Physicochemical Properties of α‐Fluoroalkyl‐Substituted Cycloalkylamines and Amino Acids

A systematic matched molecular pair analysis of α‐fluoroalkyl‐substituted alicyclic amines (C 3 –C 6 cycloalkanes and tetrahydropyran) and their benzamide models by benchmarking them against β‐ and γ‐substituted analogs is reported. Experimentally obtained acidity and lipophilicity values (p K a and Log P ) revealed an exceptionally strong and predictable impact of α‐fluoroalkyllation on the acid–base properties of the amine moiety with an approximately additive contribution of 1.6 ± 0.1 p K a units per fluorine atom. Lipophilicity trends were more nuanced, yet α‐substitution produces distinctive ΔLog P patterns consistent with competing inductive and local polarization effects near the amide fragment. Mapping the obtained dataset in Log P– p K a space highlights the cluster‐type localization of the various fluoroalkylated patterns, enabling property tuning via isosteric substitutions. Finally, multigram‐scale access to diastereopure α‐CF 3 cycloalkyl amino acids was proposed along with quantification of their ionization profiles, supporting application of these scaffolds as versatile fluorinated building blocks for drug discovery.