Insights into the mechanism of [3+2] cycloaddition reactions between N-benzyl fluoro nitrone and maleimides, its...

We present a theoretical study of the [3+2] cycloaddition (32CA) reactions of N-benzyl fluoro nitrone with a series of maleimides producing isoxazolidines. We use the Molecular Electron Density Theory at the MPWB1K/6-311G(d) level. We focus on the reaction mechanism, selectivity, solvent, and temperature effects. In addition, we perform topological analyses at the minimal and transition states to identify the intermolecular interactions. Electron Localization Function approach classifies the N-benzyl fluoro nitrone as zwitterionic (zw-) three-atom components (TACs), associated with a high energy barrier. The low polar character of the reaction is evaluated using the Conceptual Density Functional Theory analysis of the reactants, confirmed by the low global electron density transfer computed at the transition states. Computations show that these 32CA reactions follow a one-step mechanism under kinetic control, with highly asynchronous bond formation and no new covalent bond is formed at the TS. Besides, the potential energy surfaces along the reaction pathways in gas phase and in solvent are mapped. The corresponding Gibbs free energy profiles reveal that the exo-cycloadducts are kinetically and thermodynamically more favored than endo-cycloadducts, in agreement with the exo-selectivity observed experimentally. In particular, we found that solvent and temperature did not affect this selectivity and mainly influence the activation energies and the exothermic character of these 32CA reactions.