Insights into the mechanism and regioselectivity of the [3 + 2] cycloaddition reactions of cyclic nitrone to nitrile functions with a molecular electron density theory perspective

Abstract

A molecular electron density theory study is presented for [3 + 2] cycloaddition (32CA) reactions of 2,2-dimethyl-1-pyrroline-1-oxide with the nitrile functions to analyse the mechanism and experimentally observed regioselectivity. Electron localisation function (ELF) study predicts zwitter-ionic character of the cyclic nitrone, allowing its participation in zw-type 32CA reactions associated with high energy barrier demanding overcome through appropriate electrophilic–nucleophilic interactions. Analysis of the CDFT indices predict the global electronic flux from the strong nucleophilic nitrone to the electrophilic nitrile functions. These 32CA reactions are endergonic with reactions Gibbs free energies between 5.5 and 39.2 $$\text{kcal}{\cdot}\text{mol}^{-1}$$ in toluene. The ortho regiochemical pathway is preferred owing to the higher thermodynamic stability of the 2,3-dihydro-1,2,4-oxadiazole derivatives. The 32CA reaction of the nitrile function with carbomethoxy substituent is more facile relative to that with the phenyl substituent. Bonding evolution theory study predicts one-step mechanism with early TSs for the ortho pathway, while a one-step-two-stage mechanism is predicted for the meta reaction path, in conformity with the ELF and AIM topological studies at the TSs.