The Molecular Electron Density Theory (MEDT) was used for the study of the mechanism and the selectivity of the [3+2] cycloaddition reaction between quinazoline-3-oxide and methyl 3-methoxyacrylate, using the B3LYP/6-31G(d,p) DFT method. In gas phase, this [3+2] cycloaddition reaction is characterized by a completely ortho regioselectivity and a moderate exo stereoselectivity. Dichloroethane solvent did not modify the selectivities obtained in gas phase but increase the activation energies and decrease the exothermic character. Analysis of thermodynamic characters indicates that by the inclusion of the experimental conditions, the reaction becomes endergonic and thereby under thermodynamic control favouring the formation of the most stable product as observed experimentally, explaining the exo stereoselectivity. The analysis of the global electron density transfer (GEDT) at the transition states and bond order (BO) show that this reaction takes place via a very slightly synchronous and non-polar one-step mechanism. Conceptual DFT reactivity indices analysis accounts for the electrophilic character of the reagents, explaining the high obtained free activation energies, while local Parr functions analysis allows us to explain the ortho regioselectivity observed experimentally. ELF topological analysis of the most favoured reactive pathways indicates that mechanism of this 32CA reaction is one stage, one step, synchronous and non-concerted. The stability of the favourable cycloadduct is attributed to the presence of different non-conventional hydrogen bonds interactions as indicated by NCI and QTAIM analyses. Graphical Abstract.
Keywords: Cycloaddition; DFT calculations; MEDT; Mechanism; Reactivity; Selectivity.