Mechanistic Insights into the Isothiourea-Catalyzed Addition Reaction of a para -Nitrophenyl Ester and an N -Benzylpyridinium Salt

Density functional theory is used to elucidate the reaction mechanism and origin of selectivities for the isothiourea-catalyzed addition reaction of a para -nitrophenyl ester and an N-benzylpyridinium salt. The possible reaction mechanism involving various reactive sites and the corresponding regioselective pathways is investigated. Based on computational results, the most energetically favorable reaction pathway consists of nucleophilic addition of the isothiourea to the aryl ester, C–O bond cleavage, α-H elimination, C4-addition of a C(1)-ammonium enolate to the N-benzylpyridinium, and amidation. The stereoselectivity-determining step is the C4-addition of the C(1)-ammonium enolate to the N-benzylpyridinium, which mainly generates the RS -isomer. The regioselectivity is predicted by a projection of orbital coefficient vector analysis, which can be used to predict the regioselectivity by calculating the atomic reactivity of a specific atom.