transition metal-phosphine coordination complexes are common, and complexes of 1,3,2-dioxaphosphorinanes can be readily prepared. Arbuzov and co-workers (150a) reported isomeric 1:l adducts of phosphites with CuC1. Cis complexes, 1 2 7 , of 3a and 3b with Mo(C0)k have heen obtained with retention of confiquration at phosphorus (156). One-to-one molybdenum complexes a>f stereoisomeric phosphites closely related to 13a

124

125

anu IBb have also heerl reported [ 2 2 6 ; 31, R2 = X H 3 , Mo(CO)5]; the complexes were formed with retention of stereochemistry (158). It was proposed that the Mo(C9)5 group in 128 would prefer an equatorial orientation, based on earlier studies (159) 'H NMR spectral data for the isomeric complexes ( 1 2 8 ) supported different arrangements of the 5-t-butyl and 5-methyl groups. The cis complex was mainly chair conformation 1 2 9 . The trans complex was obviously conformationally heterogeneous, with a predomi-

co

I

PR3

2 28

127

129

OCH3

nance of 130a and 730b, and a minimal contribution from 1 3 0 ~ . Twist form 130b was excluded from consideration (158), but a O\

P-Mo

I

130a

OCH

(CO)

5

CH ~ 3o

/Mo(C0)5

~ p \ o c3 ,

130b 130c good structural analogy exists between this cis compound and cis-2-5-di-t-butyl-2-0x0 derivative 1 0 9 (91a), which is populated by a substantial amount of twist-boat form in solution. Equilibration studies indicated that the cis complax is more stable than the trans: the equilibrium ratio was cis/trans =

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

228

88:12. Complexes with a chloro substituent in place of the methoxy were prepared [ 1 2 8 ; R1, R2 = C1, Mo(C0)5] and equilibrated to a 95:5 cis/trans mixture. Displacement of chloride from 131 by methoxide occurred with predominant inversion but, since the less stable (trans) isomer was formed, the stereochemical results are confused by competitive epimerization of product 130 to 129. + Ethylation of 90 (R = OC2H5) with (CzH5)3O BFb- gave phosphonium salt 132a, whose 1H NMR spectrum indicated no conformational bias (160). Related salt 132b showed similar behavior (161). Interconversion between conformers of 132b seemed to be rapid on the NMR time scale, even at -81O.

k1

132a: R = OC 2H5 b : R = CH

131

2.

3

Stereochemistry of ELectrophiZic and NucZeophiZic Substitution Reactions a $ Phosphorus

2-0x0 Compounds. In this section we turn to a discussion of diastereomeric and anancomeric (19) 1,3,2-dioxaphosphorinanes, such as 4-methyl, 4,6-dimethylI and 5-t-butyl derivatives, touched on briefly in Sect. 111-B-1. These systems, especially the 4-methyl series, have been useful in the study of reaction stereochemistry at the phosphorus center. Chlorophosphite 13.3, prepared from lI3-butanediol and PCl3 (145,162), was hydrolyzed to a mixture of diastereomeric hydrogen phosphites, 19b and 19a (146,164), the latter of which predominated. Similar nonstereospecificity in phosphite hydrolysis was presented in Sect. 111-A-1 and 111-A-2 with regard to 58a (R = CH3) (80) and 57a (80,86). Nifant'ev and co-workers (134) discovered stereoselective syntheses of 19b and 19a, one involving ester exchange between dimethylphosphite and 1,3-butanediol, and the other involving

133

19b

I9a

acidic hydrolysis of the more stable isomeric phosphoramidite 134a (eq. [lo]). The liquid isomcr 19b was fuund to transform to crystalline isomer 19a, especially well in the presence

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

229

Na CH30H A

134a of additives such as acids and bases (134,135). Stec's group also reported a stereoselective synthesis of 19a from 1.35 and dry air (eq. [111) (39).

135

Structural and conformational assignments were formulated for 19a and 19b via 'H NMR and dipole moment data (134); the conformational preferences are chair structures with equatorial 4-methyl groups. Although the configurational assignments (134) for 19a and 19b conflicted with a prior assignment (146), the work of Nifant'ev (134) was later fully corroborated (33, 105). ' H NMR data for 19b and 19a ( 1 9 b : 4 J p ~ ~= 32.0 Hz, 3 J = ~ ~ 9.7, 3.5 HZ, 19a: 4 J p ~ ~= 3 1.2 H Z , 3 J = ~8.0, ~ 4.2 HZ), in comparison with data for an anancomeric pair of isomers 8a and 8b (33), permit an estimation of the conformer population for 1 9 : 19a has 95 to 100% and 19b has 55 to 60% of equatorial 4methyl conformer. Mikolajczyk (146) found that the more stable phosphite 19a combines with sulfur to give (retention of configuration) a salt of 2-hydroxy-4-methyl-2-thio-1,3,2-dioxaphosphorinane, obtained earlier by an independent route (eq. [12]) (147). Since the initial assignments of configuration for 19 were reversed ( 1 4 6 ) , the early structural correlation involving 136a is incorrect but, in a subsequent full paper (164), correct structures were presented for 19 along with the chemistry delineated in eq. [121. Replacement of hydrogen in 19a and 19b by chlorine [SO2C12 (165a), C12 (136b), N-chlorosuccinimide (136b)l occurs stereospecifically with retention of configuration (eq. [131). Dis-

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

230

placement of chloride from 1 3 9 with piperidine gave 1 4 0 with inversion (136b), whereas displacement with methanol occurred with loss of stereochemical intesrity (136b,137). Stereochemical

1

137a

138a

HC1

137b

I

[i21

Dowex 50

4 .

136a

19b

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF

231

correlations are shown in eq. [141, along with the percentage of stereospecificity. The reaction of 1,3-butanediol with POCl3, subject to thermodynamic control, gave a mixture of 139a and 139b in a ratio of ca. 8 0 : 2 0 , the same ratio observed for equilibration of phosphates 141 with NaOCH3 (136b). A 76:24 ratio of

19a

-

P

/'

C5H10NH

0 'c1

139a

140a

pFco

CH3 CSHIONH *

139b

1131

0

140b

139a to 139b was reported for a similar preparation by Stec and Mikolajczyk (137). The chlorination of 19 was also studied by Stec and Mikolajczyk (137), who were able to effect stereospecific chlorinolyses of trialkyl phosphites 137a and 137b with C12 Bromination of 137 with N-bromosuccinimide (NBS) or of at -50'. 19 with Brp at -50' gave phosphorobromidates in a parallel 139a

19a

-

232

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

f a s h i o n ( 1 3 7 ) . The s t e r e o c h e m i c a l r e a c t i o n c y c l e shown i n e q . [15] w a s g e n e r a t e d by S t e c and co-workers (compare eq. [14]) ( 1 3 7 , 1 6 5 b ) . The d i l i g o s t a t i c r e a c t i o n c y c l e shown i n e q . [ 1 6 ] w a s also c o n s t r u c t e d (166).

142b

139a t

142a

CH 2

. .

100%

'

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

233

'H NMR data for 139a ( 4 J p ~ ~ = 33.0 Hz) and 135b ( 4 J p c ~ = , 1.4 Hz), and their bromine analogues, indicated that 139a exists almost entirely in a chair conformation with an equatorial 4methyl group, while 139b is a conformational mixture composed of ca. 40-50% of a chair conformer with a equatorial 4-methyl group. The greater thermodynamic stability of 139a compared to 139b is a consequence of the disposition of substituents on phosphorus. Navech recorded similar observations with 2-phenoxy analogs of 1 3 5 : the one corresponding to 135a is ca. 100% chair conformer with an equatorial 4-methyl group, whereas the one corresponding to 139b is ca. 7 0 % of the conformer with axial 4-methyl and P-phenoxy groups (119a). 'H NMR and IR data indicated that 143a and 143b are predominantly chair conformations with an equatorial 4-methyl group (166). Mosbo and Verkade studied both the 4-methyl and ~ i s - 4 ~ 6 dimethyl-2-oxo-1,3,2-dioxaphosphorinane series (33,136aI142b). Hydrolysis of 146 (presumably the more stable isomer) in acidic or basic media afforded a mixture of phosphite diastereomers, 8b and 8a, in a ratio of 70:30 (33). The cis-4,6-dimethyl substitution sterically contrains the phosphites to chair conformations with diequatorial methyl groups (167). Equilibrium experiments demonstrated that 8a was more stable than 8 b , A G O 4 0 0 =

8a

+-

I

146

-1.6 f 1 kcal/mol (compare ref. 135). Speculation on the mechanism of phosphite hydrolysis has been presented (80,87,135,136b), but no definitive mechanism has yet been determined. Phosphite 3 , first synthesized by Denney and Denney (163) and assigned its configuration via X-ray analysis of the borane adduct (154b), was protonolyzed with anhydrous HBr to a 50:50 mixture of 8a and 8b, rather than just 8 a , as expected through an Arbuzov-type mechanism (33). The reaction of 8b and 19b with acetone in the presence of acid gave adducts 147a and 147b, whereas the epimeric phosphites (8a and 19a) were unreactive (33). Thus a distinct stereospecific dependence on the phosphorus configuration exists in the attack by acetone, which may be

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

234

3a

connected with hydroxy tautomer formation in the reactive diastereomers 8 b and 1 9 b (see eq. [17a]). The high reactivity of

147 a: R = CH3 b: R = H

1 4 8 a: R1/R2 = H/O b: R1/R2 = O/H

6 a: R1/R2 = b : R1/R2 = 5 a: Rl/R2 = b : RI/R~=

O/N(CH3)2 N(CH3)2/0 O/OCH3 OCH~/O

8 b and 19b could originate from a strong axial preference for the 2-hydroxy group in trivalent 1,3,2-dioxaphosphorinanes, as seen for the alkoxy group (see Sect. IV). Hydroxypropylation of 148a and 148b is also stereospecific (33). 0

OH

Bb Correct configurational assignments were proposed for the isomeric pairs 1 4 1 , 1 4 2 , 6, and 5 (136a,142b) on the basis of 'H NMR LIS data. Dipole moment and NMR data for both isomers of 6 and 5 indicated a strong preference for chair conformers with equatorial 4,6-methyl groups. Bartlett and Jernstedt arrived at phosphates related to 5 as intermediates in a stereoselective functionalization of homoallylic alcohols (eq. [17b]) (168). One diastereomer ( 2 4 9 ~ was ) formed predominantly (>go%), either by selective dealkylation of the intervening diethoxyphosphonium salt or by equilibration of an initially produced epimeric mixture ( 1 4 9 ) . The Michaelis-Arbuzov reaction entails condensation of a trivalent phosphorus ester w i t h an alkylating species to give an intermediate phosphonium salt, which decomposes to a phosphoryl compound (169). Hence this process could provide a variety of

B. E. MARYANOFF, R. 0. HUTCHINS AND C . A. MARYANOFF

0 -'

235

CH2 I

149a 2-R-2-oxo-1,3,2-dioxaphosphorinanes from single 2-alkoxy-1,3,2dioxaphosphorinanes. Bentrude and Hargis (170) employed this reaction to prepare 92 [for X-ray crystallography (102)l from thermodynamically less stable phosphite 13b, and 97 from 13a (isomeric purity in parentheses). Reaction of a mixture ( 3 ) enriched in less stable

2) CH30H

H'

OCH3

13b (77%) 1 ~ ~ 3 1

92 (71%)

or A

H'

13a (89%) JCH~I

97 (91%)

phosphite 3b with trityl chloride yielded, stereospecifically, a mixture enriched in 1 5 0 ( 7 8 ) , which was isolated for an X-ray diffraction study (84).

3b (72%)

150 (70%)

Bodkin and Simpson (171) reported that the reactions of certain 4-methyl-2-OR-l,3,2-dioxaphosphorinanes (R = C2H5, iC3H7) with alkyl iodides occur nonstereospecifically; however, the same phosphites did react sterospecifically with trityl fluoborate. To explain these results, pentacoordinate intermediates, which could undergo pseudorotation, were invoked (171). Interestingly, recovered phosphites from incomplete reactions showed stereomutation in that some the less stable

2 36

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

c i s phosphite had been converted t o t h e t r a n s isomer. This was r a t i o n a l i z e d by c o l l a p s e of t h e pseudorotated, p e n t a c o o r d i n a t e i n t e r m e d i a t e t o s t a r t i n g m a t e r i a l s . Denney and co-workers ( 1 7 2 ) , however, a t t r i b u t e d t h e stereomutation t o c a t a l y s i s by t r a c e s of a c i d and/or i o d i n e . Arbuzov and co-workers (150) a l s o found t h a t t h e s t e r e o s p e c i f i c i t y of t h e Arbuzov rearrangement of 137 with methyl i o d i d e depends on t h e r e a c t i o n c o n d i t i o n s , and could be made completely s t e r e o s p e c i f i c . The r e a c t i o n of 137b with benzyl c h l o r i d e was n o t s t e r e o s p e c i f i c , b u t harsh r e a c t i o n c o n d i t i o n s 22b predominated) ( 4 0 ) . had t o be employed (eq. "1;

The (Michaelis-Becker) r e a c t i o n of both 19a and 19b with benzyl i o d i d e and sodium hydride a f f o r d e d benzylphosphonates 22 with h i g h , b u t n o t complete, s t e r e o s p e c i f i c i t y ( r e t e n t i o n ) . The more s t a b l e phosphite 19a gave a 9O:lO r a t i o of 22a and 2 2 b , whereas t h e l e s s s t a b l e phosphite 1 9 b gave a 20:80 r a t i o . S t e c ' s group (173) explored t h e r e l a t e d Michaelis-Becker r e a c t i o n of 19 with methyl i o d i d e . Reaction of t h e sodium s a l t s w i t h methyl i o d i d e took place w i t h complete r e t e n t i o n b u t , when t h e a d d i t i o n of C H 3 I w a s delayed, a 92:8 mixture of 151a and

19a

NaH

151a

19b

NaH

-0

r191

B. E.

MARYANOFF, R . 0. HUTCHINS AND C . A. MARYANOFF

237

151b was o b t a i n e d , independent o f t h e s t a r t i n g p h o s p h i t e . S i n c e 19b and 19a d i d n o t e p i m e r i z e under t h e r e a c t i o n c o n d i t i o n s w i t h

C H 3 1 , t h e formation of t h e sodium s a l t and i t s e p i m e r i z a t i o n are

s l o w compared t o t h e r a t e of a l k y l a t i o n . S i n c e t h e s a l t from 19b i s o m e r i z e s t o t h e s a l t from 1 9 a , t h e f a v o r e d o r i e n t a t i o n f o r t h e sodio-oxy group i n 1,3,2-dioxaphosphorinanes i s e q u a t o r i a l . S i m i l a r s t e r e o r n u t a t i o n has been observed w i t h s a l t s of a c y c l i c hydrogenphosphites ( 1 7 4 ) . I t s h o u l d be noted t h a t t h e s t e r e o s p e c i f i c r e a c t i o n s of a c e t o n e and c h l o r a l w i t h c y c l i c hydrogen p h o s p h i t e s a r e r e l a t e d t o t h e Michaelis-Arbuzov p r o c e s s f o r P-C bond f o r m a t i o n ( 3 3 , 1 6 5 ) The r e a c t i o n of t r i a l k y l p h o s p h i t e s 137 w i t h c h l o r a l (Perkow r e a c t i o n ) , l e a d i n g t o v i n y l phosphate p r o d u c t s , i s a l s o s t e r e o s p e c i f i c (eq. [191) ( 1 7 5 ) . r

L

-

106

Bentrude and Yee (176) observed a s t e r e o s p e c i f i c ( r e t e n t i o n ) photoinduced Michaelis-Arbuzov r e a c t i o n of 13a (90% c i s ) w i t h iodobenzene t o o b t a i n 1 0 6 , a r e a c t i o n presumably i n v o l v i n g a phenyl r a d i c a l , which adds t o 13a t o g e n e r a t e an i n t e r m e d i a t e phosphoranyl r a d i c a l . The s t e r e o c h e m i s t r y of f r e e - r a d i c a l o x i d a t i o n a t t r i v a l e n t phosphorus w a s a l s o s t u d i e d ( 1 7 7 ) . T r a n s f e r o f ) sulfur oxygen from t-butoxy r a d i c a l ( ~ - C L + H ~ O - N = N - O - ~ - C L + H ~and from n - b u t y l t h i y l r a d i c a l (n-CqHqSS-n-C4Hg) t o 13b and 13a f u r n i s h e d t h e c o r r e s p o n d i n g o x i d e s and s u l f i d e s , r e s p e c t i v e l y , s t e r e o s p e c i f i c a l l y with r e t e n t i o n (177a). Neither s t e r e o s p e c i f i c i t y nor r e t e n t i o n of s t e r e o c h e m i s t r y is demanded by t h i s t y p e of r e a c t i o n , s u g g e s t e d t o i n v o l v e a t e t r a a l k o x y p h o s p h o r a n y l r a d i c a l , s i n c e t h e presumably t r i g o n a l - b i p y r a m i d a l r a d i c a l c o u l d

13a

238

STEREOCHEMISTRY OF PHOSPHORUS-CYCLDHEXANES

suffer permutational isomerism (pseudorotation). If competitive pathways do exist (eq. [20]), loss of t-CqHg* must be much faster than pseudorotation. Similar behavior was recorded for cyclic five-membered-ring phosphites (177b) and an optically active phosphine (177a). Free-radical Arbuzov reaction stereochemistries, involving CgHg-, (CH3)2N*, and cyclic phosphites, have been discussed with respect to permutational isomerization of the intermediate phosphoranyl radicals (179); the reactions were nearly stereospecific with retention. The compound with an axial lone pair (13b) was 6 to 8 times more reactive to (CH3)2N* than was 13a, in analogy to observations (125) for 137a and 137b (Sect. 111-B-1-C). Denney and Moskal (180) reported that phosphites 137a and 137b react with benzenesulfenyl chloride, under mild conditions, stereospecifically with retention to give phosphorothioates 152a and 152b, respectively. Their results were consistent with an ionic mechanism analogous to that of the Michaelis-Arbuzov reaction. Both 152a and 152b were suggested to assume preponderantly a chair conformation with the 4-methyl group equatorial.

152a

152b

Reactions of 137 and 1 9 with alkylsulfenyl chlorides proceed stereospecifically, as shown in eq. [21], (stereochemical interrelationships provided). 'H NMR data (300 MHz) indicated that 153a is virtually one chair conformer with equatorial 4-methyl and phosphoryl groups. The other isomer (153b) is also strongly favored in one chair form, with the ring methyl and methylthio groups equatorial. A disparity between the 3JpoCH(4ai (4.5 Hz) and 3JpOCH(6a) (8.0 Hz) values for 153b may be cause by some flattening or distortion of the ring and/or a small contribution from other possible conformers. A stereochemical correlation between the previously discussed anilides 143a and 143b and 153b and 1 . 5 3 ~respectively, ~ was accomplished through a novel, stereospecific P-N bond cleavage reaction, involving formation of the amide anion, treatment with CS2 to yield a thioacid salt, and methylation (eq. [211) (182). Stec and co-workers also related 153a and 153b to the trivalent heterocycles by stereospecific oxidation (N2O4) (183). Although the reaction of cyclic phosphites 137a and 137b with sulfenyl chlorides had been rationalized in terms of an ionic mechanism (180, 182), a generalization for all trivalent phosphorus esters cannot be proffered. Catechol phosphite 154 combines at low tern erature with CgHgSC1 to give a pentacoordinate intermediate ("P NMR) (184). A phosphorane can still arise through a series of ionic steps, but a direct, biphilic insertion process is also possible (185). Evidence for a phosphorane

B.

E . MARYANOFF, R.

0. HUTCHINS AND C. A. MARYANOFF

2 39

i n t e r m e d i a t e i n t h e r e a c t i o n o f 1 5 4 w i t h C 1 2 was a l s o reported ( 1 8 4 ) , and t h i s r e s u l t s h o u l d be n o t e d i n c o n s i d e r i n g t h e c h l o r i n o l y s i s o f p h o s p h i t e s s u c h as 137a and 137b. F u r t h e r m o r e , t h e r e a c t i o n s o f 137a and 137b w i t h n e o p e n t y l h y p o c h l o r i t e h a v e b e e n i n t e r p r e t e d i n terms o f ephemeral p e n t a c o o r d i n a t e i n t e r m e d i a t e s , which are s u b j e c t t o p e r m u t a t i o n a l i s o m e r i z a t i o n t h a t i s c o m p e t i t i v e w i t h i o n i z a t i o n (186). I n t e r e s t i n g l y , t h e less s t a b l e isomer 137a r e a c t e d w i t h neo-CgH11OCl much more s t e r e o s p e c i f i c a l l y t h a n d i d 137b.

R e a c t i o n o f c y c l i c p h o s p h i t e s w i t h h a l o a m i n e s [examples o f which have a l r e a d y mentioned ( 7 O I 7 1 b , 7 2 a , 1 3 7 ) ] f a l l i n t o t h e same c a t e g o r y as t h e r e a c t i o n s o f p h o s p h i t e s w i t h a l k y l and s u l f e n y l ( t h e n 10') 137b r e a c t s w i t h (CH3)zNCl t o g i v e h a l i d e s . A t -20' a 9 : l m i x t u r e o f 142a and 142b (90% r e t e n t i o n ) , a n d a t 0' 137a r e a c t s t o g i v e a 2 : 3 m i x t u r e o f 142a and 142b (60% r e t e n t i o n ) . T r e a t m e n t o f 78b w i t h ( C H 3 ) z N C l i n r e f l u x i n g benzene gave a 2 : l m i x t u r e of 142a and 142b (67% r e t e n t i o n ) (phosphoramides 142a and

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

240

142b did not isomerize thermally) (136a). Treatment of phosphite 3a with (CH3 2NC1 afforded an epimeric mixture of 6 (60% retention) (142b) In the reaction of 137a and 1 3 7 b with various chloramines (CH3)2NC1, (C2Hg)2NClI C ~ H ~ O N C ~ under ] , a variety of conditions, loss of stereochemical integrity was consistently observed (187), in contrast to the results of other workers (137). Stereospecificity varied with solvent, temperature, and choice of chloramine (187). Stereomutation here (187) could be associated with a reaction with a phosphorane intermediate. The rates of reaction of trivalent phosphorus compounds having different nucleophilicites with (C2Hg)2NCl did not follow their expected order, suggesting the prevalence of a direct insertion mechanism as opposed to an ionic one (which may still be competing) (187). Thiocyanogen combines with 19a (94%) in a nonstereospecific fashion, giving 155a and 155b in a ratio of 79:21, but 19b (97%) reacted stereospecifically, giving a 2:98 ratio (139a). Bromo derivatives 105a and 1 0 5 b were converted to 155a and 155b. re-

19a

155a

155b

spectively, with nearly complete inversion (eq. [ 2 2 ] ) . The SCNion and other nucleophiles catalyze the formation of 155a from thermodynamically less stable 1 5 5 b ; 155a probably prefers a chair conformation with equatorial 4-methyl and phosphoryl groups. Lopusifiski and co-workers assembled a group of diverse reactions into an intriguing stereochemical correlation sequence (eq. [23]) (139a,188). On the basis of hard-soft acid-base (HSAB) concepts, the thiocyanate displacement probably takes place by direct formation of the phosphoroisothiocyanatidates ( 1 5 5 ) , without the intervention of phosphorothiocyanatidates ( 1 5 9 ) ; the hard phosphoryl center is matched with the hard nitrogen site of the arnbident thiocyanate ion. However, the thiocyanogen re-

k>(:

CH

137b

Br2

KSCN

~

156b (95% cis)

137a

-(

’
155a (94% trans) 4 I

\//

Br

156a (83% trans)

*

155b (76% cis)

156b

(100%) NH3

-

O\ ,""2

cH?-

P\

0

0

(100%)

c12

-C6H11NH2 (100%)

155b (64% c i s )

A

4

(100%)

C6H1 l N H 2

(100%)

c12

158a

138a

t

I

S8

(See eq. [221)

A

(See eq. [221)

137a 137b

lie

*

s02c12

* 158b

AgCN

159a

t

1

255b A

,P,

[241

1Lo 241

242

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

actions probably involved phosphorothiocyanatidates ( 1 5 9 ) , arising by nucleophilic attack of the soft phosphinyl anion on the soft sulfur site of (-SCN)2, with a subsequent thiocyano-isothiocyano rearrangement (189). Stereochemical evidence that this rearrangement proceeds by an SN~(P)mechanism has been presented (139b). Diastereomeric phosphorothiocyanatidates ( 1 5 9 ) were synthesized by the reaction of silver cyanide with phosphorylsulfenyl chlorides of known geometry, developing the stereochemical reaction cycle shown in eq. [24]. Condensation of 158a with AgCN at -15' gave only one phosphorothiocyanatidate, 159a (31P NMR), which rapidly isomerized at ambient temperature to a 74:26 mixture of l S 5 b and 155a. The other sulfenyl chloride, 1 5 8 b , gave a 67:33 mixture of 159b and 1 5 9 a , which rearranged to mainly 155a. The lack of complete stereospecificity (inversion) in the RSCWRNCS process derives from the competing conversion of 155b to 155a. A full disclosure of this work has recently appeared (139~). Electrophilic substitution of cyanogen chloride on 137b was not stereospecific, producing a mixture of phosphorocyanidates (137b/137a of 94:6 gave 160/160b of 73:27; 137b/137a of 18:82 gave 160/160b of 78:22) (140). Apparently, 160a is thermodynamically more stable than 1 6 0 b , 160a probably adopting chiefly a chair conformation with equatorial 4-methyl and phosphoryl groups. Oxidation of 161 with N2O4 led exclusively to 160a.

160a

160b

Phosphoroisocyanidate 162 thermally rearranges to the corresponding phosphorocyanidate 1 6 3 ; the stereochemical character of this

161

isomerization is still open to question (190). Attention is now directed to the stereochemistry of nucleophilic substitution reactions at tetracoordinate phosphorus, examples of which have been mentioned in isolated circumstances [e.g., displacement of (1) halide by thiophenoxide, amines,

B.

E. MARYANOFF, R. 0. HUTCHINS AND C . A. MARYANOFF

9o(R = C1)

243

KNCSe

cH3m0 rc

CH3

162 a l k o x i d e , t h i o c y a n a t e ; ( 2 ) t h i o c y a n a t e and i s o t h i o c y a n a t e by thiocyanate i o n ] . Wadsworth and Horton (74) r e p o r t e d t h a t t h e d i s p l a c e m e n t of c h l o r i d e from 67 w i t h p i p e r i d i n e i s v i r t u a l l y s t e r e o s p e c i f i c w i t h i n v e r s i o n [ f i r s t assumed (74) and l a t e r e s t a b l i s h e d ( 7 1 b ) l ;

164a

164b

Edmunson made a s i m i l a r o b s e r v a t i o n ( 7 2 a ) . On t h e c o n t r a r y , solv o l y s i s of 67 i n methanol formed a p a i r o f d i a s t e r e o i n e r i c phosp h a t e s , 164a and 1 6 4 b , i n a r a t i o of 2 : l . Methanolysis i n t h e p r e s e n c e of s i l v e r n i t r a t e was claimed t o produce o n l y one i s o m e r , corresponding t o 1 6 4 a ; t h i s r e s u l t w a s a t t r i b u t e d t o an SNl(P) mechanism i n v o l v i n g s t e r e o s e l e c t i v e a t t a c k o f methanol on an i n t e r m e d i a t e phosphorylium i o n . The r e s u l t w i t h o u t Ag' c o u l d be i n t e r p r e t e d i n terms of an s N 2 ( P ) p r o c e s s i n v o l v i n g a p e n t a c o o r d i n a t e s p e c i e s , thus accounting f o r t h e lack of s t e r e o s p e c i f i c i t y . Methanolysis ( u s i n g NaHC03) gave e s s e n t i a l l y p u r e 164a ( i n v e r -

244

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

s i o n ) . Loss of s t e r e o c h e m i c a l i n t e g r i t y i n t h e m e t h a n o l y s i s o f 139a was mentioned i n eq. [14] (136b). Displacement on 67 w i t h d i f f e r e n t m i n e s y i e l d e d o n l y one of t h e two p o s s i b l e i s o m e r s , w i t h i n v e r s i o n o f c o n f i g u r a t i o n a t phosphorus ( 7 1 b ) . A sample o f v i g o r o u s l y p u r i f i e d 67 w a s isomeri z e d by L i C 1 , g i v i n g a 2 . 5 : l mixture (room t e m p e r a t u r e ) of 67 and 70, r e s p e c t i v e l y . However, o t h e r s a l t s ( L i C 1 0 4 and L i O T s ) were i n e f f e c t i v e under t h e same c o n d i t i o n s . Vacuum d i s t i l l a t i o n o f pure 67 a l s o caused e p i m e r i z a t i o n t o a 2 . 5 : l m i x t u r e , which gave 65 and 66 i n a 2 . 5 : l r a t i o on t r e a t m e n t w i t h p i p e r i d i n e (7I.b). The s t e r e o c h e m i c a l outcome of t h e r e a c t i o n of 67 w i t h pheno x i d e i o n s i s dependent on t h e b a s i c i t y of t h e n u c l e o p h i l e (Tab l e 9) (71b). None o f t h e phenoxy d e r i v a t i v e s i s o m e r i z e d a l o n e Table 9 S t e r e o c h e m i s t r y of t h e Reaction of 67 w i t h p a r a - S u b s t i t u t e d Phenoxide I o n s R

% I65a 57 50 40 36 6

OCH 3 CH3 H Br NO2

67

% I65b 43 50 52 64

94

ArO-Na

165a 165b i n s o l u t i o n , b u t 165b ( R = N02) was s u s c e p t i b l e t o e p i m e r i z a t i o n i n t h e p r e s e n c e of sodium p n i t r o p h e n o x i d e , u l t i m a t e l y a f f o r d i n g a 2 . 5 : l mixture of 165a and 165b (R = N02). Under heterogenous displacement c o n d i t i o n s t h e p r o p o r t i o n of 165a ( r e t e n t i o n prod u c t ) was i n c r e a s e d f o r R = H I N02, OCH3. Treatment o f 165b ( R = NOg) w i t h NaOCgHg gave 165a and 165b (R = H ) i n a 1:3 r a t i o (predominant r e t e n t i o n ) . P h o s p h o r o c h l o r i d a t e 67 underwent subs t i t u t i o n w i t h NaSCgH5 t o g i v e a 10:90 m i x t u r e o f cis- and t r a n s - 7 1 , and t r e a t m e n t of c i s - 7 1 w i t h N a O C g H 5 gave 165b ( a l m o s t complete r e t e n t i o n ) ( 7 1 b ) . Wadsworth and co-workers u l t i m a t e l y downplayed t h e s i g n i f i cance of a d i s s o c i a t i v e , S N l ( P ) , mechanism f o r t h e d i s p l a c e m e n t

€4.

E. MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF

245

reactions at a phophoryl center (7133,961, except, perhaps, for the cases of benzoyl, phosphoryl, and 2,4-dinitrophenyl phosphate esters (191). Data on the stereochemical influence of solvent and salt additives have been published (96). Evidently, the stereochemistry of nucleophilic substitution at a phosphoryl center may be complex an? thus difficult to interpret satisfactorily. Further study (192) revealed that substitution reactions were dependent on the cation employed, with Li' ion causing dramatic stereochemical reversals in the reaction of 67 with p CH~OC~HL+O-. Inch and co-workers have investigated the stereochemistry of displacement reactions on novel bicyclic phosphorinanes derived from a-D-glucopyranoside (138,193,194). On treatment with SbF3, 1676 (R = C1) produced a single phosphorofluoridate which c1

I

166 R-Px*

167h ( R

=

C1)

o = i x -

0

R

I1 CH3O

167a

OCH 3

CH3O

CH3O

167b

OCH 3

was assigned structure 167b (R = F) (138b), identical to the product from 166 and Me2NP(O)F2 (138b). Treatment of 167b (R = C1) with ethanol gave a 9:l mixture of 167a and 1 6 7 b (R = OCzHg), and with dimethylamine gave a 1O:l mixture of 167a and 167b [R = N(CH3)2] (largely inversion) (138). However, 1 6 7 b (R = C1) combined with CH3MgI to give a preponderance of retention at phosphorus, yielding a 1:5 mixture of 167a and 167b (R = CH3), possibly because of complexation of magnesium with the P=O bond (138). Stereochemical data on some displacement reactions with the phosphoroglycosides are collected in Table 10 (138b). These observations may be compared with those of Wadsworth and coworkers (70,71b,191), Bodkin and Simpson (136b), Stec and coworkers (137,1671, and Duff and Trippett (76);again, stereochemical complexity is apparent, being dependent on the particular leaving groups and nucleophiles. Reaction of 166 with CH3P(O)F2 afforded 167 ( R = CH3) and, with C2H50P(O)C12, afforded 167 (R = OC2H5) (193). In the reaction with CH3P(O)F2 the ratio of products was time-dependent, starting out at a 1:5 mixture of 167a and 167b (R = CH3)

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

246

Table 10 Stereochemistry of Phosphoroglycoside Displacements (138b) Compound

Ratio of Inversion to Retention

Reagent

23 >85

0.77

10 11

>60

ca. 0 0.2 0.35 1.77 0.25 ca. 0 ca. 0 >loo ca. 0 0.2

>loo done equivalent. bThree equivalents.

and finally giving an ca. 1:l mixture. Cyclization experiments with 168 confirmed that 167b (R = CH3) was a kinetic product (eq. [26a]). At equilibrium the ratio of 167a to 167b (R = CH3) was 4:3, which provides an estimate of the positional preference of CH3 vs. P=O in 2-oxo-~,3,2-dioxaphosphorinanes. Since the diastereomers of 168 disappeared at the same rate, the rate of epimerization (at phosphorus) had to be greater than the rate of ring closure to 1 6 7 (R = CH3). In the reaction of 166 with 1 6 7 ~(R = CH3)

thermodynamic product

+

167b (R

=

CH3)

+ 167b

(R =

CH3)

CH3)

kinetic product

168 167a ( R

=

I

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

167a (R

=

C2H5MgBr

CH3)

'

(inversion) ' 3 H L

4P' ..C6H5

5.2C'

R-(+)-169 167b

247

[26b]

( R = CH3)

S- (-)-169

C2H50P(O)C12, 167a (R = OC2Hs) predominated initially, but it eventually rearranged to form mostly 167b (R = K2H5). Since there is a commanding axial preference for OC2H5 over P=O in 2-oxo-1,3,2-dioxaphosphorinanes, the more rapid generation of 167a ( R = OC2H5) must reflect the disposition of an intervening species, possibly having a nonchair conformation. Inch and co-workers rationalized their results on intermediate phosphoranes possessing mainly twist-boat conformations (viz., 170). Thus the postulated intermediate leading to less

I70 stable 167b (R = CH3) has R 1 = CH3 and Rg = 0 (in 170), with the methyl group in a sterically unhindered pseudoequatorial position. On the other hand the postulated intermediate leading to 167a (R = CH3) would have the P-methyl group in a more sterically taxing arrangement. The same argument may be applied to the P-ethoxy case, The phosphorus configurational assignments for 167 (R = CH3) were verified by transformation of 167a and 167b (R = CH3) into highly enantiomerically enriched phosphine oxides, R-(+)169a and S-(-)-169a, respectively (eq. [26bl) (194). This constitutes a novel procedure for the synthesis of optically active phosphine oxides, analogous to the menthylphosphinate routes of Mislow and co-workers (195). Phenylmagnesium bromide causes the cleavage of only the P-O6 linkage of 167 (R = CH3) with inversion to give exclusively the 171 pair (R = CgH5) (eq. [27]). With methanolic sodium methoxide, ring-opening of 167 (R = CH3) first occurred by cleavage of the P-06 bond with inversion, giving the 172 series (R = OCH3), followed by eventual transphosphorylation to generate the 172 series (R = OCH3) (194).

248

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOIIEXNES

-

( R 167a = CH3)

R

o.

/R

CH20H

+

cH(p\~% cH3O

CH3O

XH3

OCH 3

171a

172a

172b D e r i v a t i v e s of a-D-galactopyranoside (173) were b r i e f l y s t u d i e d by Inch and co-workers (193b). When R i s CH3, 173b i s more s t a b l e , b u t 173a i s more s t a b l e w i t h R = OC2H5. I n t h e

173a

173b

s y n t h e s i s of t h e g a l a c t o p y r a n o s i d e s e r i e s (R = CH3 and O C 2 ~ 5 ) t h e l e s s s t a b l e d i a s t e r e o m e r s were k i n e t i c a l l y f a v o r e d . Comparison of t h e g a l a c t o - and glucopyranose s e r i e s i n d i c a t e s t h a t t h e s t e r e o c h e m i c a l r e q u i r e m e n t s f o r t h e r a t e of f o r m a t i o n and s t a b i l i t y of t h e 1,3,2-dioxaphosphorinane r i n g are independent of t h e r i n g f u s i o n ( c i s o r t r a n s ) . I n a f u r t h e r comparison, w h i l e t h e t r a n s - f u s e d g l u c o s e series underwent opening of t h e 1,3,2-dioxaphosphorinane r i n g r e a d i l y w i t h Grignand r e a g e n t s , t h e c i s - f u s e d g a l a c t o s e s e r i e s w a s i n e r t t o a t t a c k , even under strenuous conditions. Okruszek and S t e c o b t a i n e d p h o s p h o r o f l u o r i d a t e s 174a and 174b a c c o r d i n g t o t h e r e a c t i o n shown i n e q . [28] ( 1 4 1 , 1 9 6 ) . N u c l e o p h i l i c s u b s t i t u t i o n on 139a by 1 e q u i v o f NH4F f u r n i s h e d a mixture e n r i c h e d i n 174a (predominant i n v e r s i o n ) , b u t u s e of

B.

E . MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFP

249

133

174a ( 1 0 % )

174b (90%)

e x c e s s NH4F e q u i l i b r a t e d t h e system ( e q . [ 2 9 ] ) . ' H NMR d a t a i n d i c a t e d 174b t o be v i r t u a l l y one c h a i r conformation, w i t h an e q u a t o r i a l 4-methyl group, whereas 174a was c o n f o r m a t i o n a l l y heterogeneous w i t h a l a r g e p r o p o r t i o n of a x i a l 4-methyl conf o r m e r , r e f l e c t i n g t h e s t r o n g p r e f e r e n c e of f l u o r o f o r an a x i a l p o s i t i o n vs. a P=O bond (141,196).

139a The k i n e t i c s of h y d r o x i d e - c a t a l y z e d h y d r o l y s i s of e p i m e r i c phosphates 175 s u p p o r t e d a s t e r e o e l e c t r o n i c t h e o r y f o r t h e phosphate e s t e r h y d r o l y s i s mechanism ( 1 9 7 ) . The e q u a t o r i a l phenoxy d e r i v a t i v e 175b "hydrolyzes c o n s i d e r a b l y f a s t e r " t h a n i t s a x i a l epimer 175a. A more e x t e n s i v e r a t e s t u d y , performed by

175b

175a Y

I

' 0

N-/ OH

176 ( X I Y =

0 , OR)

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

250

Engels and Schlaeger on epimeric adenosine 3',5'-cyclic phosphates 1 7 6 , showed stereochemical rate differences in the same direction as seen with 175 (198); further discussion of this work appears in Sect. 111-D-i. 2-Thiono and 2 - S e l e n o Compounds. 'I4 NMR data and assignments for the anancomeric derivatives 2 have been published (30). Other anancomeric 2-thiono compounds ( 1 7 7 , R = CgH5, C1, OCgH5) have been described,b u t no assignment of configuration was offered (119a).

qHxR1 H

R2

S) 177 Hydrothiolysis of stereoisomeric mixture 178 gave a single phosphorothioite 2 0 a , whereas the reaction of the corresponding phosphorochloridite gave both isomers of 20 (199). Dipole moment measurements indicated a major chair conformation with the P=S group equatorial for 2Oa and 179 (199).

178 'J~H coupling constants can be a useful criterion for establishing the orientation at phosphorus in compounds having a P-H group (200). The 'JPH value for 2oa is ca. 595 Hz , compared to ca. 635 Hz for 2 0 b , and the former is known to have equatorial P=S and axial hydrogen groups. Bartle and co-workers (109) reported l J p ~= 600 Hz for 1 8 0 , which implies a preference for an equatorial P=S bond.

179

180

182

Aminomethylation of 20a occurs stereospecifically (201). The Michaelis-Becker reaction of 20a with C H ~ Iproduced a single compound ( 1 8 1 ) (201), with the same dipole moment as the material supplied from the condensation of lI3-butanedioland

B. E . MARYANOFF, R. 0. HUTCHINS AND C . A. MARYANOFF

251

CH3P(S)C12 ( 1 5 1 a ) ; t h u s t h e Michaelis-Becker r e a c t i o n i s a l l e g e d l y s t e r e o s p e c i f i c w i t h r e t e n t i o n . The c o n f o r m a t i o n a l d i s t r i b u t i o n f o r 181 was e s t i m a t e d t o b e ca. 80% 1 8 2 , which h a s t h e l e s s s t a b l e d i s p o s i t i o n of s u b s t i t u e n t s a b o u t phosphorus (see S e c t .

181 111-B-1-b) ( 1 5 1 ) . A c o n s i d e r a b l e p o p u l a t i o n of t h e conformer w i t h a x i a l 4-methyl and s e l e n o groups was i n d i c a t e d f o r 23a by t h e 4JPOCCH3 v a l u e of o n l y 1 . 0 Hz ( i n CDC13) ( 4 0 ) ; t h e o t h e r i s o m e r , 2 3 b , was v i r t u a l l y one c h a i r conformer w i t h e q u a t o r i a l 4-methyl and benzyl groups.

23a S t e c and co-workers ( 2 0 2 ) p r e p a r e d 2Oa and i t s s e l e n o a n a l o g 21a from 135. R e a c t i o n of p h o s p h o r o c h l o r i d i t e 133 w i t h H2S a f f o r d e d a mixture of i s o m e r s of 20, which i n t u r n s u p p l i e d a m i x t u r e of 183 ( X = S ) on t r e a t m e n t w i t h C C l 4 and ( C H 3 ) z N H n e t i n v e r s i o n ) ( 2 0 2 ) . R e a c t i o n of i s o m e r i c a l l y p u r e 20a w i t h C C 1 4 and ( C H 3 ) z N H proceeds w i t h 91% i n v e r s i o n , g i v i n g 183b. A s i m i l a r chemical c o r r e l a t i o n was performed on t h e 2-seleno ana-

x

= s, X = Se.

j12s

07% 83%

1 35

2ua ( X = S ) 21a ( X = se)

x x

I

s, 91% c C l 4 = Se, 83% ( C H 3 ) z N H =

193b 183b

193a

+

193b

252

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

logues. The CCl4-amine reaction was also described by a Russian group (203), who extended the process concept into a stereospecific synthesis of aryl thiophosphate derivatives (the direction of the steric course was not mentioned) (203). Diastereomerically pure 184 (X = S ) , prepared by two methods (eq. [30]), was shown by 'H NMR to have a chair conformation with equatorial 4-methyl and P=S groups (204). Alkaline hydrolysis, aminolysis, and methanolysis of 184 (X = S) occurred predominantly with inversion (92 to 100%). 133

CH3C ( 0 )SC1

1301

H20

184 (X = S)

20

Wadsworth and Tsay suggested that 1 8 5 ~and 185b (R = C1) favor a chair conformation with equatorial P=S bonds (205). Nucleophilic substitution on 185b (R = C1) by phenoxides varied in steric direction: inversion decreased with the basicity of the nuclcophile (Table 11). In contrast, treatment of various cis-arylthiophosphates 185a (R = OAr) with sodium 4-methylphenoxide resulted in nearly complete retention (>95%, O h = OCgH5, Table 11 Stereochemistry of Displacement Reactions of 185b Phenoxide 4-OCH3 4-CH3 4-Br

%

Trans (retention) 50 40 24 5

%

Cis (inversion) 50 60 76 95

~-B~c~HL,o, ~ - N o ~ c ~ H ~In o )the . displacement reactions of 185b (R = C1) and 1 8 5 ~(R = 4-NO2CgH40) added salts had a dramatic effect on the stereochemical outcome. The results on the 2thiono system generally paralleled those for the 2-0x0 system; however, equilibration of isomeric pairs 185 (R = C1, 4-N02CgH4O) was much less facile. Nevertheless, the compound was equilibrated to a 6:l ratio (185a and 1 8 5 b ) ; equilibrium composition in the corresponding 2-0x0 system was ca. 2.5:1 ( 1 6 5 ~ and 1 6 5 b ) , within the same net stereochemical bias. Substitution reactions with fused 2-thiono-1,3,2-dioxaphos-

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

253

p h o r i n a n e s 186 have been r e p o r t e d (138b,194,206). Configurat i o n a l assignments of t h i o n e s 186 (R = C H 3 , C6H5, OC2H5) were o b t a i n e d through c o r r e l a t i o n w i t h t h e 2-0x0 s e r i e s v i a o x i d a t i o n ( 2 0 7 ) w i t h m-chloroperbenzoic a c i d ( 2 0 6 ) . E t h a n o l y s i s of 186a ( R = C l ) took p l a c e w i t h predominant i n v e r s i o n b u t , when sodium e t h o x i d e was added, mostly r e t e n t i o n was observed ( 1 3 8 b ) .

185 a: R1/K2 = R/S

b : R1/R2 = S/R

186 a : R 1 / R 2 = R/S b : R1/R2 = S/R

Reaction of 186a ( R = C H j ) w i t h C6HsMgBr r e s u l t e d i n two ring-opened p r o d u c t s , 187a and 188b ( b o t h w i t h i n v e r s i o n a t phosp h o r u s ) , i n a r a t i o of ca. 4:3. Diastereomer 186b (R = CH3) gave only one p r o d u c t w i t h r e t e n t i o n , 188b ( 1 9 4 ) . R e a c t i o n of 186a ( R = C 6 H 5 ) w i t h CH3MgI a f f o r d e d one ring-opened d e r i v a t i v e ( 1 8 7 b ) w i t h i n v e r s i o n ; whereas 186b (R = C b H 5 ) gave two p r o d u c t s w i t h r e t e n t i o n , 187b and 188a, i n a r a t i o of c a . 7 : l ( 1 9 4 ) . Methanolysis of 186 (R = C H 3 , C g H 5 ) f i r s t r e s u l t e d l a r g e l y i n formation of t h e ring-opened compounds 189b and 2 9 0 b , followed by m i g r a t i o n of t h e phosphoryl moiety from 04 t o 0 6 , g i v i n g 189a and 190a. I n t h e methanolyses t h e 186b s e r i e s r e a c t e d more slow-

l y , and underwent t r a r s p h o s p h o r y l a t i o n more r a p i d l y , t h a n d i d t h e 186a s e r i e s . Methanolyses and t r a n s p h o s p h o r y l a t i o n t e n t a t i v e l y o c c u r c h i e f l y by i n v e r s i o n of c o n f i g u r a t i o n a t phosphorus (194). Displacement on 184 (X = S , S e ) w i t h methylmercaptide o c c u r r e d w i t h n e t i n v e r s i o n , g i v i n g a 191a/191b r a t i o of c a . 65:35 ( 1 8 3 ) . A 69:31 mixture o f 191a and 1 9 1 b (X = S ) w a s o b t a i n e d from 192 v i a a novel amide c l e a v a g e p r o c e d u r e , followed by

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

254

192 m e t h y l a t i o n (eq. [ 3 1 ] ) ( 1 8 2 ) . Performance of t h e same sequence on 193a and 193b r e s u l t e d i n a l k y l a t i o n only on s e l e n i u m i n a s t e r e o s p e c i f i c c o n v e r s i o n ( r e t e n t i o n ) (eq. [ 3 2 ] )

.

193b Although 184 ( X = S ) and i t s bromo analogue 195 e x p e r i e n c e n u c l e o p h i l i c d i s p l a c e m e n t ( e . g . , w i t h methoxide) w i t h complete i n v e r s i o n of c o n f i g u r a t i o n a t phosphorus, t h e c o r r e s p o n d i n g f l u o r o compound 18a mainly r e a c t s w i t h r e t e n t i o n when s u b j e c t e d t o hydroxide o r methoxide (eq. [ 3 3 ] ) ( 3 7 ) . With hydroxide t h e r a t i o of 194a and 194b (R = H ) was 35:65, and w i t h methoxide t h e

194a

194b

195

B , E . MARYANOFF, R.

0. HUTCHINS AND C . A. MARYANOFF

255

r a t i o of 194a and 194b ( R = CH3) was 16:84. The p o o r e r leavi n g group, f l u o r i d e , may have c o n f e r r e d a l o n g e r l i f e t i m e t o a p e n t a c o o r d i n a t e i n t e r m e d i a t e , a l l o w i n g time f o r p e r m u t a t i o n a l i s o m e r i z a t i o n t o compete e f f e c t i v e l y . E q u i l i b r a t i o n of 171b w i t h NH4F a f f o r d e d a f i n a l 1 8 a / 1 8 b r a t i o of 83:17. R e a c t i o n of 195

196

197a \

197b J

V

t m i x t u r e of o x i d e s ( 3 7 ) and 196 (141) w i t h NH4F o c c u r r e d w i t h c a . 80 t o 85% i n v e r s i o n ( p o s s i b l y g r e a t e r because of f l u o r i d e - i n d u c e d e p i m e r i z a t i o n ) . E q u i l i b r a t i o n of an 80:20 m i x t u r e of 197a and 1 9 7 b w i t h NH4F gave a 15:85 f i n a l m i x t u r e , comparable t o t h e r e s u l t obt a i n e d f o r t h e 2-thiono system. Thus t h e 2 - f l u o r o group h a s a s t r o n g a x i a l p r e d i l e c t i o n a g a i n s t P=S and P=Se, as w e l l as a g a i n s t P=O ( S e c t . 1 1 1 - B - 1 - a ) .

C.

Other Phosphorinane Systems 1.

Z., 2 - O x a p h o s p h o r i m n e s

The c i s and t r a n s isomers of 1 9 8 and 1 9 9 were i n i t i a l l y a s s i g n e d (208) s t r u c t u r e s based on t h e m o d i f i e d Auwers-Skita r u l e ( 2 0 9 ) . The p r e s e n c e of two phosphoryl I R maxima f o r t r a n s 198 and c i s - 1 9 9 s u g g e s t e d c o n f o r m a t i o n a l m i x t u r e s , whereas cis198 and t r a n s - 1 9 9 were o s t e n s i b l y a preponderance o f one c h a i r form, probably w i t h a x i a l ethoxy groups. 'H NMR d a t a i m p l i e d t h a t cis- and t r a n s - 1 9 9 d i f f e r mainly by a change i n o r i e n t a t i o n about t h e phosphorus atom, t h e 6-methyl group c o n s t a n t l y occupyi n g an e q u a t o r i a l p o s i t i o n ( 2 1 0 ) . E q u i l i b r a t i o n of t h e isomers

198

199

200

2 01

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

256

of 199, with CF$OOH, demonstrated trans-199 t o be more s t a b l e (-AHo = 1.50 2 0.15 kcal/mol, -AG1800 = c a . 0.5 kcal/mol) ( 2 1 0 a ) . Additional d a t a supported t h i s d e s c r i p t i o n f o r t h e isomers of 198 ( 2 1 1 ) . Although cis-198 was suggested t o be a mixture of conformers, no change i n i t s 'H NMR spectrum was recorded from -60' t o +120°. E q u i l i b r a t i o n of cis- and trans-198 showed t h a t t h e c i s isomer i s more s t a b l e by 0.3 kcal/mol. The c i s isomer o f 200 appeared t o be a mixture of t w o c h a i r conformers (eq. [ 3 4 ] ) , w h i l e t h e t r a n s isomer i s mostly one c h a i r form, b u t t h e e v i dence p r e s e n t e d i s n o t conclusive (212a). E q u i l i b r a t i o n o f cisand trans-200 i n d i c a t e d t h a t t h e t r a n s isomer i s more s t a b l e ( - A H o = 0.9 2 0.1 kcal/mol, = ca. 0.5 kcal/mol).

0

cis-200 The c i s and t r a n s isomers of 201 were suggested t o have t h e same arrangement of s u b s t i t u e n t s on phosphorus, t h u s d i f f e r i n g i n t h e i r methyl o r i e n t a t i o n . E q u i l i b r a t i o n gave a 1:l m i x t u r e , s i g n i f y i n g equal s t a b i l i t y (AH = 0 ) f o r t h e isomers. The l a c k of change i n t h e l H NMR s p e c t r a f o r t h e 201 isomers showed t h a t one Conformation was s t r o n g l y favored, presumably t h e one having an a x i a l ethoxy group (212b). X-Ray a n a l y s i s o f 202b r e v e a l e d two t y p e s o f s t r u c t u r e s f o r t h e 1,2-oxaphosphorinane r i n g i n t h e u n i t c e l l : a n e a r l y i d e a l b o a t conformation and a skew-boat conformation. The phosphoryl oxygen was found i n a pseudoaxial p o s i t i o n (213). The conformat i o n i n s o l u t i o n f o r 202b and 202a w a s claimed t o be a s l i g h t l y d i s t o r t e d b o a t s t r u c t u r e (270-MHz 'H NMR) ( 2 1 3 ) . A t w i s t - b o a t conformation was observed f o r 48a and 48b i n t h e s o l i d s t a t e , and f o r 48a i n s o l u t i o n ( s e e S e c t . 1 1 1 - C - 4 ) .

202a ( R = H )

J

p-TsC1

pyr

202b ( R = p-Ts)

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

2.

257

I , 3,2-Oxazaphosphorimnes

The 1,3,2-oxazaphosphorinane r i n g system i s found i n t h e a n t i c a n c e r agent cyclophosphamide, which i s d i s c u s s e d i n S e c t . 111-D-2. Navech and co-workers have s t u d i e d t h i s r i n g system s p e c t r o s c o p i c a l l y (53,54,118,214). A n a l y s i s of 'H NMR s p e c t r a l d a t a r e v e a l e d a s t r o n g c o n f o r m a t i o n a l p r e f e r e n c e f o r one c h a i r form f o r 203a (X = 0 , S ) ( 5 3 ) . IR d a t a (vmax P=O) f o r 203a (x = 0 ) , 203b ( X = 0 ) , and 204 ( R ' = CH2CgH5, R = CgH5, X = 0 ; R' = H I R = CgH50, X = 0) were i n t e r p r e t e d i n terms of c h a i r conformers w i t h a p r e f e r e n t i a l a x i a l phenoxy group f o r 3O n i t r o g e n compounds and e q u a t o r i a l phenoxy group 2 O n i t r o g e n compounds ( 2 1 4 a ) . I n o t h e r , unbiased d e r i v a t i v e s having a 3' n i t r o g e n , phenoxy and ethoxy were a s s i g n e d a x i a l , w h i l e d i a l k y l a m i n o was a s s i g n e d an e q u a t o r i a l o r i e n t a t i o n a l p r e f e r e n c e v s . t h e P=O bond.

203a

203b

204

Condensation of 205 w i t h (CH3)2NP(O)F2 s u p p l i e d one c y c l i c p r o d u c t , 2 0 6 , a s s i g n e d a t r a n s s t r u c t u r e , c h i e f l y a c h a i r conformation w i t h e q u a t o r i a l 4-methyl and phosphoryl groups ( 1 9 6 ) . The o r i e n t a t i o n of t h e N-methyl group was n o t a d d r e s s e d .

206

205

Aminoglycoside 207 was c o n v e r t e d i n t o a s e r i e s of f u s e d 1,3,2-oxazaphosphorinanes, 208 ( R = CH3, CgHg, C1, OR'; 2 = 0 o r S ) (215). I n t h e CH3P(O)C12 r e a c t i o n mainly 208b (R = CH3, 2 = 0 ) w a s i n i t i a l l y produced, b u t on prolonged h e a t i n g it was con-

Rp(Z)C12 Z = O o r S

CH3O

(333

207

a : X/Y

Y

= R/O o r

b : X/Y = o o r CH3O

OCH 3

208 I

s

S/R

258

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

verted to a mixture having of a 1.3:l ratio of 208b and 208a (R = CH3, 2 = 0),respectively. This result is comparable to that seen with the related 1,3,2-dioxaphosphorinane analog (138b). A 4:3 ratio of 208b to 208a (R = CgH5, Z = 0) was produced using C6HsP(O)C12 and 207; CHjP(S)C12 gave a 5:l mixture of 208a (R = CH3, Z = S). Only one isomer was detected with POCl3 and PSC13, 208b (R = C1, Z = 0 or S ) . Treatment of 208b (R = C1, 2 = 0) with NaOCH3 in CH30H, NaOC2Hs in C~HSOH,and NaO-n-CgH7 in n-C3H70H formed solely the isomers of inversion at phosphorus, that is, 208a (R = OR', Z = 0);208b (R = C1, Z = S) behaved similarly. The action of sodium 4-nitrophenoxide, at room temperature, on 208b (R = C1, Z = 0) gave rise to one product, 208a (R = 4-NO2CgH40, Z = 0),but heating of the product with excess reagent generated the epimeric phosphoramidate, 208b (R = 4-NO2CgH40, Z = 0). Although 208b (R = 4-NO2CgH40, Z = 0) and NaOCH3 reacted with complete inversion, 208a (R = 4-N02C6H4ol Z = 0 ) gave only ca. 85% inversion. It should be noted that Harrison and co-workers (215) relied on two assumptions for stereochemical assignments: (1) the chloro and more stable 4-NO2CgH40 derivatives had equatorial P=O bonds, and (2) the displacement of chloride by NaOCgHq-4-NO2 proceeded with inversion. Ring-opening reactions were studied but these will not be described herein (215,216). 3.

1,3,2-0xat h i a p h o s p h o r i n a n e s

Stereochemical studies on 1,3,2-oxathiaphosphorinanes have been limited (138bf193,206). Pairs of diastereomers of 210 and 211 (R = CH3, OC2H5) were tentatively assigned structures based on comparisons of IR phosphoryl stretching frequencies and 'P NMR chemical shifts, in analogy with the corresponding 1,3,2dioxaphosphorinanes (206) 'H NMR data indicated that the 1,3,2oxathiaphosphorinane rings assume a chair conformation. Other derivatives of 210 and 211 [R = C1, (CH3)2N, and 4-N02CgH40]

.

CH2SH

u~n3 209

J-

CH30

21 0

21 1

I

XH3

B.

E. MARYANOFF, R.

0. HUTCHINS AND C . A.

MARYANOFF

259

have been r e p o r t e d (138b). I n t h e c o n d e n s a t i o n o f 209 w i t h POCl3 o n l y one p h o s p h o r o c h l o r i d a t e , a s s i g n e d s t r u c t u r e 2 1 2 , w a s found. Treatment of 212 w i t h ( C H 3 ) 2 N H y i e l d e d o n l y one phosphoramidate, 2 1 3 , t h e p r o d u c t of i n v e r s i o n . Simple e t h a n o l y s i s o f 212 and 213 gave only i n v e r s i o n p r o d u c t s ; b u t i n t h e e t h a n o l y s i s o f 213 c a t a l y z e d by (C2H5)3N o r NaOC2H5 o n l y r e t e n t i o n w a s o b s e r v e d , p r e sumably because of thermodynamic c o n t r o l i n t h i s l a t t e r p r o c e s s .

c1

0

II

I

CH 30 OCH 3

OCH3

212 0.PO '

213

c1 I s'%CH3O 214

OCH3

I n t h e r e a c t i o n of 212 w i t h NaOCgH4-4-No2, one e q u i v a l e n t of r e a g e n t gave c l e a n i n v e r s i o n , whereas excess r e a g e n t l e d t o r e t e n t i o n , t h e l a t t e r c o n v e r s i o n a f f o r d i n g t h e a l l e g e d l y more s t a b l e a x i a l phenoxy d e r i v a t i v e . I n a s i m i l a r f a s h i o n phosphoroc h l o r i d a t e 214 (138b) r e a c t e d w i t h e t h a n o l , g i v i n g i n v e r s i o n a t phosphorus. Ring-opening 215b w i t h C6H5MgBr o c c u r r e d w i t h b o t h P-0 and P-S bond c l e a v a g e ( 1 9 5 ) . The phosphorus s t e r e o c h e m i s t r y i n t h e p r o d u c t s from P-0 f i s s i o n c o u l d n o t b e a s s i g n e d , b u t t h e P-S f i s s i o n was determined t o o c c u r w i t h r e t e n t i o n , a s s e e n i n an a c y c l i c analogy ( 2 1 7 ) . The ring-opening r e a c t i o n s o f 215 w i t h oxygen n u c l e o p h i l e s (methoxide and phenoxide) took p l a c e f i r s t by P-0 bond c l e a v a g e . The methoxide r e a c t i o n s e v e n t u a l l y gave rise t o phosphoryl t r a n s f e r from s u l f u r t o t h e n e i g h b o r i n g oxygen, a s w e l l as h y d r o l y s i s t o 209 and (CH30)2P(O)CH3; t h e phenoxide r e a c t i o n d i d n o t r e s u l t i n t r a n s p h o s p h o r y l a t i o n . The phosphoryl exchange was n o t s t e r e o s p e c i f i c , b u t proceeded c h i e f l y w i t h i n v e r s i o n . Ring-opening of t h e d i a s t e r e o m e r s of 210 (R = OC2H5) w i t h NaOCH3 and NaOCgHg o c c u r r e d o n l y w i t h P-S bond f i s s i o n . The e q u a t o r i a l OC2H5 d i a s t e r e o m e r produced o n l y 216a (complete i n v e r s i o n ) ; t h e a x i a l OCzH5 d i a s t e r e o m e r c l e a v e d w i t h n e t i n v e r s i o n a t phosphorus, g i v i n g 216b. An i n t e r e s t i n g t r a n s f o r m a t i o n o f 2-thio-1,3,2-dioxophosp h o r i n a n e s i n t o 2-0~0-1,3,2-oxathiaphosphorinanes (eq. [ 351 ) h a s been r e p o r t e d (2181, b u t s t e r e o c h e m i c a l a s p e c t s of t h i s r e a c t i o n were n o t e x p l o r e d .

260

STEREOCHEMISTRY OF PHORPHORUS-CYCLOHEXANES

21 5b

Ro\

CH3O

n..

LH

4.

