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Origin of the α‐Effect in S N 2 Reactions
Author(s) -
Hansen Thomas,
Vermeeren Pascal,
Bickelhaupt F. Matthias,
Hamlin Trevor A.
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202106053
Subject(s) - nucleophile , homo/lumo , reactivity (psychology) , chemistry , steric effects , pauli exclusion principle , density functional theory , computational chemistry , molecular orbital , medicinal chemistry , stereochemistry , catalysis , physics , molecule , quantum mechanics , organic chemistry , medicine , alternative medicine , pathology
The α‐effect is a term used to explain the dramatically enhanced reactivity of α‐nucleophiles (R−Y−X: − ) compared to their parent normal nucleophile (R−X: − ) by deviating from the classical Brønsted‐type reactivity‐basicity relationship. The exact origin of this effect is, however, still heavily under debate. In this work, we have quantum chemically analyzed the α‐effect of a set of anionic nucleophiles, including O ‐, N ‐ and S ‐based normal and α‐nucleophiles, participating in an S N 2 reaction with ethyl chloride using relativistic density functional theory at ZORA‐OLYP/QZ4P. Our activation strain and Kohn–Sham molecular orbital analyses identified two criteria an α‐nucleophile needs to fulfill in order to show α‐effect: (i) a small HOMO lobe on the nucleophilic center, pointing towards the substrate, to reduce the repulsive occupied–occupied orbital overlap and hence (steric) Pauli repulsion with the substrate; and (ii) a sufficiently high energy HOMO to overcome the loss of favorable HOMO–LUMO orbital overlap with the substrate, as a consequence of the first criterion, by reducing the HOMO–LUMO orbital energy gap. If one of these two criteria is not fulfilled, one can expect no α‐effect or inverse α‐effect.