The gas-phase S(N)2 reactions of chloride with ethyl and neopentyl chlorides and their a-cyano derivatives have been explored with B3LYP, CBS-QB3, and PDDG/PM3 calculations. Calculations predict that the steric effect of the tent-butyl group raises the activation energy by about 6 kcal/mol relative to methyl in both cases. Solvent effects have been computed with QM/MM Monte Carlo simulations for DMSO, methanol, and water, as well as with a polarizable continuum model, CPCM. Solvents cause a large increase in the activation energies of these reactions but have a very small differential effect on the ethyl and neopentyl substrates and their cyano derivatives. The theoretical results contrast with previous conclusions that were based upon gas-phase rate measurements.