I , 3,2-Dithiaphosphorimnes

Some chemical work on simple 1,3,2-dithiaphosphorinanes did not include any stereochemical information (219). Analysis of the deuterium-decoupled 'H NMR spectra of 41 and 217 indicated a strong preference for one chair conformer for 41 (3Jpsc~= 28.0 and 8.9 HZ; 3 J =~10.8 ~ and 2.9 HZ), with an equatorial 5-phenyl group and, presumably, an axial 2-phenoxy group; and a conformational mixture for 217 ( 3 J p ~ =c ~24.5 Hz and 17.7 Hz; 3 J = ~8.0~ and 4.6 Hz), with a predominance of a chair conformer with equatorial 5-phenyl and 2-phenoxy substituents (46). The 11-ppm difference in 631P for 41 and 217 supported an orientational difference at the phosphorus center (46). The conformational behavior of these diastereomers was unlike the behavior of the isosteric 1,3,2-dioxaphosphorinane diastereomers (46). A possibility thus exists for increased

6. 13. MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF

261

i n t e r v e n t i o n of a t w i s t form i n t h e c o n f o r m a t i o n a l e q u i l i b r i u m f o r 2 1 7 , a view f o r t i f i e d by t h e following. d i s c u s s i o n concerni n g 48a and 4 8 b . S t e r e o s p e c i f i c o x i d a t i o n of 44 w i t h 3% H202 f u r n i s h e d 48a ( 4 9 ) , v e r i f y i n g t h e o r i g i n a l assignment of c o n f i g u r a t i o n f o r 44 ( 4 7 ) . The c o n f i g u r a t i o n of 48a was e s t a b l i s h e d by 'H NMR d a t a (49) and, more r e c e n t l y , by X-ray a n a l y s i s ( 2 2 0 ) . The c o n f i g u r a t i o n of d i a s t e r e o m e r 4 8 b , o b t a i n e d a s t h e major p r o d u c t from d i r e c t c o n d e n s a t i o n ( 4 9 ) , w a s a l s o determined from 'H NMR (49) and X-ray (220) d a t a . Although 48b a d o p t s e s s e n t i a l l y one c h a i r conformation (>go%) w i t h e q u a t o r i a l 5 - t - b u t y l and 2-phenyl subs t i t u e n t s , 48a i s s u b s t a n t i a l l y c o n f o r m a t i o n a l l y h e t e r o g e n e o u s . The c o n f o r m a t i o n a l e q u i l i b r i u m f o r 48a w a s i n t e r p r e t e d a s a m i x t u r e of a c h a i r conformer w i t h e q u a t o r i a l t - b u t y l and a x i a l phenyl g r o u p s , and a t w i s t form ( 2 2 8 ) ; t h e NMR d a t a s u g g e s t e d very l i t t l e c o n t r i b u t i o n of t h e c h a i r form w i t h an a x i a l t - b u t y l

c( 48a

C g H g P ( O ) c 1 2* H'

\

48b

C6H5

group. Complexation of 48a w i t h E u ( f o d ) 3 had no s i g n i f i c a n t i n f l u e n c e on t h e c o n f o r m a t i o n a l d i s t r i b u t i o n ( 4 9 ) , i n c o n t r a s t t o o b s e r v a t i o n s made by Bentrude and co-workers f o r t h e r e l a t e d 2-0X0-1,3,2-dioxaphosphorinane system ( 9 1 b , 1 2 9 , 1 3 0 ) . A p a r a l l e l i s m may be drawn between t h e isomers of 48 and t h e i s o m e r i c p a i r 41 and 21 7 , mentioned above.

'"'XSf CH3

218

219 a : R = CH3; b : R = C 1

C : R = N(i-C3H7)2 d : R = N-t-CqHg ( i - C 3 H 7 ) e : R = N-t-CqHg (CH3)

s

R

220 ( R = C g H 5 , O C H 3 t CH3, C2H5, t - C q H g )

f : 1-aziridino E v i d e n t l y , t h e i n t r o d u c t i o n of proximate s u l f u r and phosphorus atoms i n t o a cyclohexane r i n g s i g n i f i c a n t l y lowers t h e c h a i r - b o a t f r e e - e n e r g y d i f f e r e n c e , such t h a t t w i s t forms may s u b s t a n t i a l l y p o p u l a t e t h e c o n f o r m a t i o n a l e q u i l i b r i a . A comp a r i s o n of c h a i r - b o a t energy d i f f e r e n c e s ( A G O ) f o r cyclohexane (ca. 5.3 kcal/mol) ( 2 2 1 ) , 1,3-dioxane ( c a . 8 . 3 kcal/mol) ( 1 1 4 ) , and 1 , 3 - d i t h i a n e (ca. 1 . 7 kcal/mol) (222) c l e a r l y r e f l e c t s t h i s

262

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

behavior. Furthermore, the chair-boat energy difference for 109, which corresponds to insertion of a phosphorus atom into a 1,3dioxane ring, may be as low as 1.0 kcal/mol(91);that fortricoordinate derivative 13b is ca. 1.5 to 2.0 kcal/mol (35). Extrapolation of this information to 2-oxo-l,3,2-dithiaphosphorinanes (e.g., 48) points to a further reduction in AGO(chair-boat) in this system. Indeed, X-ray determinations for 48a and 48b revealed that both molecules adopt twist conformations in the solid state (220), an unprecedented observation which suggests that such rings have ready access to the twist arrangement. On the other hand tricoordinate compound 44 adopts a chair conformation (as shown) in the solid state, as do the 2-thiones 219a and 219b (P=S bond equatorial) (223), 229c (P=S bond axial) (224), and 219f (P=S bond equatorial) (224b). Derivatives 219c, 219d, and 219e apparently prefer a single chair conformation in solution (224a). 1,3,2-Dioxaphosphorinane 116a, related to 48a, adopts a chair conformation with axial 5-t-butyl and equatorial 2-t-butyl groups in the solid state, whereas 116b adopts a chair conformation with equatorial 5-t-butyl and axial 2-phenyl groups (102b). lH NMR spectral data for a series of 2-oxo-1,3,2-dithiaphosphorinanes (220) displayed nonequivalent 5,5-dimethyl groups, indicative of a bias toward one chair form (51). Displacement of conformational equilibrium with solvent (as indicated by solventdependent 3Jpsc~values) was noted, but no clear conclusions could be drawn regarding the intervention of twist forms. However, the near equivalency of the two 3 J p values ~ ~ ~for 220 (R = ~ 6 ~ alkyl) 5 , suggested an averaging in the conformational equilibria (1.e. , a mixture of chair and/or twist forms) (225). 'H NMR data for a series of 2-thiono-l,3,2-dithiaphosphorinanes have been reported (22613). Examples of unconstrained, saturated six-membered-ring compounds (lacking trigonal atoms) that adopt flexible twist conformations in preference to the chair forms are rare; however, a few exceptions to the chair preference have been noted (227229). 5.

1,3,2-Diazaphosphorinanes

On the basis of IR spectral evidence Navech and co-workers (118,230) suggested that the preferred conformation of 221 (R = H, CH3) and some of its congeners (222-224, X = 0 ) (presumed to be chair structures) was that with an axial P=O bond. The 3 J p ~ ~ ~ values seemed to support the chair assignments but permitted no conclusion regarding the orientation of groups on phosphorus. The 2-thiono compounds were analogized to the 2-0x0 series. Isomeric mixtures of 225a and 225b [R = OCH3, N(CH3)2] were analyzed by 6 3 1 P and IR data (231). Assuming equatorial 4-methyl groups, 225a and 225b were claimed to differ in the disposition of substituents on phosphorus. Conformational aspects involving

B.

E . MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

263

222

221

CH 3

225 a : R1/R2 = R/O b : R1/R2 = O/R

224

226

t h e n i t r o g e n s t e r e o c e n t e r s were n o t c o n s i d e r e d ( 2 3 1 ) , a l t h o u g h t h e p o s s i b i l i t y e x i s t s t h a t t h e n i t r o g e n atoms are p l a n a r , as s e e n f o r t h e r i n g n i t r o g e n i n t h e X-ray c r y s t a l s t r u c k u r e of isophosphamide ( 2 2 6 ) ( 2 3 2 ) . F l u o r o d e r i v a t i v e s 225a and 225b ( R = F) were p r e p a r e d by Amos and co-workers ( 1 9 6 ) . The isomer r a t i o of t h e m i x t u r e produced from t h e 1,3-diamine and (CH3) 2NP ( 3 ) F 2 was u n a l t e r e d a f t e r e q u i l i b r a t i o n with f l u o r i d e , suggesting t h a t t h e condensation i s probably thermodynamically c o n t r o l l e d . I n comparison, a mixt u r e of isomers was n o t o b t a i n e d i n t h e p r e p a r a t i o n o f oxaza a n a l o g 206. An a x i a l f l u o r o o r i e n t a t i o n f o r b o t h i s o m e r s of 186 (R = F) was proposed ( 2 J p ~ and IR d a t a ) , which, i f v a l i d , i m p l i e s t h a t a 4-methyl group i s n o t a n e f f e c t i v e b i a s i n g s u b s t i t u e n t . I n t e r e s t i n g l y , t h e N,N'-dimethyl groups i n each isomer were a s s i g n e d d i f f e r e n t o r i e n t a t i o n s (one a x i a l , one e q u a t o r i a l ) on ~ e s~ f3o r t h e anisochronous t h e b a s i s of d i f f e r e n t 4 J ~ p v~a l u N,N'-methyl resonances. The 'H NMR spectrum f o r 227 (R = CH3) showed i s o c h r o n o u s gem-dimethyl groups and an average r i n g methylene r e g i o n ; t h e 'H NMR spectrum f o r 227 ( R = H ) was s i m i l a r ( 2 3 3 ) . O x i d a t i o n o f i s o m e r i c m i x t u r e 38 ( c a . 1:l) w i t h H 2 0 2 gave 228 a s a m i x t u r e o f i s o m e r s , b u t t h e 'H NMR spectrum f o r 228 showed o n l y one 5-methyl d o u b l e t and a d e c e p t i v e l y s i m p l e r i n g methylene r e g i o n . Tentat i v e l y , 227 ( R = H and CH3) and 228 a p p e a r t o be NMR a v e r a g e d , implying t h a t t h e y a r e an unbiased m i x t u r e of c h a i r forms, a t w i s t o r b o a t - t y p e s t r u c t u r e , o r a combination of t h e s e two poss i b i l i t i e s . I t i s noteworthy t h a t s i m i l a r 'H NMR o b s e r v a t i o n s have been r e c o r d e d w i t h t h e analogous 2-phenyl-1,3,2-diazaboracyclohexanes, which p r o b a b l y have n e a r l y p l a n a r n i t r o g e n atoms (234). The s t r u c t u r a l i n f o r m a t i o n a v a i l a b l e t h u s f a r on t h e 2-0x01,3,2-diazaphosphorinanes s h o u l d be r e g a r d e d as h i g h l y t e n t a t i v e u n t i l a d d i t i o n a l c a r e f u l and s y s t e m a t i c s t u d i e s a p p e a r i n p r i n t .

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

264

6.

Phosphorinanes ( 2 3 5 )

The conformational p r e f e r e n c e o f t h e N-proton i n p i p e r i d i n e h a s been t h e o b j e c t o f i n t e n s e i n t e r e s t and c o n t r o v e r s y f o r many y e a r s ( 2 6 ) . Although an a x i a l E-H group was claimed t o b e t h e more stable conformation (26,2361, Anet and Yavari (237) r e c e n t l y have proved t h a t t h e e q u a t o r i a l N-H conformation p r e dominates ( a t l e a s t a t ca. -150'). Extension of work (236) t o phosphorinane ( 2 2 9 ) , t h e phosphorus a n a l o g o f p i p e r i d i n e , r e v e a l e d t h a t t h e p r o t o n i n 229 w a s s t r o n g l y f a v o r e d i n t h e a x i a l p o s i t i o n of a c h a i r s t r u c t u r e ( a s shown). More i n f o r m a t i o n on t h e t r i c o o r d i n a t e system i s p r e s e n t -

H

229

230 a : R = S 231 4 : Rl/R2 = CH3/S b : R = CH3 b : Rl/R2 = S/CH3

e d i n S e c t . IV. S u l f i d e 230 w a s a l s o a s s i g n e d a c h a i r conformat i o n w i t h a x i a l P-H; however, no c o n c l u s i o n s c o u l d be o f f e r e d on methiodide 230b (236). A l a r g e group of phosphorinane-1-sulfides h a s been s t u d i e d by Quin and co-workers ( 4 3 a , 4 3 d , 2 3 8 a I b ) . X-Ray a n a l y s i s of 231a r e v e a l e d t h a t both p o s s i b l e c h a i r conformations 232a and 2323) e x i s t i n t h e c r y s t a l , i n a r a t i o of 2:l--an unusual o b s e r v a t i o n

232a

233

i n c o n f o r m a t i o n a l s t u d i e s of simple s a t u r a t e d r i n g systems (43d, 238a). The o t h e r s u l f i d e , 231b, had conformation 233 i n t h e s o l i d s t a t e ( 4 3 d , 2 3 8 a ) . X-Ray a n a l y s e s of t h e 4-methyl a n a l o g u e s , 31a and 31b, showed s i n g l e c h a i r conformations w i t h a x i a l 4hydroxy groups and a d i f f e r e n t arrangement of groups on phosphorus (43dI238a). A n X-ray a n a l y s i s of t h e t r a n s s q u a r e - p l a n a r complex 234 showed b o t h phosphorinane r i n g s i n a c h a i r conforma-

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E. MARYANOFF, R.

265

0. HUTCHINS AND C . A. MARYANOFF S

II

CH3O

[cH30

OH

OH

234

31a

31b

t i o n ; however, t h e phenyl groups were o r i e n t e d d i f f e r e n t l y i n each l i g a n d : a x i a l i n one and e q u a t o r i a l i n t h e o t h e r ( 2 3 9 ) . The co-occurrence of two d i f f e r e n t c h a i r conformations i n t h e s o l i d s t a t e p o i n t s t o a r e l a t i v e l y s m a l l energy d i f f e r e n c e between t h e two forms i n q u e s t i o n (51 kcal/mol). Both phosphorinane r i n g s of 235 have a c h a i r conformation w i t h t h e P=S bond o r i e n t e d a x i a l l y , i n t h e s o l i d s t a t e (239b). 1 3 C NMR chemical s h i f t d a t a f o r 238 [ R = CH3, C 2 H 5 , ( C H 3 ) 3 C , C g H g ] support a preponderance of a c h a i r conformer w i t h an e q u a t o r i a l R group ( 4 3 a I 2 3 8 a ) ; X-ray a n a l y s i s of 236 ( R = C H ~ ) shows a c h a i r s t r u c t u r e w i t h t h e methyl group e q u a t o r i a l (23833, 238c). Although some phosphorinane-1-oxides were prepared ( 2 3 8 a ) , t h e conformational p r o p e r t i e s of t h e s e compounds remain l a r g e l y unreported. However, some conformationally b i a s e d 1-oxide d e r i v a t i v e s have been discussed (238b). E q u i l i b r a t i o n s t u d i e s on 237 ( X = lone p a i r , 0, S , Se) have appeared, along with a d i s c u s s i o n of t h e r e l a t i v e s t a b i l i t y of t h e t h r e e i s o l a b l e diastereomers ( 2 4 0 a ) .

235

236

237

Two of t h e e i g h t p o s s i b l e diastereomers of 238 were i s o l a t e d by Pepperman and S i d d a l l (240b), and assigned s t r u c t u r e s 239a and 239b based on 'H NMR d a t a .

266

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

239a

239b

Condensation of 240 with CgHgPH2 afforded two epimeric, bridged phosphorinanes ( 2 4 1 ) , of which 241a greatly predominated (244). Oxidation of 241a with H202 gave 2 4 2 , which was also obtained by benzylation of 241 and subsequent alkaline fragmenta-

24 0

241a

242

243 (R = CH3, CHzCgHg)

tion of 243 (with 90% retention). An independent synthesis of 242 involved the process outlined in eq. [361. Benzyl phosphine 244 was quaternized, and basic hydrolysis of 245 gave 70% retention of configuration at phosphorus (eq. [37]). X-lay data (242) corroborated the stereochemistry reported by Kashman and 0

Awerbouch, which was first ascertained through 'H NMR arguments (241).

244

245

+

isomer

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0. HUTCHINS AND C. A. MARYANOFF

267

A s t e r e o c h e m i c a l s t u d y of 9-phenyl-9-phosphabicyclo[3.3.~]nonane d e r i v a t i v e s has been r e p o r t e d ( 2 4 3 ) . A d d i t i o n of CgHgPH2 t o 246 gave a m i x t u r e of phosphines 247 (243,244). The o x i d e s from 247 were s e p a r a t e d , and t h e i r s t e r e o c h e m i s t r y was a s s i g n e d ( 2 4 3 ) . Each i s o m e r i c o x i d e (248) was reduced s t e r e o s e l e c t i v e l y

24 6

24 7

w i t h NaBH4 t o g i v e t h e c o r r e s p o n d i n g a l c o h o l s (2491, which w e r e d e h y d r a t e d t o 250 (eq. [ 3 8 ] ) . With s t r o n g a c i d 250a w a s c o n v e r t ed t o 250b, by e i t h e r a t r a n s - a n n u l a r h y d r i d e - s h i f t p r o c e s s o r

a : Rl/R2 = CgH5/0

b : R1/R2 =

O/CgH5

an a c i d - c a t a l y z e d oxygen-exchange r e a c t i o n a t phosphorus ( e q . [ 3 9 ] ) . 13C NMR s p e c t r a l d a t a p r o v i d e d e v i d e n c e f o r a p r e f e r e n c e of c h a i r - c h a i r conformations i n 248, 250, and 56, b u t f o r c h a i r b o a t conformations i n 249 ( 2 4 3 ) . The X-ray s t r u c t u r e of a s q u a r e p l a n a r n i c k e l ( I 1 ) complex of 56, [ t r a n s - ( 5 6 ) ] 2 - N i C 1 2 , showed a double c h a i r conformation i n t h e s o l i d s t a t e ( 2 4 5 ) .

56 B i c y c l i c phosphorinane o x i d e s 251 and 252, c o n s t r a i n e d i n t o b o a t r i n g conformations, were s t u d i e d by Wetzel and Kenyon ( 2 4 6 ) .

268

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

251

252

The alkaline cleavage reaction of benzyl phosphonium salts, briefly mentioned above, is stereochemically interesting (247). Fragmentation of acyclic salts by aqueous hydroxide normally occurs with inversion of configuration at phosphorus (248). Benzyl phosphetanium salts hydrolyze with mixed stereochemistry (249); benzyl phospholanium salts are transferred to phosphine oxides with complete retention (250); and phosphepanium salts undergo hydrolysis with complete inversion (251). Hydrolysis of cis-phosphorinanium salt 253a gave a mixture of 48% cis-oxide (retention) and 52% trans-oxide (inversion), whereas the trans salt 253b gave 22% cis-254 (inversion) and 70% trans-254 (retention) (252). The alkaline cleavages proceed via two diastereomeric intermediates 255a and 2 5 5 b . Unfavorable steric interactions between the methyl and benzyl groups in 2 5 5 b were proposed as a possible source of the diminished inversion for the trans salt. Although hydrolysis of benzyl phosphetanium salts gave a loss of stereospecificity, the cis and trans pairs each gave mixtures of phosphine oxides with identical diastereomeric composition. In this case epimerization occurred faster than hydrolysis, giving an equilibrium mixture of oxides, whereas in the phosphorinanium fragmentation kinetic control was evident. Thus there are two competing reaction pathways: the "McEwen mechanism,I' affording inversion, and a "phospholanium mechanism," affording retention (248,250-252). A comparison of the base cleavage of 253a and 253b with the corresponding 4-t-butyl derivatives has been published (43f), together with a OH-

253a OH-

\ /

254

2532,

255a

255b

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

269

mechanistic discussion (not considered here because of space limitations). Nonstereospecificity has been observed in the alkaline hydrolysis of lI4-diphosphorinanediastereomers, 256a and 256b (253a). On the other hand hydroxide cleavage of 2 5 7 ~

256 U:

Rl/R2 = CgHtj/CH2CgHg

b : R1/R2 = CH2CgHg/CgHg

257

and 257b occurred with complete retention of configuration at phosphorus (253b).

D.

Biological Aspects

1.

C y c l i c Nucleotides

The cyclic nucleotide adenosine 3',5'-phosphate (c-AMP), 2 5 8 , is a ubiquitous hormonal messenger, involved in the regulation of many cellular processes (e.g., lipolysis, protein synthesis, and active transport) (254). The biological importance

258

259

of other endogenous cyclic nucleotides, such as guanosine 3',5'phosphate (c-GMP), 2 5 9 , has also been recognized (255). A general chemical review on cyclic nucleotide derivatives is available (256). The crystal and molecular structure of c-AMP has been determined by X-ray diffraction (257), which shows two molecules per asymmetric unit, having different conformations about the glycosidic bond (see 260a and 2 6 0 b ) (other details being rather constant); the 1,3,2-dioxaphosphorinane ring adopts a chair conformation and the ribose ring is puckered in both cases. The

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

270

OH 260a (anti conformer)

260b (syn conformer)

molecular structure of an isosteric phosphonate analog, 261, possessing biological acrivity, was siidllar. to that of the syn form of c-AMP (260b) (258). The axial ethyl ester of c-AMP ( 1 7 6 , X = 0, Y = OCzH5) has an anti base-ring conformation and a flattened chair 1,3,2-dioxaphosphorinane ring (X-ray data) (259).

4 oT--d

'OH

0\

261

0

262 The crystal and molecular structure (260) of the (CzH5)3NH+ salt of uridine 3',5'-phosphate (c-UMP), 262, demonstrated the (anti) geometry shown (two molecules per asymmetric unit), in accord with other cyclic nucleotides. In c-GMP, 259 (sodium, tetrahydrate), the phosphate ring assumes a chair conformation, flattened at the phosphorus end, with a syn arrangement about the glycosyl bond (261a). Methyl a-D-glucopyranoside 4,6phosphate (263, cyclohexylammonium salt) also exhibits a chair form for the 1,3,2-dioxaphosphorinane ring (261b). In the 2deoxyriboside thymidine 3',5'-N,N-dimethylphosphoramidate, prepared by oxidation of the product from thymidine and tris(dimethylamino)phosphine (262a), the dimethylamino group is equatorially oriented and the phosphorus end of the molecule is highly puckered (X-ray data) (262b), compared to, for example , phosphate triester 176 (X = 0,Y = 0C2H5) (259). X-Ray data are also available for some five- (10833,263) and seven- (264a) membered-ring nucleotides, and a highly simplified derivative of a 5-membered-ring nucleotide (264b). Of greater interest is the conformation of the cyclic nucleotides in solution, since this more accurately represents

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0. HUTCHINS AND C. A. MARYANOFF

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a b i o l o g i c a l s i t u a t i o n . The p r e f e r r e d c o n f o r m a t i o n o f c-AMP i n a n aqueous m i l i e u w a s d e t e r m i n e d by 'H NMR l a n t h a n i d e - s h i f t s t u d i e s ( 2 6 5 ) , which i n d i c a t e d t h a t t h e ribose a n d p h o s p h o r i n a n e r i n g c o n f o r m a t i o n s are c o n s i s t e n t w i t h t h e s o l i d - s t a t e s t r u c t u r e s . A s y n c o n f o r m a t i o n o f t h e g l y c o s y l bond p r e d o m i n a t e d (see 2 6 U b ) . 'H r e l a x a t i o n measurements ( T I and T g ) from l a n t h a n i d e - s h i f t e d s p e c t r a o f c-AMP, and t h e changes t h e r e o n i n d u c e d by Gd+31 s u p p o r t e d t h e same p r e f e r r e d c o n f o r m a t i o n s ( 2 6 5 b ) . O t h e r NMR s t u d i e s o f 3 ' , 5 ' - n u c l e o t i d e s a l s o r e v e a l e d a sirnilari t y between t h e s o l u t i o n and s o l i d - s t a t e c o n f o r m a t i o n s f o r t h e r i n g s ( 5 7 , 5 8 , 2 6 6 ) . S p i n - s p i n c o u p l i n g c o n s t a n t s for conformat i o n a l l y b j ased ( a n i o n i c ) p h o s p h a t e six-membered r i n g s were e s t a b l i s h e d i n numerous s t u d i e s ( 5 7 a , 5 8 , 2 6 6 a I 2 6 7 ) . Blackburn and co-workers ( 5 7 a ) d e t e r m i n e d ( l H NMR d a t a ) t h a t t h e f u r a n o s e and c y c l i c p h o s p h a t e r i n g s are " r i g i d " i n c-AMP, c-TMP ( 2 ' deoxy-c-UMP), and d i b u t y r y l c-AMP. The p h o s p h a t e r i n g assumes a c h a i r c o n f o r m a t i o n , t h e f u r a n o s e r i n g s o f c-AMP a n d d i b u t y r y l c-AMP are i n a 3'-endo-4'-exo c o n f o r m a t i o n , and t h e f u r a n o s e r i n g o f c-TMP i s i n a 4 ' - e x o c o n f o r m a t i o n . 13C NMR d a t a s u p p o r t t h e c o n c l u s i o n s d e r i v e d from t h e 'H NMR i n v e s t i g a t i o n ( 5 7 b ) . C y c l i c UMP, GMP, and CMP have p h o s p h a t e r i n g c o n f o r m a t i o n s a k i n t o t h o s e o f c-AMP and c-TMP. L e e and Sarma ( 5 8 ) , i n s t u d y i n g 18 d i f f e r e n t n u c l e o s i d e d e r i v a t i v e s by NMR s p e c t r o s c o p y , c o n c l u d e d t h a t t h e p h o s p h a t e r i n g s i n c-AMP, c-GMP, c-UMP, c-CMP, 2 ' d e o x y - c - W , a n d c-TMP a d o p t a s l i g h t l y f l a t t e n e d , " r i g i d " c h a i r c o n f o r m a t i o n . Kainosho and A j i s a k a (266b) s u g g e s t e d a 3'-endo c o n f o r m a t i o n f o r t h e s u g a r m o i e t i e s o f c-AMP, c-UMP, c-GMP, cCMP, and c-IMP, and a c h a i r c o n f o r m a t i o n f o r t h e p h o s p h o r i n a n e r i n g ( i n d e p e n d e n t o f t h e h e t e r o c y c l i c s u b s t i t u e n t ) , b a s e d on l a n t h a n i d e i o n - a s s i s t e d 'H NMR a n a l y s e s . The c o n f o r m a t i o n o f t h e 2'-deoxy d e r i v a t i v e c-TMP w a s found t o b e 4'-exo i n t h e l a n t h a n i d e i o n - a s s i s t e d work, as w e l l (26613). The c o n f o r m a t i o n o f n u c l e o s i d e s c a n b e d e s c r i b e d l a r g e l y by t h e t o r s i o n a l a n g l e s a t t h e C l I - N l g l y c o s i d i c l i n k a g e , t h e f u r a n o s e r i n g C-C bonds, a n d t h e C4-C5' bond. X-Ray data r e v e a l t h a t t h e s e a n g l e s f a l l i n t o narrow r a n g e s ( 2 6 8 a ) . Although t h e g l y c o s i d i c bond h a s been found i n e i t h e r s y n or a n t i o r i e n t a t i o n s i n t h e c r y s t a l ( 2 6 8 a ) , p y r i m i d i n e n u c l e o s i d e s and n u c l e o t i d e s show a s t r o n g p r e f e r e n c e f o r t h e a n t i d i s p o s i t i o n i n a n aqueous environment ( e . g . , see p r e d o m i n a n t c o n f o r m a t i o n f o r t h y m i d i n e , 2 6 4 ; c-UMP, 2 6 2 , i s a n t i i n t h e s o l i d s t a t e ) ( 2 6 0 ) . With t h e f u r a n o s e and p h o s p h a t e r i n g s i n c y c l i c 3 ' , 5 ' - n u c l e o t i d e s l a r g e l y r e s t r i c t e d t o t h e t+T3 (3'-endo, 4 ' - e x o ) and c h a i r conformations, r e s p e c t i v e l y , t h e only conformational v a r i a b l e r e m a i n i n g i s r o t a t i o n a b o u t t h e g l y c o s y l bond. A n a l y s i s o f t h i s t o r s i o n by p o t e n t i a l e n e r g y c a l c u l a t i o n s i n d i c a t e d t h a t p y r i m i d i n e b a s e s U, T , and C p r e f e r t h e a n t i r a n g e o f c o n f o r m a t i o n s (26823). The c a l c u l a t i o n s p r e d i c t e d t h a t c-GMP and c-IMP f a v o r t h e s y n c o n f o r m a t i o n o v e r t h e a n t i by 95:5 and 70:30, r e s p e c t i v e l y , w h i l e c-AMP p r e f e r s t h e a n t i c o n f o r m a t i o n o v e r t h e s y n by 70:30 (26833). A r e c e n t NMR s t u d y ( 2 6 8 ~ )i n d i c a t e d a s y n / a n t i r a t i o

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

272

HO 2 63

2 64

of 1:l for C-AMP in aqueous solution (at pH 2.0). The relatively large degree of rotational freedom of noncyclic nucleotides, compared to their cyclic counterparts, may have some bearing on comparative biological properties. One outstanding facet of cyclic nucleotides is their hydrolysis to noncyclic nucleotides, with or without enzymic assistance, a process that has received considerable attention (269). Generally, cyclic nucleoside phosphates have high heats of hydrolysis. Cyclic AMP has a free energy and enthalpy of hydrolysis 2 kcal/mol higher than that for the conversion of ATP to ADP and inorganic phosphate (269a) and, interestingly, the heat of hydrolysis of simple six-ring cyclic phosphate 265 is 8 kcal/mol less than that for c-AMP. The latter comparison affords some indication of the strain (270) contained in the ribofurano-

265

266

267

side 3,5-phosphate system (see Table 12). Representative enthalpies of hydrolysis are presented in Table 12. Table 12 Enthalpies of Hydrolysis (263a) ~

Phosphodiester (C2H50)2POg-

266 265 267

C-AMP ( 2 5 8 ) 2' ,3'-AMP 263 2 68

~

-AH (kcal/mol) 2.5

6.9 3.8

2.5 11.5 (5'-bond; 12.1 for 3'-bond) 9 . 4 (2'-bond) 6.9

11.7

B. E. MARYANOFF, R . 0. HUTCHINS AND C.

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Phosphate basicity is dependent on angle strain and axial/ equatorial orientation in six-membered rings (27,271). This stereochemical aspect (271b) has obvious relevance to cyclic 3',5'-nucleotides, wherein the two exocyclic P-0 bonds could be differentiated by electrophiles or cations. Hong and co-workers

