Computational investigation of the effect of α-alkylation on S_N2 reactivity: Acid-catalyzed hydrolysis of alcohols

Computed potential energy barriers (HF, B3LYP and MP2/6-31G*; vacuum and PCM water) for simple S_N2 identity reactions H₂O + R-OH₂⁺→⁺H₂O-R + OH₂ tend to decrease along the series R = Me, Et, Prⁱ and Bu^t, in contrast with those calculated for Cl^- + R-Cl→Cl-R + Cl^-. The S_N2 reaction profile for H₂O + Bu^t-OH₂⁺ shows a sequence of three steps, each with a transition structure corresponding to the internal rotation of a single methyl substituent. The same three rotations also appear in the S_N2 reaction profile for Cl^- + Bu^t-Cl, but as distinct stages of a concerted process with a single transition structure; only the second methyl group undergoes internal rotation in the transition vector itself. Simulation of reactions H₂O + R-OH₂⁺, using the AM1/COSMO method for treatment of aqueous solvation, illustrates the changing energy surface topography accompanying S_N2/S_N1 mechanistic changeover along the series R = Me, Et, Prⁱ and Bu^t, and permits determination of kinetic isotope effects for both pathways with each alkyl group. Mechanistic change occurs by alteration of the relative energies of the TSs along these competing paths. Computational modelling allows investigation of experimentally unobserved reaction mechanisms, such as S_N1 for primary substrates.