Ávila Eloah P, de Almeida Mauro V, Pliego Josefredo R
Departamento de Ciências Naturais, Universidade Federal de São João del-Rei, São João del-Rei, MG 36301-160, Brazil.
Departamento de Química, Universidade Federal de Juiz de Fora, Campus Universitário, Martelos, Juiz de Fora, MG 36036-330, Brazil.
ACS Omega. 2025 Jul 16;10(29):32372-32383. doi: 10.1021/acsomega.5c04699. eCollection 2025 Jul 29.
Nucleophilic fluorination of primary alkyl halides using KF salt and catalyzed and mediated by crown ether and bulky alcohols is an established method for monofluorination of organic compounds. However, in the presence of a small concentration of water molecules in the organic solvent, alcohol side products are formed. This is an intriguing finding because water molecules are unreactive toward the S2 reaction. Further, the formation of a hydroxide ion via deprotonation of water by the fluoride ion faces the problem of very different p values in acetonitrile solution, which were calculated to be 19.5 for HF and 41.9 for HO. This work explores the mechanism behind this side reaction via theoretical calculations and experiments. We found that the deprotonation of HO is driven by the formation of the stable HF ion, leading to the small concentration of the KOH-(18-crown-6) complex. This species exhibits higher reactivity compared to the KF-(18-crown-6) complex in the S2 process, which offsets its lower concentration and results in a competitive side reaction. Thus, the present study elucidates the mechanism involved in the alcohol side product formation and indicates that the presence of the KHF(18-crown-6) complex can inhibit this side reaction. Furthermore, this work indicates that complex reaction systems require an analysis beyond the comparative barriers in the free energy profile, and multiple equilibria must be accounted for.
使用KF盐并由冠醚和体积较大的醇催化及介导的伯烷基卤化物的亲核氟化反应是有机化合物单氟化的一种既定方法。然而，在有机溶剂中存在低浓度水分子的情况下，会形成醇类副产物。这是一个有趣的发现，因为水分子对S2反应没有反应活性。此外，通过氟离子使水去质子化形成氢氧根离子面临着乙腈溶液中p值差异极大的问题，计算得出HF的p值为19.5，HO的p值为41.9。这项工作通过理论计算和实验探索了这种副反应背后的机理。我们发现HO的去质子化是由稳定的HF离子的形成驱动的，导致形成低浓度的KOH-(18-冠-6)络合物。在S2过程中，该物种与KF-(18-冠-6)络合物相比表现出更高的反应活性，这抵消了其较低的浓度并导致竞争性副反应。因此，本研究阐明了醇类副产物形成所涉及的机理，并表明KHF(18-冠-6)络合物的存在可以抑制这种副反应。此外，这项工作表明复杂的反应体系需要超越自由能分布中比较势垒的分析，并必须考虑多个平衡。
