CF 2 H, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH 3 ?

The effects of the CF 2 H moiety on H-bond (HB) acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers, or electron-withdrawing groups, are discussed. It was found that the CF 2 H group acts as a HB donor with a strong dependence on the attached functional group ( A = 0.035–0.165). Regarding lipophilicity, the CF 2 H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH 3, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH 3 /CF 2 H exchange at the α position. Interestingly, this exchange significantly affects not only the polarity and the volume of the solutes but also their HB-accepting ability, the main factors influencing log P oct . Accordingly, this study may be helpful in the rational design of drugs containing this moiety.