268

269

(271b) reported that diazomethane reacts preferentially with the axial oxygen of 2 6 9 , in the presence of relatively noncoor(CH~)I+N+] , but with the dinating cations [e.g. , Na+, Cs', equatorial oxygen in the presence of Li+ and NHL,+, the difference being ascribed to the strong affinity of the latter ions for the more basic, axial coordination site. A theoretical argument for the much greater basicity of the axial P-0 group has been expounded by Verkade (27,271a). The association of the basicity properties with biological activity remains to be demonstrated. In the reaction of c-AMP with diazoalkanes axial esters were formed as readily as or in preference to equatorial esters (198a); c-UMP and some derivatives gave similar results (198b). In Sects. 111-B-2-a and 111-B-2-b the stereochemistry relating to pyranoside cyclic phosphorus compounds was discussed. Since interest in furanoside derivatives is closely allied with nucleotide chemistry, the topic is dealt with in this section. Reports on diastereomeric, nonbiologic furanoside cyclic phosphorus derivatives have been sparse (272). A number of papers have appeared concerning the preparation of diastereomeric derivatives of synthetic cyclic nucleoside phosphates (epimeric at phosphorus) (198,259,262,273). In many cases no attempt was made to identjfy diastereomers, but some reports exist in which epimers have been separated and/or characterized. Eckstein (27313) separated the two isomers of uridine 2',3'-cyclophosphorothioate ( 2 7 0 ) by crystallization of triethylammonium salts. XRay analysis of the crystalline diastereomer of 270 showed the P=S bond in an endo position (i.e., anti to the ribose-ring 2', 3' hydrogen atoms) (see 270a) (26333). Both isomers of 270 were substrates for pancreatic ribonuclease (273b). The kinetics of the RNase A catalyzed hydrolysis showed marked differences for the compounds (Table 13). Epimer 270a had the same affinity (K,,,) as its cyclic phosphate congener 2 7 1 , but a fivefold lower rate constant (k+2) (2741, whereas epimer 270b bound much more weakly to the enzyme (eightfold lower) with the same k+2 value as that for 270a. This implies that the sulfur atom in 270a is

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

274

s'r'ori

270a

272 (CAMPS)

270 n o t p r i m a r i l y i n v o l v e d i n b i n d i n g t o t h e enzyme, b u t i n 270b t h e t h e s u l f u r atom i n t e r f e r e s w i t h t h e b i n d i n g p r o c e s s ; a l t e r n a t i v e l y , t h e r e s u l t s may be e x p l a i n e d i n t e r m s o f d i f f e r e n t i a l a v a i l a b i l i t y of t h e a n i o n i c oxygen f o r complexation w i t h a s i t e on

Table 1 3 Binding and H y d r o l y s i s Rate C o n s t a n t s (27313)

Compound uridine-2',3'-cyclic 270a (endo s u l f u r ) 270b (ex0 s u l f u r )

phosphate ( 2 7 1 )

6.3 x 6.2 10-3 50 10-3

2.5 0.5 0.5

t h e enzyme. The guanosine analogue o f 270 w a s o b t a i n e d as a mixture of d i a s t e r e o m e r s t h a t c o u l d n o t b e s e p a r a t e d ( 2 7 3 i ) . I n t h e r e a c t i o n of t h e mixture o f guanosine epimers w i t h R N a s e T 1 , i n water-methanol, o n l y t h e a l l e g e d endo P=S isomer underwent reaction. A f t e r an i n i t i a l f a i l u r e ( 2 7 3 d ) , t h e p h o s p h o r o t h i o a t e analogue of c-AMP ( 2 7 2 ) was p r e p a r e d a s a m i x t u r e of d i a s t e r e omers, which w a s very slowly hydrolyzed by p h o s p h o d i e s t e r a s e (beef h e a r t and r a b b i t b r a i n c o r t e x ) ( 2 7 3 e ) . With t h e former enzyme 272 bound about t h e s a m e as c-AMP, a n d t h e two epimers were hydrolyzed a t t h e same r a t e . I n t e r p r e t a t i o n o f t h e r e s u l t s is complicated by t h e simultaneous p r e s e n c e of b o t h d i a s t e r e omers, which may have d i f f e r e n t a f f i n i t i e s f o r t h e enzyme. Mixture 272 w a s about one-half as a c t i v e a s c-AMP i n s t i m u l a t i n g p r o t e i n k i n a s e ; t h e a p p a r e n t b i n d i n g of 272 w a s 10 t o 2 0 t i m e s g r e a t e r t h a n t h a t of c-AMP. Nothing i s known a b o u t t h e b i o l o g i c a l a c t i v i t i e s of t h e i n d i v i d u a l epimers o f 2 7 2 , s i n c e t h e y have y e t t o be s e p a r a t e d . One may s p e c u l a t e t h a t s i n c e t h e exo P=S d i s p o s i t i o n i n 270 ( v i z . , 270b) i s l e s s a c c e p t a b l e t o t h e r i b o n u c l e a s e enzyme system, t h e e q u a t o r i a l ( o r exo) P=S bond epimer of 272 may a l s o be less b i o l o g i c a l l y a c c e p t a b l e t h a n t h e a x i a l (endo) P=S compound. F u r t h e r work h e r e i s e a g e r l y a w a i t e d , a s it a l s o h a s r e l e v a n c e t o t h e P=O b a s i c i t y c o n c e p t s

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advanced by Verkade (271). A recent stereospecific synthesis of thymidine 3',5'-phosphorothioate diastereomers should be applicable to the stereo-controlled synthesis of the diastereomers of 272 (273m). The two diastereomers of 273 (of unknown relative configuration) show different behavior in stimulation of c-AMP-dependent protein kinase (bovine skeletal muscle) (273k). The (ca. twofold) more active isomer had a K , similar to its phosphate congener,

273

274

275 a : R = H b : R.= CH2CH2C1

and was hydrolyzed by phosphodiesterase (beef heart); the other epimer of 273 was not attacked by the phosphodiesterase enzyme, even on incubation for several days, although it did appear to bind to the enzyme (acting as an inhibitor). Both diastereomers were resistant to hydrolysis by rabbit-brain phosphodiesterase. Significantly, the work of Eckstein and co-workers with nucleoside phosphorothioates has provided information on enzyme mechanisms (275). In particular, the diastereomeric derivatives of 270 served to probe the stereochemistry of enzymatic transformations by virtue of the extra molecular information intrinsic to the chirality at phosphorus. In Sect. 111-B-2-a we mentioned the unequal (exocyclic) hydrolysis of diastereomeric phosphates. A series of c-AMP triesters ( 2 7 4 ) was synthesized from the free acid and diazoalkanes, and the diastereomeric mixtures were separated (198a). In hydrolysis of the triesters, which occurs by benzylic C-0 bond cleavage (2730), the equatorial isomer was found to react ca. four times faster than the axial isomer (see Table 14); the triesters showTable 14 Half-Life (Hr) at 50' in H20 (198a) ~

~~

R in triester

Axial isomer

Equatorial isomer too unstable 0.5 (3.0a) a3 73

aIn Mops buffer (pH 6.5) at 30'.

216

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

ed l i t t l e (in vitro) a c t i v a t i o n of c-AMP-dependent p r o t e i n k i n a s e , and were n o t s u i t a b l e as s u b s t r a t e s f o r c-AMP phosphod i e s t e r a s e (in vitro) (198a).

2.

Cyclophosphamide and Related Compounds

Cyclophosphamide ( 2 7 6 ) , 2 7 5 a , i s a c l i n i c a l l y u s e f u l a n t i tumor drug, which has l i t t l e c y t o t o x i c a c t i v i t y u n t i l a c t i v a t e d by t h e mixed-function oxidase system of l i v e r microsomes ( 2 7 7 ) . Thus a c t i v e m e t a b o l i t e s of 275a a r e a l s o o f i n t e r e s t . Pharmacolog i c a l l y , 275a may a l s o be u s e f u l as an immunolytic and a n t i inflammatory a g e n t . X-Ray s t r u c t u r a l d a t a a r e a v a i l a b l e f o r 275a and some of i t s r e l a t i v e s . The monohydrate of 275a shows a c h a i r conformat i o n f o r t h e 1,3,2-oxazaphosphorinane r i n g w i t h a n e q u a t o r i a l amino group ( 2 7 8 ) . The c r y s t a l s t r u c t u r e of isophosphamide ( 2 2 6 ) a l s o shows a c h a i r s t r u c t u r e w i t h t h e l e s s bulky NHCH2CH2C12 group i n an e q u a t o r i a l p o s i t i o n ; t h e r i n g n i t r o g e n atom possesses a v i r t u a l l y p l a n a r geometry ( a n g l e sum = 353') ( 2 3 2 ) . The g e n e r a l s t r u c t u r e of triphosphamide ( 2 7 5 b ) i s close t o t h a t of 226 and 275a (279a). Ketophosphamide 276a e x h i b i t s a nonchair s t r u c t u r e , presumably due t o t h e p r e s e n c e of an e n d o c y c l i c carbony1 moiety (27933). The 4-hydroperoxy ( 2 7 6 b ) (280aI280b) and 4-peroxy ( 2 7 7 ) (280c) d e r i v a t i v e s , s y n t h e t i c a l l y o b t a i n e d by

226

276 a: R = 0

b:

277

R = H I OOH C : R = H I OH

Fenton o x i d a t i o n o f 2 7 5 a , have c h a i r r i n g s w i t h e q u a t o r i a l amino groups and a x i a l l y connected 4-hydroperoxy and 4-peroxy groups, r e s p e c t i v e l y ; no e q u a t o r i a l oxygenation w a s observed ( 2 8 0 ) . Camerman and co-workers (280a) suggested t h a t t h e in vivo metab o l i t e 2 7 6 ~may have t h e same r e l a t i v e c o n f i g u r a t i o n . X-Ray a n a l y s e s of b o t h isomers o f 4-hydroperoxyisophosphamide showed a x i a l 4-peroxy groups and a change i n o r i e n t a t i o n a t phosphorus; t h e major ( c i s ) isomer (assumed t o be t h e thermodynamically more stable one) has an e q u a t o r i a l amino group (280b). Recently, 4hydroperoxyisophosphamide and r e l a t e d d e r i v a t i v e s were s t u d i e d by Takanizawa and co-workers (281). Acid-catalyzed e q u i l i b r a t i o n a f f o r d e d a 1:l mixture of 4-hydroperoxy d i a s t e r e o m e r s , both of which favor a x i a l 4-peroxy, conformations i n s o l u t i o n ; b o t h d i a stereomers e x h i b i t e d antitumor a c t i v i t y (281).

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'H and 1 3 C NMR work on 2 7 5 a a t t e s t e d t o a r e l a t i v e l y low b a r r i e r t o r i n g i n v e r s i o n ( 2 8 2 ) , a s expected from t h e e a r l i e r suggestions r e l a t i n g t o t h i s r i n g s y s t e m ( s e e S e c t . 1 1 1 - C - 2 ) . The s y n t h e s i s of enantiomeric cyclophosphamides was achieved independently by S t e c and co-workers (283a), and by Zon (283b). Since t h e (-)-enantiomer was i s o l a t e d from t h e u r i n e o f p a t i e n t s . d o s e d with racemic 2 7 5 a , a s t e r e o s p e c i f i c metabolism must t a k e p l a c e i n v i v o (284). I n a t e s t a g a i n s t mouse plasma tumor c e l l s (ADJ/PC6), t h e (-)-form was twice as e f f e c t i v e (IDgg) a s t h e (+)-form ( 2 8 4 ) . The a b s o l u t e c o n f i g u r a t i o n s of ( - ) - 2 7 5 a and ( + ) - 2 7 5 a were determined t o be S and R , r e s p e c t i v e l y , by anomalous d i s p e r s i o n X-ray c r y s t a l l o g r a p h y ( 2 8 5 ) . S t e c and co-workers (55) r e p o r t e d t h e s y n t h e s i s and conf i g u r a t i o n a l assignments of t h e f o u r o p t i c a l l y a c t i v e forms of 5 5 , c o r r e c t i n g e a r l i e r c i s / t r a n s assignments (286). 'H NMR coupling c o n s t a n t d a t a e s t a b l i s h e d t h a t (2Sr4R)-55 i s v i r t u a l l y

(2SI4R)-55 (55b)

55

one c h a i r conformer, whereas 13C NMR coupling c o n s t a n t s i n d i c a t e d t h a t (2RI4R)-55 i s conformationally heterogeneous (eq. [ 4 0 ] ) . N o a p p r e c i a b l e d i f f e r e n c e i n a c t i v i t y of t h e c i s and t r a n s isomers of 5 5 a g a i n s t L1210 leukemia i n v i v o w a s observed (286) ; both isomers were l e s s a c t i v e t h a n cyclophosphamide ( 2 7 5 a ) , probably because of l e s s e f f i c i e n t microsomal o x i d a t i o n a t C 4 (286,287).

H

N (CH2CH2Cl) 2 I

( 2 ~ , 4 ~ ) - 5(55a) 5

278

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

I V . STRUCTURE, CONFORMATION, AND STEREOCHEMISTRY OF CYCLOHEXANE RINGS CONTAINING TRICOORDINATE PHOSPHORUS A.

Introduction

The relatively high barriers to pyramidal inversion for most tricoordinate phosphorus derivatives (288,289) confers isolability at convenient temperatures to diastereomers of appropriately substituted phosphorus heterocycles, facilitating study of their stereochemical and conformational properties. The pyramidal inversion process furnishes a means for thermally equilibrating diastereomeric pairs to obtain thermodynamic parameters. Thus in anancorneric (19) derivatives the conformational preferences of substituents on phosphorus may be ascertained.

B. 1,3,2-Dioxaphosphorinanes The 1,3,2-dioxaphospholanesand, especially, the 1,3,2dioxaphosphorinanes have occupied a central position in stereochemical investigations of tricoordinate, saturated phosphorus heterocycles, primarily because of their similarity to widely studied carbocyclic five- and six-membered-ring analogs. In the early 1960s Goldwhite (290) recognized the accumulation of evidence (291,292) that pointed to the conformational stability of trivalent phosphorus, and suggested configurational stability in dioxaphospholanes 278 (R = C 1 ) and 279 ( R = C 1 , OCH3) , based on 'H NMR data. Thus 279a and 279b were shown to be a mixture of noninterconverting geometric isomers at ambient temperature, but separation or assignment of isomers was not essayed. Further exploration demonstrated (293) that derivatives of 279 ( b - e ) are configurationally stable up to 150'; 279a underwent concentration-dependent ligand reorganization, resulting in stereomutation at phosphorus (294). Similar observations of pyramidal stability were made with derivatives 280; also no inversion of 281 was observed by 'H NMR up to 200' (295). As eviqence mounted for the configurational stability of trivalent phosphorus (296), considerable interest was aroused. Denney and Denney (163) reported that the less stable isomers of the diastereomeric pairs 3,, 1 3 7 , and 281 rapidly isomerize to the more stable forms on treatment with methanol. Only partial H3 c

H3cT1)

3c$:jLR

-R

H3C

H3C

278

279

a:

R = C1 b : R = oCH3 C: R = W g H 5 d : R = N(CH3)z e : R = CgH5

[O)-.

0

280

R = C1, OCH3, F , OAc, OCgH5, 0c ( O ) C g H 5

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0. HUTCHINS AND C . A. MARYANOFF

279

s e p a r a t i o n of t h e geometric isomers w a s a c h i e v e d , however, because i s o m e r i z a t i o n i s very s e n s i t i v e t o a c i d c a t a l y s i s ( 1 4 5 ) . With t h e f i r m r e a l i z a t i o n of t h e pyramidal s t a b i l i t y o f . t r i c o o r d i n a t e phosphorus, s e v e r a l s t u d i e s employing NMR s p e c t r o scopy (30-32,35,39,42,91,130,136a,140,141,142b,149,166b,170,176, 183,297-301), d i p o l e moment measurements (149,15lb,154a,302) , e l e c t r o n d i f f r a c t i o n ( 3 0 3 ) , and c o r r e l a t i o n s i n v o l v i n g assumed s t e r e o c h e m i c a l p a t h s i n d i s p l a c e m e n t r e a c t i o n s a t phosphorus (84,102,141,145,154b,183) were conducted w i t h an a i m a t d e l i n e a t i n g t h e geometry and conformations of six-membered-ring (and t o a lesser e x t e n t five-membered-ring) compounds. S e v e r a l groups have e s t a b l i s h e d t h a t alkoxy o r a r y l o x y ( 3 0 , 42,149,170,300b,302c) and c h l o r o (30,42,149,170,300,302bf303) s u b s t i t u e n t s on t r i v a l e n t phosphorus p r e f e r an a x i a l d i s p o s i t i o n i n t h e c h a i r conformation. Thus Bentrude and Hargis (170) r e p o r t ed t h a t t h e c i s isomers of 2-R-5-t-butyl-1,3,2-dioxaphosphorin-

H3c4-;

,P-CCH3

281

H3pL? 0/

1 3 7 R = OCH3

282

R = OC2H5

H3)?b-0CH3 0/

H3C

3

a n e s , 284a and 2 8 4 b , a r e more stable t h a n t h e t r a n s i s o m e r s . 'H NMR a n a l y s i s s u p p o r t e d an e q u a t o r i a l o r i e n t a t i o n f o r t h e t - b u t y l group i n both cases. The c o n f i g u r a t i o n a b o u t phosphorus was c o r r e l a t e d with 96 by s t e r e o s p e c i f i c o x i d a t i o n on 2 8 4 b Lt-CqHqOOH ( 3 0 4 ) ] , and t h e s t r u c t u r e of 284b was confirmed by X-ray a n a l y s i s of 92 ( d e r i v e d from 2 8 4 b ) ( 1 0 2 ) . On t h e s t r e n g t h of d i p o l e moment measurements (on borane a d d u c t s ) and 'H NMR d a t a , Verkade and co-workers (42) demonstrated t h e a x i a l p r e f e r ence f o r t h e methoxy group i n s e v e r a l 2-alkoxy-1,3,2-dioxaphosp h o r i n a n e s , 3 and 8 9 . Likewise, Bodkin and Simpson ( 1 4 9 ) , employi n g 'H NMR s p e c t r o s c o p y and d i p o l e moment measurements , e s t a b l i s h e d t h a t t h e more s t a b l e s t e r e o i s o m e r of 282 p o s s e s s e s t h e t r a n s c o n f i g u r a t i o n , w i t h a x i a l ethoxy and e q u a t o r i a l methyl groups. The l e s s s t a b l e c i s isomer ( d e r i v e d from phosphorochlori d i t e 1 3 3 ) was p o s t u l a t e d t o c o n s i s t of a m i x t u r e o f r a p i d l y i n t e r c o n v e r t i n g c h a i r confomers, t h e form w i t h e q u a t o r i a l methyl and ethoxy groups b e i n g p r i n c i p a l l y p o p u l a t e d ; t h e r e b y a p r e dominantly a x i a l c h l o r o group was s u g g e s t e d f o r 1 3 3 ( 1 4 9 ) .

1

96

89

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

280

D i r e c t NkIR evidence f o r t h e a x i a l p r e f e r e n c e o f c h l o r o and alkoxy s u b s t i t u e n t s on phosphorus w a s p r o v i d e d by Haemers and co-workers ( 3 0 ) . They o b t a i n e d c h a r a c t e r i s t i c 'H NMR d a t a f o r t h e c i s and t r a n s isomers of 1 and 3 , whose r i n g s are immobilized by t h e n a t u r e of t h e a l k y l s u b s t i t u t i o n . T h e i r work i n d i c a t e d t h a t t h e d i s p o s i t i o n of t h e phosphorus l o n e p a i r may have h a r d l y i n ~t h~ e 1,3,2any e f f e c t on t h e r e l a t i v e magnitudes of 3 J p O dioxaphosphorinanes, b u t t h i s independence i s f r e q u e n t l y n o t obs e r v e d i n phosphine d e r i v a t i v e s (35,295,297,301).

a:

283

R = c1 b : R = O C H ~( 1 3 ) C : R = CgH5 d : R = l'-- C i H 7 e: R = C H ~ f : R = t-CqHg (14) 9 : R = (CH3)zN h : R = CH3NH (15)

284

285

a: b

R1 = 0 R 2 = O

More r e c e n t l y , a x i a l p r e f e r e n c e s have been found f o r o t h e r p o l a r s u b s t i t u e n t s i n c l u d i n g f l u o r o ( 1 4 1 ) , cyan0 ( 1 4 0 ) , t h i o alkoxy ( 1 8 3 ) , a n i l i n o (166b) , 1 - a z i r i d i n o (301) , and p o s s i b l y d i a l k y l p h o s p h i n o ( 3 0 5 ) , p r i m a r i l y by NMR t e c h n i q u e s . A 2-hydrogen s u b s t i t u e n t a l s o p r e f e r s t o occupy an a x i a l p o s i t i o n ( 3 9 ) . The a x i a l p r e f e r e n c e f o r e l e c t r o n e g a t i v e groups i s n o t s u r p r i s i n g , s i n c e it c o u l d be a s c r i b e d , a t l e a s t i n p a r t , t o t h e g e n e r a l i z e d anomeric e f f e c t (306) (vide i n f r a ) , which, f o r example, produces a x i a l p r e f e r e n c e s i n analogous 1 , 3 - d i o x a n e s ( 3 0 6 , 3 0 7 ) . However, Bentrude and co-workers (35,176) found t h a t 284c, having e q u a t o r i a l 5 - t - b u t y l and a x i a l phenyl g r o u p s , is m o r e s t a b l e t h a n 2 8 3 ~ ;s i m i l a r c o n c l u s i o n s f o r 283d and 284d (35,229) and f o r 283e and 2 8 4 e (35) followed. On t h e o t h e r hand t - b u t y l (351, dimethylamino (35,91b,130,136a,142b), l - p i p e r i d i n o ( 3 0 1 ) , and methylamino (35,91bI130) groups w e r e found t o p r e f e r e q u a t o r i a l o r i e n t a t i o n s i n 1,3,2-dioxaphosphorinanes. Isomer assignments have been accomplished i n g e n e r a l through NMR d a t a and/or d i p o l e moment measurements ( f o r R = methylamino, p i p e r i d i n o , and dimethylamino) (91bI130,136a,142b), and s t e r e o s p e c i f i c o x i d a t i o n a t phosphorus (308) t o t h e corresponding o x i d e s . S t r u c t u r e s of o x i d e s of 2 8 3 c , e , f w e r e d e t e r mined by X-ray a n a l y s i s ( 1 0 2 ) . I t i s noteworthy t h a t l a n t h a n i d e s h i f t r e a g e n t s (309) o f f e r a u s e f u l t o o l f o r i d e n t i f y i n g cist r a n s i s o m e r s , such a s t h e 2-oxides of 2 8 3 and 284 (see 2 8 5 ) (91b,129,130,132,136a;142b). Complexation w i t h t h e phosphoryl oxygen d i s t i n g u i s h e s t h e trans-2-oxides 285a by a s u b s t a n t i a l downfield s h i f t of t h e proximate 4 , 6 - a x i a l p r o t o n s .

B.

E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

281

E s t i m a t i o n s of c o n f o r m a t i o n a l p o p u l a t i o n s f o r c i s and t r a n s d i a s t e r e o m e r s 2 8 3 and 284 were made v i a p r o t o n c o u p l i n g and chemical s h i f t d a t a . For t h e c i s forms t h e conformations w i t h e q u a t o r i a l 5 - t - b u t y l and a x i a l P-R s u b s t i t u e n t s g r e a t l y p r e dominate f o r R = C 1 ( 1 7 0 ) , alkoxy (170) , methyl ( 3 5 ) , i - p r o p y l ( 3 5 ) , and phenyl ( 3 5 ) . However, when R w a s t - b u t y l ( 3 5 ) , methylamino ( 9 1 b ) , o r dimethylamino ( 9 1 b ) , t h e c i s i s o m e r s w e r e obs e r v e d t o be c o n f o r m a t i o n a l l y h e t e r o g e n e o u s , composed of e q u i l i brium m i x t u r e s of c h a i r and t w i s t forms ( 9 1 b ) . I n t h e p r e c e d i n g cases t h e i s o m e r i c c i s - t r a n s p a i r s were t h e r m a l l y e q u i l i b r a t e d , and t h e e q u i l i b r i u m p o p u l a t i o n s were measured. The f r e e - e n e r g y d i f f e r e n c e s (AG v a l u e s ) between i s o m e r s are p r e s e n t e d i n Table 1 5 , a l o n g w i t h t h e e s t i m a t e d d i s t r i b u t i o n of t h e isomers 2 8 3 and 284 A,B,C ( 3 5 ) . From t h e s e d a t a (Table 1 5 ) t h e approximate conformational f r e e - e n e r g y (AG) v a l u e s c o u l d b e e s t i m a t e d , p r o v i d i n g rough e s t i m a t e s f o r t h e c o r r e s p o n d i n g AG v a l u e s of t h e groups a t t a c h e d t o t h e 2 - p o s i t i o n i n l f 3 , 2 - d i o x a phosphorinanes; t h e c o n f o r m a t i o n a l f r e e - e n e r g y v a l u e s a r e p r e s e n t e d i n T a b l e 16 ( 3 5 ) . Table 1 5 E q u i l i b r i u m Data f o r 1,3,2-Dioxaphosphorinanes (284+283)

cis- ( 2 8 4 )

284A

R

284B/284C

(35)

trans- (283)

283A/283B

283C

AGo2980~

~~

93 92 84 74

7 90 11 42

6 3

1.5 0.4 10.5-12.0 18-21 93 4.7 83 55

3.6

-

-

5.5 4.0

1;5 kcal/mol 1.45 0.98 0.62 -1.5 1.3 -0.94 -0.12

I

+e2p

'

R '

R

2834

283B

283C

282

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

Table 16 Conformational Free-Energy (AG5980K) Values for 2-Substituents in 1,3,2-Dioxaphosphorinanes ( 2 8 4 A j 2 8 3 A ) and 1,3-Dioxanes

R

Keq

c1 CH3O C6H5 CH3 i-C3H7 CH 3NH (CH31 2N t-CqHg

> 62 2230 ? 19 7-8 3.5-4.1 0.76 0.13 <0.004

ca. AGj980~(a*eq) (284Aj283A)a

AG!!980K 1,3-Dioxanesb

>2.4 kcal/mol L3.2 h.1 1.1-1.2 0.7-0.8

0.36 kcal/mol 0.62 -3.12 -3.98 -4.17

-0.15

-1.2 <-3.2

aEstimated as the conversion of 2844 to 2834 from the values iven for them in Table 15. 'References 115 and 307b. In the 4,6-dimethyl compounds, 286a and 2 8 6 b , similar conclusions were reached (142b) when R was methoxy or dimethylamino, via dipole moment and NMR data, except that the less stable isomers retained a chair conformation with diequatorial 4,6methyl groups because of the severe interactions that result from diaxial placement of 1,3 methyl groups in cyclohexane systems. The less stable 4-methyl compound 287 was suggested to be an 85:15 mixture of 287a and 2 8 7 b , respectively [eq. (4211 (301). R

1

CH3 28 6a y(CH3)2

427

CH3 287a (85%)

CH3 286b

-*

3 7 P - N (CH31 2

287b (15%)

r421

Phosphonite 288 equilibrates with dirneric (12-memberedring) and trimeric (18-membered-ring) forms, 289 and 2 9 0 , each of which exists as two different diastereomers (310). The two diastereomers of 289 formed in a statistical (1:l) ratio. At a given temperature the relative amounts of 288, 2 8 9 , and 290 in the equilibrium mixture are governed by the starting concentration of monomer 288. The tendency for 1,3,2-dioxaphos-

B. E. MARYANOFF, R. 0. HUTCHINS AND C . A. MARYANOFF

283

phorinanes to oligomerize depends on the phosphorus substituents, with an order of facility t-CqHg > i - C 3 H 7 > C 2 H 5 > CH3 > CgH5 (311). Dimerization of 1,3,2-dioxaphospholanes and 1,3,2-dioxaphosphepanes to 10- (312) and 14-membered-ring (311) molecules has also been reported. These novel macrocycles may serve as effective ligands for metal cations and ammonium ions.

PC ' H3

H3C/p\020H

H3C

CH3

290

&I3

288

The isosteric 2-chloro-1,3,2-dioxaarsenane system adopts a chair conformation with an axial preference for the 2-chloro group (dipole moment and Kerr constant data) (313a). Aksnes (313b) suggested that 2-chloro-, 2-bromo-, 2-methoxy-, and 2phenoxy-lI3,2-dioxaarsenanes have a strongly biased chair conformation with axial 2-substituents. A recent discussion of 1,3,2-dioxaphospholane stereochemistry has been given by Bentrude and Tan (314a). An electron diffraction study of 2-chloro-1,3,2-dioxaphospholane has been reported (314b).

C.

1,3,2-Dithiaphosphorinunes

Although very few investigations of trivalent lf3,2-dithiaphosphorinanes have been disclosed (47,48,50f51,226a),the limited data support conclusions on the overall geometry and orientational preferences of phosphorus substituents as observed for the 1,3,2-dioxa analogs. Hutchins and Maryanoff (47) and Robert and co-workers (48,226a) concluded from NMR data that the 1,3,2-dithiaphosphorinane ring adopts a chair conformation (perhap slightly flattened), and that the axial orientation for phosphorus substituents greatly predominates in 291 (R2 = H , CH3) with R1 = C g H 5 , OCH3, C 1 , CH3, C 2 H 5 , and 1-aziridinyl, while the equatorial position is highly favored for R1 = . N ( i - C 3 H 7 ) ( t - C q H q ) , N ( i - C 3 H 7 ) 2 , and t-butyl. A mixture of conformations is present for R1 = NH-t-CqHg (Keq = 1 to 1.5 and R l = 1-piperidino (Keq = 1.5 to 3.0).

=,--+P-R1

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

284

+J1

piR2 s 31

R2 H3C

R2

R2

291a

291b Rz = H o r CH3

292: R1/R2 = H/lone p a i r 50a: R1/R2 = OC2Hs/lp 5 0 b : R l / R 2 = lp/OC2H5 52a: R1/R2 = C l / l p 52b: R1/R2 = lp/C1

N i f a n t ' e v and co-workers (50) concluded from NMR s t u d i e s o f 50 and 51 t h a t t h e more stable isomers have t h e t r a n s conf i g u r a t i o n (50a and 5 I a ) . The p r e f e r r e d o r i e n t a t i o n a t phosphorus i n 292, 50a, 50b, 51a, and 51b i s a x i a l . Thus 'H and/or 1 3 C NMR d a t a i n d i c a t e d t h a t 5 l a assumes a c h a i r conformation w i t h an e q u a t o r i a l 4-methyl group, whereas 50b and 5 I b are c h i e f l y c h a i r conformers w i t h an a x i a l 4-methyl group. Notably , t h e three-bond coupling , 3 J p ~,bbetween t h e 'P nucleus and t h e 4 , 6 - e q u a t o r i a l p r o t o n s i n t h e compounds w i t h an a x i a l P s u b s t i t u e n t ( v i s . , 2 9 1 ~ )i s very weak ( 0 t o 1.4 Hz); t h e four-bond coupling between phosphorus and t h e e q u a t o r i a l 5-proton (4Jp~5 1 i s uniquely l a r g e (7.5 t o 10 Hz) On t h e o t h e r hand, i n t h e grgup of compounds w i t h an e q u a t o r i a l P s u b s t i t u e n t ( v i z . , 291b) t h e corresponding e q u a t o r i a l three-bond c o u p l i n g , 3 J p ~ ,a i s l a r g e (16.5 t o 26.0 H Z ) and 4 ~ p H 5 e is s m a l l ( c a . 1 HZ). Both t h e 31P-1H coupling c o n s t a n t s and t h e Jpcs v a l u e s a r e dramatic a l l y dependent on t h e o r i e n t a t i o n a t hosphorus: f o r a x i a l E-R 3Jpc = 0.5 Hz and f o r e q u a t o r i a l E-R 'JPc5 = 11.5 Hz. The unu s u a l 3 J p ~ Cd a~ t a o b t a i n e d f o r t h e t r i v a l e n t 1,3 ,2-dithiaphosphori n a n e compounds i n d i c a t e t h a t a Karplus r e l a t i o n does n o t apply t o v i c i n a l PSCH coupling c o n s t a n t s ( 5 1 ) . A n u c l e a r Overhauser experiment on 291a ( R 1 = CH3, R 2 = CH3) confirmed t h e proximity of t h e P-CH3 group and t h e a x i a l 4,6-protons ( 4 7 , 5 1 ) . F u r t h e r v e r i f i c a t i o n of t h e assignments came from an X-ray a n a l y s i s ( 2 2 0 ) o f 44 ( t h e more s t a b l e o f two diastereomers ( 4 7 , 5 1 ) , which showed a c h a i r conformation, s l i g h t l y f l a t t e n e d a t t h e phosphorus end of t h e r i n g , and an a x i a l 2-phenyl group. Minor isomer 293 h a s n o t y e t been i s o l a t e d , although it has been d e t e c t e d by NMR (47,511.

