Regioselectivity of Epoxide Ring-Openings via S_N2 Reactions Under Basic and Acidic Conditions

We have quantum chemically analyzed the ring-opening reaction of the model non-symmetrical epoxide 2,2-dimethyloxirane under basic and acidic conditions using density functional theory at OLYP/TZ2P. For the first time, our combined activation strain and Kohn–Sham molecular orbital analysis approach have revealed the interplay of physical factors that control the regioselectivity of these chemical reactions. Ring-opening under basic conditions occurs in a regime of strong interaction between the nucleophile (OH^–) and the epoxide and the interaction is governed by the steric (Pauli) repulsion. The latter steers the attack preferentially towards the sterically less encumbered C^β. Under acidic conditions, the interaction between the nucleophile (H₂O) and the epoxide is weak and, now, the regioselectivity is governed by the activation strain. Protonation of the epoxide induces elongation of the weaker (CH₃)₂C^α–O bond, and effectively predistorts the substrate for the attack at the sterically more hindered side, which goes with a less destabilizing overall strain energy. Our quantitative analysis significantly builds on the widely accepted rationales behind the regioselectivity of these ring-opening reactions and provide a concrete framework for understanding these indispensable textbook reactions.