Modulation of the H‑Bond Basicity of Functional Groups by α‑Fluorine-Containing Functions and its Implications for Lipophilicity and Bioisosterism

Modulation
of the H-bond basicity (pKHB) of various
functional groups (FGs) by attaching fluorine functions
and its impact on lipophilicity and bioisosterism considerations are
described. In general, H/F replacement at the α-position to
H-bond acceptors leads to a decrease of the pKHB value, resulting, in many cases, in a dramatic increase
in the compounds’ lipophilicity (log Po/w). In the case of α-CF2H, we found
that these properties may also be affected by intramolecular H-bonds
between CF2H and the FG. A computational study of ketone
and sulfone series revealed that α-fluorination can significantly
affect overall polarity, charge distribution, and conformational preference.
The unique case of α-di- and trifluoromethyl ketones, which
exist in octanol/water phases as ketone, hemiketal, and gem-diol forms,
in equilibrium, prevents direct log Po/w determination by conventional methods, and therefore, the
specific log Po/w values of these
species were determined directly, for the first time, using Linclau’s 19F NMR-based method.