.

44

B. E. MARYANOFF, R. 0. HUTCHINS AND C . A . MARYANOFF

285

The o n l y q u a n t i t a t i v e s t u d y , i n t h i s area, o f conformationa 1 p r e f e r e n c e s f o r phosphorus s u b s t i t u e n t s i n v o l v e d measurements of t h e thermal e q u i l i b r a t i o n of 44 and 293. From t h e Ke + and t h e measured k i n e t i c s of i n t e r c o n v e r s i o n , AGqg8o~and A 2980K w e r e determined t o be 1.91 5 0.2 kcal/mol and 31.4 kcal/rnol, r e s p e c t i v e l y ( 4 7 , 5 1 ) . A comparison of A c 5 9 8 0 ~of 1 . 9 kcal/mol w i t h t h a t of 1 . 8 kcal/mol f o r t h e c o r r e s p o n d i n g 1,3,2-dioxaphosphorinanes (283c and 2 8 4 ~ )s u g g e s t s s i m i l a r c o n f o r m a t i o n a l pref e r e n c e s f o r P - s u b s t i t u e n t s i n t h e two Xing systems. Thermal e q u i l i b r a t i o n of 49a and 49b ( i n i t i a l l y o b t a i n e d a s a 3:2 mixt u r e ) gave a 9 : l f i n a l r a t i o (GLC, 'H NMR), c o r r e s p o n d i n g t o AGa430~= 2.05 kcal/mol ( 5 1 ) . F o r 44 and 293 Keq w a s c a . 6.5 a t 175OC, g i v i n g A G % ~ ~ o=K 1.65 kcal/mol. Some e s t i m a t e s of conf o r m a t i o n a l p r e f e r e n c e s can be g l e a n e d from t h e d a t a on 291 ( R g = H ) r e p o r t e d by Martin and co-workers ( 4 8 ) . Such e s t i m a t e s from 3 J a~r e ~compiled i n T a b l e 1 7 . 31P-1H and 31P-13C coupli n g s , n o t used h e r e f o r f e a r t h a t t h e y may v a r y w i t h t h e P subs t i t u e n t i n d e p e n d e n t l y o f c o n f o r m a t i o n a l f a c t o r s ( 4 5 ) , are cons i s t e n t w i t h t h e e s t i m a t e s i n Table 1 7 ( 4 8 ) .

z

Table 1 7 E s t i m a t e d Conformational Preferences f o r 2-Substituents i n 1,3,2-Dithiaphosphori.nanes (291, R 2 = H ) R1 CH3 C6H5 OCH 3

c1

C2HqN-

NH- t-Cq Hg

C5H1ONt-CqHg N (i-C3H7) ( t - C q H g )

85-95 90-100 90-100 95-100 90-100 40-50 25-30 10-15 0- 10

The P-chloro d e r i v a t i v e 291 (R1 = C 1 , R 2 = CH3) was obs e r v e d ( l H NMR) (51) t o be much less l a b i l e w i t h r e s p e c t t o c h l o r i n e exchange t h a n t h e c o r r e s p o n d i n g d i o x a o r d i a z a a n a l ogues. I n f a c t , both m o i s t u r e and a c i d were i n e f f e c t i v e i n i n i t i a t i n g t h e exchange r e a c t i o n ; however, when c h l o r i d e i o n was added, exchange w a s r a p i d . T h i s s u g g e s t s t h a t t h e mechanism of exchange i n t h e d i o x a and d i a z a s y s t e m may i n v o l v e a s i m i l a r chloride-induced processl s i n c e f a c i l e h y d r o l y s i s of t h e s e l a t t e r systems would p r o v i d e t h e needed c h l o r i d e a n i o n s . I n t h i s r e g a r d c h l o r i d e anion does g r e a t l y a c c e l e r a t e exchange i n t h e d i o x a r i n g system (42,315).

286

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

Interestingly, lI3,2-dithiaphosphorinanes oligomerize in a manner similar to 1,3,2-dioxaphosphorinanes. Thus an equilibrium between 46 and 12-membered-ring dimers 294a and 294b can be achieved at 160' (relative ratio, 46/294a/294b = 6:3:1) (316).

Isosteric 2-chloro-1,3,2-dithiaarsenane is strongly biased into one chair conformation, probably with an axial 2-chloro group (317). The conformational equilibrium for the analogous 2-phenyl compound is also one-sided, but the disposition of the phosphorus substituent is ambiguous (313b). Robert and co-workers (318a) have reported 'H NMR data on the homologous lI3,2-dithiaphospholane system. Unusually small 3 J p values ~ ~ ~ were also seen in this series for a variety of derivatives. An X-ray structural determination for a trivalent 1,3,2-dithiaphospholane has been published (318b).

D.

1,3,2-Diazaphosphorinanes

The very limited information available for lI3,2-diazaphosphorinanes (45,50,51,231) indicates that a normal chair conformation is adopted with a strong bias toward one form, for 295 (R1 = C 1 , O C H 3 , C H 3 , C z H 5 , C g H 5 ; R2 = H , C H 3 ) . N o definitive description of the disposition of substituents on phosphorus has yet been offered. The absence of a nuclear Overhauser enhancement in 295 ( R l , R 2 = C H 3 ) upon irradiation of the P-methyl group (45), and the apparent predominance of cis isomer 296 and trans isomer 297 tentatively indicate the conformational properties of this ring system: methyl and dimethylamino favor equatorial, methoxy favors axial, orientations. Nifant'ev and

B.

E. MARYANOFF, R.

0. HUTCHINS AND C. A.

MARYANOFF

287

CH3

I

CH3

295

296

297

co-workers ( 5 0 ) s t u d i e d t h e 298 s e r i e s , i n which t h e N , N ' - t b u t y l s u t s t i t u e n t s should s t r o n g l y populate e q u a t o r i a l p o s i t i o n s . 'H NMR d a t a showed t h a t 298a and 298c a r e b i a s e d t o w a r d one c h a i r form. Based on 13C NMR y e f f e c t s , 298a-298c were c l a i m e d t o have an a x i a l p r e f e r e n c e f o r t h e s u b s t i t u e n t s o n p h o s p h o r u s . O t h e r work ( 5 1 ) i m p l i e d t h a t C 1 and OCH3 f a v o r a n a x i a l o r i e n t a t i o n and t h a t C H 3 , C 2 H 5 , and CgH5 f a v o r a n e q u a t o r i a l o r i e n t a tion. F o r t h e 2-chloro-1,3,2-diazaphosphorinanes, l i k e t h e 1 , 3 , 2 d i o x a and 1 , 3 , 2 - d i t h i a d e r i v a t i v e s , h a l o g e n exchange r e a d i l y t a k e s p l a c e ; t h e a p p a r e n t s t e r e o c h e m i c a l r i g i d i t y is l o s t under exchange c o n d i t i o n s . T r e a t m e n t o f 295 (R1 = C 1 , R p = C H 3 ) w i t h PCl5 g e n e r a t e d diaminophosphenium i o n 299 w i t h a t t e n d a n t l o s s o f stereochemical " r i g i d i t y " of t h e r i n g (319). The q u e s t i o n o f o r i e n t a t i o n o f t h e N-methyl g r o u p s i n 295 w a s approached by u s i n g 'H a n d 31P NMR, which p o i n t e d t o e q u a t o r i a l p o s i t i o n i n g o f t h e 1 , 3 - m e t h y l g r o u p s . An a n g u l a r dependence o f N-P plr-dn bonding w a s s u g g e s t e d from comparison o f 31P chemi c a l s h i f t s f o r 295 (R1 = C6H5, R2 = H ) , i n which b o t h n i t r o g e n l o n e p a i r s may b e a x i a l , and t h e r i g i d b i c y c l i c s t r u c t u r e s 39, 40, and 300, i n which one ( 3 9 ) or two ( 4 0 , 300) l o n e p a i r s a r e c o n s t r a i n e d t o e q u a t o r i a l a r r a n g e m e n t s . A stepwise d e s h i e l d i n g w a s o b s e r v e d i n g o i n g from 295 (R1 = CgH5, R p = H ) t o 3 9 , t o 4 0 , and 300, as e x p e c t e d from t h e more e f f i c i e n t o v e r l a p p r o v i d e d by an a x i a l l o n e p a i r ( 4 5 ) .

298 a : R = H b: R = C 1 c : R = OCpH5

299

39

Ring 3~pNcHv a l u e s f o r t h e 295 s e r i e s v a r y d r a s t i c a l l y w i t h t h e P - s u b s t i t u e n t , from ca. 1 0 Hz f o r 4 , 6 - a x i a l and e q u a t o r i a l ~ 5 ~ HZ , with p r o t o n s w i t h R 1 = C 1 t o 3JpNCH, = 0 HZ and 3 J p ~ =

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288

R1 = C6H5. The 3 J p ~ Values ~ ~ 3 for 295 (R2 = C6H5; R2 = CH3, H) and (at least the major isomer of) 38 are 14 to 15 Hz, but 3 ~ p N c Hfor ~ 39 is only 12 HZ; the g-CH3 in the latter ( 3 9 ) is also shifted upfield by 0.1 ppm. Further study of the two possible isomers of 38 and 3 9 would help to unveil stereochemical uncertainties surrounding lf3,2-diazaphosphorinane stereochemistry.

300

40

E.

38

Phosphorinanes

Geometrical isomerism in substituted phosphorinanes was demonstrated in 1965 by Quin and co-workers ( 4 3 b , 3 2 0 ) , who prepared a series of isomeric phosphorinanols 301 [R = H, C2H5r

HO

301a

R

301b

302 R, R = 0 303 R, R = OCH3

CH2C02C2H5r CH~CHZOH,C6H5, t-CqHg ( 3 3 ) ] and successfully separated the C2H5, C6Hgr and t-CqHg derivatives. The assignment of cis and trans isomers was tentatively accomplished by IR and NMR properties (43b,320), which led to the (then) unprecedented suggestion that a methyl group on phosphorus could readily occupy either axial or equatorial positions. The assignments were corroborated through X-ray analysis of the t-butyl derivative 33a ( 3 0 2 a , R = t-CqHg) (321), which adopts a chair conformation with axial methyl and hydroxy groups. X-Ray analyses,of rings unbiased by carbon substitution, 302 and 3 0 3 , likewise showed chair conformations, with the P-phenyl group axial in both cases (322). In the same vein Lambe-t and co-workers (236,323) deduced from 'H NMR data that the parent compound, phosphacyclohexane 229, exists almost entirely in the axial P-H conformation. Thus a body of evidence denoted a situation in which substituents on phosphorus in phosphorinanes prefer (or at least are unhindered in) the axial orientation.

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To place these observations on a quantitative basis, Quin and Featherman (324) investigated the conformational equilibria between simple 1-substituted phosphorinanes (26-28, 30) ( e q . [43]) by low-temperature 31P and 'H NMR spectroscopy. From the R

I

A

-

AGO = -RT In K

-

229 R = H 26 R = CH3 27 R = C2H5 28 R = i-C3H7 30 R = CgH5

mp-R B

variable temperature behavior of the equi ibria, thermo-jnamic parameters were determined (Table 18). A surprising result is revealed by the data: while the relativelypmall enthalpy difference (AHo) between the isomers favors the equatorial conformation (B) at low temperatures, the entropy difference ( A S o ) cancels Table 18 Thermodynamic Parameters for Phosphorinane Derivatives (324), and Comparison with Data for Cyclohexane (325)

No.

26 27 30 28

R

methyl ethyl phenyl i-propyl

AH0

AS (e.g .)

-0.7 -0.7

-3.4 -3.2 -2.6

(kcal/mol)

-0.6

O

AGO, kcal/mol

163OK

-0.1

-0.2

-0.17

-0.5

300°K

ad

0.7 0.27 0.4 0.2 9.3 8.6 0.33

AGO for *clohexyl-R -1.70 -1.75 -3.0

-2.15

this preference as the temperature is increased, so the axial conformation (A) predominates over the equatorial one. At room temperature the axial form (A) predominates. The preference (AGO) for the equatorial conformer at low temperature, resulting mostly from the AHo term, still was quite small compared to that in cyclohexane (325) systems (Table 18). The equatorial preference for 26 at -130OC of only 2:l is remarkably low when compared to that of methylcyclohexane (99:l at -110OC) (326) or N-methylpiperidine (95:l at -15OOC) (327a). 1-Methylarsenane, which assumes a chair conformation, has an equal population (l:l, AGO = 0) of axial and equatorial conformers at -144OC (327b).

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290

Barriers to ring inversion ( A c f ) for 26-28 and 30, determined by DNMR (324b), were in the range 8.4 to 9.3 kcal/mol (Table 18), slightly lower than the barrier for cyclohexane and methylcyclohexane of 10 to 11 kcal/mol (328). The value of A d for 26 (8.7 kcal/mol) compares with a A& of 11.8 kcal/mol for N-methylpiperidine (26) and 6.8 kcal/mol for 1-methylarsenane (327a), the relative order roughly corresponding to the atomic radius of the heteroatom. Quin and Lee (238b) have reported on the stereochemical consequences of mono-C-methylation of positions 3 or 4 of 1methylphosphorinane. The energetics were found to be dominated by the added methyl group. Quin and collaborators have reported reliable 13C NMR procedures for the assignment of diastereomeric phosphorinanes (43a,43cI238b). Lambert and co-workers (43e) have discussed the application of 1 3 C NMR to the determination of conformational preferences of 1-substituents in phosphorinanes, and in pentamethylene heterocycles in general. The effect of steric environment on 31P chemical shifts has also been explored (238b,329).

I

C6H5 304

305

Diazaphosphorinane 304 was tentatively assigned a chair conformation with an axially favored - C H ~ N H C ~group H ~ (330). The barriers to pyramidal inversion at phosphorus of 1,3-diphosphorinanes 305 [MR2 = C(CH3)2, Ge(C2Hs)2, Si(CH3)2] were studied by Hauser and co-workers (331).

F.

Origin of the Axial Preference for Substi tuents on Phosphorus

The,most noteworthy aspect of conformational studies of phosphorus heterocycles is the observation that substituents on phosphorus are relatively unstrained in an axial orientation. This axial preference contrasts with the situation in cyclohexane, where relatively strong equatorial preferences for, inter alia, alkyl groups is reflected in large, negative conformational energies ( - A G O axial $ equatorial), ranging from 1.7 kcal/mol for methyl to >4.4 kcal/mol for t-butyl (325). Early in the development of conformational theory methyland other alkyl-substituted cyclohexanes were examined intensively, and the concept of equatorial preferences as the norm was embedded in traditional thinking (326,332). This generality has

B. E . MARYANOFF, R.

0. HUTCHINS AND C . A. MARYANOFF

291

been augmented by t h e d i s c o v e r y of e q u a t o r i a l p r e f e r e n c e s f o r a l k y l groups i n v a r i o u s six-membered h e t e r o c y c l i c systems such a s 1,3-dioxanes (20,115,305b,307b), 1 , 3 - d i t h i a n e s ( 2 2 2 ) , and 1 , 3 - o x a t h i a n e s ( a l t h o u g h t h e degree of p r e f e r e n c e v a r i e s w i t h t h e r i n g system and p o s i t i o n o f s u b s t i t u t i o n ) . A s t r o n g e q u a t o r i a l p r e f e r e n c e h a s a l s o been demonstrated f o r t h e methyl group i n N-methylpiperidine a t ambient t e m p e r a t u r e ( A G O = -3.0 kcal/mol) ( 3 3 3 ) . However, i n v e s t i g a t i o n s of o t h e r h e t e r o c y c l i c systems have shown t h a t an e q u a t o r i a l o r i e n t a t i o n f o r s u b s t i t u e n t s on heteroatoms i s n o t u n i v e r s a l l y p r e f e r r e d . S-Alkylthianium s a l t s d i s p l a y g r e a t l y diminished e q u a t o r i a l p r e f e r e n c e s ( - A G O = 0.0 t o 0 . 3 kcal/mol) ( 3 3 5 ) , and t h e p r e v i o u s l y d i s c u s s e d l - a l k y l p h o s p h o r i n a n e s have a predominance of a x i a l 1 - a l k y l groups a t ambient t e m p e r a t u r e s ( A G O = 0.19 t o 0.35 kcal/mol) (324) C a l c u l a t i o n s f o r 1-methylsilacyclohexane p r e d i c t e s s e n t i a l l y no conformationa 1 f a v o r i n g f o r t h e methyl group ( A G O = 0.0 t o 0.2) ( 3 3 4 ) . Other examples (26) o f a x i a l p r e f e r e n c e s have been n o t e d f o r p r o t o n a t e d t h i a n e , t h i a n e - 1 - o x i d e , and thiane-1-(N-tosy1)irni.de ( 3 3 6 ) ; s e l e n a n e d e r i v a t i v e s (336g,337) ; a r s i n a n e d e r i v a t i v e s (43e ,313, 3 2 7 b ) ; and 2-0~0-1,3,2-dioxathianes ( 3 3 8 ) . Suggested e x p l a n a t i o n s f o r t h e tendency of s u b s t i t u e n t s on c e r t a i n heteroatoms (of cyclohexane r i n g s ) t o assume an a x i a l o r i e n t a t i o n i n c l u d e : (1) replacement of t h e normal 1 , 3 s y n - a x i a l r e p u l s i o n s found i n c y c l o h e x y l r i n g s w i t h a t t r a c t i v e 1 , 3 s y n - a x i a l i n t e r a c t i c n s (336g,337), and (2) r e l i e f o f 1 , 3 syna x i a l r e p u l s i o n s by a s u b s t a n t i a l f l a t t e n i n g of t h e r i n g a t t h e heteroatom end (32413). The l a t t e r i n t e r p r e t a t i o n i s p h y s i c a l l y r e p r e s e n t e d i n X-ray c r y s t a l l o g r a p h i c s t u d i e s , which show f l a t t e n e d r i n g s f o r S-methylthianium s a l t s (335) and f o r phosp h o r i n a n e s 302a and 302b ( 3 2 2 ) . A l l i n g e r and Wertz proposed (332d) t h a t t h e e q u a t o r i a l p r e f e r e n c e d i s p l a y e d by methylcyclohexane i s caused by f o u r u n f a v o r a b l e v i c i n a l gauche hydrogenhydrogen i n t e r a c t i o n s when t h e methyl group i s a x i a l , a s opposed t o o n l y two u n f a v o r a b l e i n t e r a c t i o n s when t h e methyl i s e q u a t o r i a l (and n o t t o t h e u s u a l l y assumed r e p u l s i v e s y n - a x i a l methylhydrogen i n t e r a c t i o n s ) . The Allinger-Wertz i n t e r p r e t a t i o n i m p l i e s t h a t removal of such gauche i n t e r a c t i o n s by replacement of a carbon w i t h a heteroatom b e a r i n g l o n e e l e c t r o n p a i r s s h o u l d d e p r e s s t h e e q u a t o r i a l p r e f e r e n c e . However, t h e h y p o t h e s i s reg a r d i n g methylcyclohexane h a s been c h a l l e n g e d ( 3 3 2 e ) , and it does n o t account f o r t h e s i m i l a r c o n f o r m a t i o n a l e n e r g i e s of groups a t t h e 2 - p o s i t i o n i n 1 , 3 - d i t h i a n e s o r t h e e l e v a t e d A G O v a l u e s (compared t o cyclohexane) o b s e r v e d f o r 2 - s u b s t i t u e n t s i n l I 3 - d i o x a n e s . The a l l e v i a t i o n of gauche i n t e r a c t i o n s may p a r t l y account f o r t h e a p p a r e n t i n c r e a s e d f l e x i b i l i t y of h e t e r o c y c l e s , t h a t i s , t h e f l a t t e n i n g of t h e h e t e r o a t o m p o r t i o n o f t h e r i n g , which r e d u c e s r e p u l s i v e i n t e r a c t i o n s a t t h e s y n - a x i a l p o s i t i o n s . The placement of a d d i t i o n a l heteroatoms a d j a c e n t t o phosphorus , a s i n l 1 3 , 2 - d i o x a - , 1,3 ,2-di t h i a - , and 1,3 ,2-diazaphosphorinanes, introduces a d d i t i o n a l c o n s i d e r a t i o n s i n t o t h e d e t e r mination of c o n f o r m a t i o n a l p r e f e r e n c e s . T h i s i s r e a d i l y a p p a r e n t

.

292

STEREOCHEMISTY OF PHOSPHORUS-CYCLOHEXANES

from a comparison of group c o n f o r m a t i o n a l e n e r g i e s f o r l - a l k y l phosphorinanes ( T a b l e 1 8 ) w i t h t h e c o r r e s p o n d i n g v a l u e s f o r 1,3,2-dioxaphosphorinanes ( T a b l e 1 5 ) . Thus, f o r example, b o t h 1methyl and 1-phenyl groups show s u b s t a n t i a l l y enhanced a x i a l p r e f e r e n c e s i n 1,3,2-dioxaphosphorinanes ( A G c H ~ = 1.1 t o 1 . 2 kcal/mol; A G c ~ H L~ 1.8 kcal/mol) (35), t h a n i n t h e p a r e n t phosphorinane system ( A G c H ~ = 0.25 kcal/mol; AGC6H5 = 0.19 kcal/mol) (324). I n a d d i t i o n , t h e s t r o n g a x i a l p r e f e r e n c e s d i s p l a y e d by small, p o l a r s u b s t i t u e n t s i n 1,3,2-dioxaphosphorinanes ( A G C H ~ O 2 3.2 kcal/mol; A G C l > 1.5 kcal/mol) (35) and i n l I 3 , 2 - d i t h i a p h o s phorinanes p o i n t s t o a n e x a g g e r a t i o n of a x i a l p r e f e r e n c e s due t o a d j a c e n t r i n g oxygen or s u l f u r atoms. Although t h i s f a v o r i n g i s p r e d i c t e d by t h e " g e n e r a l i z e d anomeric e f f e c t , " i n which p o l a r groups ( e . g . , CH30, C 1 ) a t t h e 2 - p o s i t i o n i n 1,3-dioxanes show a marked a x i a l f a v o r i n g , t h e p r e f e r e n c e i s c o n s i d e r a b l y g r e a t e r i n 1,3,2-dioxaphosphorinanes, i n d i c a t i n g an i n t e r a c t i o n between t h e r i n g oxygens ( o r s u l f u r s ) and t h e phosphorus. A n e x p l a n a t i o n and e v a l u a t i o n of t h i s i n t e r a c t i o n may be p r o v i d e d by t h e "gauche e f f e c t " (339), a t h e o r e t i c a l r u l e t h a t can p r e d i c t t h e r e l a t i v e s t a b i l i t i e s of r o t a t i o n a l isomers c o n t a i n i n g a d j a c e n t e l e c t r o n p a i r s and/or p o l a r bonds. Thus t h e gauche e f f e c t a t t r i b u t e s maximum s t a b i l i z a t i o n t o t h e conformation w i t h t h e maximum numb e r of gauche arrangements o f e l e c t r o n p a i r s ( b a r r i n g r e p u l s i v e s t e r i c i n t e r a c t i o n s ) and p o l a r bonds w i t h t h e s t i p u l a t i o n t h a t t h e f a v o r i n g of a d j a c e n t p o l a r bonds outweighs t h e f a v o r i n g of a p o l a r bond a d j a c e n t t o t w o l o n e p a i r s . Perhaps t h e clearest d e s c r i p t i o n of t h e r e l e v a n t i n t e r a c t i o n s i n v o l v e s a comparision of t h e i n t e r n a l r o t a t i o n a l p o t e n t i a l f u n c t i o n p r o v i d e d by Radom, Hehre, and Pople (340) f o r CH3NHOH compared t o 2 - s u b s t i t u t e d 1,3,2-dioxaphosphorinanes. Calc u l a t i o n s p r e d i c t t h a t s t r u c t u r e s 306A and 306B are t h e two stable conformations f o r CH3NHOH, and t h i s was confirmed by experiment (341). Rotamer 306C r e p r e s e n t s a p o t e n t i a l energy

306A

306B

306C

maximum, c a l c u l a t e d t o be ca. 4.0 kcal/mol h i g h e r i n energy t h a n 306B. By analogy (35) t h e c o r r e s p o n d i n g forms 307B and 307C f o r 2-R-1,3,2-dioxaphosphorinanes r e p r e s e n t t h e R-axial and Re q u a t o r i a l forms, r e s p e c t i v e l y . Thus 307B w i t h a x i a l a l k y l corresponds t o t h e more s t a b l e conformation. The t h e o r e t i c a l r a t i o n a l e f o r t h e p r e f e r r e d r o t a t i o n a l conformers stems from a bonding s t a b i l i z a t i o n shown f o r CHsNHOH

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293

( 3 0 8 ) , i n which d o n a t i o n from t h e h i g h e s t e n e r g y l o n e p a i r on oxygen t o t h e p a r t i a l l y v a c a n t 2 p o r b i t a l on n i t r o g e n (a t y p e o f back-bonding) i s maximized by c o n f o r m a t i o n 306A ( o r 3 0 6 B ) . T h i s s t a b i l i z a t i o n i s a p p a r e n t l y enhar.ced by r e p l a c e m e n t o f Ra l k y l by a more e l e c t r o n e g a t i v e g r o u p and t h u s p r e s e n t s a t h e o r e t i c a l argument f o r t h e anomeric e f f e c t found i n s y s t e m s h a v i n g e l e c t r o n e g a t i v e groups a d j a c e n t t o l o n e p a i r s o f e l e c t r o n s . A r e l a t e d t r e a t m e n t (342) of s u c h i n t e r a c t i o n s p i c t u r e s t h e stabil i z a t i o n of p e r t i n e n t conformations as a r e s u l t o f d o n a t i o n o f an a d j a c e n t l o n e p a i r i n t o a n e i g h b o r i n g a* o r b i t a l , and s u c h d o n a t i o n h a s t h e same o r i e n t a t i o n a l r e q u i r e m e n t as shown i n 306A and 306B. L i k e w i s e , t h e s t a b i l i z a t i o n i s i n c r e a s e d when t h e u * a n t i b o n d i n g o r b i t a l e n e r g y i s lowered by a u g m e n t a t i o n o f t h e p o l a r i t y bf t h e bond ( i . e . , w i t h C 1 and C H 3 O ) . S i m i l a r i n t e r a c t i o n s a r e a l s o r e l e v a n t t o t h e lI3,2-dithiaphosphorinane sy-

stem.

Superimposed on t h e e l e c t r o n i c i n t e r a c t i o n s d e p i c t e d h e r e a r e t h e s t e r i c i n t e r a c t i o n s s u f f e r e d by a n a x i a l s u b s t i t u e n t on phosphorus w i t h t h e 1 , 3 - a x i a l hydrogens. T h i s i s r e f l e c t e d i n t h e d e c r e a s e of AG (ax+eq): CH3 > i-C3H7 > t - C q H g ( T a b l e 1 5 ) ; a p p a r e n t l y w i t h t h e v e r y b u l k y t-C,+Hq g r o u p , t h i s s t e r i c i n t e r a c t i o n dominates such t h a t an e q u a t o r i a l o r i e n t a t i o n i s p r e f e r r e d i n b o t h 1,3,2-dioxaphosphorinanes ( 3 5 ) and 1 , 3 , 2 - d i t h i a phosphorinanes (47'48'51). The p r e f e r r e d e q u a t o r i a l o r i e n t a t i o n d e m o n s t r a t e d f o r t h e ( C H 3 ) 2 N and CH3NH groups ( 3 5 , 1 3 0 ) a p p a r e n t l y a r i s e s from a pn-dn i n t e r a c t i o n which i s maximized when t h e n i t r o g e n i s e q u a t o r i a l . A s d e m o n s t r a t e d by microwave s t u d i e s , t h e p r e f e r r e d conformat i o n f o r F2PNH2 i s t h a t shown i n 309 ( 3 4 3 ) , which may r e f l e c t p - o r b i t a l b a c k - d o n a t i o n from n i t r o g e n i n t o t h e a v a i l a b l e phosp h o r u s d o r b i t a l s . The c o r r e s p o n d i n g , f a v o r e d c o n f o r m a t i o n f o r t h e a x i a l N ( C H 3 ) 2 group i n a 1,3,2-dioxaphosphorinane, 310a, would e x p e r i e n c e s e v e r e s y n - a x i a l i n t e r a c t i o n s w i t h t h e 4 , 6 - a x i a l hydrogens. E l e c t r o n i c a l l y u n f a v o r e d c o n f o r m a t i o n 310b, i n which t h e o f f e n d i n g N-methyls are directed away from t h e r i n g , would be a l i k e l y , b u t p o o r , a l t e r n a t i v e . On t h e o t h e r hand t h e e q u a t o r i a l ( C H 3 ) z N can a d o p t c o n f o r m a t i o n 310c, i n which maximal p v d n s t a b i l i z a t i o n i s a l l o w e d and s t e r i c problems are a b s e n t . D i v e r s e d i s c u s s i o n s on t h e o r i g i n of t h e a x i a l p r e f e r e n c e o f s u b s t i t u e n t s o n phosphorus i n t r i c o o r d i n a t e and t e t r a c o o r d i n a t e compounds h a v e been p r e s e n t e d e l s e w h e r e ( 2 7 , 3 5 , 1 4 2 b , 3 2 4 b ) .

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STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

310b

310a

V.

