Transition States and Energetics of Nucleophilic Additions of Thiols to Substituted α,β-Unsaturated Ketones: Substituent Effects Involve Enone Stabilization, Product Branching, and Solvation

CBS-QB3 enthalpies of reaction have been computed for the conjugate additions of MeSH to six alpha,beta-unsaturated ketones. Compared with addition to methyl vinyl ketone, the reaction becomes 1-3 kcal mol(-1) less exothermic when an alpha-Me, beta-Me, or beta-Ph substituent is present on the C = C bond. The lower exothermicity for the substituted enones occurs because the substituted reactant is stabilized more by hyperconjugation or conjugation than the product is stabilized by branching. Substituent effects on the activation energies for the rate-determining step of the thiol addition (reaction of the enone with MeS-) were also computed. Loss of reactant stabilization, and not steric hindrance, is the main factor responsible for controlling the relative activation energies in the gas phase. The substituent effects are further magnified in solution; in water (simulated by CPCM calculations), the addition of MeS- to an enone is disfavored by 2-6 kcal mol(-1) when one or two methyl groups are present or the C = C bond (Delta Delta G double dagger). The use of CBS-QB3 gas-phase energies in conjunction with CPCM solvation corrections provides kinetic data in good agreement with experimental substituent effects. When the energetics of the thiol additions were calculated with several popular density functional theory and ab initio methods (B3LYP, MPW1PW91, B1B95, PBEO, B2PLYP, and MP2), some substantial inaccuracies were noted. However, M06-2X (with a large basis set), B2PLYP-D, and SCS-MP2 gave results within 1 kcal mol(-1) of the CBS-QB3 benchmark values.