Regioselectivity of Epoxide Ring-Openings via SN2 Reactions Under Basic and Acidic Conditions

Thomas Hansen, Pascal Vermeeren, Anissa Haim, Maarten J.H. van Dorp, Jeroen D.C. Codée, F. Matthias Bickelhaupt*, Trevor A. Hamlin

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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 Cβ. 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)2Cα–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.

Original languageEnglish
Pages (from-to)3822-3828
Number of pages7
JournalEuropean Journal of Organic Chemistry
Issue number25
Early online date28 May 2020
Publication statusPublished - 7 Jul 2020


  • Activation strain model
  • Density functional calculations
  • Epoxides
  • Nucleophilic substitution
  • Reactivity


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