31 Oc

Stereochemi s t r y o f Compounds w i t h Cyclohexane Rings C o n t a i n i n g P e n t a c o o r d i n a t e Phosphorus

A f a s c i n a t i n g p r o p e r t y o f p e n t a c o o r d i n a t e phosphorus compounds i s t h e occurrence of i n t r a m o l e c u l a r exchange of l i g a n d s about t h e c e n t r a l phosphorus atom, a p r o c e s s commonly r e f e r r e d t o a s pseudorotation. The permutation of l i g a n d s about t h e ( g r o u n d s t a t e ) t r i g o n a l bipyramidal ( l o c a l D3h) phosphorus c a n be e f f e c t e d by d i f f e r e n t mechanisms, two of which, t h e Berry and t u r n s t i l e mechanisms, have been proposed t o t a k e p l a c e i n r e a l systems. The more p r e v a l e n t B e r r y mechanism involves t h e p a i r wise p o s i t i o n a l exchange of two a p i c a l and two e q u a t o r i a l groups (with one s t a t i o n a r y e q u a t o r i a l group a c t i n g as a p i v o t l i g a n d ) ; t h e t r a n s i t i o n s t a t e f o r t h i s mechanism has l o c a l C4, symmetry. A l a r g e body of work has been published on t h i s s u b j e c t , includi n g many reviews ( 9 4 , 3 4 4 ) . Pentacoordinate s p e c i e s , which have t h e o p t i o n of i n t r a molecular l i g a n d r e o r g a n i z a t i o n , are produced a s i n t e r m e d i a t e s i n a v a r i e t y of r e a c t i o n s a t phosphorus. Some stereochemical a s p e c t s of t h i s have a l r e a d y been p r e s e n t e d i n preceding segments of t h i s review. I n t h i s s e c t i o n t h e d i s c u s s i o n i s l i m i t e d t o r e l a t i v e l y s t a b l e , observable phosphoranes. M u e t t e r t i e s and co-workers ( 3 4 5 ) o b t a i n e d 311, which shows no pseudorotation a t 100'; 311 may be s t r o n g l y conformationally b i a s e d t o t h e s t r u c t u r e w i t h a p i c a l f l u o r i n e s and a d i e q u a t o r i a l b r i d g i n g six-membered r i n g . Compound 312 does pseudorotate a t room temperature, and on cooling adopts a s t r u c t u r e i n which t h e

(-+

c i - F

F 311

F

312

r i n g i s d i e q u a t o r i a l . I n g e n e r a l , because of t h e a p i c o p h i l i c i t y of e l e c t r o n e g a t i v e s u b s t i t u e n t s , R3PF2 compounds do n o t show p s e u d o r o t a t i o n a t room temperature, u n l i k e RPF4 and R2PF3 compounds. Superimposition of r i n g - b r i d g i n g c o n s t r a i n t s f u r t h e r a f f e c t s pseudorotation: three-atom b r i d g i n g i s r e s t r i c t e d t o a n a p i c a l - e q u a t o r i a l c o n n e c t i v i t y . C a l c u l a t i o n s have p r e d i c t e d a

B.

295

E. .MARYANOFF, R. 0. HUTCHINS AND C . A . MARYANOFF

p r e f e r e n c e of t h e p h o s p h o r i n a n e r i n g f o r a d i e q u a t o r i a l o r i e n t a t i o n i n a t r i g o r i a l b i p y r a m i d a l phosphorane (346). The 1:l a d d u c t s o f 1 2 , B r 2 , and C 1 z w i t h 1-methyl- and 1-phenylphosphorinane a r e markedly i o n i c m o l e c u l a r complexes ( s e e 3 1 3 ) r a t h e r t h a n phosphoranes (347). Complexes o f t h e c o r r e s p o n d i n g (1:l) a r s e n i c compounds w i t h c h l o r i n e and bromine are c o n v e r s e l y t r i g o n a l b i p y r a m i d a l , c o v a l e n t a d d u c t s .

cpt: x-

314

315

Oxyphosphoranes have r e c e i v e d c o n s i d e r a b l e a t t e n t i o n . An X-ray s t r u c t u r a l a n a l y s i s of 314 r e v e a l s a d i s t o r t e d t r i g o n a l b i p y r a m i d w i t h t h e five-membered r i n g s p a n n i n g a p i c a l - e q u a t o r i a l p o s i t i o n s ( r i n g oxygen a p i c a l , n i t r o g e n e q u a t o r i a l ) . O t h e r c a g e d , p o l y c y c l i c phosphoranes w i t h p h o s p h o r u s - c o n t a i n i n g c y c l o h e x a n e r i n g s have been s t u d i e d from a s t r u c t u r a l and m e c h a n i s t i c viewp o i n t (348,349). Compounds s u c h a s 315 h a v e b e e n s u g g e s t e d t o undergo p e r m u t a t i o n a l i s o m e r i z a t i o n by a t u r n s t i l e mechanism (344b,348). Denney and co-workers (350) p r e p a r e d compounds w i t h one o r two 1,3,2-dioxaphosphorinane r i n g s i n c o r p o r a t e d i n a p e n t a c o o r d i n a t e s t r u c t u r e . The 'H NMR s p e c t r a o f a l l o f t h e s e compounds were b e s t e x p l a i n e d by r a p i d i n t r a m o l e c u l a r l i g a n d reorg a n i z a t i o n . I n 317 one r i n g must be e q u a t o r i a l - e q u a t o r i a l , t h u s

t h e s i n g l e s u b s t i t u e n t i s a p i c a l . V a r i a b l e - t e m p e r a t u r e NMR s p e c t r a o f 316a, 316b, 3 1 6 d , a n d 317a were unchanged t o ca. -60'. Compound 316c showed two d o u b l e t s f o r t h e methylene p r o t o n s o f one r i n g a t - 6 5 O , a t t r i b u t e d t o t h e p r e v a l e n c e o f 3 1 8 . The

296

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

spectra of 317b and 3 1 7 ~underwent changes on c o o l i n g , compatible w i t h s t r u c t u r e s i n which t h e l o n e l i g a n d assumes an e q u a t o r i a l p o s i t i o n and t h e two r i n g s a r e each a p i c a l - e q u a t o r i a l . P s e u d o r o t a t i o n s t i l l o c c u r s , b u t by r i n g exchange o n l y ; t h e R group i s t h e p i v o t a l l i g a n d (see 3 2 9 ) . T r i p p e t t and co-workers conducted v a r i a b l e - t e m p e r a t u r e NMR s t u d i e s on many s p i r o p h o s phoranes , i n c l u d i n g 31 7b, 31 7c , and 31 7d (351) X-Ray a n a l y s i s

.

320

319

o f 320 was s a i d t o show an a p i c a l - e q u a t o r i a l 1,3,2-oxazaphosphorinane r i n g i n a boat conformation ( 3 5 1 a ) . The importance of l o n e - p a i r o r i e n t a t i o n i n d e t e r m i n i n g conformer s t a b i l i t y of phosphoranes i s s u g g e s t e d by t h e p r e f e r e n c e o f t h e n i t r o g e n f o r t h e e q u a t o r i a l p l a n e i n 320; however, c r y s t a l - p a c k i n g f o r c e s may be p a r t l y r e s p o n s i b l e f o r t h i s o b s e r v a t i o n . (CF3)g C 0

c s"-6

/ OCcHc.

/OCgH5

"$:::

F3C

CF3

321

For 321 a b a r r i e r t o p s e u d o r o t a t i o n of 5.9 kcal/mol was measured (351). The i s o m e r i z a t i o n w i t h 321 may i n v o l v e c h a i r o r b o a t forms of t h e 1,3,2-dioxaphosphorinane r i n g ; no i n f o r m a t i o n i s a v a i l a b l e on t h e s o l u t i o n conformation of t h e phosphorinane r i n g i n 320 o r 321. There i s ample room f o r f u r t h e r s t u d y i n t h e c o n f o r m a t i o n a l a n a l y s i s of cyclohexane r i n g s c o n t a i n i n g p e n t a c o o r d i n a t e phosp h o r u s , an a r e a i n which t h e s u r f a c e h a s o n l y been s c r a t c h e d . Some i n f o r m a t i o n i s a v a i l a b l e on c o n f o r m a t i o n a l p r e f e r e n c e s a b o u t t h e phosphorus atom, b u t v e r y - l i t t l e i s known a b o u t t h e con-

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

297

formational properties of the six-membered ring. These considerations are pertinent to mechanisms of nucleophilic substitution at tetracoordinate phosphorus in phosphorus-containing six-membered rings (352).

VI.

OVERVIEW

Over the past 25 years the area of conformational analysis has been extensively investigated with respect to aliphatic, alicyclic, and heterocyclic organic compounds (16-23). Recent interest has focused on, among other things, saturated six-membered heterocycles containing main-group elements from the second, third, and fourth rows of the Periodic Table (26,27; this chapter). In this realm new stereochemical and conformationa1 experiences have been encountered. For example, although substituents attached to carbon and nitrogen atoms in saturated, six-membered rings usually prefer an equatorial orientation, the same groups display this tendency to a much weaker degree when attached to atoms such as sulfur, phosphorus, selenium, and arsenic--indeed, axial preferences are often observed. This conformational novelty has stimulated much interest and study, especially on phosphorus-containing cyclohexane systems (phosphorinanes) (26,27; this chapter). As brought out in this chapter, dipolar interactions, attractive van der Waals forces, and ring distortion have been advanced by different researchers to rationalize the axial favoring (or equatorial disfavoring) phenomena. We believe that, depending on the system under study, various combinations of these three factors are involved. An exciting revelation is the propensity for certain 1,3,2dithiaphosphorinane derivatives to assume twist conformations, whereas this does not occur with analogous 1,3,2-dioxaphosphorinanes or phosphorinanes. Importantly, the favoring of the twist form is not apparently caused by molecular constraints; it is naturally adopted. Further study in this area should be fruitful. The structural and conformational properties of 1,3,2-diazaphosphorinanes are vague at this time. But observations peculiar to this system herald another potentially interesting area for future work. X-Ray data for this class of compounds are long overdue. For the 1,3,2-dioxaphosphorinanes nucleophilic and electrophilic reactions have furnished a wealth of novel chemistry of stereochemical significance. However, regarding the other phosphorus-containing cyclohexanes, a vast territory remains largely m e xplored . The biological relevance of phosphorus-containing cyclohexanes is evident from Sect. 111-D. For example, modification of cyclic nucleotides can lead to derivatives that have different susceptibilities to hydrolysis by phosphodiesterase. Application of some of the chemistry and structural information

298

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXES

d e r i v e d from s i m p l e s y s t e m s t o t h e c y c l i c n u c l e o t i d e s c o u l d p r o v i d e new compounds w i t h u n u s u a l ( a n d p e r h a p s u s e f u l ) b i o l o g i c a l properties.

ACKNOWLEDGMENTS The a u t h o r s e x p r e s s t h e i r w a r m g r a t i t u d e t o M s . Roseann Gramlich and M s . P a t r i c i a Evanco f o r s k i l l f u l t y p i n g o f t h e m a n u s c r i p t ; w e a l s o t h a n k M s . Grace L a l l e y f o r a s s i s t a n c e w i t h s t r u c t u r a l drawings. B. E . M. t h a n k s D r . M. J . Z e l e s k o a n d D r . J. A. Meschino o f M c N e i l L a b o r a t o r i e s f o r t h e i r s u p p o r t o f t h i s e n d e a v o r , and C. A. M. w i s h e s t o t h a n k P r o f . E. C . T a y l o r ( P r i n c e t o n U n i v e r s i t y ) f o r h i s encouragement. A number o f researchers furnished us w i t h t h e i r r e s u l t s p r i o r t o publication, and f o r t h i s w e e x p r e s s our a p p r e c i a t i o n .

REFERENCES AND NOTES 1.

F. G. Mann, "The H e t e r o c y c l i c D e r i v a t i v e s o f Phosphorus, A r s e n i c , Antimony, Bismuth, a n d S i l i c o n , " i n The Chemistry of Heterocyclic Compounds, A. W e i s s b e r g e r , Ed., I n t e r s c i e n c e , New York, 1950. 2. G. M. K o s a l o p o f f , Organophosphorus Compounds, W i l e y , N e w York, 1950. 3. R. F. Hudson, Structure and Mechanism in Organophosphorus Chemistry, Academic P r e s s , New York, 1965. 4. A. J. Kirby and S. G. Warren, The Organic Chemistry of Phosphorus, E l s e v i e r , Amsterdam,'1967. 5 . J. Emsley and D. H a l l , The Chemistry of Phosphorus, Wiley, New York, 1976. 6. F. G. Mann, The Heterocyclic Derivatives of Phosphorus, Arsenic, Antimony, and Bismuth, 2nd e d . , W i l e y - I n t e r s c i e n c e , New York, 1970. 7. ( a ) K. D. B e r l i n and D. M. Hellwege, Top Phosphorus Chem., 6 , 1 ( 1 9 6 9 ) ; (b) S. D. Venkataramu, G. D. Macdonell, W. R. Purdum, M. El-Deek, a n d K. D. B e r l i n , Chem. Rev., 27, 121 (1977). 8. (a) M. J . G a l l a g h e r a n d I. D. J e n k i n s , Top Stereochem., 3, 1 ( 1 9 6 8 ) ; ( b ) M. J. G a l l a g h e r , i n Stereochemistry of Heterocyclic Compounds, P a r t 2 , W. L. F. Armarego, Ed. , Wiley, N e w York, 1977. 9. G. Zon and K. M i s l o w , Forschr. Chem. Forsch., 1 9 , 6 1 ( 1 9 7 1 ) . 10. R. F. Hudson and M. Green, Angew. Chem., Int. Ed. Engl., 2 , 11 (1963). 11. L. Horner, Pure Appl. Chem., 9 , 225 ( 1 9 6 4 ) . 1 2 . W. E. McEwen, Top. Phosphorus Chem., 2 , 1 ( 1 9 6 5 ) . 1 3 . 31P NMR: (a) M. M. C r u t c h f i e l d , C. H. Dungan, J . H . L e t c h e r , V. Mark, and J. R. Van Wazer, Top. Phosphorus Chem., 5 ( 1 9 6 7 ) ; ( b ) J. R. Van Wazer, Detn. Org. Struct. Phys. Methods, 4, 323 ( 1 9 7 1 ) .

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IR: D. E. C. Corbridge, Top. Phosphorus Chem., 6, 235 (1969). 15. (a) D. E. C. Corbridge, The Structure Chemistry of Phosphorus, Elsevier, Amsterdam, 1974; (b) L. S. Khaikin and L. V. Vilkov, RUSS. Chem. Rev., 41, 1060 (1972). 16. E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A . Morrison, Conformational Analysis, Wiley, New York, 1965. 17. E. L. Eliel, Stereochemistry of Carbon Compounds, McGrawHill, New York, 1962. 18. M. Hanack, Conformation Theory, Academic Press, New York, 1965. 19. G. Chiurdoglu, Conformational Analysis, Academic Press , New York, 1971. 20. E. L. Eliel, ACC. Chem. Res., 3 , 1 (1970). 21. C. Romers, C. Altona, H. R. Buys, and E. Havinga, Top. Stereochem., 4 , 39 (1969). 22. C. H. Bushweller, Mech. React. Sulfur Compd., 5 , 75 (1969) 23. F. G. Riddell, 9. Rev. Chem. SOC., 2 1 , 364 (1967). 24. The terms phosphacyclohexane and phosphorinane have been used throughout the chemical literature to describe sixmembered rings containing phosphorus. We adhere to the latter terminology in this chapter; thus , for example, 1,3,2-dithiaphosphbrinane is employed instead of 2-phospha1,3-dithiacyclohexane. 25. For example, G. Amitai, Y. Ashani, Y. Grunfeld, A. Kalir, and S. Cohen, J. Med. Chem., 1 9 , 810 (1976). 26. J. B. Lambert and S. I. Featherman, Chem. Rev., 75, 611 (1975). 27. J. G. Verkade, Phosphorus S u l f u r , 2 , 251 (1976). 28. (a) H. Booth, Prog. Nucl. M a w . Reson. Spectrosc., 5 . 149 (1969); (b) W. A. Thomas, Ann. Rev. Nucl. Magn. Reson. Spectrosc., 1 , 43 (1968). 29. (a) J. A. Mosbo and J. G. Verkade, J. Org. Chem., 42, 1549 (1977); (b) M. J. Gallagher, in Stereochemistry of Heterocyclic Compounds, Part 2, W. L. F . Armarego, Ed., Wiley, New York, 1977, pp. 340-343. M. Haemers, R. Ottinger, J. Reisse, and D. Zimmermann, 30 Tetrahedron Lett., 461 (1971). 31. M. Haemers, R. Ottinger, D. Zimmermann, and J. Reisse, Tetrahedron Lett., 2241 (1973). 32. M. Haemers, R. Ottinger, D. Zimmermann, and J. Reisse, Tetrahedron, 29, 3539 (1973). 33. J. A. Mosbo and J. G. Verkade, J. Am. Chem. SOC., 9 5 , 204 (1973). 34. D. Bouchu and J. Dreux, Tetrahedron Lett., 3151 (1976). 35. W. G. Bentrude, H. W. Tan, and K. C. Yee, J. Am. Chem. SOC., 9 7 , 573 (1975). 36. L. D. Hall and R. B. Malcolm, Can. J. Chem., 50, 2092 (1972). 37. M. Mikolajczyk, T. Krzywafiski, and B. Ziemnicka, Tetrahedron Lett., 1607 (1975). 38. A. A. Borisenko, N. M. Sergeyev, E. E. Nifant'ev, and Y.

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39. 40. 41. 42. 43.

44.

45.

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336.

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A. Hauser, A. Zschunko, K. I s s l e i b , and W. B b t t c h e r , P h o s p h o r u s , 5 , 261 ( 1 9 7 5 ) . ( a ) E. J. P r o s e n , W. H. J o h n s o n , and F. D. R o s s i n i , J. R e s . Natl. Bur. S t a n d . , 3 9 , 1 7 3 ( 1 9 6 7 ) ; (b) r e f . 1 6 , p . 44; ( c ) H. Booth and J . R. E v e r e t t , J. C h e m . SOC., C h e m . C o m m u n . , 278 ( 1 9 7 6 ) ; ( d ) D. H. Wertz and N . L. A l l i n g e r , T e t r a h e d r o n , 30, 1579 ( 1 9 7 4 ) ; ( e ) S. F i t z w a t e r a n d L. S . B a r t e l l , J. Am. C h e m . SOC., 98, 5107 ( 1 9 7 6 ) ; E. O s a w a , J. B. C o l l i n s , a n d P. v. R. S c h l e y e r , T e t r a h e d r o n ,

3 3 , 2667 ( 1 9 7 7 ) . L. E l i e l and F. W. V i e r h a p p e r , J. Am. C h e m . Soc., 9 7 , 2424 ( 1 9 7 5 ) ; M. J. T . Robinson, J . C h e m . SOC., C h e m . Commun., 844 ( 1 9 7 5 ) ; D. C. A p p l e t o n , J. McKenna, L. B. Sim, and A. R. Walley, J. Am. C h e m . Soc., 98, 292 ( 1 9 7 6 ) . The v a l u e s were computed u s i n g s e m i e m p i r i c a l f o r c e - f i e l d methods. M. J. T r i b b l e and N. L. A l l i n g e r , T e t r a h e d r o n , 28, 2147 ( 1 9 7 2 ) ; R. J. O u e l l e t t e , J. Am. C h e m . Soc., 9 6 , 2421 (1Y74). E. L. E l i e l , R. L. Willer, A. T. McPhail, and K. D. Onan, J . Am. C h e m . SOC., 9 6 , 3021 ( 1 9 7 4 ) ; E. L. E l i e l a n d R. L. Willer, J. Am. C h e m . SOC., 99, 1936 ( 1 9 7 7 ) . ( a ) J. B. Lambert, D. S. B a i l e y , and C. E. Mixan, J. Org. C h e m . , 3 7 , 377 ( 1 9 7 2 ) ; ( b ) J . B. Lambert, R. G . Keske, and D. K. Weary, J. Am. C h e m . SOC., 8 9 , 5921 ( 1 9 6 7 ) ; ( c ) J . B. Lambert, D. S. B a i l e y , and R. G . Keske, J . Org. C h e m . , 3 1 , 3429 ( 1 9 6 6 ) ; ( d ) J . B. Lambert, C. E . Mixan, and D. S . B a i l e y , C h e m . C o m m u n . , 316 ( 1 9 7 1 ) ; ( e ) C . R . J o h n s o n and D. B. McCants, J r . , J. Am. C h e m . SOC., 8 7 , 1109 ( 1 9 6 5 ) ; ( f ) J. C. M a r t i n and J. J . Uebel, J . Am. C h e m . SOC., 8 6 , 2936 ( 1 9 6 4 ) ; ( 9 ) J. B. Lambert, C . E. Mixan, and D. H. Johnson, J. Am. C h e m . S O C . , 95, 4634 ( 1 9 7 3 ) . J. B. Lambert, C. E . Mixan, and D. H. J o h n s o n , T e t r a h e d r o n L e t t . , 4335 ( 1 9 7 2 ) . P. A l b r i k t s e n , A c t a C h e m . S c a n d . , 2 6 , 1783 ( 1 9 7 2 ) ; H. F . van Woerden and A. T. Vries-Miedema, T e t r a h e d r o n L e t t . , 1687 ( 1 9 7 1 ) . E.

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S. Wolfe, A c c . C h e m . R e s . , 5, 102 (1972); S. Wolfe, A . Rauk, L. M. Tel, and I. G. Csizmadia, J . C h e m . SOC., B , 136 (1971). 340. L. Radom, W. J. Hehre, and J. A. Pople, J. Am. C h e m . SOC., 9 4 , 2371 (1972). 341. P. A. Giguere and I. D. Liu, C a n . J . C h e m . , 3 0 , 948 (1952). 342. S. David, 0. Eisenstein, W. J. Hehre, L. Salem, and R. Hoffman, J. Am. C h e m . SOC., 9 5 , 3806 (1973). 343. A. H. Brittain, J. E. Smith, P. L. Lee, K. Cohn, and R. H. Schwendeman, i b i d . , 9 3 , 6772 (1971). 344. K. Mislow, A c c . C h e m . Hes., 3, 321 (1970) and references cited therein; (b) F. Ramirez and I. Ugi, B u l l . SOC. C h i m . F r . , 453 (1974) and references cited therein. 345. E. L. Muetterties, W. Mahler, and R. Schmutzler, I n o r g . C h e m . , 2, 613 (1963). P. Gillespie, P. Hoffmann, M. Klusacek, D. Marquarding, 346 S. Pfohl, F. Ramirez, E. A. Tsolis, and I. Ugi, A n g e w . C h e m . , I n t l . E d i t . E n g l . , 1 0 , 687 (1971). 347. J. B. Lambert and H.-N. Sun, J . O r g . C h e m . , 4 2 , 1315 (1977). W. C. Hamilton, J. S. Ricci, Jr., F. Ramirez, L. Kramer, 348 and P. Stern, J . Am. C h e m . SOC., 95, 6335 (1973). 349. F. Ramirez, I. Ugi, F. Lin, S. Pfohl, P. Hoffman, and D. Marquarding, T e t r a h e d r o n , 3 0 , 371 (1974); B. S. Campbell, N. J. De'Ath, D. B. Denney, D. Z . Denney, I. S. Kipnis, and T. B. Min, J . Am. C h e m . SOC., 9 8 , 2924 (1976). 350. B. C. Chang, W. E. Conrad, D. B. Denney, D. Z. Denney, R. Edelman, R. L. Powell, and D. W. White, i b i d . , 9 3 , 4004 (1971). 351. (a) S. A. Bone, S. Trippett, and P. J. Whittle, J. C h e m . SOC., P e r k i n I , 80 (1977); (b) i b i d . , 437 (1977). For example, in the reaction of cyclic phosphonates with 352 aldehydes: E. Breuer and D. M. Bannet, T e t r a h e d r o n , 3 4 , 997 (1978).

339.

-

-

-

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

318

ADDENDUM Because of the time gap between manuscript preparation and the publication of monographs of this type, coupled with high activity in this area, we deemed it worthwhile to update this review. Coverage of relevant chemical literature has been extended up to December 1978. S e c t i o n I. A review on the Kerr effect and its application to organophosphorus compounds has appeared in print (353). The Kerr effect has been used in the conformational analysis of tri- and tetracoordinate 1,3,2-dioxaphosphorinanes. S e c t i o n III.A.3. Phosphorylation of hexofuranosides with (C2HsN)3P furnished sugar-derived l-phospha-2,7,8-trioxabicyclo (3.2.lloctape compounds (354). The formation of bicyclic phosphites, such as D-glucofuranoside 322, was governed by a cis relationship of the vicinal substituents at C-3 and C-4 of the tetrahydrofuran ring.

322

H 3C'

141 R 142 R 151 R

323 OCH3 = N(CH3)2 = CH3 =

S e c t i o n 111.B. 1.a. Dipole moment data indicated that N(CH3)z and N(C2Hg)z strongly prefer an equatorial orientation in 2-dialkylamino-2-oxo-l,3,2-dioxaphosphorinanes with no biasing substituents on ring carbons 4, 5, and 6 (355). 220-MHz 'H N"R data for both isomers of 141, 142, and 151 were analyzed in depth (356). Compounds 141a (trans), 142b (cis), 151a (cis), and 151b (trans) each exist as a single chair conformation (295%) with the 4-methyl group equatorial. Both 141b and 142a, which with an equatorial 4-methyl group in a chair conformer have an unfavorable orientation of the phosphorus substituents, exist as conformational mixtures. Mosbo, using vicinal coupling constants, suggested that 141a contained 60% equatorial chair, 20% axial chair, and 20% boat (viz. 323) conformers; and that 242b contained 68% equatorial chair, 16% axial chair, and 16% boat (323) conformers. Small amounts (10-20%) of boat (or twist) conformers may be present in conformational mixtures of 1,3,2-dioxaphosphorinanes, which are reported to be composed of two interconverting chair conformers (e.g., 144b and 301). S e c t i o n III.B.1.b. Investigation of 324 by X-ray crystallography revealed a twist conformation in the solid state (357).

B.

E . MARYANOFF, R . 0. HUTCHINS AND C . A. MARYANOFF

319

T h i s i s n o t u n r e a s o n a b l e s i n c e b o t h p o s s i b l e c h a i r forms o f 324 s u f f e r severe 1 , 3 syn-axial i n t e r a c t i o n s .

324 325

S e c t i o n III.B. 1.c. Bis[p-5,5-dimethyl-lI3,2-dioxaphosphorinano] hexacarbonyldiiron, i n t h e s o l i d s t a t e , h a s a " b u t t e r f l y " geometry, t y p i c a l o f s u c h complexes, and c o n t a i n s c h a i r d i o x a p h o s p h o r i n a n e r i i , g s ( 3 5 8 a ) . The r i n g s a r e t i l t e d w i t h respect t o t h e Fe-Fe a x i s , so t h a t o n e i r o n atom i s a x i a l and t h e o t h e r i s e q u a t o r i a l w i t h r e s p e c t t o a s i n g l e p h o s p h o r i n a n e r i n g . Given t h e approximate C 2 symmetry ( 3 2 5 ) , e a c h i r o n atom i s a x i a l i n one r i n g and e q u a t o r i a l i n t h e o t h e r . 'H NMR o f 325 showed a s i n g l e r e s o n a n c e f o r t h e 5 , 5 - d i m e t h y l g r o u p s (from -75 t o 1 0 0 ° C ) , r e f l e c t i n g f l u x i o n a l p r o p e r t i e s i n s o l u t i o n (phosphorinane r i n g i n v e r s i o n ) ( 3 5 8 b ) . O b s e r v a t i o n o f t h e r i n g methylene s i g n a l s (60 M H Z , 26-79O) d i s c l o s e d a l o s s o f 5 J p ~ attributable t o fluxion of t h e Fe-P-Fe-P r i n g a t h i g h e r t e m p e r a t u r e s . S e c t i o n III.B. 2.a . N u c l e o p h i l i c d i s p l a c e m e n t o f 4 - n i t r o phenoxide from 165a ( R = N02) and 165b ( R = N02) by 4-methylphenoxide was s t u d i e d ( 3 5 9 ) . S u b s t i t u t i o n o c c u r r e d w i t h b o t h i n v e r s i o n and r e t e n t i o n a t p h o s p h o r u s , t h e r e l a t i v e amount of which w a s dependent on t h e c a t i o n and s o l v e n t i n v o l v e d . A h i g h d e g r e e o f a s s o c i a t i o n between t h e c a t i o n ( e . g . , l i t h i u m ) a n d oxy-anion f a v o r e d r e t e n t i o n . S t e r e o s p e c i f i c c h l o r i n o l y s i s ( C 1 2 or S02C12) of phosphorot h i o n a t e s 138a and 138b was shown t o i n v o l v e diastereomeric phosphonium i n t e r m e d i a t e s ( v i z . 3 2 6 ) by 3 1 P NMR ( 3 6 0 ) .

S e c t i o n III.c. 1 . One o f t h e two i s o m e r s ( 3 2 7 , E c o n f i g u r a t i o n ) formed i n t h e r e a c t i o n o f ( C 2 H 5 ) 2 P ( O ) C ( N 2 ) C ( O ) C g H g w i t h a c c t a l d e h y d e was i d e n t i f i e d by X-ray c r y s t a l l o g r a p h y ( 3 6 1 ) . The u n s a t u r a t e d h e t e r o c y c l i c r i n g a d o p t s a f l a t t e n e d h a l f - c h a i r con-

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

320

formation with pseudoaxial P-phenyl and pseudoequatorial methyl groups. Sodium borohydride reduction of 328 afforded sugar-derived oxaphosphorinane 329, which has a chair phosphorinane ring; the configuration at phosphorus was not established (362). S e c t i o n III.C.2. An NMR study of 330 indicated one predominant chair conformation with an axial P-H bond (363). Dipole moment measurements on several derivatives of 331 (X = 0 ) indicated chair conformers with axial P-substituents (364). X-Ray analysis of 332 revealed a twist structure in the solid state (365). 'H NMR studies indicated the preference of a twist conformer in solution as well. The trans isomer related to 332 is also a twist conformer in the solid state, but favors a chair conformer in solution [equatorial t-CqHg and N(CH3)2] (365). X-Ray analysis of 332 ( R = OCgH5, R' = CH3, R" = H, X = S) showed a chair structure with the P = S bond equatorial; the ring nitrogen was nearly planar (366a).

329

OH

N

330

H

I

R' 331 (R" = H or CH3)

S e c t i o n III.C.4. 'HI 13C, and 31P NMR data for 2-thiono1 ,3 ,2-dithiaphosphorinanes 219a-219e and 219 [R = OCH3 , C6II5 , t-CqHg, 2,2-dimethylaziridinyl (DMA), and t-ChHgNHI were analyzed (22613). When R = C1, OCH3r or DMA, the molecule adopts a chair conformation, with an axial R group; when R = bulky R2N (as in

2 1 9 ~ - 2 1 9 e ) ,the molecule adopts a chair conformation with an equatorial R group; and when R = CgHgr CH3, N(CH3)2, or NH-tCqHg, the molecule exists as a chair-chair mixture. S e c t i o n III.C.6. A large series of 1,4-heterophosphorinanium salts 333 (Y = 0 , S, NH, NCH3) were prepared by Samaan (366b). The configuration and conformation of the salts, formed as isoR

321

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A. MARYANOFF

219

335 a : X = lone pair (lp) b: X = O

336

meric mixtures from divinylphosphonium compounds and H2Y, were studied by 'H and 13C NMR spectroscopy. Interesting sugar analogs with phosphorus as the ring heteroatom have been synthesized (367). Treatment of 3340 with aqueous HC1 gave 335a, which was directly oxidized to 335b; the configuration at phosphorus in 335b was not established (367b). Treatment of 334b with aqueous HC1, followed by acetylation, gave a mixture of D-glucopyranose and L-idopyranose compounds (367a). A crystalline material, identified as 336 by X-ray crystallography (368), was isolated from the sugar mixture (367a). 13C (and jlP) NMR data (369) for 337a-337d reinforced original stereochemical assignments (43f). An X-ray analysis of 337c displayed a chair conformation with t-butyl and phenyl groups equatorial (369). Equilibration of 337c and 337d with 6N HC1 at 125' produced a 25/75 mixture, respectively, indicative of the conformational preference for equatorial phenyl vs. P=O (43f). Alkaline cleavage of stereoisomerically pure benzylphosphonium salts from 337a and 3373 gave mixtures of oxides 337c/ 337d (66/34 and 21/79, respectively) (43f). The corresponding 4-methyl series gave corresponding oxide ratios of 48/52 and 22/78 (252). Hydroxide-induced cleavage of methylphosphonium salts from 337a and 337b (by displacement of phenyl) gave mixtures of oxides 3 3 7 s and 337e (62/38 and 25/75, respectively) (43f) and cleavage of the phenylphosphonium salt from 337a ( 3 3 7 b ) gave oxides 337c and 337d (40/60).

