Revised mechanistic explanation for the alcohol-promoted amination of benzylic fluorides under highly concentrated conditions: Computational and experimental evidence on a model substrate

•The alcohol-promoted nucleophilic substitution of benzylic fluorides has been studied.•The reaction is very tolerant of variations on the promoting alcohol.•An updated mechanistic proposal is given.•Catalytic use of alcohol promoters is possible.

The nucleophilic substitution of a benzylic fluoride by morpholine promoted by alcohols in neutral conditions has been studied extensively by DFT calculations and structure–activity analysis. This CF activation strategy is possible through hydrogen-bond donation from the alcohol. The experiments demonstrate that this reaction is very tolerant of variations on the promoting alcohol, yet some activators are significantly weaker. These results were supported by DFT calculations, which indicate that three OH groups around the fluorine atom at the transition-state are better to activate the CF bond, but only two of them can originate from a single triol molecule, at least for the triol under study. A revised mechanistic explanation has been proposed and provides a better understanding of experimental results. Finally, the use of a catalytic amount of triol was also investigated.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide