Synthesis, Physicochemical Properties, and Computational Analysis of Tris(fluoromethyl)Alkyl Building Blocks

A concise and scalable synthesis of tris(fluoromethyl)alkyl-building blocks (including amines, carboxylic acids, alcohols, and bromides) starting from commercially available 3,3-bis(bromomethyl)oxetane is reported. Comprehensive physicochemical profiling of the corresponding amines and carboxylic acids (by measuring their pK_a and LogP values), benchmarked against less fluorinated and nonfluorinated counterparts, showed that the tris(fluoromethyl)methyl (β,β′,β′′-trifluro-tert-butyl, (FCH₂)₃C, TFTB) group mimics the electronic and polarity-modulating properties of CF₃ and CF₃CH₂ substituents despite substantially larger steric volume. Conformational analysis shows that the (FCH₂)₃C group adopts a restricted set of low-energy conformations governed by through-space electrostatic interactions, with C═O···H─C and C─F···H─C contacts playing a crucial stabilizing role. Molecular electrostatic potential analysis rationalizes both the anomalous lipophilicity trends and the CF₃-like polarity modulation of this group. Together, these data confirm the TFTB group as a valuable motif for isosteric replacement in drug design.