Concerted Nucleophilic Aromatic Substitutions

Nucleophilic aromatic substitution (S(N)Ar) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for S(N)Ar reactions involves a two-step addition–elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use (12)C/(13)C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical S(N)Ar reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of (19)F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C–F bonds.