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

A systematic matched molecular pair analysis of α-fluoroalkyl-substituted alicyclic amines (C₃–C₆ cycloalkanes and tetrahydropyran) and their benzamide models by benchmarking them against β- and γ-substituted analogs is reported. Experimentally obtained acidity and lipophilicity values (pK_a and LogP) 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 pK_a units per fluorine atom. Lipophilicity trends were more nuanced, yet α-substitution produces distinctive ΔLogP patterns consistent with competing inductive and local polarization effects near the amide fragment. Mapping the obtained dataset in LogP–pK_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-CF₃ 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.