;+~rn9isomerismof Carbon Compounds I In the early stages of a science or of a particular branch of science, many concepts are necessarily of a pragmatic or operational nat,ure. As t.he science develops there is a tendency for these 'oncepts to be placed on a broader and more t,heoretical or abstract basis. For example, an early definition of "element" rras "a simple mat,erial that cannot be broken down into simpler materials." The beginnings of a change in this concept may be seen in Mendeleev's prediction of then unknown elements and their properties. After further development of the atomic t,heory and Rutherford's discovery of transmutation, the definition given above was changed by the addition of the phrase "by ordinary chemical means." The more modern definition is: "An element is a kind of mat.t,erall of 11-hose atoms hare the same atomic number" ( 1 ) . This is based on fundamental concepts and does not depend on someone's abi1it.y (or lack of it) to decompose cert.ain species of mat,t,er. Some chemist.^ still use concept,s and definit.ions in t,he field of stereochemist,ry v.hich are operational in nat.ure, and t,here seems to he considerable confusion on t,he subject not only in relat,ively recent text,books of organic chemistry but in more advanced writings on st,ereorhemist.ry. The purpose of the present discussion is to suggest a different. setting for the classification of the various t,ypes of stereoisomerism comnlonly encountered in organic chemistry, with t.he view to providing a better correlation with presently used concepts of atomic and molecular structure. Based upon the models of organic structures which have developed from molecular orbit,al t h e o ~ emphasis , is placed on the t,heoret.ical chemical significance of t.he models while t,he t,opological aspects, i.e., t,he presence or absence of symmetry or the nature of the dissymmetry, are ronsidered t,o be secondary. First of all, for purposes of this discussion, the traditional distinction between st,ructural isomerism aild stereoisomerism should be reaffirmed, clearly limiting considerat.ion to t,he relationships among compounds having the same structure. "St,ructure" here refers t,o the order in whirh the atoms in a molecule are bonded t,o each other, and has no geometrical significance even t,hough t,his may be implied by the way st~ructuwl fornlulas are rommonly mritt,en ( 2 ) . Stereoisomers (though literally "solid isomers") ma.y be defined as compounds having the same molecular struct,ure but r i t h the atoms in t,he molecule differing in their geometrical arrangement with respect to each obher. These two types of isomerism are in a sense independent of each ot,her, but one may consider stereoisomerism as being superimposed on structural isomerism, t,hus in-
creasing the total number of isomers possible for a given molecular formula. Stereoisomerism is commonly considered to be of two types, optical and geometrical. Optical isomerism is due to molecular asymmetry which may result from one or more tetrahedral atoms with four different groups attached, or may result from restricted rotation mithin the molecule. The statement "Isomerism depending on restricted rotat.ion about, a carbon-carbon bond is known as geometrical isomerism" (3) is hardly satisfactory for it does not exclude many examples normally included in optical isomerism. It is generally recognized t,hat, optical isomers cannot be defined as stereoisomers which exhibit optical activity yet the writ,er of one modem textbook uses optical activity as the criterion in the following may (4) : "Geometrical isomers may be defined most conveniently as a set of stereoisomers no member of which is optically active." This is an operational approach which depends upon our ability to detect the activity. Aside from any ohject.ions to such a definition on theoretical grounds, t-here is the practical problem of t,he proper classification of compounds that may be asymmetric but vhose optical rotations are so close to zero that detection is unsatisfactory or impossible. (Furthermore, opt,ical activity depends on conditions, such as temperature or wave length, and a compound optically active at, one temperature might be inactive at another.) Before going on to state and interpret his own definition. Wheland indicates the difficult,^ as follows: In view of the vagueness which thus generally attends thr terms "optical" and "geomet~rienl"isomerism, a consideration oi the meanings of these trrms is desirable here. Such a, consideratiou is made rather diflicult,, ho\\-evor, hy the fact that no complete agreement exists among chemists as to exactly u-here the dividing line between t h t\ro ~ types of stereoisomerism is t o he drnnn . . .It is therefore clearly impassible far any definition of opbical and geometriral isomerim to lead to a classification of ~tcreoisomersin complete agreement with the usage of all rhemi& (5).
