Origin of the α‐Effect in S(N)2 Reactions

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.