Unveiling the mechanism and selectivity of the [3 + 2] cycloaddition reactions of nitrone with acetylene derivatives leading to anticancer 4-isoxazoline derivatives from the MEDT perspective

Abstract

The [3 + 2] cycloaddition reactions of N-methyl-C-(2-furyl) nitrone (a) with a series of acetylene derivatives (4b), (5b), and (6b) have been studied at the B3LYP-D3/6-31G(d) computational level within the framework of Molecular Electron Density Theory. Topological analysis allows classifying the nitrone (a) as a zwitterionic (zw-) three-atom component (TAC) associated with high energy barrier. These 32CA reactions follow a one-step mechanism under kinetic control with highly asynchronous bond formation. Bonding Evolution Theory (BET) analysis indicates that no new covalent CO and CC bonds form at the transition states (TSs). Interestingly, the global electron density transfer (GEDT) between 0.08 and 0.18 e predicts low polar character of forward electron density transfer (FEDF) type with the electronic flux from the nitrone (a) to the acetylene derivatives. Electron localization function (ELF) and atom-in-molecules (AIM) topological analysis of the electron density at the TS structures characterize the non-concerted nature of these one-step zw-type 32CA reactions.