CF2H, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH3?

Abstract

The effects of the CF₂H 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 CF₂H group acts as a HB donor with a strong dependence on the attached functional group ( A = 0.035-0.165). Regarding lipophilicity, the CF₂H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH₃, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH₃/CF₂H 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.