Mechanism and Origin of Regioselectivity in the Phosphine-Catalyzed Heine Reaction

Herein, we present a comprehensive computational study of the reaction mechanism and regioselectivity patterns of the phosphine-catalyzed Heine reaction involving <i>N</i>-benzoylaziridines. Density functional theory (DFT) calculations reveal that the regioselectivity of the process takes place under kinetic control, favoring the formation of the corresponding 4-substituted oxazoline derivatives. Conformational analysis indicates that the predominantly populated ground-state conformation of aziridine does not represent the kinetically active species. Exploration of the conformational space in the transition state (TS) region shows that the preferred pathway for the nucleophilic ring-opening process involves a TS structure where the benzoyl moiety adopts a nearly coplanar arrangement. Furthermore, the main factors controlling the observed regioselectivity as well as the impact of substituents on the reactivity, are quantitatively rationalized using the activation strain model of reactivity in combination with energy decomposition analysis.