Influence of compression upon kinetic isotope effects for S(N)2 methyl transfer: A computational reappraisal

Secondary alpha -D-3 kinetic isotope effects (KIEs) have been calculated us ing ab initio HF and B3LYP methods with 6-31G and 6-31G* bases for four met hyl transfer reactions of the general type R3N + CH3-NR3+. Comparison of R = CH3 (B) with R = H (A) serves to investigate the effect of varying the nu cleophile and nucleofuge by alkylation of the entering and leaving amine mo ieties. The changes in KIE, transition-structure (TS) looseness, and energy barrier do not accord with the generalization of Wolfe and co-workers (J. Am. Chem. Sec. 1993, IIS, 10147). Reactions C and D are intramolecular meth yl transfers between the bridgeheads of inside-methylated [1.1.1]cryptand a nd 1,7-diazabicyclo[5.5.5]heptadecane, respectively, in which the N . . .N distances are significantly smaller than in B. Comparison of B with either C or D serves to investigate the effect of compression along the N-C-N axis . The energy barriers for C and D are markedly lower than for B, and, altho ugh their TS's are tighter than for B, their reactant complexes (RC's) are even tighter. Progress from RC to TS in the compressed systems is accompani ed by a decrease in strain. The inverse alpha -D-3 KIEs for C and D are dom inated by zero-point energy changes, but the contribution from the CH stret ching modes is less inverse than that for B. The more inverse B3LYP KIEs fo r C and D arise because there is a significant increase in the relaxed vale nce force constant for bending the H-C-alpha-N-1g angle in going from RC to TS. These calculated results are consistent with Schowen's compression hyp othesis for enzymatic methyl transfer.