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 (p) 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 p value, resulting, in many cases, in a dramatic increase in the compounds' lipophilicity (log ). In the case of α-CFH, we found that these properties may also be affected by intramolecular H-bonds between CFH 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 determination by conventional methods, and therefore, the specific log values of these species were determined directly, for the first time, using Linclau's F NMR-based method.