Formamide-Catalyzed Nucleophilic Substitutions: Mechanistic Insight and Rationalization of Catalytic Activity

Herein, detailed mechanistic investigations into formamide-catalyzed nucleophilic substitution (S-N) of alcohols are reported. Alkoxyiminium chlorides and hexafluorophosphates were synthesized and characterized as a key intermediate of the catalytic cycle. The determination of reaction orders and control experiments indicated that the nucleophilic attack of the formamide catalyst onto the reagent BzCl is the rate-determining step. Linear free energy relationship revealed a correlation between the quantified Lewis basicity strength of formamides by means of B-11 NMR spectroscopy and their catalytic activity in S-N-transformations. The observed difference in catalytic ability was attributed to the natural bond order charge, dipole moment, and Sterimol parameter B-5. Importantly, this rationalization enables the prediction of the capacity of formamides to promote S-N-type transformations in general.