Concerted nucleophilic aromatic substitutions

Nucleophilic aromatic substitution (SNAr) 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 SNAr reactions involves a two-step addition-elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use C-12/C-13 kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of F-19 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.