TY - JOUR
T1 - Regioselectivity of Epoxide Ring-Openings via SN2 Reactions Under Basic and Acidic Conditions
AU - Hansen, Thomas
AU - Vermeeren, Pascal
AU - Haim, Anissa
AU - van Dorp, Maarten J.H.
AU - Codée, Jeroen D.C.
AU - Bickelhaupt, F. Matthias
AU - Hamlin, Trevor A.
PY - 2020/7/7
Y1 - 2020/7/7
N2 - 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.
AB - 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.
KW - Activation strain model
KW - Density functional calculations
KW - Epoxides
KW - Nucleophilic substitution
KW - Reactivity
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U2 - 10.1002/ejoc.202000590
DO - 10.1002/ejoc.202000590
M3 - Article
AN - SCOPUS:85087182628
VL - 2020
SP - 3822
EP - 3828
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
SN - 1434-193X
IS - 25
ER -