Mechanistic Insights into Lewis Acid-Catalyzed Formal [3 + 2] Cycloadditions of Aziridines: A Molecular Electron Density Theory Study

The Lewis acid (LA)-promoted formal [3 + 2] cycloaddition (32CA) reaction of 2-phenyl-1-tosylaziridine (2PTA) with ketone has been studied within the framework of Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) computational level in dichloromethane. This formal 32CA reaction proceeds through a stepwise mechanism, involving an initial BF3 LA-promoted aziridine ring-opening process, followed by a ring-closure process to yield the 1,3-oxazolidine product. The activation enthalpy of the most favorable C2–N1 breaking bond step, ΔH≠ = 6.42 kcal·mol−1, is 20.98 kcal·mol−1 lower than that of the non-catalyzed process, the aziridine ring-opening process being totally C2 regioselective and stereospecific. A topological analysis of the electron localization function (ELF) reveals that the most favorable transition state structure exhibits C2 carbocationic character; in this structure, the C2–N1 single bond has broken, while the C2–O4 single bond has not yet formed. A relative interacting atomic energy (RIAE) analysis of the aziridine ring-opening step reveals that the stabilization of the sulfonamide/LA leaving group and that of the ketone frameworks are the key factors responsible for the reduction in the activation barrier in the presence of LAs. LAs shift the mechanism of the aziridine ring-opening process from SN2-like in the non-catalyzed reaction to SN1-like in the LA-promoted process, which occurs with the inversion of the C2 carbon.