Ernest L. Eliel Untversity of North Carol~na Chapel Hill. 27514
I
I
Conformational Analysis-The Years
Conformational analysis is an important topic in Organic Chemistry, treated in virtually all elementary organic textbooks. Yet as a discinline it is onlv 25 vears old. even though the fact that c;clohexane and othe; six-membered rings could exist in chair and boat forms was recognized by Sachse as early as 1890 (I, 2). I t was not, however, until the avpearance of a pioneerine oaper -. . bv Derek H. R. Barton in 19i0 (3) that the idea of the puckered cyclohexane ring, now eenerallv discussed under the headine of "conformational analys-is," found rapid and widespread acceptance. In the next few lines we shall brieflv discuss the situation prior to 1950, the basic tenets of conformational analysis as put forward by Barton, and the reason for their rapid and eager acceptance. This will be followed by a discussion of the major developments in conformational analysis in the last 25 years and a brief report on the present status of the subject. Conformational ideas did not spring forth full-blown in 1950; many earlier pioneers contributed to the final culmination of the subject and one of them, Odd Hassel, was recognized by the joint award (together with Barton) of the 1969 Nobel Prize in Chemistrv (4). Others have made important contributions. The school of J. BoEseken a t the Technical University in Delft in Holland-notably Boeseken's able coworkers, H. G. Derx and P. H. Hermans (5, 6)-in the 1920's recoenized conformational factors in the compfexation of alicyckc and acyclic 1,2-glycols with boric acid and in the rate of acetonide formation of these substances. The chair shape of hexachlorocyclohexane was seen (through X-ray crystallography) by Bilicke and coworkers a t the California Institute of Technology (7) in the late 1920's, and Kohlrausch and coworkers (8) a t Graz, Austria, perceived, through Raman spectroscopy, the existence of what are now called axial and equatorial substituents in cyclohexanes. Simultaneously, cyclohexane geometry was studied by Hassel through dipole moment measurements. X-rav diffraction. and later electron diffraction (9). .. The importance of conformation (i.e., rotational arrangement) in the reactivitv of acvclic molecules aooears first to have been recognized in the classical invesiigation (6) of Hermans on the hvdrobenzoins. CnHsCHOHCHOHCsHs and was extended b i ~ e i s s b e r g e &and Wolfs studies fi0j of the correspondine chlorides. CnHsCHClCHCICnHs: a systematic ex&ratiok of this field,starting from the simplest molecules such as 1.2-dihaloethanes. was launched hv ~ i z u s h i m aand his school in 1933 (11) and carried out over a period of many years. K. Pitzer and his collaborators made major contributions by focussing on the existence of a barrier to rotation in ethane (12) and by interpreting the very accurate heat of combustion data of Rossini and coworkers (13) in terms of cyclohexane conformation (14). Despite all this work, and despite the clear implication, from molecular models which were commonly used in the 1940's and 1950's, that cyclohexane was non-planar, most chemists, especially organic chemists, depicted the molecule as a planar hexagon even as late as 1948. The reason, no doubt, is that stereochemical thinking a t that time wag still largely "static," i.e. i t dealt with molecular structure. This article was originally published in German: ChemikerZeitung, 97.582 (1913). 762 / Jwrnal of Chemlcal Education
Last 25
Stereochemical implications regarding molecular reactivity were just beginning to be appreciated as a result of the pioneering work on reaction mechanisms by the schools of Hughes and Ingold, Lucas, Winstein, and Bartlett. Above all, static stereochemistry was confined almost entirely to the counting of isomers and for that purpose i t was (and still is) sufficient to think of cyclohexane in its average planar form, thanks t o the fact that the two possible, chairshaped ring conformations are in very rapid equilibrium (esn. (1))
with an enerw -.barrier to the "flivping" - - - of but 10 kcallmole corresponding to a ring inversion rate of approximately 100,000 s-' a t room temperature. The insight of Pitzer's group (14) that thermodynamic stability i f cyclohexane derivatives rests on conformational details which could not be understood in terms of planar formula seems to have been lost on most organic chemists of the time because they failed to recognize the chemical implication of the thermodynamic principles. (The same was true of physical chemists but presumably for different reasons: they were not cognizant of the chemical reactions of cyclobexanoid svstems which were suscentible of internretation in conformational terms.) Daver In his 1950 . . (3). . . . Barton set forth the basic tenets of conformational analysis: 1) Compounds with equatorial substituents are generally more stable than compounds with axial substituents-i.e., the equilibrium shown in eqn. (1) is dis~lacedto the riebt. This nrinciole also aoalies to chemica~k~uilibration p&cesses o i the &pe shown-in eqn. (2) "thermodvnamicallv controlled mocesses"): . . (so-called . 2) The fact that axial substituent;are generally-
