Origin of the alpha-effect in S(N)2 reactions

Abstract

The alpha-effect is a term used to explain the dramatically enhanced reactivity of alpha-nucleophiles (R-Y-X:(-)) compared to their parent normal nucleophile (R-X:(-)) by deviating from the classical Bronsted-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 alpha-effect of a set of anionic nucleophiles, including O-, N- and S-based normal and alpha-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 alpha-nucleophile needs to fulfill in order to show alpha-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 alpha-effect or inverse alpha-effect.