A mechanistic continuum of nucleophilic aromatic substitution reactions with azole nucleophiles

• Published in: Chemical science (Cambridge) Vol. 16; no. 22; pp. 10019 - 10029
• Main Authors: Toll, Harrison W., Zhang, Xiaoyi, Gao, Tong, Dal Poggetto, Guilherme, Reibarkh, Mikhail, Lee, Joshua J., Yang, Katherine J., Kwan, Eugene E., Turek, Amanda K.
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 04.06.2025; The Royal Society of Chemistry
• Subjects: Catalysis; Chemistry; Density functional theory; Fluorides; Isotope effect; Nucleophiles; Substitution reactions
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/D5SC01856K

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