Revealing the Mechanism of Alcohol Side Product Formation in Crown Ether-Mediated Nucleophilic Fluorination Using Acetonitrile as Solvent.

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 SN2 reaction. Further, the formation of a hydroxide ion via deprotonation of water by the fluoride ion faces the problem of very different pK a values in acetonitrile solution, which were calculated to be 19.5 for HF and 41.9 for H2O. This work explores the mechanism behind this side reaction via theoretical calculations and experiments. We found that the deprotonation of H2O is driven by the formation of the stable HF2 - 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 SN2 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 KHF2(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.