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 SN2 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.
Bibliographical noteFunding Information:
This work was supported by the Netherlands Organization for Scientific Research (NWO) and the Dutch Astrochemistry Network (DAN) for financial support. We thank Pieter C. M. Laan for exploring the viability of this project.
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- activation strain model
- density functional calculations