近日，英国牛津大学Véronique Gouverneur团队报道了氟化钾催化醇的Appel氟化反应。相关论文发表在2026年7月30日出版的《科学》杂志上。

Appel卤化反应广泛用于将醇转化为烷基卤化物，但该方法不适用于制备烷基氟化物，因为氟离子会被以二氟磷烷的形式捕获。

研究组引入了实验室稳定的新戊氧基鏻盐，以解决这一长期存在的难题。利用这些试剂，多种醇可在氢键相转移催化条件下与氟化钾发生氟化反应，该反应体系为实现醇的对映选择性氟化提供了一条途径。机理方面，反应首先形成新戊氧基氟磷烷，该中间体优先与醇底物发生可逆交换，而非生成二氟磷烷。

催化剂有助于氟化钾的溶解以及磷–氟键的解离，从而促使烷氧基鏻氟离子对发生构型翻转的氟化反应。催化循环的周转得益于催化剂对氟离子的结合能力强于对反应副产物氧化膦的结合，而氧化膦可作为合成鏻盐试剂的起始原料进行回收利用。

附：英文原文

Title: Catalytic Appel fluorination of alcohols with potassium fluoride

Author: Anirban Mondal, Job J. C. Struijs, Caleb J. N. Doyle, Zijun Chen, Zian Wang, Worawit Tangamornchaipattana, Christophe Allais, Paul F. Richardson, Jared Piper, Robert S. Paton, Simon Aldridge, Véronique Gouverneur

Issue&Volume: 2026-07-30

Abstract: Appel halogenation reactions are widely used to convert alcohols to alkyl halides but are not suitable to prepare alkyl fluorides because fluoride is sequestered as a difluorophosphorane. In this work, we introduce bench-stable neopentoxyphosphonium salts to solve this enduring challenge. With these reagents, various alcohols undergo fluorination with potassium fluoride under hydrogen bonding phase-transfer catalysis, a manifold offering a pathway to enantioselective fluorination of alcohols. Mechanistically, a neopentoxyfluorophosphorane is formed, which undergoes reversible exchange with the alcohol substrate in preference to difluorophosphorane formation. The catalyst assists with potassium fluoride solubilization and with phosphorus–fluorine bond dissociation, leading to the alkoxyphosphonium fluoride ion pair undergoing stereoinvertive fluorination. Turnover results from stronger binding of the catalyst to fluoride than phosphine oxide, the by-product of the reaction, which is recyclable as starting material for the synthesis of the phosphonium reagents.

DOI: aec6298

Source: https://www.science.org/doi/10.1126/science.aec6298