more compressed than equatorial ones leads to differential reactivity; in many processes equatorial substituents react faster as a result of "steric hindrance" in the transition state for the axial isomer; an example is the saponification of an equatorial ester which is about 20 times as fast as that of the corresponding axial one (15).However, there are also reactions in which ground-state compression leads to an acceleration in rate for the a i a l isomer, for example, chromic acid oxidation of alcohols (16). 3) In many reactions, the geometric or conformational disposition of the bonds formed or broken during the reaction has a crucial effect on the reaction rate. This effect, the so-called "stereoelectronic effect" is often so large as to make possible one reaction to the exclusion of another. Thus, as shown in eqn. (3) the action of silver oxide on a trans-diaxial bromohydrin (I) (but not on its trans-diequatorial stereoisomer(I1) leads t o the epoxide whereas
,.., the cis-hromohydrins 111 and IV (axial-equatorial) give rise to the ketone. presumahlv by HBr elimination to the en01 or by a hydrideAshift117): In an imoortant subseauent paper (18LBarton extended conformatibnal analysisAto the-explanation of physical such as adsorotion affinitv and infrared soec.oroperties. . troscopy; &her physical properties, notably nmr spectral properties, were later also found t o be strongly conformation dependent (see below). Barton's ideas were electrifving and received rapid acceptance. Some personal recoileckons may illustrate the ~ o i n t In . 1948-1949, I was collaboratiw on a ~ r o ~ o s voed n a t the himhine synthesis with A. ~ u r ~ s t a h l e r , t h easedior University of Notre Dame, who subsequently proceeded to Harvard University for his PhD degree and was there a t the time (durine the 1949-1950 academic year) when Barton developed and exposed his ideas. Burg&ahler wrote enthusiastic letters about Barton's lectures and soon showed how conformational thinking could he a ~ n l i e dto the then known chemistry of yohimgine which had, of course, studied carefully hut which up to that point had been rather mysterious to us. Why, for example, did yohimbine sulfate undereo simole dehvdration with base whereas the sulfate of the stereoisomer, corynauthine, underwent decarhoxvlative dehvdration (19.20)? As shown in eqn. (4) the proEess is readily understandable in conformational terms if one accepts that the stereoelectronic reauirement for bond breaking in concerted eliminations is a trans-diaxial disposition of the appropriate bonds (21).
-
One might be curious to enquire why, after 60 years of lying fallow, conformational ideas in Barton's bands were so rapidly developed and so eagerly accepted. There were probably two reasons, one connected with Barton's own background, the other with the circumstances under which the develoumeut orkinated. As mentioned earlier, the failure of conformational analysis to take hold prior to 1950 was probably due to a lack of simultaneous comprehension and appreciation of physicochemical principles on one hand and organic reactivity on the other. Organic chemists in those days were not prone to cast their knowledge of reactions in physico-chemical or mechanistic principles and physical chemkts, by and large, were not familiar with the reactions which demanded explanation. Barton bridged the gulf. He received his PhD degree (in 1942, a t Imperial College) with Sir Ian Heilhron and E. R. H. Jones in the area of natural products hut World War I1 forced him to work on thermal elimination reactions and after the war he taught physical chemistry for four years and dedicated his attention to the mechanism of pyrolytic elimination and to calculations of nonbonded interactions. Thus, in 1950, he was ready to turn this newlv gained understandine of mechanism to his earlier acquGe2 knowledge of natural products. The time was ripe. Laree numbers of oreanic chemists interested in the natural products area were working on steroids, including Fieser a t Harvard with whom his visiting professorship brought him in close contact. The pioneering work of Wieland, Windaus, Ruzicka, and others had focussed attention on steroids, the successful synthetic route from dioscorea composita discovered by Marker (22) and executed by Rosenkranz and later Djerassi and collaborators a t the Syntex Lahoratories in Mexico City made steroids readily available, and the discovery of the therapeutic properties of cortisone and its analogs generated intense theoretical and practical interest in steroid chemistry a t the end of the 1940's. Steroids, as i t turns out, provide an ideal "playing ground" for conformational ideas. There are two reasons for that. One is that six-membered rings, because of the relative deep energy mold of the chair form (as mentioned earlier, it takes 10 kcal of activation energy t o deform the chair in a major way), carry suhstituents of well-defined conformation: equatorial and axial. The same is not true of five-membered rings and rings larger than six-membered, a point t o which we shall return below. Secondly, the rings in steroids (as in any trans-decalin system) are conformationally locked (i.e. prevented from "flipping") by the diequatorial ring fusion