The confusion and overlapping in t,he classificatio~i of the isomerism of such compounds as the cyclohexane-1,2-dicarboxylic acids is indicat,ed by Wheland a t this point. In spite of this pessimism, and after a discussion of "dissymmet,ry" he offers a definition (6): "Geometrical isomers can now be defined as stereoisomers which do not differ in t,he configuration of any dissymmetric grouping." Whether "in complete agreement with the wage of all chemists" or not, this is a rather unequivmal definit.ion. But it is based on topological relationships and is not closely related to t.he structural concepts of the molecular orbital model. "Conformation" is another t,erm in common use that Volume 38, Number 7, January 196 7
/ 23
is subject to some ambiguity if not actual confusion. Some authors treat the subject under the general heading of stereochemistry but in a manner which implies that it is not a type of stereoismerim. Some definitions of geometrical isomerism are so broad that conformations seem to be included as merely one type of geometrical isomers. At the other extreme, conformation is sometimes defined so broadly that all types of stereoisomers might fall within the meaning of the term (7). As an intermediate example, well known chemists in the field have stated that By coniormtion is meant any arrangement in space of the ntoms of a molecule that can arise hy rotation ahout a single bond and that is capable of finite existence (8).
This clearly includes cases of both optical and geometrical isomers-for example, some of the substituted biphenyls and terphenyls, respectively. But in the diseussions of eonformational analysis and the heights of energy barriers, these polyphenyl compounds, and other optical or geometrical isomers of this type, are commonly ignored. The authors quoted above also make the following statement: Conformatiam (as defined here) constitute definite chemical species which, however, are not separable by presently avsilahle methods (9).
I n other words, a chemical individual of this type vhen first isolated immediately ceases to he a "eonformation" and becomes an isomer. This is not in conflict with their previously quoted statement but places a restriction on the definition that is definitely operational in nature, and is in this respect reminiscent of the older definit,ionsof an element. A Suggested Classiflcotion To avoid some of t,hese shortcomings in the traditional division into optical and geometrical isomerism (with conformation still groping for a place in the scheme), and a t the same time to relate the classifieation more closely to the molecular orbital model, a different approach is suggested. Stereoisomers are placed in two general divisions with the distinction based on the type of change that some part of t,he strueture undergoes in converting one isomer into another. Only the type of change which t,he model undergoes, not the chemist's ability to cause or prevent the change in an actual compound, is of concern here. One of these divisions is called "inversional" isomerism. Inversional isomers are stereoisomers which are formallQ interconvertible only by inversion of one or more carbon atoms with the breaking of one or more sigma bonds and the formation of a corresponding number of sigma bonds. This might involve the hack side attack associated with the Walden inversion or the transitional t,rivalent carbon at.om associated with some racemizations. (This assumes that the inversion does not take place as proposed by Werner (10) to explain racemization.) The second main division is called "rotational" isomerism. Rotational isomers are stweoisomers which are formally interconvertible by the rotation of one part of the molecule with respect to the rest of the molecule about a sigma bond as the axis of rotation without the necessity of disrupting and reforming sigma bonds. (It is important to note that a sigma bond, not a single bond, is referred to here and thus the definition includes the 24
/
Journal of Chemical Education
"forced rotation" of the conventional double bond, which in terms of the molecular orbital model involves a change in the overlapping of p orbitals as the rotation about the sigma bond takes place.) Such transformations may be made by breaking and making sigma bonds, but the distinguishing feature here is that, formally, rotation is sufficient and sigma bonds need not be involved directly. Each of these divisions, inversional isomerism and rotational isomerism, will be considered in turn for illustration and clarification. Examples of "lnversional" Isomerism
Many of the classical examples of stereoisomers come under the heading of inversional isomerism. For instance, the lactic acids, the tartaric acids and the many aldohexoses are of this type. But also included are the stereoisomeric disubstituted eyeloalkanes which may or may not have asymmetric carbon atoms present in the molecule. The isomerism of the 1,2-dihydroxycyclohexanes and of the 1,4dihydroxyeyclohexanes are included in the same classification, instead of calling the former optical isomers and the latter geometrical isomers. Similarities become more evident among compounds like the tartaric acids (I) and the 1,2-dihydroxyeyclohexanes (11), in comparison with the similarities of the monomethyl esters of the tartaric acids (111) and the 1,2-dihydroxy-3,s-dimethylcyclohexanes (IV). COOH