C6H5

= o

322

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

Hydroxide cleavage of methoxyphosphonium salts obtained by methylation of 337c and 337d occurs with complete inversion of configuration, if homogeneous conditions are employed (370). Under heterogeneous conditions, some attack at carbon (giving retention) is observed (352bI370). S e ct i o n III.D.l. Condensation of thymidine with hexamethylphosphorus triamide yielded cylic nucleotide 3 3 8 a , having an equatorial amino group (371). Stereospecific oxidation with N2O4 gave 338b. Methanolysis of 338a at 70' afforded a mixture (60/40) of diastereomeric triesters. An X-ray analysis of 338b shows the dioxaphosphorinane in a chair conformation with the dimethylamino group equatorial (262b,371) Analogs of c-AMP, 339a and 3 3 9 b , were prepared as mixtures of diastereomers which were separated by chromatography (372). Reaction of 339a with CH2N2 resulted in ring cleavage, but reaction of 3391, furnished a stable methylthio derivative. The P-N bonds in 339a and 339b were more stable to acid hydrolysis than those in the corresponding compounds with the P=O The diastereomers were stereochemically assigned using 3C and 31P NMR data. A diastereomeric pair of 2',3' cyclic nucleotides was also prepared, separated, and stereochemically identified. Benkovic and co-workers utilized snake-venom phosphodiesterase to destroy one stereoisomer of adenosine monophosphorothioate p-nitrophenylester (AMPS-NPE). The intact AMPS-NPE isomer was cyclized under base catalysis to a single diastereomer of CAMPS ( 2 7 2 ) , assignment of which is in progress (373a). S e c t i o n I I I . D. 2. Optical resolution of cyclophosphamide ( 2 7 5 a ) was accomplished by recrystallization of diastereomeric a-naphthylphenylmethylsilyl derivatives, and cleavage of the endocyclic Si-N bond with cyclohexylammonium fluoride (37333). Several 4-hydroperoxyisophosphamide analogs were synthesized by ozonolytic cyclization of 3-butenylphosphorodiamidates (374a), a reaction employed earlier to make 4-hydroperoxycyclophosphamide ( 2 7 6 b ) (374b), an active metabolite of 275a. Two stereoisomers were obtained for the isophosphamide series (281, 374a), whereas only a cis isomer was isolated in the synthesis of 276b (37413). Treatment of the unfractioned mixture of 340a and 340b with dilute NaOH produced cyclic peroxides 341a and 341b in a 5:l ratio (eq [ 4 4 ] ) . Both 340a/340b and 341a/341b were interconvertible by the action of acid, giving equilibrium mixtures of 5:l and 3:4, respectively (374a). High antileukemic activity in vivo was observed for the hydroperoxy analogs (374a). Separate incubation kinetic studies with ( + ) - and ( - ) - 2 7 5 a in microsoma1 preparations gave nearly the same Vmax and Km values (375a). Other experiments also suggested an unusually low

.

Youp-

B. E. MARYANOFF, R. 0. HUTCHINS AND C.

A.

MARYANOFF

323

34 Oa

NaOH

[441

degree of biological stereoselectivity associated with metabolism of ( + ) - and ( - ) - 2 7 5 a . Animal testing of the enantiomers against mouse L1210 leukemia showed little therapeutic difference. A synthesis of ( + ) - and ( - ) - 2 2 6 from separable diastereomers in analogy to work with 275a (283) was reported by Zon's group (375b) Verkade and co-workers studied the solution stereochemistry of 275a and its (pairs of) cis- and tran5-4,6-dimethyl derivatives (375~).Using the two anancomeric ~is-4~6-dimethyl compounds as models, they concluded that the dominant conformer of 275a in solution has an equatorial amino group. Zon's group has reported on some 5-bromocyclophosphamide compounds, which undergo interesting base-induced intramolecular cyclizations to 3,5-dehydro derivatives (375d). Section 1 v . B . Eight-membered-ring heterocycle 342 was suggested as having a chair-chair conformation with an equatorial P-methyl qroup (376a). This contrasts with the preferred axial orientation in the 1,3,2-dioxaphosphorinane system.

.

324

STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXANES

Section I V . C. Borisenko and co-workers (376b) reported 'HI 13C, and 31P NMR spectra for a variety of trivalent lI3,2-dithiaphosphorinanes. Section IV.D. The s nthesis and stereochemistry of series 343 was reported (377); 3yP NMR chemical shifts were correlated with conformation. An NMR study of the stereochemistry of series 344 was reported (363); 344 (R = HI C1, CgH5, OC2H5, N(CH3)2) were claimed to exist in a chair conformation with axial R. Section I V . E . Pyramidal inversion at phosphorus in 337a and 337b was used to obtain thermodynamic mixtures (from both sides of the equilibrium) at three temperatures (369). At 417OK, K was 1.44 (AGO = -0.30 kcal/mol) and at 454OK, Keq was 1.21 = -0.17 kcal/mol) , corresponding to a preference for trans isomer 337b. This result contrasts with results of Featherman and Quin (324), which for 1-phenylphosphorinane indicated an axial preference for phenyl at 300°K (AGO = 0.20 kcal/mol) and exhibited a trend toward less positive AGO values at lower temperatures. The barrier to pyramidal inversion at 454'K was 36.0 kcal/mol; a AG# (448'K) of 36.6 kcal/mol was found for the corresponding lI3,2-dithiaphosphorinane 44 (51). Semi-empirical force-field calculations on phosphorinanes were published (378). For phosphorinane itself ( 2 2 9 ) the calculated energy difference was 1.2 kcal/mol, favoring the axial proton on phosphorus. This preference was attributed to torsional energetics and "gauche hydrogen" interaction. Calculated values for P-methyl (-0.5) , ethyl (-0.5) , i-propyl (-0.6), and phenyl (0.2) were in reasonable agreement with experimental values, save for P-phenyl which was more strongly favored equatorially in the calculations. Diastereomers of substituted 1,3-oxaphosphorinanes ( 3 4 5 ) , prepared by condensation of hydroxyphosphines and aldehydes, were studied by 13C and 31P NMR (379). Conformational equilibra were dominated by the equatorial preference of R1 fphenyl or t-butyl). Trans, trans isomer 346 was suggested to exist as a nixture of chair (346a) and twist (346b) conformers, a sign of instability for the equatorial disposition of P-phenyl in 346a.

(22'

CH 3

346a

5H6''

346b

Section I V . F. Allinger and Voithenberg (378) reported molecular mechanics computations on phosphorinanes ( v i d e supra). CNW/2 calculations for conformations of 2-R-lI3,2-dioxaphosphorinanes (R = H, C1, dimethylamino) and 2-R-2-thiono analogs (R = H I C1, OCH3) were reported (380).

B. E. MARYANOFF, R. 0. HUTCHINS AND C. A . MARYANOFF

325

Section V . P e r m u t a t i o n a l i s o m e r i z a t i o n o f 347 ( o b s e r v e d above 35") was s t u d i e d by v a r i a b l e t e m p e r a t u r e NMR ( 3 8 1 ) .

345

34 7

REFERENCES 353. 354.

355, 356. 357. 358.

359. 360. 361. 362. 363.

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367.

R. P. A r s h i n o v a , R u s s . C h e m . R e v . , 4 6 , 809 ( 1 9 7 7 ) . E. E . N i f a n t ' e v , P. M. K o r o t e e v , Z . K. Zhane, A . A. B o r i s e n k o , and N . K. Kochetkov, T e t r a h e d r o n L e t t . , 4125 ( 1 9 7 7 ) ; F o r e a r l i e r work see r e f 1 and 2 c i t e d t h e r e i n . R. P. Arshinova and R. N . G u b a i d u l l i n , B u l l . A c a d . S c i . U S S R , 2 6 , 986 ( 1 9 7 7 ) ; R U S S . E d i t . , 1076 ( 1 9 7 7 ) . J . A. Mosbo, O r g . Magn. R e s o n . , 1 1 , 281 ( 1 9 7 8 ) . R. K i n a s , W. J . S t e c , a n d C. Kriiger, P h o s p h o r u s a n d S u l f u r ,

4 , 295 ( 1 9 7 8 ) . ( a ) W. K. Dean, B. L. H e y l , a n d D. G . Van D e r v e e r , I n o r g . C h e m . , 1 7 , 1909 ( 1 9 7 8 ) ; (b) C. M. B a r t i s h and C . S . K r a i h a n z e l , i b i d . , 1 7 , 735 ( 1 9 7 8 ) . M. Bauman and W. S . Wadsworth, J r . , J . Am. C h e m . S O C . , 100, 6388 ( 1 9 7 8 ) . J. M i c h a l s k i , J . M i k o l a j c z a k , and A. Skowrobska, i b i d . , 1 0 0 , 5386 ( 1 9 7 8 ) . G . Maas, M. R e g i t z , and W. I l l g e r , C h e m . B e r . , 111, 726 (1978). H. P a u l s e n and W. B a r t s c h , i b i d . , 1 0 8 , 1229 ( 1 9 7 5 ) . E . E . N i f a n t ' e v , A . A . B o r i s e n k o , S . E. S o r o k i n a , M. K. Grachev, and A. I . Z a v a l i s h i n a , Z h . O b s h c h . K h i m . , 4 7 , 2474 ( 1 9 7 7 ) ; Chem. A b s t r . , 88, 61897m ( 1 9 7 8 ) . R. P . A r s h i n o v a , R . Kraemer, and J . Navech, P h o s p h o r u s a n d S u l f u r , 3 , 281 ( 1 9 7 7 ) . G. S. B a j w a , W. G. B e n t r u d e , N . S . P a n t a l e o , M. G. Newton, and J. H. H a r g i s , J. Am. C h e m . SOC., 1 0 1 , 1602 ( 1 9 7 9 ) . ( a ) J. Karolak-Wojciechowska, M. Wieczorek, A . Zwierzak, and S . Zawadzki, J. C h e m . Soc., P e r k i n T r a n s . I , 1 4 6 ( 1 9 7 9 ) ; ( b ) S. Samaan, C h e m . B e r . , 111, 579 ( 1 9 7 8 ) . ( a ) M . Yamashita, Y . N a k a t s u k a s a , M . Yoshikane, M . Yoshida, T. O g a t a , and S. Inokawa, C a r b o h y d r . Res., 5 9 , C 1 2 ( 1 9 7 7 ) ; ( b ) R. L. W h i s t l e r and C.-C. Wang, J . Org. C h e m . , 3 3 , 4455 ( 1 9 6 8 ) ; ( c ) R. L. Whistler and A. K . M . Anisuzzaman, i n " S y n t h e t i c Methods f o r C a r b o h y d r a t e s , " H. S . E l Khadem, e d . , ACS Symposium Series 39, Am. Chem. SOC., Washington,

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STEREOCHEMISTRY OF PHOSPHORUS-CYCLOHEXAES D.C., 1976, pp 150-152; ( d ) K. Seo and S . Inokawa, B u l l . SOC. Chern. J p n . , 4 6 , 3301 ( 1 9 7 3 ) ; 4 8 , 1237 ( 1 9 7 5 ) ; ( e ) S. Inokawa, H. Kitagawa, K. S e o , H. Yoshida, and T. O g a t a , Carbohydr. Res. 30, 127 (1973).

,

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377.

378. 379. 380. 381.

( a ) M. Yamashita, Y . N a k a t s u k a s a , S. Inokawa, K. H i r o t s u , and J. C l a r d y , C h e m . L e t t . , 8 7 1 ( 1 9 7 8 ) ; (b) M. Yamashita, Y. Nakatsukasa, H. Yoshida, T. O g a t a , S. Inokawa, K. H i r o t s u , and J. C l a r d y , C a r b o h y d r . R e s . , 70, 247 ( 1 9 7 9 ) . G. D. Macdonell, K. D . B e r l i n , J . R. Baker, S . E . E a l i c k , E . van d e r H e l m , a n d K . L. Marsi, J. Am. C h e m . S O C . , 1 0 0 , 4535 ( 1 9 7 8 ) . K. L . Marsi and J . L. J a s p e r s e , J . Org. C h e m . , 4 3 , 760 (1978). G. S. B a j w a and W. G . B e n t r u d e , T e t r a h e d r o n L e t t . , 421 (1978). M. Morr a n d L. E r n s t , C h e m . Ber., 111, 2152 ( 1 9 7 8 ) . A l s o see r e f 273n. ( a ) S. J . Benkovic, p r i v a t e communication, 1979; ( b ) T. Kawashima, R. D. K r o s h e f s k y , R. A. Kok, and J. G. Verkade, J. Org. C h e m . , 43, 1111 ( 1 9 7 8 ) . ( a ) A . Takamizawa, S. Matsumoto, T . Iwata, I . Makino, K. Yamaguchi, N . Uchida, H. Kasai, 0. S h i r a t o r i , a n d S . T a k a s e , J . Med. C h e m . , 2 1 , 208 ( 1 9 7 8 ) ; (b) A. Takamizawa, S. Matsumoto, T . Iwata, Y . T o c h i n o , K. K a t a g i r i , K. Yamaguchi, a n d 0. S h i r a t o r i , i b i d . , 18, 376 ( 1 9 7 5 ) . F.-P. T s u i , J. A. B r a n d t , and G. Zon, B i o c h e m . P h a r m a c o l . , 28, 367 ( 1 9 7 9 ) ; ( b ) S. M. Ludeman, D. L. B a r t l e t t , and G. Zon, J. Org. C h e m . , 4 4 , 1 1 6 3 ( 1 9 7 9 ) ; ( c ) D. W. W h i t e , D. E. Gibbs, and J. G. Verkade, J. A m . C h e m . SOC. , 101 , 1937 ( 1 9 7 9 ) ; (d) S. M. Ludeman, G. Zon, and W. Egan, J. Med. Chem., 2 2 , 151 (1979). ( a ) J . P. D u t a s t a and J. B. Robert, J. Am. C h e m . SOC., 1 0 0 , 1925 ( 1 9 7 8 ) ; ( b ) A. A. B o r i s e n k o , S . F . S o r o k i n a , A. I . Z a v a l i s h i n a , N. M. S e r g e e v , and E . E. N i f a n t ' e v , 2 . O b s h c h . K h i m . , 4 8 , 1 2 5 1 ( 1 9 7 8 ) ; Chern. A b s t r . , 8 9 , 1 0 7 8 4 5 ~ (1978). E . E . N i f a n t ' e v , A. I. Z a v a l i s h i n a , S. F . S o r o k i n a , A. A. B o r i s e n k o , E. I. Smirnova, and I. V. G u s t o v a , Z . O b s h c h . K h i m . , 4 7 , 1960 (1977) ; C h e m . A b s t r . , 88, 50814f ( 1 9 7 8 ) . N. L. A l l i n g e r and H. Von V o i t h e n b e r g , T e t r a h e d r o n , 3 4 , 627 ( 1 9 7 8 ) . A. Zschunke, H. Meyer, E. L e i s s r i n g , H. Oehme, a n d K. I s s l i e b , P h o s p h o r u s a n d S u l f u r , 5 , 81 ( 1 9 7 8 ) . R . P . A r s h i n o v a , Dokl. A k a d . Nauk S S S R , 238, 858 ( 1 9 7 8 ) ; C h e m . A b s t r . , 88, 1 5 1 9 1 5 ~( 1 9 7 8 ) . B. A. Arbuzov, Y. Y. S a m i t o v , Y. M. Mareev, and V . S . Vinogradova, Izv. A k a d . Nauk S S S R , Ser. K h i m . , 2000 ( 1 9 7 7 ) ; C h e m . A b s t r . , 88, 23055c ( 1 9 7 8 ) .

Topics in Stereochemisty, Volume11 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1979 by John Wiley & Sons, Inc.

SUBJECT INDEX*

A c e t o n i t r i l e , r e d u c t i o n s i n , 57 A c e t y l e n i c a l c o h o l s , 10 Activation parameters, i n l i t h i u m aluminum h y d r i d e r e d u c t i o n s , 66 Adamantoid phosphoranes, 295 Adenosine 3 ' 5 ' - c y c l i c phosp h a t e s , see AMP, c y c l i c Alkoxyaluminum h y d r i d e s , d i s p r o p o r t i o n a t i o n o f , 56 Alkoxyborohydrides, d i s p r o p o r t i o n a t i o n o f , 56 2-A1 k y l k e t o n e e f f e c t , 81 1-Alkylphosphorinanes, 291 Allinger-Wertz h y p o t h e s i s , 291 A l l y l i c a l c o h o l s , hydrogen bond i n , 11 Amide c l e a v a g e , 253 Aminoalcohols, v i c i n a l , i n [4.2 . O l b i c y c l o o c t a n e s e r i e s , 28 i n cyclohexane s e r i e s , 29 i n c y c l o p e n t a n e s e r i e s , 28 i n d e c a l i n s e r i e s , 29 i n t r a m o l e c u l a r hydrogen bonding i n , 8 i n perhydroindane s e r i e s , 29 2-Aminocyclohexanols, 27, 4 0 cis-4-Aminocyclohexanol , 25 2-Aminocyclopentanols, 27 Aminoglycoside d e r i v a t i v e , 257 Aminomethylation, 250 AMP, c y c l i c , 1 9 4 , 250, 269, 271 p h o s p h o d i e s t e r a s e , 276 phosphonate a n a l o g o f , 270 p r e f e r r e d conformation o f , 271 p r o t e i n k i n a se , dependent on, 275, 276

p r o t o n NMR r e l a x a t i o n measurements i n , 271 r e a c t i o n with diazoalkane, 273 Amplitudes, l a r g e , 99, 1 0 2 Anharmonicity, e l e c t r i c a l , 110 Anomeric e f f e c t , 21 g e n e r a l i z e d , 280, 292 Antimony t r i f l u o r i d e , 249 A n t i p e r i p l a n a r e f f e c t , 70, 75 Arbusov r e a c t i o n , 206, 210, 211, 234, 236-238 A r s i n a n e d e r i v a t i v e s , 291 Asymmetric i n d u c t i o n , 71 Axial h y d r o x y l , 11 I R absorption of, 6 syn-Axial i n t e r a c t i o n s , 291 , 293 Axial p r e f e r e n c e , i n phosphorina n e s , 290 of e l e c t r o n e g a t i v e s u b s t i t u e n t on phosphorus, 280 Band p r o g r e s s i o n s , 114 Barriers, 1 2 5 , 1 3 4 , 1 3 6 , 1 4 0 , 142, 146, 1 5 2 , 157 t o pyramidal i n v e r s i o n , 290 t o r i n g i n v e r s i o n , 290 B e n z e n e s u l f e n y l c h l o r i d e , 209 Benzophenone, 63, 8 3 Benzyl a l c o h o l , 10 N - B e n z y l a n i l i n e s , 34 endo-2-Benzyl-2-azabicyclo[ 2 . 2 . l 1 h e p t a n - 6 - o l I 22 Benzylphosphetanium s a l t s , 268 Benzylphospholanium s a l t s , 268 Benzylphosphonium s a l t s , a l k a l i n e c l e a v a g e o f , 268 B e r r y mechanism, 294 B-H s t r e t c h i n g f r e q u e n c i e s ( I R ) , 226

*Addendum t o f i n a l c h a p t e r n o t i n c l u d e d i n i n d e x .

327

3 28

SUBJECT I N D E X

Carboxylic acids, intramolecular hydrogen bonding in, 34 Cation, effect on reduction rates of, 57 Chair-boat energy difference, see Boat-chair equilibr ium Chloride exchange, 285 Chlorination, of phosphites, 231 Chlorinolysis of phosphites, 207, 212, 229, 232, 239 2-Chloroalkanols, intramlecular, hydrogen bond in, 9 Chlorocyclobutane, 110 2-Chlorocyclohexanol, anancomeric , hydrogen bond in, 10 Chloromagnesium aluminum hydride, 78 rn-Chloroperbenzoic acid, oxidation with, 253 Chlorphosphite, hydrolysis of, 228, 233 2-Chloropropanal, 71 Cholestan-5-01-4-one, 15 Cholestan-5-01-6-one, 15 I3C, see Carbon-13 shift Chromanol, 11 Camphor, 79 CMP, cyclic, 271 Combination bands, 114 Carbon-13 shift, chemical, in Complexation of ketones, 61 cyclic phosphorus comComplex metal hydrides, 54 pounds, 195, 196, 202, composition in solution 265, 290 y effect on, 202, 205, 287 of, 54 Carbon disulfide, sulfurization mechanism of ketone xeducwith, 232, 238 tion by, 56 Conformation, of nitrogen Carbon-phosphorus coupling constereocenter, in 1 ,3 ,2stants, in cyclic phosphorus compounds, 195, d iazaphosphorinanes, 200-205, 214, 285. See 262 at phosphorus, in 1,3,2also l~~~ coupling constants dithiaphosphorinanes, Carbon tetrachloride-amine 284 Conformational energy, of reaction, 252 Carbonyl band absorption, v= ,O intramolecular hydrogen bond, 42 of, 17 Carbonyl overtone band, 4, 12, 16 Conformational enthalpy, 38

Bicyclo[3.l.0]hexane, 128, 131 Bicyclo[3.3.l]nonanes, 210 Bispidinol system, 28 Boat-chair equilibrium, 7, 15, 21, 28, 29, 204, 206, 217, 221, 261 Boat conformation, 15, 16, 21, 132, 206, 211, 256, 296 in 4-piperidinolsI 28 intramolecular hydrogen bond in, 25 Borane-phosphite adducts, 226 Brominolysis, of phosphate, 231 2-Bromocyclohexanols, anancomeric, 10 4-t-Butylcyclohexano1s, 7 2-t-Butylcyclohexanone, 81 4-t-Butylcyclohexanone, 54, 67, 68, 76 3-t-Butylcyclopentanone, 86 trans-2-t-Butyldioxan-5-01, 22 t-Butyl group, axial, 217, 221, 223, 227, 262 equatorial, 280 l-t-Butyl-2-methylazetidin-301, 23

SUBJECT INDEX Conformational entropy, 38 Conformational equilibrium, in decahydroquinoline, 41 in 1,3-dioxanesI 40 in 1,3-dithianesI 39 Conformational interconversion, 99 Conformational preference, 37, 38 of N-proton in piperidine, 264 for 2-substituents, in l13,2-diazaphosphorinanes, 286, 287 in 1,3-dioxanes, 282 in 1,3,2-dioxaphosphorinanes, 222, 223, 282 in 1,2,3-dithiaphosphorinanes, 285, 286 in 2-oxo-l ,3 ,2-dioxaphosphorinanes, 217-223, 282 in phosphorinanes, 288-290 rationale for, 290-293 in 2-seleno-1,3,2-dioxaphosphorinanes , 2 23- 225 in 2-thiono-l,3,2-dioxaphosphorinanes, 223-226 Contact ion pairs, 55, 60, 61 Co-occurrence of two different chair conformations, in solid state, 265 Coupling constants, carbn-phosphorus , see Carbon-phosphorus coupling constants proton-phosphorus, see Protonphosphorus coupling constants proton-proton, see Proton proton coup1ing constants see a l s o under J Crown ethers, 57, 64 Cryptate, 59, 64 Cubic term, 101 2-Cyanoalcohols, 36 Cyanogen chloride, 242 Cyanolysis, 242

329 Cyclic AMP, see AMP, cyclic Cyclic CMP, see CMP, cyclic Cyclic GMP, see GMP, cyclic Cyclic phosphates, hydrolysis of, 272 Cyclic TMP, see TMP, cyclic Cyclic UMP, see UMP, cyclic Cyclobutane, 146 Cyclobutanone, 116 Cyclohexane-1,2-diol monoacetate, 18 Cyclohexane-1,3-diol m n o acetate, 19 Cyclohexane-l,2-diols, 20 Cyclohexanone, 63 Cyclopentane, 115, 148, 152 Cyclopentane-1,2-diol monoacetate, 18 Cyclopentane-1,2-diols, 20, 27 Cyclopentanone, 153 Cyclopentene, 142 Cyclophosphamide, 194, 257, 276, 277 Cyclopropylmethanol, 11

Decahydroisoquinolinols, 26 Decahydroquinoline,. conformational equilibrium in, 41 Decahydroquinolin-9,lO-diol system, 27 Decahydroquinolinols, 26, 41 Decalin series, vic-aminoalcohols in, 29 1,4-Dialkylcycloheptane-l,4diols, 20 Dialkylamino group, equatorial , 280 Diaminophosphenium ion, 287 Diatomic molecule, 99 1,3,2-Diazaphosphaadamantane, 203, 287 1,3,2-Diazaphosphabicyclo[3.3.l]nonane, 203, 287 1,5,9-Diazaphosphabicyc~ol3.3.11 nonane, 287 lI3,5-Diazaphosphorinane, 290 Di-t-butoxyaluminumhydride, 77

330 Dibutyryl-c-AMP, 271 Difference bands, 114 1,l-Difluorocyclobutane, 108 Diglyme, reductions in, 57 2,5-DihydrofuranI 126, 137 2,5-DihydropyrroleI138 Dimer of lithium aluminum hydride, 63 cis-2-Dimethylaminocyclohexano l s , 29 1,5-Dimethylbicyclo[3.3.llnon2-en-9-01, 11

SUBJECT INDEX AVOH,

hydrogen bond in, 8 3, 9, 12, 24

Electron cloud interaction, 11 Energy barrier, see Barriers Enthalpy, conformational, 38 Entropy, conformational, 38 Enzymatic transformations, stereochemistry of , 275 6-Epimesambinol, 22 Equatorial hydroxyl, 11 IR absorption of, 6 Equilibration, thermal, of 2,2-Dimethyl-4-t-butylcyclohexanone, 68 1,3,2-dithiaphosphorinanes, 285 r-2-cis-6-Dimethyl-cis-4-tEquilibrium reaction of hydrogen butylcyclohexanone, 84 phosphites, 228 cis-3,4-Dimethylcyclopentanone, Erythro isomers, intramolecular 86 1,2-Dimethylenecyclobutane, 124, hydrogen bond in, 8, 33 135 cis-2-Ethyl-4-t-butylcyclohexanDimethy1formamide, reductions one, 84 2-Ethylcyclohexanone, 84 in, 57 1,2-Diols, intramolecular hydro- Ethyl E-hydroxycaproate, 17 Ethyl B-hydroxypropionate, 17 gen bond in, 8 lI3,2-Dioxaarsenane system, 283 w-Ethylmercaptoalkanols, 31 3,6-Dioxabicyclo(3.1.01 hexane, Far-infrared spectrophotometer, 129 108 2,4,3-Dioxaphosphabicyclo[3.3.1] Far-infrared spectroscopy, 105 nonane, 210 1,3,2-Dioxaphospholanes, 278, Five-membered ring, 99, 126, 128, 283 153 1,3,2-Dioxaphosphorinanes, 211 Flattening of ring, at heteroequilibrium data for, 281 atom, 291 oligomerization of , 282 Fluoride, equilibration with, 263 1,4-DioxeneI 157 Fluoride exchange reaction, at l13-Diphosphorinanes, 290 phosphorus, 248, 255 1,4-Diphosphorinane salts, hy2-Fluorocyclohexanols, anancodrolysis of, 269 meric, hydrogen bond in, 10 1,3-Disilacyclobutane, 141 2-Fluorophenol, intramolecular Disproportionation, of a1koxyhydrogen bond in, 9 aluminum hydrides, 56, 59 Fluorophosphite, 249 of alkoxyborohydrides, 56 Fluorophosphoranes, 294 lI3,2-Dithiaarsenane,286 Force constant, 101 1,3,2-DithiaphospholaneI 286 Four-membered ring, 99 1,3,2-Dithiaphosphorinanes, oli- Free energy, conformational, 37, gomerization of, 286 38 d l isomers, intramolecular Functional group selectivity, 54

SUBJECT I N D E X

F u r a n o s i d e s , c y c l i c phosphorus d e r i v a t i v e s o f , 273

331

i n c a r b o x y l i c a c i d s , 34 conformational free energy i n , 41, 42 G a l a c t o p y r a n o s i d e , 248 by COOH donor group, 34 Gauche e f f e c t , 292 c o r r e l a t i o n with r e l a t i v e G e n e r a l i z e d anomeric e f f e c t , 280, b a s i c i t y , 31 292 i n 1 , 3 - d i t h i a n e s I 39 Glucofuranoside d e r i v a t i v e s , 256 e n t h a l p y o f , 9, 20, 21 Glucopyranoside d e r i v a t i v e s , 245, e n t r o p y and AoH f a c t o r s i n , 3, 20, 30, 34 246, 253 G l y c o s i d i c bond, c o n f o r m a t i o n s i n e r y t h r o isomers, 33 a b o u t , 269 factors affecting strength GMP, c y c l i c , 194, 269, 271 of, 3 G r a n a t a n o l , 7, 28 i n o-methoxybenzoic a c i d s , 35 Guanosine 3 ' ,5'-monophosphate, by NH donor group, 34 see GMP, c y c l i c i n n i t r o a l c o h o l s , 36 i n ortho-substituted phenols , " H a l f - c h a i r " conformation, 210 , 33 215 i n ortho-substituted thio2-Haloalkanols, i n t r a m o l e c u l a r p h e n o l s , 33 hydrogen bond i n , 9 i n 3 - p i p e r i d i n o l s I 42 Haloamines, 239 by SH donor g r o u p s , 33 2-Halocyclohexanols, i n t r a s t r e n g t h o f , 3 , 11, 24, 32 i n t h r e o i s o m e r s , 33 m o l e c u l a r hydrogen bond i n , 9, 10 t r a n s a n n u l a r , 32 Halogen exchange, 287 r e l a t i v e s t r e n g t h o f , 9, 1 0 5-Halomethyl-5-methyl-l,3Hydrogen pho s p h ites , e q u i l ib r a d i o x a n e s , 214 t i o n r e a c t i o n s o f , 233 5-Halomethyl-5-methylphosphor e a c t i o n w i t h a c e t o n e , 234 c h l o r i d a t e s , conformasodium s a l t s o f , 236 s t e r e o m u t a t i o n of s a l t s of , t i o n o f , 213 2-HalophenolsI i n t r a m o l e c u l a r 23 7 hydrogen bonds i n , 9 Hydroperoxides, hydroxyl absorpHammett s t u d i e s , 57 t i o n frequencies i n , 5 4-Hydroperoxyisophospharnide, 276 Harmonic o s c i l l a t o r , 100, 101 Homoall y l i c a l c o h o l s , stereoH y d r o t h i o l y s i s , 250, 251 selective functionalizaH y d r o x y a l k y l f e r r o c e n e , 35 t i o n o f , 234 2-Hydroxybiphenyl, 1 0 Hydrogen bond, b i f u r c a t e d , 34 12 4-Hydroxy-2-butanoneI i n t e r m o l e c u l a r , 36 1-Hydroxycarvomenthone, 14 intramolecular, i n acyclic y-Hydroxycyclohexanecarboxylic a m i n o a l c o h o l s , 30 a c i d e s t e r s , 18 i n y-alkoxycarboxylic B-Hydroxyester, hydrogen bonda c i d s , 55 ing i n , 17 i n boat conformers, 25 1-Hydroxyisocarvomenthone, 14 bonding d i s t a n c e i n , 2 , 8 , Hydroxyketones, 1 2 24 Hydroxyl band, i n t e g r a t e d i n -

