Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 17, Pages 9401-9406Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202015614
Keywords
acidity; fluorine effect; monofluoromethylating reagents; nucleophilic monofluoromethylation
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Funding
- Natural Science Foundation of China [21933004, 21772098]
- Fundamental Research Funds for the Central Universities
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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.
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.
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