Quantitative Evaluation of Fluoroalkyl Anion Donor Abilities of Nucleophilic Fluoroalkylating Reagents

ABSTRACT A quantitative understanding of the ability of nucleophilic fluoroalkylating reagents to donate fluoroalkyl anions (–C n F 2n+1 or – CF 2 H) remains elusive, limiting predictive reaction design. Here, we report a systematic investigation of fluoroalkyl anion donor ability based on computed X–R f bond heterolytic dissociation enthalpies via density functional theory (DFT). Across a diverse set of reagents, the intrinsic thermodynamic cost of fluoroalkyl anion release spans a wide range (21.5–221.8 kcal mol − 1 ), but is dramatically reduced in the presence of activators, with effective donor abilities varying from strongly endergonic to exergonic regimes (−20.1–34.8 kcal mol − 1 ). This work establishes a quantitative fluoroalkyl anion donor ability scale that correlates well with experimental observations and offers an in‐depth mechanistic understanding of the factors regulating fluoroalkyl transfer. The quantitative scale developed herein enables direct comparison across reagent classes and offers a predictive basis for the rational design of nucleophilic fluoroalkylation reactions.