The above methods are applicable only to sets of diastereoisomers that contain meso forms.

The method of ring formation, already illustrated in connection with dihydroshikimie acid (Fig. 5-15), is more general, but caution must be exercised in draving conclusions. For examle, it is quite clear from consideration of models that only the cis isomer of cyclopropane-1,2-dicarboxyle acid (Fig. 7-1, Ivb) can form an intramolecular (cyclic) Fig. 7-7. Proof of configuration of the 2,5-dimethylcyclopentane-1,1-dicaboxyle acid. Anhydride, whereas in the trans isomer (Fig. 7-1, IVa) the carboxyle groups are too for anhybride fomations. In fact, of the two known acids, only one forms cyclic anhydride apon treatment with acetyl chloride, 6and it seems quite safe to assign that of the two isomers of 3hydroxycyclohexanecarboxylic acid (Fig. 7-9) the one that forms a cyclic lactone must be thecis isomers. 7 However, the method is not foolproof; thus, for example, both isomers of cyclohexane1,2-dicarboxylic acid form a cyclic anhydride upon treatmen with acetyl chloride, although anhydriad formation from the cis isomer appears to be more facile.8 In fact, closere of a five-membered ring ( as axists in the anhydride) across adjacent trans bonds appears entirely reasonable from models in cyclohexane and larger rings (ef. Chaps. 8 and 10), although, as mentioned erlier, 1,3 and 1,4 ring closure can occur anly cis in a six-membered ring. In case of doubt, it is obviously desirable to subject both isomers (cis and trans) to thr ring-closure reaction that is to be used in the establishnment of configuration. Fig. 7-8. Reaction of 2-chlorocyclohexanols with alkali. Sometimes mechanistic considerations may be invoked in configurational assignments. For example, of the two 2-chlorocyclohexanols (Fig. 7-8), only one forms an epoxide upon treatment with mineral base whereas the other is rather sluggishly converted to a ketone.9 Since epoxide formation is a displacement reaction of the SN2 type and involves rearward attack, as shown in acyclic cases,10 it is reasonable to assume that the epoxide-forming chlorohydrin is the trans isomer and the other is the cis. The argument becomes much weaker when it is based on mechanistically less well-understood analogies. In this category is the assumption often made in the past that the Fig. 7-9. Configurational correlation of 3-methylcyclohexanol with 3-hydroxycyclohexanecaboxylic acid. Isomer formed predominatly in catalytic hydrogenation in acid medium of an aromatic ring or a ketone ( such as a mehylcyclohexanone) is the cis isomer. As will be explamend in Chap 8, this assumption os now known to be sometimes incorrect, and reasoning of this type should be used only with great circumspection and when the analogies being made are quite alose and reasonably well understood. Arguments based on physical properties are on a similar footing. When the rings are small and therefore relatively rigid and the relation of the property to be studied to gonfiguration is well understood, reliable result may be obtained. For example, 11 the first dissociation constant of ciscyclopropane-1,2-dicarboxylic acid corresponds to a pKa of 3.33 whereas the trans isomer has a pKa of 3.65; for the second proton, pKa is 6.47 for the cis isomer and 6.15 for the trans isomer. The greater strength of the cis diacid and lesser acid strength of the corresponding monoanion are to be expected on the basis of the greater proximity of the funetional groups in the cis isomer and could

