Concerted nucleophilic aromatic substitutions

• Published in: Nature chemistry Vol. 10; no. 9; pp. 917 - 923
• Main Authors: Kwan, Eugene E., Zeng, Yuwen, Besser, Harrison A., Jacobsen, Eric N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 639/638/403/934; 639/638/563/606; Analytical Chemistry; Benzene Derivatives - chemistry; Biochemistry; Carbon - chemistry; Carbon Isotopes - chemistry; Chemical research; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Computer applications; Fluorine - chemistry; Fractionation; Inorganic Chemistry; Isotope effect; Isotope fractionation; Isotope Labeling; Isotopes; Kinetics; Magnetic Resonance Spectroscopy; NMR; Nuclear magnetic resonance; Organic Chemistry; Physical Chemistry; Substitution reactions
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-018-0079-7

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. Nucleophilic aromatic substitution reactions have long been thought to occur primarily via stepwise mechanisms. New and sensitive methodology for measuring carbon kinetic isotope effects now shows that most such substitutions actually occur through concerted mechanisms.