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J Org Chem. 2008 Sep 19;73(18):7290-9. doi: 10.1021/jo801215z. Epub 2008 Aug 9.

Nucleophilicity and leaving-group ability in frontside and backside S(N)2 reactions.

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  • 1Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, Scheikundig Laboratorium der Vrije Universiteit, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands.


Nucleophilic substitution is ubiquitous in chemistry and well studied. Nucleophilicity and leaving-group ability have been related to various reactant properties, such as electronegativity, size, polarizability, and others. Yet, the state-of-the-art is to some extent still phenomenological. Here, we try to arrive at a straightforward, causal relationship between the reactants' electronic structure and their S(N)2 reactivity. To this end, we have explored the potential energy surfaces of the backside as well as frontside S(N)2 reactions of X(-) + CH3Y with X, Y = F, Cl, Br, and I, using relativistic density functional theory (DFT) at ZORA-OLYP/TZ2P. These explorations provide us with a consistent overview of trends, over a wide range of reactivities and pathways, which were analyzed using the activation strain model of chemical reactivity. A clear picture emerges from these analyses: nucleophilicity is determined by the electron-donor capability of the nucleophile (i.e., energy and shape of the X(-) np atomic orbital), and leaving-group ability derives directly from carbon-leaving group (C-Y) bond strength.

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