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

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 C - O and C - C 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.