Erin. trans-decalinoidring fusion in 5-a-sfemids
~~T
yohiibine sulfate
mrynanthine sulfate
This, in turn means that an equatorial suhstituent remains equatorial and an axial suhstituent remains axial, in contrast t o what happens in simple substituted cyclohexanes of the type shown in eqn. (1). Thus the "equatorial" and "polar"~s~hstituentsreferred to in arto on's early papers ("polar" a t that time meaning what "axial" denotes now (23); Hassel used < ( e a v w r = standing) and n(ac~pcvos= reclining) for axial and equatorial) were unequivocally confined to their positions, a circumstance which greatly facilitated an understanding of their cnnformational behavior. I t is interesting that, somewhat before the appearance of Barton's 1950 paper, there were a t least two other important correlations of conformation with chemical hehavior. One of these was a series of papers by R. E. Reeves (24) on the effect of conformation on the formation of cuorammonium complexes in glycosides. The other was a sequence of articles, published over a period of years, from the research group of V. Prelog, concerned with the effect of what was then called "Konstellation" in large and medium sized Volume 52, Number 12 December 1975 / 763
rings on a wide variety of reactions, such as the equilibrium of cyanohydrin formation in cycloalkanones (25,26), (Prelog later accepted the term conformation-originally coined by Hayworth in sugar chemistry (27).) Prelog's ideas, while widely disseminated, were not easy to adapt to simpler systems, since the highly flexible medium-sized rings have much less well defined conformations than the six-membered rings studied by Barton in steroids, terpenes, and alkaloids. I t took a t least another ten years until the intricate details of the conformation of medium-sized rings became better understood, largely due to the elegant work of Sicher (28) and the X-ray studies by Dunitz (29). Reeves' papers dealt with a very specific process and a very specific (albeit rather important) class of compounds and did not imbue the reader with the generality of the concepts involved. In fact, although carbohydrate chemistry is an interesting and important area of application of conformational analysis, and even though some of the important insights into conformation came from sugar chemists (27, 30-32). it is onlv in the last vear or two that a successful "marriage" (or perhaps a bet& word would be "reconciliation") of carbohydrate chemistry and conformational analysis has been effected through a textbook (33) which consistentlv illustrates the facts of the former field in terms of the concepts of the latter. The history of conformational analysis in the period 1950-1965 has been extensively documented first in reviews (31, 34-36) and, more recently, in several textbooks and monographs (37-39). The reader is referred t o these summaries for both factual and historical information. Here only the most important scientific events of this period can be briefly touched upon. The first enlargement df conformational thinking,the application of Barton's concepts to conformationally mo- bile systems of the type shown in eqn. (1) in retrospect turns out to be a continuation of Hassel's ideas. Hassel recognized that simple substituted cyclohexanes (such as chlorocyclohexane) exist as two types of molecules, axially and equatorially substituted ones, in rapid equilihrium, with the equatorial isomer generally predominating (eqn. (1)) and he was able to estimate the approximate position of equilibrium by electron diffraction study. Barton had largelv confined himself. in the statement of the earlier mentioned conformational principles, to conformationally biased ("anancomeric"). (40) . . svstems. What haDDens if a system is not anancomeric-wifi the reactivity of the system reflect that of the equatorialisomer or that of the axial isomer or both? The problem had been considered in preliminary fashion by Eliel (41), who recognized that the minor conformational isomer might well account for most of the reaction, and by Curtin (42) who, in the well-known Curtin Hammett principle, stated that if the two equilibrating conformations can give rise to two different reaction products, the ratio of the products is not related to the eqklihrium shown in eqn. (I),but rather to the height of the transition states leading to the products. But it was only in 1955-1957 that the quantitative picture emerged (43): The specific rate of reaction (k) of a conformationally heterogeneous system, such as that shown in eqn. (1)is the weighted average of the rates of the two conformational isomers (conformers)
