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Concerted nucleophilic aromatic substitutions
Nature Chemistry ( IF 21.8 ) Pub Date : 2018-07-16 , DOI: 10.1038/s41557-018-0079-7
Eugene E. Kwan , Yuwen Zeng , Harrison A. Besser , Eric N. Jacobsen

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.



中文翻译:

一致的亲核芳香取代

亲核芳香取代(S Ñ AR)是在医药和化学研究中最广泛采用的反应类之一,为芳香环的支架的变形例提供广泛有用的平台。S N Ar反应的公认机理包括通过离散的,非芳香族的Meisenheimer配合物进行两步加成-消除序列。在这里,我们使用12 C / 13 C动力学同位素效应(KIE)研究和计算分析来提供证据,证明典型的S N Ar反应实际上是通过协同机制进行的。通过利用19的高灵敏度的新技术使KIE测量成为可能F作为NMR核来定量同位素分馏的程度。这种灵敏的技术允许在一整夜的采集中测量10 mg天然丰度物质上的KIE。结果,它提供了一种实用的工具,可以对形成或破坏CF键的反应进行详细的机理分析。

更新日期:2018-07-18
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