Reactivity, mechanism, and origin of selectivity of the [3 + 2] cycloaddition between cyclic 3,4-dihydroisoquinoline-N-oxide and N-vinylpyrrole: a computational MEDT investigation

The [3 + 2] cycloaddition reaction (32CA) involving 3,4-dihydroisoquinoline-N-oxides (TAC 1) and N-vinylpyrrole (alkene 2) was analyzed computationally using B3LYP/6-31G(d,p) and WB97XD/6-311G(d,p)//B3LYP/6-31G(d,p) theoretical levels within Molecular Electron Density Theory. The ELF analysis of the TCA 1 reagent reveals that this three-atom-component possesses a zwitterionic behavior. The investigation of conceptual DFT reactivity indices indicates that both reagents exhibit similar electronic behaviors, which accounts for the obtained high activation energies. The analysis of local Parr functions elucidates the experimentally observed ortho regioselectivity. The examination of several energy profiles and transition state structures geometries show that this zw-type 32CA reaction proceeds through asynchronous one-step non-polar process, favoring the formation of the ortho-endo cycloadduct, as observed in the experiment. The solvent effects slightly increase the activation energy of the process without altering the obtained gas phase selectivities. The analysis of thermodynamic parameters revealed that this zw-type 32CA reaction occurs under kinetic control exhibiting ortho regioselectivity and endo stereoselectivity, with exothermic and exergonic properties. NCI and QTAIM analysis reveals the existence of several conventional such as O…H and non-conventional such as C…H and H…H favorable interactions in the structure of the most favorable ortho-endo approach. Mechanism’s analysis using ELF method shows that this reaction occurs through one-step two-stage process.