COOH
I
1
COOH
COOH I
Q
Q
Q
OH H
OH OH
OH
COOCH, COOCHJ I I I 1 H-C-OH HO-C-H
COOH
I
I
COOH
H
COOH
I
YOOCH, 1
HO-C-H
I I
I
COOH
COOH
YOOCH, 1 H-C-OH
I I
COOH
I11
The stereoisomers of the spirane compounds (V) are also included in the group of inversional isomers, whether an even number or an odd number of rings is involved, thus placing structures that are similar chemically in the same group. One feature is common to all of the sets of isomers mentioned. I n all cases the transformation of a strueture from one stereoisomer to another must involve the
ships that are not primarily chemical in nature. Br
disruption and formation of sigma bonds, resulting in the inversion of one or more carbon atoms. Examples of "Rotational" lsornerirm As indicated previously, the other principal type of stereoisomerism, rotational isomerism, concerns isomers whose interconversion does not necessarily involve the disruption of sigma bonds, but rather may take place by the rotation of one part of the molecule with respect to the rest of the molecule about a sigma bond as the axis. This is the type of isomer whose isolation has depended upon the degree to which this rotmationis restricted under the experimental conditions involved in the isolation. The major causes of restricted rotation are restriction due to pi bond hindrance, restriction due to non-bonded hindrance, and restriction due to sigma bond hindrance. I n some cases only one of these causes may be operating while in others more t.han one may contribute, but usually one of them predominates. Inversional isomerism and rotational isomerism, as types of stereoisomerism, are superimposed on structural isomerism. I n a similar manner rotational isomerism is superimposed on inversional isomerism. For example, in biphenyl systems the existence of isomers resulting from restricted rotation is independent of any inversional isomerism in either part of the molecule alone, but if such is present it merely increases the total number of stereoisomers possible. However this is not an overlapping of classification in the sense used by Wheland in the case of the cyclohexane-1,2dicarboxylic acids any more than structural and stereoisomerism are overlapping classifications. The different geometrical arrangements of the atoms which distinguish the molecules of inversional isomers will be referred to as "configurations," while the different arrangements giving rise to rotational isomers will be called "conformations." Pi Bond Hindrance
Among the compounds which serve as examples of rotational isomerism, the first to be isolated were the substituted ethylenes, and the existence of such isomers was attributed to the restricted rotation of the double bond. However, the double bond may be looked upon as being made up of one sigma bond with the restricted rotation resulting from the overlapping of the p orbitals to form the pi bond. This overlapping usually constitutes a sufficient barrier to rotation to make it possible to isolate the isomers a t room t,emperature. This constitutes one of the three classes of rotational isomerism, designated as rotational isomerism due to pi bond hindrance. The sterecisomeric compounds of the allene type (VI) belong to this same class of rotational isomers whether there is an even or an odd number of cumulative double bonds; again, structures that are similar chemically are in the same group rather t.han being divided into two groups on the basis of relation-
Br
Br
Br
It is of interest to note that while in the case of the usual double bond there is an sp2 hybridization of the carbon orbitals giving the three coplanar sigma bonds, in the case of the middle carbon of an allene system there is sp hybridization and two linear sigma bonds. The sigma bonds are then made up of overlapping sp-sp2 orbitals, and the planes of the two pi bonds are a t right angles to each other, intersecting on the line of the two sigma bonds. This is the axis about which rotation is considered to occur in transforming one compound into its isomer. Conjugated systems present an interesting situation which falls naturally int,o an extension of the rotational isomer concept. I n 1,3-butadiene, for example, the overlapping of the p orbitals between the second and third carbon atoms would be expected to cause some restriction of rotation. The molecule is considered to be essentially planar and to have a resonanace energy of about 3 to 31/2kcal per mole. Although the cis and trans isomers are not capable of isolation a t room temperature with present techniques, we may rrell afisume that they actually represent preferred arrangements (VII).