332 tensity of, 5, 39 Hydroxyl group, free OH band of, 2, 5, 6 rotamers in, 17, 18 solvent effects on, 6 overtone band of, 2 Hydroxyl groups, absorption frequencies of, in alcohols, 6 in hydroperoxides, 5 in oximes, 5 in phenols, 6 in silanol systems, 5 rotamer types in, 6 6-Hydroxyl-2-methyl-2-azabicyclo 12.2. Zloctane, 22 4-Hydroxymenthone, 15 a- (Hydroxymethyl)aziridines, 30 Hydroxymethylcyclohexanols, 20 5-Hydroxymethyl-1,3-dioxane, 21 2-Hydroxymethyl-3-methyl-indolizidine, 23 1O-Hydroxymethylquinolizidine, 23 5-Hydroxy-2-pentanoneI12 a-Hydroxyphosphonates, 209 Hydroxyphosphoryl compounds, 36 3-Hydroxypiperidiner 24, 26 2-Hydroxypregn-4-ene-3,20diones, 15 l-Hydroxy-2-propanoneI12 4-Hydroxytetrahydroquinoline, 11 3-Hydroxytetrahydrothiopyran-4ones, 32 4-Hydroxythiacycloheptane, 32 Hyperconjugation, 69, 84 Hypophosphites, oxidation of, 229 Indolizidinols, 24 Infrared spectroscopy, see Mid infrared spectroscopy Integrated intensity, of infrared band, 37, 39 Interferometer, 108 2-Iodocyclohexanols, conformational equilbria in, 10

SUBJECT INDEX Ion pairs, contact, see Contact ion pairs solvent separated, see Solvent-separated ion pairs Isobutyraldehyde, 64 Isomethadols, 30 Isophosphamide, 263, 276 cis-2-Isopropyl-4-t-butylcyclohexanone, 84 2-Jsopropylcyclohexanone, 84 Isotope effect, see Kinetic isotope effect; Secondary isotope effect Isotopic shift, 136, 141, 148,156 ~ J coupling ~ C constants, 200, 201 l J p ~coupling constants, 250 2 ~ p ccoupling constants, 200, 201, 203 2 J p ~coupling constants, 263 'JPH coupling constants, 203 coupling constants, 197, 3JHn 199, 202-204, 229, 260, 285 3 J p O C ~coupling constants, 197, 205, 214, 216, 218, 219, 221, 224 Jpxcc coupling constants, 197, 200-202, 204, 260, 262, 284 3 JpXCH coupling constants, 197, 199, 204, 205, 284, 286, 287 4JFPNCH coupling constants, 263 4JpXCCH coupling constants, 199, 205, 229, 233, 251, 284 Ketones, complexation of, 63, 65, 72, 83 stereoselective reduction of, 54, 67 Ketophosphamide, 276 Kinetic isotope effect, 57, 66, 67

SUBJECT INDEX

333

Lanthanide-induced shifts, 205, 220-222, 234, 261, 271, 280 Lewis acid complexes of phosphochloridates, 219, 220 Ligand exchange, intramolecular, 294 LIS, see Lanthanide-induced shifts Lithium alkoxyaluminum hydrides, 56 disproportionation of, 59 Lithium alkoxyborohydrides, 56 Lithium aluminum hydride, 55, 59, 67 activation energy for reduction by, 66 dimer of, 63 mechanism of ketone reduction by, 59 monomer of, 63 Lithium borohydride, 55 Lithium tri-t-butoxyaluminohydride, 59, 60, 76 Lithium trimethoxyaluminohydride, 60, 77 McEwen mechanism, 268 Macrocyclic dithiophosphonites, 286 Mac rocyc1ic pho sphonites, 282 Magnesium aluminum hydride, 18 Mandelic acid, 35 Mechanism of hydride reduction, 59 p-Menthane-trans-2,3-diol,

5

Menthyl phosphinate, 247 Mesityl phenyl ketone, 62, 66 Meso isomers, intramolecular hydrogen bond in, 8 Metabolism, stereospecific, 277 Metal hydrides, complex, see Complex metal hydrides Methanolysis, of cyclic phosphates, 213 of phosphorochloridates, 243 o-Methoxyphenoxyacetic acid, 35

o-Methoxyphenylthioacetic acids, 35 Methyl a-D-glucopyranoside 4,6phosphate, 270 1-Methylarsenane, 289 3-Methy1-3-azabicyclo[3.3.11

nonan-9B-olI 22 o-Methylbenzophenone, 83 2-Methylbutanal, 71

2-Methyl-4-t-butylcyclohexanone,

82, 84 2-Methylcyclohexanone, 81 2-Methylcyclopentanone, 85 3-Methylcyclopentanone, 86

trans-2-Methy1-1,3-dioxan-5-01,

22 Methylenecyclobutane, 118 Methylene rocking, 137, 156 exo-2-Methyl-7-norbornanoneI 74 1-Methylsilacyclohexane, 291 Michaelis-Becker reaction, 236, 250 Microwave spectroscopy, 115 Microwave studies on F2PNH2, 293 Mid infrared spectroscopy, 111, 137, 142, 159 Mid Raman spectroscopy, 111, 137, 142, 159 Models, empirical, for predicting stereochemistry, 73 Molybdenum carbonyl complexes, 226, 227 Morse function, 100, 101 N-Chloropiperidine, 208, 212, 216 Neopentyl hypochlorite, 239 N-(2-Hydroxyethyl)propynylamines,

31 Nitroalcanols, hydrogen bond in, 36 Nitrogen atoms, planar, 262 N-Methyl-4-phenyl-4-piperid in01 , 28 N-Methylpiperidine, 291 N,N,N I ,N" ,N"' ,N" -Hexamethyltr iethylenetetraamine, 63 N204 oxidation of phosphites,

334 see Phosphites, oxidation of I Non-chair structure, in ketophosphamide, 276 7-NorbornanoneI 74 Norcamphor, 80 N- (w-Phenoxyalkyl)anilines, 34 N-(a-Phenylalkyl)aniline, 34 Nuclear Overhauser effect, 284, 286 Nucleophilic substitution, at phosphorus, 245, 253, 254, 259 by alcohols, 230, 242, 252 by mines, 208, 211, 216, 230, 242, 252 by carbon disulfide, 254 by fluoride, 249 by methyl mercaptide, 253 by phenoxide, 258 by thiocyanate, 240 by thiophenoxide, 209 by water, 252 Nucleosides, acyclic, conformation of, 271

0-ethylation, of phosphate, 228 Olefinic alcohol, 10 One-dimensional potential functions, 119 Orbital distortion, 69, 75 Orbital symmetry, 68 Overtone, 101, 110, 146 3-Oxabicyclo[3.1.01 hexane, 131 ,1,3-C)xaphosphorinane salts, hydroxide cleavage of, 269 Oxetanone-3, 105 Oxidase, mixed function, 276 Oxidation, of phosphites, see Phosphites, oxidation of Oximes, OH absorption frequency in, 5

2-0xo-1,3,2-dioxaphosphorinanes,

208, 215 conformational preference in, 217, 219, 220

SUBJECT INDEX

twist cdnformation in, 212 2-0~0-1,3,2-dioxathianes, 291 Oxyphosphoranes, 295 31P, see Phosphorus-31 Pancreatic ribonuclease, see Ribonuclease A Pentacoordinate intermediate, 238 Pentamethyl-4-phenyl-4-piperidinol, 28 Perkow reaction, 237 Perhydroindane series, vicaminoalcohols in, 29 Perturbation theory, 101, 138 8-Phenethyl alcohol, 10 Phenolic hydroxyl, infrared absorption of, 6 Phenols, ortho-substituted, hydrogen bonding in, 33 Phenoxide exchange, at phosphorus, 252 Phenyl azide, 232 4-Phenylcycloheptane-1,4-diols, 20 2-Phenyl-1,3,2-diazaboracyclohexanes, 263 9-Phenyl-6-epimesambino1, 22 Phenylglyoxylic acid, 35 Phenylquinolizidinols, 23, 29, 41 1-Phosphabicyclo[ 2.2.1 I heptane, 267 9-Phosphabicyclo[3.3.llnonane, 266, 267 1-Phosphabicyclo[2.2.2loctane, 267 8-Phosphabicyclo[3.2.lloctane, 266 Phosphates, cyclic, 212, 231, 233 conformational equilibrium in, 213, 214 equilibration of , 231, 244, 253 hydrolysis of, 249 Phosphepanium salts, 268

SUBJECT INDEX Phosphine, r e a c t i o n w i t h benzaldehyde, 265 Phosphine o x i d e s , e q u i l i b r a t i o n o f , 267 o p t i c a l l y a c t i v e , 247, 267 Phosphites, brominolysis o f , 2 1 1 , 231 c h l o r i n a t i o n o f , 231 c h l o r i n o l y s i s o f , 231, 239 equilibration reactions of, 234 h y d r o l y s i s o f , 209, 210 o x i d a t i o n o f , by t - b u t y l hydro p e r o x i d e , 232, 237 by hydrogen p e r o x i d e , 261, 263 by N2O4, 2 1 2 , 231, 238, 242, 249, 255 by pyridine-N-oxide, 232 by t r i e t h y l a m i n e o x i d e , 232 r e a c t i o n o f , w i t h a c e t o n e , 210 with alkylsulfenyl chlorides, 238 s u l f u r i z a t i o n o f , 225, 229, 232, 237 t r i a l k y l , reaction with c h l o r a l , 237 P h o s p h o d i e s t e r a s e , 274 Phospholanium mechanism, 268 Phosphonates, c y c l i c , 206, 210, 211 equilibration reactions o f , 255, 256 Phosphonium s a l t s , a l k a l i n e , h y d r o l y s i s o f , 266 Phosphoramidates, 208, 209, 2 1 2 , 231, 233 h y d r o l y s i s o f , 228 Phosphorane i n t e r m e d i a t e s , 247 Phosphoranyl r a d i c a l , 237 , 238 Fhosphorinanium s a l t , 268 Phosphorobromidates, 231 P h o s p h o r o c h l o r i d a t e s , 207-209, 212, 219, 231 conformational equilibrium i n , 213 Fhosphorocyanidates, 242

33 5 P h o s p h o r o f l u o r i d a t e s , 245, 248 P h o s p h o r o i s o c y a n i d a t e s , rearrangement r e a c t i o n o f , 24 2 P h o s p h o r o s e l e n o a t e s , 225 Phosphoroselenocyanate, 24 3 Phosphorothioate analog o f c y c l i c AMP, 274 P h o s p h o r o t h i o a t e s , 209, 238 Phosphorothiocyanatidates, 24 2 Phosphorus-carbon c o u p l i n g , see Carbon-phosphorus coupling constants Phosphorus-31, chemical s h i f t s , i n c y c l i c phosphorus compounds, 195-197, 202-204, 258, 287, 290 NMR, a t low t e m p e r a t u r e , 289 Phosphoryl I R s t r e t c h i n g f r e quency, 205, 219, 258 Phosphorylsulfenyl c h l o r i d e s , 24 2 P h o s p h o r y l t h i o u r e a s , 241 Photo-arylation, of phosphites, 237 3-Piperidinol a l k a l o i d s , 30 3 - P i p e r i d i n o l s y s t e m s , 26 4 - P i p e r i d i n o 1 , 25 boat form i n , 27 P-N bond c l e a v a g e r e a c t i o n , 238 P o t e n t i a l energy f u n c t i o n , 991 101, 116 asymmetric, 1 3 0 Schroeder-Lippincott, 1 0 , 33 two-dimensional , 1 4 8 p.rr-dn i n t e r a c t i o n , 293 P r o d u c t development c o n t r o l , 6 7 , 74 Promedol, 28 Proton-carbon c o u p l i n g c o n s t a n t s , , i n c y c l i c phosphorus compounds, 197 P r o t o n chemical s h i f t s , i n c y c l i c phosphorus compounds, 195, 196 P r o t o n NMR s p e c t r o s c o p y , l o w t e m p e r a t u r e , 289

336 Proton-phosphorus c o u p l i n g cons t a n t s , i n c y c l i c phosphorus compounds, 195, 197199, 202-204, 285. See a l s o under J Proton-proton c o u p l i n g c o n s t a n t s , i n c y c l i c phosphorus compounds, 195, 197-199, 202, 2 04 P s e u d o r o t a t i o n , 148, 152 hindered , 1 5 0 a t phosphorus, 238, 294, 296 Pseudotropine, 7 Pyramidal i n v e r s i o n , 278 b a r r i e r t o , 285 P y r i d i n e , r e d u c t i o n s i n , 57 P y r o l i z i d i n o l s , 24 Q u a d r a t i c t e r m , 138 Q u a r t i c t e r m , 137, 1 3 8 Q u i n o l i z i d i n o l , 24, 25 Raman s p e c t r o s c o p y , 109. See a l s o Mid Raman s p e c t r o scopy R a t e s o f r e d u c t i o n , 57, 60-64, 74. See a l s o Reduction, rates o f Rate s t u d i e s , c o m p e t i t i v e , 74 Rearrangement r e a c t i o n s , o f t h i o and s e l e n o p h o s p h a t e s , 225 o f 2-thio-1,3,2-dioxophosphorina n e s , 259 Reduced mass, 101, 1 1 9 , 123, 136, 138, 141, 148, 172 Reduction, o f 4-t-butylcyclohexanone, s t e r e o c h e m i s t r y o f , 76 o f camphor, s t e r e o c h e m i s t r y o f , 79 of cyclopentanones, s t e r e o chemistry o f , 8 5 o f 2-methylcyclohexanone, s t e r e o c h e m i s t r y o f , 81 o f norcamphor, s t e r e o c h e m i s t r y o f , 80 r a t e s o f , 56, 57, 59, 61, 62, 74

SUBJECT INDEX e f f e c t o f c a t i o n o n , 57, 60 e f f e c t of polarization of c a r b o n y l bond o n , 64 e f f e c t o f p o l a r i z a t i o n of h y d r i d e on, 64 e f f e c t of s o l v e n t on, 57, 6 2 , 63 stereochemistry o f , e f f e c t o f a 2 - a l k y l group o n , 8 2 , 87 e f f e c t o f change i n conf o r m a t i o n o n , 78 e f f e c t o f c o n c e n t r a t i o n on, 77 see a l s o S t e r e o c h e m i s t r y o f reduction o f 3 ,3 ,5 - t r i m e t h y l c y c l o hexanone, s t e r e o c h e m i s t r y o f , 78 Ribonuclease A , 273, 274 Ring p u c k e r i n g , 99, 114, 1 2 3 , 1 2 6 , 1 2 8 , 135, 141, 146, 148 Ring t w i s t i n g , 99, 1 2 6 , 1 2 8 , 137, 148, 156 Rocking v i b r a t i o n , 1 4 1 Rotamers, of hydroxyl group, 6, 11, 1 3 , 25 R o t a t i o n a l c o n s t a n t s , 116 S a l i c y c l i c a c i d , 35 S - a l k y l t h i a n i u m s a l t s , 291 Schroeder-Lippincott p o t e n t i a l f u n c t i o n , 1 0 , 33 S c h r a d i n g e r e q u a t i o n , 100, 141, 148 two-dimensional , 1 2 6 S c i s s o r i n g mde, 146 Secondary i s o t o p e e f f e c t , 67 Selenane d e r i v a t i v e s , 291 Selenophosphofluoridates , 255 S i l a c y c l o b u t a n e , 1 0 5 , 110 S i l a n o l systems, hydroxyl f r e quency i n , 5 S i l v e r c y a n i d e , 242 Six-membered r i n g , 1 2 8 Skew boat, 1 5

SUBJECT INDEX Sodium a l k o x y b o r o b y d r i d e s , 56 Sodium aluminum h y d r i d e , 55, 60 Sodium b o r o h y d r i d e , 55, 56 Solanum a l k a l o i d s , 30 S o l v e n t , e f f e c t on r e d u c t i o n r a t e o f , 57 Solvent-separated ion p a i r s , 55, 60, 61 Spirophosphoranes, 296 Stereochemical c o n t r o l , t h e o r i e s o f , 68 Stereochemical r e a c t i o n c y c l e , 231, 232, 241 Stereochemistry o f reduction, 60, 61, 63, 73, 75, 7779, 81, 8 2 , 85, a7 e f f e c t o f c a t i o n o n , 63 e f f e c t of concentration on, 77 e f f e c t o f conformation on, 78 e f f e c t of r e a c t a n t ratio on, 60 e f f e c t of temperature on, 75 p r e d i c t i o n o f , by e m p i r i c a l models, 73 see a l s o Reduction, stereoc h e m i s t r y o f ; and under compound r e d u c e d S t e r e o s e l e c t i v e r e d u c t i o n , 54, 67, 72 w i t h NaBH4, 267 S tereoselec t i v i t y , 54 S t e r i c approach c o n t r o l , 67, 74 S t e r i c h i n d r a n c e , 68, 72 S u l f e n y l h a l i d e s , 239, 242 Sul f u r i z a t i o n , by a c e t y l s u l f e n y l c h l o r i d e , 252 a t phosphorus, 253 Symmetric t o p , 1 0 5 T a y l o r s e r i e s , 100-102 Temperature, e f f e c t o f , on stereochemistry of

337 r e d u c t i o n , 75 Terpene a l c o h o l s , 1 0 Tetraalkoxyphosphoranyl r a d i c a l , 237 Tetrahydrofuran, 152 Tetrahydropyran-3-01, 32 T e t r a h y d r o q u i n o l i n o l s , 11, 26 Tetrahydrothiopyran-3-01, 32 T e t r a l o l , 11 Thermodynamic p a r a m e t e r s , f o r p h o s p h o r i n a n e , 290 Thiane, p r o t o n a t e d , 291 Thiane-1-N-tosylimi.de, 291 Thiane-1-oxide, 291 Thietanone-3, 1 1 5 , 1 2 1 Thiochromanol , 11 Thiocyanate displacement, 24 0 Thiocyano-isothiocyano rearrangement , 242 Thiocyanogen, 240 T h i o g l y c o s i d e s , 258 Thiophenols, o r t h o - s u b s t i t u t e d , hydrogen bonding i n , 33 T h i o p h o s p h a t e s , 225 T h i o p h o s p h o f l u o r i d a t e s , 254 Three-membered r i n g , 128 Threo isomers, i n t r a m o l e c u l a r hydrogen bonding i n , 8 , 33 Thymidine 3',5'-N,N-dimethylphosphoramidate, 270 T i n h y d r i d e r e d u c t i o n , 229 TMP, c y c l i c , 271 T o r s i o n a l s t r a i n , 68, 73, 75 T r a n s e s t e r i f i c a t i o n , 228 T r a n s i t i o n metal-phosphine complexes, 211, 227, 264, 267 T r a n s i t i o n s t a t e , a c y c l i c , 58 f o r asymmetric i n d u c t i o n , 71 c y c l i c , 58 e f f e c t o f , on stereochemistry o f r e d u c t i o n , 75 f o u r - c e n t e r , 58 l i n e a r , 58 i n l i t h i u m aluminum h y d r i d e r e d u c t i o n s , 61, 65

338 product-like, 74 reactant-like,. 74 in sodium borohydride reductions, 58 Transphosphorylation, 253, 259 Trigonal bipyramidal phosphorus, 294 2,2,4-Trimethylcyclohexanone, 85 3,3,5-Trimethylcyclohexanone, 67, 68, 78 Trimethyleneimine, 145 Trimethylene oxide, 114, 134 Trimethylene sulfide, 118 Tri-n-octyl-n-propylamniurn aluminum hydride, 62 Triphosphamide, 276 Triple ions, 55 Trityl chloride, 235 Trityl fluoborate, 235 Tropanol, 22 Y-Tropine, see Pseudotropine Turnstile mechanism, 294, 295 Twist chair equilibrium, see

SUBJECT INDEX Boat-chair equilibrium Twist conformation, 217, 221, 222, 224, 227, 247, 256, 261, 262, 281 of 1 ,3 ,2-dioxaphosphorinanes, 209 of 2-0x0-1 ,3 ,2-dioxaphosphorinanes, 212 UMP, cyclic, 270, 271 Uridine , 2 I ,3 ' -cyclophosphorothioate, 273 Uridine 3',5'-phosphate, see UMP, cyclic

Vibration-rotation interaction, 142 Vinyl phosphate, 237 Water band, in IR spectrum, 4 X-ray analysis, of cyclic phosphonates, 210, 215 of phosphoramidates, 208

Topics in Stereochemisty, Volume11 Edited by Ernest L. Eliel, Norman L. Allinger Copyright © 1979 by John Wiley & Sons, Inc.

CUMULATIVE INDEX, VOLUMES 1-1 1

A b s o l u t e C o n f i g u r a t i o n o f P l a n a r and A x i a l l y Dissymmetric Molecules (Krow) A b s o l u t e S t e r e o c h e m i s t r y o f C h e l a t e Complexes

(Saito)

Acetylenes, Stereochemistry o f E l e c t r o p h i l i c A d d i t i o n s (Fahe y ) Analogy Model , S t e r e o c h e m i c a l (Ugi and Ruch) Asymmetric S y n t h e s i s , New Approaches i n (Kagan and F i a u d ) A t o m i c I n v e r s i o n , Pyramidal ( L a m b e r t ) A x i a l l y and P l a n a r Dissymmetric M o l e c u l e s , A b s o l u t e C o n f i g u r a t i o n of (Krow)

Barriers , Conformational , and I n t e r c o n v e r s i o n Pathways i n Some Small Ring Molecules ( M a l l o y , Bauman, and C a r r e i r a ) B a r t o n , D.H.R. , and Hassel, 0.--Fundamental Con t r ibu t i o n s t o Co n f o rma t i o n a l Anal y s i s

(Barton, Hassel)

Carbene A d d i t i o n s t o O l e f i n s , S t e r e o c h e m i s t r y o f (Closs) Carbenes, S t r u c t u r e of (Closs) s p 2 - s p 3 Carbon-Carbon S i n g l e Bonds, R o t a t i o n a l Isomerism a b o u t ( K a r a b a t s o s and F e n o g l i o ) Carbonium I o n s , Simple, t h e E l e c t r o n i c S t r u c t u r e and S t e r e o c h e m i s t r y o f ( B u s s , S h l e y e r and Allen) C h e l a t e Complexes, A b s o l u t e S t e r e o c h e m i s t r y o f

(Saito)

C h i r a l i t y Due t o t h e P r e s e n c e o f Hydrogin I s o t o p e s a t Noncyclic P o s i t i o n s (Ariqoni and Eliel) C h i r a l L a n t h a n i d e S h i f t Reagents ( S u l l i v a n ) C l a s s i c a l S t e r e o c h e m i s t r y , The F o u n d a t i o n s o f

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Conformational A n a l y s i s of I n t r a m o l e c u l a r Hydrogen-Bonded Compounds i n D i l u t e Solut i o n by I n f r a r e d Spectroscopy (Aaron) Conformational A n a l y s i s o f Six-membered Rings ( K e l l i e and R i d d e l l ) Conformational A n a l y s i s and S t e r i c E f f e c t s i n Metal C h e l a t e s ( B u c k i n g h a m and S a r g e s o n ) Conformational A n a l y s i s and T o r s i o n Angles

(Bucourt)

Conformational Barriers and I n t e r c o n v e r s i o n Pathways i n Some Small Ring Molecules ( M a l l o y , Bauman and C a r r e i r a ) Conformational Changes , D e t e r m i n a t i o n of Associated Energy by U l t r a s o n i c Absorption and V i b r a t i o n a l Spectroscopy (Wyn- Jones and Pethrick)

Conformational Changes by R o t a t i o n a b o u t sp2-sp3 Carbon-Carbon S i n g l e Bonds ( K a r a b a t s o s and F e n o g l i o ) Conformational E n e r g i e s , Table o f (Hirsch) Conformational I n t e r c o n v e r s i o n Mechanisms, Multi-step (Dale) Conformations o f 5-Membered Rings ( F u c h s ) Conjugated Cyclohexenones, K i n e t i c 1,2 Addit i o n o f Anions t o , S t e r i c Course o f

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1,2-Ewxides, Stereochemical Aspects o f t h e Synthesis of (Berti) EPR, i n S t e r e o c h e m i s t r y o f N i t r o x i d e s (Janzen) Five-Membered Rings, Conformations o f (Fuchs) Foundations o f C l a s s i c a l S t e r e o c h e m i s t r y (Mason) Geometry and Conformational P r o p e r t i e s of Some F i v e - and Six-Membered H e t e r o c y c l i c Compounds C o n t a i n i n g Oxygen o r S u l f u r (Rorners, A 1 tona , Buys and Havinga)

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Hassel, 0. and B a r t o n , D.H.R. Fundamental C o n t r i b u t i o n s t o Conformational A n a l y s i s (Hassel, Barton) H e l i x Models, of O p t i c a l A c t i v i t y (Brewster) H e t e r o c y c l i c Compounds, Five- and Six-Membered, C o n t a i n i n g Oxygen o r S u l f u r , Geometry and Conformational P r o p e r t i e s o f (Romers, A 1 t o n a , B u y s and Havinga) H e t e r o c y c l i c Four-Membered Rings, S t e r e o c h e m i s t r y o f (Moriarty) Heterotopism (Mislow and Raban) Hydrogen-Bonded Compounds , I n t r a m o l e c u l a r , i n D i l u t e S o l u t i o n , Conformational A n a l y s i s o f , by I n f r a r e d Spectroscopy (Aaron) Hydrogen I s o t o p e s a t Noncyclic P o s i t i o n s , C h i r a l i t y Due t o t h e P r e s e n c e of (Arigoni and E l i e l ) I n f r a r e d S p e c t r o s c o p y , Conformational A n a l y s i s o f I n t r a m o l e c u l a r Hydrogen-Bonded Compounds i n D i l u t e S o l u t i o n by (Aaron) I n t r a m o l e c u l a r Hydrogen-Bonded Compounds, i n D i l u t e S o l u t i o n , Conformational A n a l y s i s o f , by I n f r a r e d Spectroscopy (Aaron) I n t r a m l e c u l a r Rate P r o c e s s e s (Binsch) I n v e r s i o n , Atomic, Pyramidal (Lambert) I s o m e r i z a t i o n , F a s t , About Double Bonds (Kal inowski and K e s s l e r ) Ketones, C y c l i c and B i c y c l i c , Reduction o f , by Complex Metal Hydrides (Boone and Ashby)

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Mass Spectrometry and t h e S t e r e o c h e m i s t r y o f Organic Molecules (Green) Metal C h e l a t e s , Conformational A n a l y s i s and S t e r i c E f f e c t s i n ( B u c k i n g h a m and S a r g e s o n ) Metal Hydrides, Complex, Reduction o f C y c l i c and B i c y c l i c Ketones by ( B o o n e and A s h b y ) Metallocenes, S t e r e o c h e m i s t r y o f ( S c h l c g l ) M u l t i - s t e p Conformational I n t e r c o n v e r s i o n Mechanisms ( D a l e ) Nitroxides, Stereochemistry o f (Janzen) Non-Chair Conformations of Six-Membered Rings Kellie and R i d d e l l ) Nuclear Magnetic Resonance, 3C, S t e r e o c h e m i c a l Aspects o f (Wilson and S t o t h e r s ) Nuclear Magnetic Resonance, f o r Study o f I n t r a Molecular Rate P r o c e s s e s ( B i n s c h ) Nuclear Overhauser E f f e c t , Some Chemical Applic a t i o n s o f ( B e l l and S a u n d e r s )

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(McKenna)

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A b s o l u t e C o n f i g u r a t i o n o f (Krow) Polymer S t e r e o c h e m i s t r y , Concepts of (Goodman) P o l y p e p t i d e S t e r e o c h e m i s t r y (Goodman, V e r d i n i , Choi and Masuda) Pyramidal A t o m i c I n v e r s i o n ( L a m b e r t )

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R a d i c a l s , Cyclohexyl and V i n y l i c , The S t e r e o c h e m i s t r y o f (Simamura) Reduction, of C y c l i c and B i c y c l i c Ketones by Complex Metal Hydrides (Boone and A s h b y ) Resolving-Agents and R e s o l u t i o n s i n Organic Chemistry (Wilen) R o t a t i o n a l Isomerism a b o u t s p 2 - s p 3 CarbonCarbon S i n g l e Bonds ( K a r a b a t s o s and

Fenogl i o )

Small Ring Molecules, Conformational Barriers and I n t e r c o n v e r s i o n Pathways i n Some ( M a l l o y , Bauman and C a r r e i r a ) S t e r e o c h e m i c a l Aspects o f 3 C N m r S p e c t r o s c o p y (Wilson and Stothers) S t e r e o c h e m i c a l Aspects o f Phosphorus-containing Cyclohexanes ( M a r y a n o f f , H u t c h i n s and

Maryanoff)

11

53

6

107

5

167

11

97

8

11

S t e r e o c h e m i s t r y , C l a s s i c a l , The F o u n d a t i o n s o f

(Mason)

S t e r e o c h e m i s t r y , Dynamic, A Mathematical Theory of (Ugi and R u c h ) S t e r e o c h e m i s t r y o f C h e l a t e Complexes ( S a i t o ) S t e r e o c h e m i s t r y o f Cyclobutane and Heteroc y c l i c Analogs ( M o r i a r t y ) S t e r e o c h e m i s t r y of N i t r o x i d e s ( J a n z e n ) S t e r e o c h e m i s t r y of Organic Molecules, and Mass S p e c t r o m e t r y (Green) S t e r e o i s o m e r i c R e l a t i o n s h i p s , o f Groups i n Molecules ( M i s l o w and Raban) S t e r o i d s , C r y s t a l S t r u c t u r e s o f (Duax, Weeks and Rohrer) S t r u c t u r e s , C r y s t a l , o f S t e r o i d s (Duax, Weeks and Rohrer) T o r s i o n Angle Concept i n Conformational Analysis (Bucourt)

186

9

1

4 10

99 95

8

6

271 177

9

35

1

1

9

271

9

271

8

159

344

CUMULATIVE INDEX, VOLUMES 1-11 VOL

U l t r a s o n i c Absorption and V i b r a t i o n a l Spectroscopy, Use o f , t o Determine t h e Energies Associated with Conformational Changes ( W y n - J o n e s and P e t h r i c k )

.

PAGE

5

205

V b r a t i o n a l Spectroscopy and U l t r a s o n i c

Absorption, Use o f , t o Determine t h e Energies Associated with Conformational Changes ( W y n - J o n e s and Pethrick) Vinylic Radicals, and Cyclohexyl, The Stereochemistry of ( S i m a m u r a )

5

205

4

1

W i t t i g Reaction, Stereochemistry of (Schlosser)

5

1