k = n,k,
+ n.h,
where n, and n, are the mole fractions of the equatorial and axial conformers, respectively, and k, and k. are the respective specific rates (rate constants). (A corresponding equation for weighted quantities applies to a numher of other molecular properties, such as chemical shifts in the
'
Prelog's comprehensive work in the area of stereochemistry, of which the studies of medium-sized rings form a part, has been recognized by the awards jointly with J. W. Cornforth, of the 1975 Nobel Prize in Chemistry. 764 / Journal of ChemicalEducation
nmr, coupling constants, molecular polarization (as expressed by the square of the dipole moment), and enthalpy, among others.) I t hecame important t o find suitable models to measure k, and k. since-the equilihrium depicted in eqn. (1) is too fast for individual conformations to be ca~tured.'Winstein and Holness (43a) suggested the use of 4-c-hutyl-substitut. ed cyclohexyl compounds eqn. (2) as substrates for measurement of k. and k., respectively; knowing k,, k,, and k, n. = 1) and they were able to compute n, and n. (n, hence k = n.ln, (eqn. (1)). This idea was used extensively in the 1950's and led to approximate equilihrium constants for a numher of suhstituents; equilihrium constants of this type derived by the above method and others have been tabulated (44). Unfortunately, the kinetic method of conformational analysis, as i t has been called, later proved to he inaccurate, because the 4-t-hutyl-substituted models (eqn. (2)) and the unsubstituted compounds in their individual conformations (eon. (1)) have sliehtlv different shapes (especially in the ;espective transiti& states) and, therefore, slinhtlv different s~ecificreaction rates (45). ort tun at&, &any of the earl; results were, nevertheless, a t least a~proximatelvcorrect. ~irectecpilihratiokof "locked" or anancomeric conformational isomers (eon. (2)) orovides an alternative method for measuring conformationil equilihria (46) which is still believed to give good results. Deformations affect this method also (the equilibrium in eqo. (2) is not exactly the same as that in eqn. (I), X = OH), hut they affect ground state equilibria much less than they do reaction rates and the error introduced by the use of model compounds seems to be auite minor. ~ n k i m p o r t a ninsight t gained from the kinetic method is that a molecule mav react in a conformation different from that which predominates in the ground state. This is true of biochemical (enzvmatic) as well as of non-enzvmatic chemical reactions. Thus, while cyclohexyl p-toluen~sulfonate exists ~redominantlvin the eouatorial conformation and the equatorial model, trans-4-t-hutylcyclohexyl p toluenesulfonate undergoes no bimolecular elimination with base (though the axial cis isomer does), cyclohexyl ptoluenesulfonate can, nevertheless, undergo elimination through the minor proportion of axial isomer (eqn. (5)) (43~).
+
*,-
W X
I moir,
lo-'
.-'
The next major and still continuing advance in conformational analysis is concerned with the applications of nuclear magnetic resonance spectroscopy (nmr). In 1958 (47) Lemieux. Bernstein. and coworkers (a team comnririne hoth organic and physical chemists!) showed that nmr is a powerful tool in the investigation of the conformation and, hence, configuration of sugars and related molecules. Both chemical shift and coupling constants are conformation dependent; thus, in a cyclohexane, the axial hydrogens (protons) generallv resonate at hieher field than the eauatorial ones and may he distinguishid in this way. This fact may he utilized onlv t o assign conformation and confieuration (47) hut also td assess t c e position of mobile conforkationa1 equilibria of the t w e shown in eon. . (1). . . Here the axial proton next to the eqiatorial X-group has a resonance frequency v, distinct from that of the equatorial proton next to the axial X-group (v,). The same weighting procedure applies as in the kinetic method for the actual shift of this
-
pressed in s-' or Hz), the two spectra seen at low temperature will coalesce into one; and, from the lineshapes of the nmr signals in the vicinity of the coalescence point, i.e. a t temperatures somewhat below and somewhat above the coalescence temperature, one can calculate the activation parameters of the interconversion process. Through this kind of experiment i t is known t b a t t h e act~vation"parameters for the inversion of the cyclohexane chair (eqn. (I), X = H) are AGf = 10.3 kcallmole a t -67'C, AH' = 10.8 kcallmole, AS: = 2.8 eu. Several reviews on this method with numerous examples of conformational processes have been published (5355). Another important application of conformational analysis around 1960 is related. to the technique of optical rotatory dispersion (ORD). While this is an old method, i t was fashioned into a useful tool of structure elucidation largely throuah the extensive work of C. Dierassi in the late 1950's (56). Perusal of Djerassi's book makes i t