A mechanistic continuum of nucleophilic aromatic substitution reactions with azole nucleophiles.

Nucleophilic aromatic substitution (SAr) is a broadly used method for generating structural complexity in pharmaceuticals. Although SAr reactions were long assumed to be stepwise, recent kinetic isotope effect (KIE) studies have shown that many SAr reactions are actually concerted. However, it remains unclear how variations in substrate structure affect whether a reaction is stepwise, concerted, or borderline. In this paper, we show that reactions between indole and moderately electron-deficient aryl fluorides proceed by a borderline mechanism and are subject to general base catalysis. These findings are consistent with density functional theory (DFT) calculations, which also predict that borderline mechanisms are operative for a broad range of industrially relevant SAr reactions involving azole nucleophiles. The predicted transition structures vary smoothly independent of the mechanism, suggesting that these SAr reactions exist on a mechanistic continuum. The findings of widespread general base catalysis and a mechanistic continuum will guide future efforts to devise general models of SAr reactivity.