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

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 Poct. Accordingly, this study may be helpful in the rational design of drugs containing this moiety.本文探讨了二氟甲基（CF2H）基团直接连接于芳香环或烷基、醚/硫醚、吸电子基团等官能团时，对各类化合物氢键（HB）酸度与亲脂性的影响。研究发现，CF2H基团可作为氢键供体，其供体能力与所连接的官能团密切相关（A=0.035~0.165）。就亲脂性而言，当CF2H基团连接至芳香环或烷基时，其可作为亲脂性更强的羟基（OH）生物电子等排体，而分别作为与巯基（SH）、甲基（CH3）亲脂性相近或更低的生物电子等排体。此外，在α位发生甲基（CH3）与CF2H基团的交换后，醚类、亚砜类及砜类化合物的亲脂性会显著提升。值得注意的是，该交换不仅会显著影响溶质的极性与体积，还会改变其氢键受体能力——而这些正是影响正辛醇-水分配系数（log Poct）的核心因素。因此，本研究可为含该基团的药物合理设计提供有益参考。