Department of Organic Chemistry, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
Schulich Faculty of Chemistry Technion, Israel Institute of Technology, Technion City, Haifa 3200008, Israel.
J Med Chem. 2021 Apr 22;64(8):4516-4531. doi: 10.1021/acs.jmedchem.0c01868. Epub 2021 Apr 12.
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.
描述了通过引入氟官能团来调节各种功能基团（FGs）的氢键碱性（p）及其对亲脂性和生物等排体考虑的影响。一般来说，H/F 在氢键受体的α-位取代会导致 p 值降低，在许多情况下会导致化合物亲脂性（logP）的急剧增加。在 α-CFH 的情况下，我们发现这些性质也可能受到 CFH 和 FG 之间的分子内氢键的影响。酮和砜系列的计算研究表明，α-氟化可显著影响整体极性、电荷分布和构象偏好。独特的 α-二氟和三氟甲基酮的情况是，它们在辛醇/水相中以酮、半缩酮和偕二醇形式处于平衡状态，这阻止了常规方法直接进行 log 值的测定，因此，首次使用 Linclau 的基于 F NMR 的方法直接确定了这些物质的特定 log 值。
