亲核芳香族取代
化学
亲核细胞
动力学同位素效应
亲核取代
协同反应
计算化学
芳香性
亲电芳香族取代
自由基亲核芳香族取代
组合化学
有机化学
分子
氘
物理
量子力学
催化作用
作者
Eugene E. Kwan,Yanwei Zeng,Harrison A. Besser,Eric N. Jacobsen
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2018-07-16
卷期号:10 (9): 917-923
被引量:189
标识
DOI:10.1038/s41557-018-0079-7
摘要
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 12C/13C 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 19F 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.
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