Modulation of the H-Bond Basicity of Functional Groups by α-Fluorine-Containing Functions and its Implications for Lipophilicity and Bioisosterism
Yossi Zafrani, Galit Parvari, Dafna Amir, Lee Ghindes‐Azaria, Shlomi Elias, Alexander Pevzner, G. Fridkin, Anat Berliner, Eytan Gershonov, Yoav Eichen, Sigal Saphier, Shahaf Katalan
Abstract
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.