Computational investigation of the effect of alpha-alkylation on S(N)2 reactivity: acid-catalyzed hydrolysis of alcohols

Computed potential energy barriers (HF, B3LYP and MP2/6-31G*; vacuum and PC M water) for simple S(N)2 identity reactions H2O + R-OH2+ --> +H2O-R + OH2 tend to decrease along the series R = Me, Et, Pr-i and Bu-t, in contrast wi th those calculated for Cl- + R-Cl-->Cl-R + Cl-. The S(N)2 reaction profile for H2O + Bu-t-OH2+ shows a sequence of three steps, each with a transitio n structure corresponding to the internal rotation of a single methyl subst ituent. The same three rotations also appear in the S(N)2 reaction profile for Cl- + Bu-t-Cl, but as distinct stages of a concerted process with a sin gle transition structure; only the second methyl group undergoes internal r otation in the transition vector itself. Simulation of reactions H2O + R-OH 2+, using the AM1/COSMO method for treatment of aqueous solvation, illustra tes the changing energy surface topography accompanying S(N)2/S(N)1 mechani stic changeover along the series R = Me, Et, Pr-i and Bu-t, and permits det ermination of kinetic isotope effects for both pathways with each alkyl gro up. Mechanistic change occurs by alteration of the relative energies of the TSs along these competing paths. Computational modelling allows investigat ion of experimentally unobserved reaction mechanisms, such as S(N)1 for pri mary substrates.