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.