Complete inversion of configuration in aliphatic nucleophilic substitution reactions with small inner-sphere stabilization

The stereochemistry of the nucleophilic reaction of the enolate anion of 1,4-dihydro-4-methoxycarbonyl-1-methylpyridine (1(-)) with (R)-(-)- and (S)-(+)-2-bromobutane has been investigated and correlated with the inner-sphere stabilization of the reactions calculated from the ratio k(SUB)/k(ET), where k(SUB) is the rate of substitution and k(ET) the expected rate of electron transfer. It was shown that 1(-) reacts with 2-bromobutane with nearly complete inversion of configuration (99.7%). A complete shift in stereochemistry of the nucleophilic reactions of 1(-) with alkyl halides from racemization to complete inversion is induced by a small increase in the inner-sphere stabilization of the transition state from 0 to 3 kcal mol(-1). The results in this work suggest that the S(N)2 inversion process in general is extremely sensitive towards inner-sphere stabilization.