Resolution of Racemates

As noted earlier, chiral compounds synthesized from achiral starting materials and reagents are generally racemic (i.e. a 50:50 mixture of enantiomers). Separation of racemates into their component enantiomers is a process called resolution. Since enantiomers have identical physical properties, such as solubility and melting point, resolution is extremely difficult. Diastereomers, on the other hand, have different physical properties, and this fact is used to achieve resolution of racemates. Reaction of a racemate with an enantiomerically pure chiral reagent gives a mixture of diastereomers, which can be separated. Reversing the first reaction then leads to the separated enantiomers plus the recovered reagent.

Many kinds of chemical and physical reactions, including salt formation, may be used to achieve the diastereomeric intermediates needed for separation. The following diagram illustrates this general principle by showing how a nut having a right-handed thread (R) could serve as a "reagent" to discriminate and separate a mixture of right- and left-handed bolts of identical size and weight. Only the two right-handed partners can interact to give a fully-threaded intermediate, so separation is fairly simple. The resolving moiety, i.e. the nut, is then removed, leaving the bolts separated into their right and left-handed forms. Chemical reactions of enantiomers are normally not so dramatically different, but a practical distinction is nevertheless possible.

To learn more about chemical procedures for achieving resolution Click Here.

Conformational Enantiomorphism

Conformational Enantiomorphism

The Fischer projection formula of meso-tartaric acid has a plane of symmetry bisecting the C2–C3 bond, as shown on the left in the diagram below, so this structure is clearly achiral. The eclipsed orientation of bonds that is assumed in the Fischer drawing is, however, an unstable conformation, and we should examine the staggered conformers that undoubtedly make up most of the sample molecules. The four structures that are shown to the right of the Fischer projection consist of the achiral Fischer conformation (A) and three staggered conformers, all displayed in both sawhorse and Newman projections. The second and fourth conformations (B & D) are dissymmetric, and are in fact enantiomeric structures. The third conformer (C) has a center of symmetry and is achiral.

Conformations of meso-Tartaric Acid

eclipsed, achiral
staggered, chiral
staggered, achiral
staggered, chiral

Since a significant proportion of the meso-tartaric acid molecules in a sample will have chiral conformations, the achiral properties of the sample (e.g. optical inactivity) should not be attributed to the symmetry of the Fischer formula. Equilibria among the various conformations are rapidly established, and the proportion of each conformer present at equilibrium depends on its relative potential energy (the most stable conformers predominate). Since enantiomers have equal potential energies, they will be present in equal concentration, thus canceling their macroscopic optical activity and other chiral behavior. Simply put, any chiral species that are present are racemic.

It is interesting to note that chiral conformations are present in most conformationally mobile compounds, even in the absence of any chiral centers. The gauche conformers of butane, for example, are chiral and are present in equal concentration in any sample of this hydrocarbon. The following illustration shows the enantiomeric relationship of these conformers, which are an example of a chiral axis rather than a chiral center.

Conformations of Biphenyls

Another class of compounds that display conformational enantiomorphism are the substituted biphenyls. As shown in the following diagram, biphenyl itself is not planar, one benzene ring being slightly twisted or canted in relation to the other as a consequence of steric crowding. This crowding will be demonstrated by clicking on the diagram. The resulting chiral conformation, having a dihedral angle of about 45º, equilibrates rapidly with its enantiomer by rotation about the connecting single bond. Note that a conformation having a 90º dihedral angle is achiral, as a consequence of a plane of symmetry.

If each of the phenyl rings of a biphenyl has two different ortho or meta substituents (one may be hydrogen), even the twisted 90º dihedral angle conformer becomes chiral. In order to interconvert such conformers with their mirror image structures, a rotation through the higher energy coplanar form must be made. The ease with which this interconversion occurs will depend on the size of the ortho substituents, since these groups must slide past each other. The 2,2'-dicarboxylic acid on the left below cannot be resolved at room temperature, since thermal (kinetic) energy is sufficient to provide the necessary activation energy for racemization. The two additionally substituted diacids to its right have a higher activation energy for racemization, and can be resolved if care is taken to avoid heating them. As a rule, an activation energy barrier of 16 to 19 kcal/mole is required to prevent spontaneous room temperature racemization of substituted biphenyls. Since fluorine is smaller than a nitro group, the center compound racemizes more rapidly on heating than does the nitro compound to its right. Conformational isomers that are isolable due to high energy barriers are called atropisomers.

