Unraveling the α-effect in α-fluorinated carbanionic nucleophiles: origins and synthetic implications†

Abstract

The α-effect refers to the dramatically enhanced reactivity of α-nucleophiles bearing a heteroatom with an adjacent lone-pair (R–Y–X:⁻) compared to normal nucleophiles (R–X:⁻), as predicted by Brønsted-type correlation. Despite extensive research, the underlying mechanisms of this phenomenon remain debated, and previous studies have predominantly focused on O-, N-, and S-based nucleophiles, leaving carbanions—key intermediates in organic synthesis—comparatively underexplored. Here, we present an in-depth computational investigation into the intriguing influence of α-fluorine substitution on carbanion nucleophilicity. Despite fluorine's strong electron-withdrawing capability, our results reveal that α-fluorocarbanions could exhibit the α-effect when they satisfy Hamlin's two criteria originally proposed for heteroatom-based anionic α-nucleophiles. This study extends the scope of the α-effect from heteroatom-based nucleophiles to carbanionic nucleophiles, offering new insights into this fundamental chemical phenomenon.