Toll Harrison W, Zhang Xiaoyi, Gao Tong, Dal Poggetto Guilherme, Reibarkh Mikhail, Lee Joshua J, Yang Katherine J, Kwan Eugene E, Turek Amanda K
Department of Chemistry, Williams College 47 Lab Campus Drive Williamstown Massachusetts 01267 USA
Analytical Research and Development, MRL, Merck & Co., Inc. Rahway New Jersey 07065 USA.
Chem Sci. 2025 Apr 30. doi: 10.1039/d5sc01856k.
Nucleophilic aromatic substitution (SAr) is a broadly used method for generating structural complexity in pharmaceuticals. Although SAr reactions were long assumed to be stepwise, recent kinetic isotope effect (KIE) studies have shown that many SAr reactions are actually concerted. However, it remains unclear how variations in substrate structure affect whether a reaction is stepwise, concerted, or borderline. In this paper, we show that reactions between indole and moderately electron-deficient aryl fluorides proceed by a borderline mechanism and are subject to general base catalysis. These findings are consistent with density functional theory (DFT) calculations, which also predict that borderline mechanisms are operative for a broad range of industrially relevant SAr reactions involving azole nucleophiles. The predicted transition structures vary smoothly independent of the mechanism, suggesting that these SAr reactions exist on a mechanistic continuum. The findings of widespread general base catalysis and a mechanistic continuum will guide future efforts to devise general models of SAr reactivity.
亲核芳香取代反应（SAr）是一种在药物中广泛用于产生结构复杂性的方法。尽管长期以来人们一直认为SAr反应是分步进行的，但最近的动力学同位素效应（KIE）研究表明，许多SAr反应实际上是协同进行的。然而，目前尚不清楚底物结构的变化如何影响反应是分步、协同还是介于两者之间。在本文中，我们表明吲哚与中等缺电子芳基氟化物之间的反应通过介于两者之间的机理进行，并受到广义碱催化。这些发现与密度泛函理论（DFT）计算结果一致，该计算还预测介于两者之间的机理适用于广泛的涉及唑类亲核试剂的工业相关SAr反应。预测的过渡结构与机理无关而平滑变化，这表明这些SAr反应存在于一个机理连续体上。广泛存在的广义碱催化和机理连续体的发现将指导未来设计SAr反应性通用模型的努力。