By clicking on the diagram, three additional examples of resolvable biphenyls will be displayed. The 2,2'-disulfonic acid (compound A) can be resolved with care, confirming the larger size of SO3H compared with CO2H. Compounds B and C provide additional insight into the racemization of biphenyls. Although these biphenyls have identical ortho substituents, the meta nitro substituent adjacent to the methoxyl group in C exerts a buttressing influence that increases the effective size of that ortho substituent. 
Finally, by clicking on the diagram a second time two additional examples of substituted biphenyls will be shown. The left hand compound is held in a twisted conformation by the bridging carbon chain. Racemization requires passing through a planar configuration, and the increased angle and eclipsing strain in this structure contribute to a large activation energy. Consequently, this compound is easily resolved into enantiomeric stereoisomers. The right hand compound is heavily ortho-substituted and most certainly resists assuming a planar configuration. However, the right benzene ring has two identical ortho substituents, so the stable 90º dihedral angle conformer has a plane of symmetry. All chiral twisted conformers are present as racemates, so this compound cannot be resolved.

To see models of biphenyl and a chiral tetrasubstituted derivative   .

Stereoisomers of Disubstituted Cyclohexanes

Stereoisomerism in Disubstituted Cyclohexanes

The distinction between configurational stereoisomers and the conformers they may assume is well-illustrated by the disubstituted cyclohexanes. The following discussion uses the various isomers of dichlorocyclohexane as examples. The 1,1-dichloro isomer is omitted because it is an unexceptionalconstitutional isomer of the others, and has no centers of chirality (asymmetric carbon atoms). The 1,2- and 1,3-dichlorocyclohexanes each have two centers of chirality, bearing the same set of substituents. The cis & trans-1,4-dichlorocyclohexanes do not have any chiral centers, since the two ring groups on the substituted carbons are identical.

There are three configurational isomers of 1,2-dichlorocyclohexane and three configurational isomers of 1,3-dichlorocyclohexane. These are shown in the following table.

The 1,2-DichlorocyclohexanesThe 1,3-Dichlorocyclohexanes
Examine Conformations of
Examine Conformations of
Examine Conformations of
Examine Conformations of

All the 1,2-dichloro isomers are constitutional isomers of the 1,3-dichloro isomers. In each category (1,2- & 1,3-), the (R,R)-trans isomer and the (S,S)-trans isomer are enantiomers. The cis isomer is a diastereomer of the trans isomers. Finally, all of these isomers may exist as a mixture of two (or more) conformational isomers, as shown in the table.

The chair conformer of the cis 1,2-dichloro isomer is chiral. It exists as a 50:50 mixture of enantiomeric conformations, which interconvert so rapidly they cannot be resolved (ie. separated). Since the cis isomer has two centers of chirality (asymmetric carbons) and is optically inactive, it is a meso-compound. The corresponding trans isomers also exist as rapidly interconverting chiral conformations. The diequatorial conformer predominates in each case, the (R,R) conformations being mirror images of the (S,S) conformations. All these conformations are diastereomeric with the cis conformations.

The diequatorial chair conformer of the cis 1,3-dichloro isomer is achiral. It is the major component of a fast equilibrium with the diaxial conformer, which is also achiral. This isomer is also a meso compound. The corresponding trans isomers also undergo a rapid conformational interconversion. For these isomers, however, this interconversion produces an identical conformer, so each enantiomer (R,R) and (S,S) has predominately a single chiral conformation. These enantiomeric conformations are diastereomeric with the cis conformations.

The 1,4-dichlorocyclohexanes may exist as cis or trans stereoisomers. Both are achiral, since the disubstituted six-membered ring has a plane of symmetry. These isomers are diastereomers of each other, and are constitutional isomers of the 1,2- and 1,3- isomers.

The 1,4-Dichlorocyclohexanes

All the chair conformers of these isomers are achiral, and the diequatorial conformer of the trans isomer is the predominate species at equilibrium.