very, evident that svstematization of ORD would hardlv have been ~ossible dithout an understanding of the foundations of conformational analysis. One of the most useful applications of ORD to the study of constitution, configuration, and conformation is the octant rule (57) which rests on strictlv conformational principles as do most of the more recent ;mpirical rules of configuration assignment by OHD and CD (circular dichroism) spectra. I t was indicated earlier that the total structure of a substance, which includes conformation as well as constitution and configuration, can be determined by such direct methods as X-ray diffraction or neutron diffraction in the solid state or electron diffraction (as well as microwave spectroscopy) in the vapor. Obviously i t would be very useful if structure could be calculated a priori, i.e., without resort to experiment. A pioneering and very ambitious initial step in this regard was taken by Westheimer (58) who calculated the shape and energy of the transition state for biphenyl isomerization. The geometry, and energy, of a number of molecules in the ground state can be calculated similarly. The approach to this problem has been recently reviewed in this Journal (59, 60) and so will not be repeated here. The method has been quite successful in calculating conformation and enerev -. of a number of a l i ~ h a t i cand carbocyclic molecules (6146). One of the prettiest applications of this techniaue has been in the elucidation of the conforacid mation of 4,4,8,8-tetramethylcyclodecane-l-carboxylic (VIII) (67).
proton; for i t turns out that, because of the rapid equilibration of the conformers shown in eqn. (1) on the nrnr time scale,2 the room temperature nrnr spectrum displays, not the individual protons of the two contributing conformations, but an average of the two ( u ) such that v = n,u.
+ nova
or (in terms of chemical shift) 6 =& n,6, In the application of this method t o the determination of conformational equilibria the choice of model compounds is, again important. The use of 4-t-butyl-substituted compounds (48) (V)-(VII) proved quite successful in yielding a rather large number of data but was later criticized (496) as beine inaccurate: the inaccuracv. .. in manv instances.. aD. to be quite minor, however. A theoretically more accurate method (49) consists in coolina the substance to he studied to a temperature where i n t e r c b e r s i o n of the conformers (eqn. (1)) becomes slow on the nrnr time scale (usually around -10O0C) and then observing the actual signal areas of the axial and equatorial protons. This gives equilibria at -lOO°C and extrapolation to room temperature is not straightforward; the obvious alternative of using the low-temperature shifts for 6, and 6, and the room temperature shifts for 6 does not work well, because the chemical shifts themselves are markedly temperature dependent. Coupling constants are powerful tools in conformational assienments as was earlv recoenized (47): auantitative exploration is largely based on t i e ~ a r & ;&ation for vicinal protons (50) which, sliahtlv modified from the orieinal " form, may be expressed as J = 422 - 0.5cosr 4.5c& where r is the torsional angle between the vicinal protons under investigation. I t may be seen that J decreases from a value of above 8 Hz a t .r = 0°, through a value of -5 Hz a t T = 60' to a value of zero a t -80' and then increases to a value above 9 Hz a t 180°. Structures (V)-(VII) shows the variation of chemical shifts (45) and coupling constants (51) with conformation. Since coupling
+
+
(VI J:'
= 11.07
Hz
J/'- 431 Hz '.6 -837 ~m
IVI) J." = 2.72 Hz J."=3,WHz '.6 =3.53 ppm
1W) d" =977Hz Z' =3%1 Hz
S = 3.51ppm
constants of conformationally heterogeneous systems are averaged in the same way as other properties ~ J=n.J, n.J, (6) they also afford a means to calculate conformational equilibria;' and since coupling constants do not vary sensibly with temperature, i t is, in principle, possible t o derive J, and J. from low-temperature spectra and J from a roomtemperature spectrum and then to use eqn. (6) t o calculate n, and n.. A rather elegant application of this method to the conformation of a number of polyhalosubstituted ethanes has recently been published (52). Nmr spectroscopy is a convenient tool to measure rates of relative fast reactions, i.e., reactions whose activation energy is between 5 and 25 kcallmole. Many of the unimolecular changes whose rates have been measured by this method are conformational interconversions, such as that in eqn. (1). If the reaction is fast relative to the separation of the signals in the nrnr spectrum, then, as explained above, a sinele. averaeed nrnr spectrum is observed: if the rate is ~ l o w , ~ t wspecira o (for the two interconverting species) are displaved. (These two extremes mav be seen for the same reaction-the former at high, the iatter a t low temperature.) In the intermediate case, where the rate of interconversion approaches the separation of the signals (both ex-
+
o
o
c
.