have been used to assign the configurations of the acid. With the cyclopentane-1,2-dicarboxylic acids the situation is already not quite so clearcut, for although pK2 is smaller for the trans acid (5.91) than for the cis (6.51), pK1 is also smaller for the trans isomer (3.89 vs .37). In the cyclohexanedicarboxylic acids the non-planar shape of the ring must definitely be taken into account; these will be considered in Chap. 8. Dipole moments could, in principle, be used to establish configuration; thus one would predict that cis-1,2-dichlorocyclopentane should have a larger dipole moment than the trans isomer. Data of this type are available in six-membered rings where again the situation is more complecated than in the smaller systems; they will be considered in Chap. 8. Infrared spectra may also be helpful in assigning cofiguration. For example, ciscyclopentane-1,2-diol in dilute carbon tetradhloride solution shows12 hydroxyl stretching frequencies due to hydrogen-bonded hydroxyl at 3572cm.-1 as well as due to free hydroxyl at 3633cm.-1, whereas the trans isomer, in which the hydroxyl groups are too far apart for intra molecular bonding, shows only the unbonded absorption at 3620 cm.-1. Of particular valuein the assignmetn of relative configuration is X-ray diffraction. Elucidation of the configuration of the antibiotic fumagillin 12a provides an elegant example of this method. Empirical assignments based on differences in density, refractive index, and other physical properties whose origin is not so well understood have been made in some intances but are often of doubtfut reliability; proper use of such data will be discussed in Sec. 8-4. As in the case of acyclic stereoisomers, once the configuration of certain compounds has been established, that of others can be elucidated by a process of chemical correlation. For examle, the configuration of cis-3-methylcyclohexanol has been established by correlation with the known configuration ( see above) of 3-hyydroxycyclohexanecaboxylic acid, as shown in Fig. 7-9.13 Such correlations involve a complication not present in the configurational correlation of optical isomers (sec. 5-4a ). The equilibrium between enantiomers necassatily corresponds to a 50-50 mixture, so that any reaction in an attempted correlation which racemiizes the asymmetric atom will immediately be detected byy the resultant loss of optical activity. However, the equilibrium between cis-trans isomers may be quite far from 50-50, and if, by mischangce, one of the asymmetric carbons. This fact may escape notice. For example if (and this is a most unlikely eventuality) the lithium aluminum hydride reduction of cis-3-hydroxycyclohexanecarboxylic had involved epimerization of the carboxyl group to the trans position, the 3-methylcyclohexanol obytained as shown in Fig. 7-9 would be the trans isomer to which the cis configuration might than have been erroneously assigned. To avoid this pitfall, it is necessary to undertake the transformations involved in the correlation starting with both geometricalisomers. Iff a line, then both epimeric starting materials will be so equilibrated and will necessarily give riseto the same product or mixture of products. The fact,established specifically in the case shown in Fig. 7-9. That the two epimeric starting materials give differrent (epimeric)products rules out the possibility of an equilibration of this type.

Hal:201 b. as a funetion of the Nature and Deggre of Substitution of the Ring Atoms. Little is known about the effect of introduccing hetero atoms into the ring on the case of ring closere. Inasmuch as some of the diftieculty of forming medium-sized rings is due to transannular hydrogen interactions ( ef. s, or o- would facilitate ring closure by diminishing these interactions. In fact, the introduction of a single hetero atom seems to have little effect: Ring closure, of -chlorosulfides, RS(CH2)nCl, to cyclic sulfonium salts fails for cycles containing botween 8 and 13 atoms. Compounds of the type shown in Fig. 7-19 could be formed readily by the reaction shown for n between 2 and 10, the rate of ring closure dropping off gradually with inucreasing n, with no rate minimum appearing for 9- to 11membered rings. This system, however, cantains not only two hetero (oxygen) atoms but also two benzene carbons which are part of the ring, so that transannular hydrogen interactions would be expected to be a great deal less important here than in polymhethylene carbocycles. The effect of alkyl substituents in general is to facilitate ring closure, at least where small and common rings are cooncerned. (little information is available along this line on medium and large rings). This effect (the thorpelngold effect) runs parallel to the corrresponding effect on ring stability discussed in Sec. 7-2c. A very clear-cut example is the effect of substitutional on the rate of epoxide formation from chlorohydrins under the influence of base shown in Table 7-4. A number of other examples of the effect may be found in the literature. Fig. 7-19. Cyclic ethers of eatechol Ingold