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The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous α‐Fluorine Effect
Author(s) -
Zheng Hanliang,
Li Zhen,
Jing Jianfang,
Xue XiaoSong,
Cheng JinPei
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202015614
Subject(s) - chemistry , fluorine , nucleophile , carbanion , reagent , substituent , medicinal chemistry , computational chemistry , methane , dimethyl sulfoxide , nucleophilic substitution , organic chemistry , catalysis
Fluorine incorporation into organic molecules is expected to lower the p K 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 p K 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 p K a of (phenylsulfonyl)methane derivatives and Mayr's nucleophilicity parameter ( N ) of the corresponding carbanions.