:
C
,
H HsC CH,
lWlI1
When Dunitz first determined the structure of this compound by X-ray analysis, there appeared to be "disorder" (i.e. indefiniteness in atomic positions) in one corner of the molecule with C-C-C bond angles of the unlikely magnitude of 135'. An a priori calculation of the conformation of the molecule by Lifson interestingly revealed two conformations differing by 1 kcal/mole in total energy. The two species may be calculated to be present in proportions of 85 and 15% and their respective shapes could be clearly preThe inversion is rapid on the nmr time scale because the frequency difference between the two conformations (v. - u., of the order of 30 Hz) is much less than the rate of inversion of the two conformers lot t h e order cnf 10; rec-' or 10' Hz,. This rewlts from t h e very large wavelength of the mdintam nhsorhrd in nrnr excitation (radiofrequeney).Averaging does not, of course, occur in infrared or ultraviolet spectra where each conformer is seen separately (Franck-Condon principle) because the wavelength of the radiation absorbed is very much shorter and the frequency difference between conformers, therefore, much greater than their rate of inversion. Volume 52, Number 12. December 1975
/ 765
dicted from the calculation. When the X-ray spectrum to be expected of a mixture of these two precise conformations in approximately the proportions indicated was calculated, excellent agreement with the observed X-ray spectrum was obtained (67)! Clearly here the X-ray spectroscopy provides compelling evidence for the resuit of the calculation whereas the X-ray data alone could not have been readily interpreted and the calculation alone would have had to be considered speculative. This is a fine example of the interaction between experiment and calculation of which, hopefully, more cases will be seen in the future. We shall conclude this account with a hrief survey of two more recent applications of conformational analysis. We have already mentioned the important relation between conformational analysis and proton nmr. Recently, as the result of the develooment of Fourier transform nmr soectroscopy, it has become a matter of routine to observe'the resonance of the naturallv occurrine (1.1% abundance) 13C nuclei in organic molecuies. Not s&risingly, it turns out that I3C nmr (or cmr) is iust as deoendent on conformational factors as its protonnmr (pmrj. However, where pmr spectra are both complicated and simplified by extensive spin coupling and the information therein contained, cmr spectra can he obtained free of coupling complications if recorded under conditions of proton "noise decoupling" (i.e. broad-hand decoupling of all protons). The stark simplicity of the spectra thus obtained permits an interpretation of the carbon chemical shifts in terms of the suhstitution pattern of the compound. Here, as in so many other areas of organic chemistry, the results are most easily interpreted in the conformationally rigid and well understood cyclohexane system and Dalling and Grant (68) were able to express the cmr chemical shifts of all the carhon in a series of polymethylcyclohexane in terms of a very few basic parameters: the chemical shifts induced in a cyclohexane carhon by equatorial and axial a- and 8-methyl groups (downfield shiftine to varvine decrees). the effect of an axial y-methyl group (upfieli shirtingj'and the chemical shifts of axial and eauatorial methvl . erouos - . (the stericallv more crowded axial kbstituent resonates a t higher field, implying that the upfield shift of a ring carbon caused by axial y-methyl is also due to its steric proximity). Only small chemical shifts seem to be engendered by equatorial methyl groups a t the y-position or by either equatorial or axial groups as far away as the 8-positions. These ideas are now extensively pursued further, e.g. in heterocyclic systems (69, 70). The last topic to be discussed is one of particular interest to the author: the conformational analysis of saturated heterocycles. Heteroatom-containing rings occur in sugars and alkaloids, among other substances, and their conformation is, therefore, of practical as well as theoretical interest. Yet it is only in the last few years that such ring systems have been systematically studied and a numberofreviews are now available (71-75). A detailed discussion is not possible here, hut the important features may he illustrated with the schematized formula of a 1f -dioxane (a much-studied representative of the class of saturated six-membered heterocycles) (IX).
