A mechanistic continuum of nucleophilic aromatic substitution reactions with azole nucleophiles

Nucleophilic aromatic substitution (S_NAr) is a broadly used method for generating structural complexity in pharmaceuticals. Although S_NAr reactions were long assumed to be stepwise, recent kinetic isotope effect (KIE) studies have shown that many S_NAr 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 S_NAr reactions involving azole nucleophiles. The predicted transition structures vary smoothly independent of the mechanism, suggesting that these S_NAr 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 S_NAr reactivity.