Unveiling the Mg(ii) promoted [3+2] cycloaddition reaction of mesitonitrile oxide to Baylis-Hilman adduct from the molecular electron density theory perspective

The Grignard reagent promoted [3+2] cycloaddition (32CA) reaction of mesitonitrile oxide (MNO) with Baylis-Hilman adduct (BHA) has been studied within the Molecular Electron Density Theory (MEDT) at the omega B97X-D/6-311G(d,p) computational level. Topological analysis of the Electron Localization Function (ELF) allows classifying MNO as a zwitterionic three-atom-component (TAC), participating in zw-type 32CA reactions. In spite of the strong nucleophilic character of MNO, the low electrophilic character of BHA and the BHA:Mg(ii) complex make the corresponding 32CA reactions to have a very low polar character, respectively. The reaction presents total ortho regioselectivity to afford 2-isoxazolines, while the diastereoselectivity is reversed in the Mg(ii)-promoted 32CA reaction relative to that in the absence of the Mg(ii) cation, in complete agreement with the experiments. The preferred transition state structure (TS) associated with the Mg(ii)-promoted process shows complexation of the magnesium atom with the oxygens of MNO and BHA (hydroxyl oxygen), with the corresponding critical points (CPs) showing non-covalent interactions (NCIs) in the AIM-RDG isosurfaces. This MEDT study provides a complete comprehension of the role of the Grignard reagent in the zw-type 32CA reactions of nitrile oxides with Baylis-Hilman adduct; although formation of the BHA:Mg(ii) complex slightly accelerates the 32CA reaction to decrease the activation Gibbs free energy by 3.1 kcal mol(-1), the more remarkable role of the Mg(ii) cation is the change of the diastereoselectivity of these 32CA reactions involving a chiral ethylene.