The application of this idea to 2,4-hexadiene indicates the possibility of six isomers. The transtrans-trans isomer (the staggered chain arrangement often depicted) would probably be the most stable; the cis-cis-cis isomer the least stable (due largely to methyl group interact,ions); and the cis-trans-& isomer of intermediate stability. These three of the six possible conformations are s h o ~ (VIII). ~n
VIII Volume 38, Number I , January 1961
j 25
Non-Bonded Hindrance
Compounds such as the ort,ho substituted biphenyls are the best known examples of the second type of rotational isomers, those resulting from non-bonded hindrance. Here the tendency of overlapping p orbitals to cause coplanarity of the two benzene rings (a necessary condition for resonance interaction between them) is overshadowed by the so-called steric hindrance of the groups in the ortho positions when these groups are sufficientlylarge. Again it should he pointed out that these compounds are placed in this class whether they are optically act,ive (as in the case of certain biphenyl and polyphenyl compounds with an even number of rings) or optically inactive (as in the case of some terphenyl and polyphenyl compounds with an odd number of rings). Thus (like the allenes or the spiranes) compounds which are similar in structure and chemical nature are not divided into separate classifications merely on the basis of the presence or absence of symmetry. For each structure shown (IX) two conformations are possible (11,12). HOOC
I
NO,
I
NO? COOH
Br OH HO OH H,C Br
I
I /
I
H3C HO OH CHs IS
It has been recognized that in a sense each molecule vith an infinitesimal difference in t,he angle between the planes of the two benzene rings might be considered as a different isomer. This, of course, would mean an infinity of isomers. Actually, this aspect has been ignored in the literature to a large extent and all molecules with angles in the whole range of positions between two energy harriers have been considered as one isomer. Thus those molecules with the same configuration and whose conformations correspond to positions between adjacent maxima of the pot,ential energy curve constitute a single rotational isomer. This viewpoint has been adnpted for the present discussion. In recent years considerable attention has been given to the study of ethane and some of its derivatives in what has come to be known as "conformational analysis." Since the existence of these conformations is due t o essentially the same situation as the existence of t,he biphenyl type of stereoisomer, these variations of the ethane derivatives (and thus similarvariations of all saturated aliphatic compounds) also may be classed as rotatioual isomers due to non-bonded hindrance. For example, consider a compound such as sum-tetra-hutylethane. Assuming sufficient hindrance to rotation, this structure would exist in three stereoisomeric forms. These are represented below in perspective formulas (X) and in the Newman projection formulas (XI).
26
/
Journal o f Chemicol Fducotion
I t would be of interest to synt.hesize, if possible, a compound such as 2,2-diisopropyl-3,3diethylglutaric acid (XII). The syntheses of other glutaric acid COOH
homologs with increasingly larger groups in the 2 and 3 positions might then be attemptec!. While the carboxyl groups are in the trans position no cyclic anhydride can form, but in either of the skew arrangements the anhydride would he expected to form. This might provide a means of separating and isolating the trans form from the other two. I n the case of ethane derivatives having the same set of three diierent groups attached to each carbon (as in the tartaric acids) there are three conformations for each of the three configurations, making a total of nine stereoisomers. When the asymmetric carbon atoms are dissimilar twelve stereoisomers are possible. Sigma Bond Hindrance
The conformations of cyclohexane and its derivatives exemplify the third class of rotational isomerism, that, due to sigma bond hindrance of rotation. I n many cases non-bonded hindrance is also involved. Considering the figure as a generalized potential energy diagram of the cyclohexane system, 6he minima at. B and D represent the chair and boat forms. I n all
cases the harrier at -4 vould he due almost completely to sigma bond hindrance-that is, the resistance to extreme deformation of t,he tetrahedral carbon bonds and the eventual rupture of the ring. -it. E this mould also be the principal factor, although in a boat form non-bonded hindrance due to interaction of the cis 1,4 hydrogen atoms may also be involved. The barrier at, C between the chair and boat forms, or between two chair forms, is also a result of a combination of the same two factors. The barrier (similar to C of the figure) between different boat forms of substituted cyclohexanes is probably due primarily to non-bonded hindrance. These examples serve to il1ustrat.e the fact that rotational isomerism is not likely to result from sigma bond hindrance alone, but commonly arises from a combination of sigma bond and non-bonded hindrance.
