The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous alpha-Fluorine Effect

Fluorine incorporation into organic molecules is expected to lower the pK(a) of neighboring functionality via its strong electron-withdrawing effect, and this strategy has been widely exploited in diverse disciplines. Herein, we report a striking anomalous alpha-fluorine substitution effect on the alpha-C-sp3-H acidity. We have experimentally measured the pK(a) values of a series of popular nucleophilic monofluoromethylating reagents alpha-fluoro(phenylsulfonyl)methane derivatives as well as their C-H analogues by Bordwell's overlapping indicator method in dimethyl sulfoxide solution. Contrary to expectations, we found that alpha-fluorine substituent does not generally enhance but rather weaken the alpha-C-sp3-H acidity of most (phenylsulfonyl)methane derivatives. DFT computations reproduce and provide insight into the anomalous alpha-fluorine effect. A correlation was identified between the C-H pK(a) of (phenylsulfonyl)methane derivatives and Mayr's nucleophilicity parameter (N) of the corresponding carbanions.

Automated summary

This study reveals that despite the expected enhancement of acidity by fluorine on alpha-C-sp3-H, in reality, it often weakens the acidity of most (phenylsulfonyl)methane derivatives. Density functional theory computations were able to reproduce and provide insight into this anomalous alpha-fluorine effect, correlating the C-H pK(a) values of (phenylsulfonyl)methane derivatives with Mayr's nucleophilicity parameter (N) of the corresponding carbanions.