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

Herein,
detailed mechanistic investigations into formamide-catalyzed
nucleophilic substitution (SN) 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 11B NMR spectroscopy
and their catalytic activity in SN-transformations.
The observed difference in catalytic ability was attributed to the
natural bond order charge, dipole moment, and Sterimol parameter B5. Importantly, this rationalization enables the prediction
of the capacity of formamides to promote SN-type transformations in general.