Thus superimposed on the configurations from the inversional isomerism that occurs when a six-membered ring is suitably substituted, there are eight different conformations possible as a result of restricted rotation about the sigma bonds between tshe atoms which comprise the ring. Of these, two are chair conformatiom and six are boat conformations. The same situation exists in the case of the pyranose forms of the aldohexoses (XIII), and some of t.hese have been studied rather extensively (13).
so-called "isomers" are unknown and that ttheir existence cannot he shown by isolation of the compounds. On the other hand, it is often advantageous to make use of concepts which go beyond the present state of actual knowledge and experimentat,ion. In this connection it is of interest t,hat in 1875 van't Hoff (17) pointed out that allenes of the type ahC=C=Cde should be capable of existence in optically active stereoisomeric forms, and it was 60 years before such compounds were isolated (18). This broader and perhaps more fundamental classification t.o include in better perspective all organic stereoisomers, whether presently isolated or not, would seem to be advantageous. I t should be stated that t.he proposed classification is concerned wit,h the broad divisions of stereoisomerism and does not imply t,hat. symmet.ry propert,ies and topological relations may not. be applied properly and usefully in the designation of t,he ronfiguration or c~nformat~ion of individual models. Analonouslv. " , we do not base broad chemical classifications of organic compounds on such properties as melting point, density, etc., alt,hough we do find these useful in the designation of individual compounds. (The same may be said for the use of t,he terms "symmetrical" and "unsymmet,ricaln as applied t,o disnhstituted ethylenes or certain poly-suhstitut,ed benzene derivatives.) Furt,her, the proposed classificat.ionis not an attempt, a t a specification system for individual models such as that presented by Cahn, Ingold, and Prelog (IQ), nor is it in conflict with that system. The relation to orbital t.heory may make the proposed system useful by suggesting new approaches to hot,h old and new relationships.
-
For the different sugars, depending on the configuration, different conformations are favored as shown by certain react,ions such as complex format,ion, or the formation of anhydro sugars. Methyl 2,6-anhydroar-D-altropyranoside illustrates how one of the boat forms of the sugar may be locked int,o posit,ion (14). This is represented in two different ways (XIV).
Literature Cited
The formulas XV (15) and XVI (16) are less familiar but more st,riking examples of structures that may exist. in two isolatable conformations as the result of both non-bonded and sigma hond hindrance to rot,ation. In the biphenyl derivative (XV) the two rings are not coplanar; the hindrance to rotation in one direct,ion is due almost entirely to the non-bonded interaction bet,ween the two carboxyl groups, while t,he rotation in the opposite direction is prevented entirely by sigma bonds. Although the phenanthrene system (XVI) has been described as a case of stereoisomerism involving hond distortion, it appears that the nonplanar conformation of the rings need involve only rotat,ion about t,he sigma bonds of the atoms which make up the cent,er ring. The general similarity between these rases of rotational isomerism is quite apparent. COOH
COOH
CH,COOH
(1) T'AULING, I,., "College Chemi~try,"W. H. Freeman & Co., S m Francisco, 1950,p. 59. (2) WHELAND, (7. W., "Advanced Organic Chemistry," .John Wiley h Sonn. Inc., Nrw York, 1949,pp. 85-88. (3) C ~ s o x ,J., "Essentid Principles of Organic Chemistry,'' I'rentice-Hall, h e . , Englewood Cliff?, N. J., 1956, p. ,.a=
,U".
(4) N ~ L L E R C., R., "Chemistry of Organic Compounds," 2nd od., W. B. Saunders Go., Philadelphia, 1957,q. 354. (5) WHEI,ANI>, G. W., "Advanced Organic Cheml~try,"John Wilcy h Sons, Ine., New York, 1949,p. 218. (6) Ihid.,p. 222. (7) ARTON ON, 1). H.R., in "~'or8pertive8in organic Chemistry," T o m , A,, editor, Int,ersrience Puhli~hers,Inr., New York, 1956, p. 78. 18) I)AUBEX,W. G., A N D PITZER,K. S., in "Steric Effecta in Organic Chemistry," NEWMAN, M. S., editor, John Wiley $ Sons, Ino., New York, 1956,p. 3. (9) I l i d . , p. 51. (I0 WERNER, A,, "Lehrbnch der St,ereorhemie," Gust,ave Fischer, Jena. 1904,p. 48ff. G. H.. AX" KEXER. J., J. Chevr. Soe., 121, 614 (11) CHRISTIE. (1922). P.R., A N D AIXMC,I
