The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous α-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 α-fluorine substitution effect on the α-C_sp3-H acidity. We have experimentally measured the pK_a values of a series of popular nucleophilic monofluoromethylating reagents α-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 α-fluorine substituent does not generally enhance but rather weaken the α-C_sp3-H acidity of most (phenylsulfonyl)methane derivatives. DFT computations reproduce and provide insight into the anomalous α-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.