+J I
0,
gens a t C-4.6 than would be an axial substituent in cvclohexyl-R. The situation is aggravated by the known puckering of the 1,s-dioxane molecule at C-2 which further pushes Rinto the ring and increases its conformational energy (e.g. from 1.7 kcallmole for R = CH3 in cyclohexane to 4.0 kcall mole). 2) The axial substituent R' a t C-5 is less encnmbered than a corresponding substitutent in cyclohexane (76) because the syn-axial hydrogens a t the 1- and 3-positions are absent; the lone pairs of the oxygen atoms evidently cause little or no steric interference, for the conformational energy of a 5-methyl substituent (R' = CH3) is only 0.8 kcallmole compared to the standard 1.7 kcallmole value in cyclohexane. 3) If R is a polar group, such as CH30, dipolar factors will make it more stable in the axial than in the equatorial position. This is the so-called anomeric effect (77, 78). 4) If R' is a polar group, such as chlorine, tKen, because of dipole interactions, the axial position is destabilized over what it would he in cyclohexane (79, 80). 5) A strong solvent dependence is, expectedly, found for conforrnational eauilihria where R or R' is a oolar group, but the solvent'effect is not as closely related tb the dielectric constant of the medium as mieht have been anticipated (80, 81). 6 ) Some unexpected effects are found; for example, R' = F prefers the axial over the equatorial position (80, 82) for reasons not yet understood. 7) When R' is a dipolar group of the type X+-Y- (examples: NOz, SO, SOz, CN, etc.) the axial conformation is preferred (79, 80. 83) and this preference is enhanced for oositivelv charged substituenis attached, such as NR3+ (84j, as a rLsult of electrostatic attraction between the axial substituent a t C-5 and the negatively charged oxygens a t C-l,3. I t is also interesting that some saturated heterocycles, especially sulfur-containing ones, have readily accessible twist or hoat forms (85, 86)-a fact which has revived the interest in these forms (87) which are normally of rather high energy (e.g. 5.5 kcallmole above the chair form in cyclohexane). As we conclude this very hrief and sketchy survey, the reader may have a complaint and a question. The complaint refers to the f a d that in an historical review of conformational analysis we have never defined the term "conformation." This omission has heen deliberate, for, though conformational analysis has been a very fruitful field, there is still no generally accepted definition of what conformation is. Some prefer to limit the term to the various arrangements of molecules possible by virtue of rotation about single bonds (as in ethane or butane) but allowing also for some valence angle deformation (so as to include the ring inversion in cyclohexane as a conformational change). Others wish to include rotation about all bonds, including double bonds. and while this ooint of view is not prevalen'i, it needs to he considered forihe reason that the change of bond order from one to two is madual. not disronti'nuous, and rotation about bonds of intermediate order (such as the C-N bond in amidesj has recentlv attracted attention (88). Still others include such as the inversion of amines (VI) among conformational changes. While it may be argued that such a change had better he considered configurational rather than conformational, it must also be pointed out that there are cases, such as the change from axial N-H to equatorial N-H in piperidine (VII)
R'
(IX)
(The diaxial conformation (IX) is drawn for the sake of illustration; it is not the stable conformation.) The important features of this molecule (and similar ones) are the following: 1) The axial substituent R a t C-2 is much more crowded than an axial suhstituent in cyclohexane (76), hecause, as a consequence of the shorter C-0 bond distance (as compared to C-C), R is closer to the syn-axial hydro766 / Journal of ChernicalEducatbn
I
H
IVII~)
ivlle, ra=r>
tVlla1 nitrwen inversion and ring r e v e m ~ l
Inter-Science, John Wiloy & Son., New York. 1963, pp. 709-769. (331 Stoddart, J. F.. "Stereahemistry of Carbohydrates. "Wilcy-Inf~eienee, New Yark, 1971. ( 3 4 Barton. D. H. R., Erporiendo. Suppl., 11.121 11955): Barton, D. H. R,and Cwkson, R. c., Q U ~ , nau.. ~ . 10. 44 (1956): ~ s n o nD. , H. R, in '~h-,
