There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCFH) - log P(XCH)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.

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.

Modulation of the H-bond basicity (pK HB) 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 pK HB value, resulting, in many cases, in a dramatic increase in the compounds’ lipophilicity (log P o/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 P o/w determination by conventional methods, and therefore, the specific log P o/w values of these species were determined directly, for the first time, using Linclau’s 19F NMR-based method.

Recent years have witnessed a growing interest in the development of novel synthetic methods and new reagents for the synthesis of difluoromethylated compounds. Dozens of studies have been published on this topic each year over the past few years. These studies are focused on direct and indirect difluoromethylation of various organic functionalities via nucleophilic-, electrophilic-, radical-, carbene- or metal-mediated mechanisms. The present short review covers the very recent studies, published between mid-2017 and early 2019, on the synthesis of compounds containing a CF2H group. A brief summary of the physicochemical properties and medicinal applications of difluoromethylated compounds is also included.1 Introduction2 Nucleophilic Difluoromethylation2.1 Metal-Mediated Nucleophilic Difluoromethylation2.2 Non-Metal Difluoromethyl Nucleophiles3 Radical Difluoromethylation3.1 Metal-Induced Radical Difluoromethylation3.2 Non-Metal-Induced Radical Difluoromethylation3.3 Electrochemically Induced Radical Difluoromethylation4 Carbene-Based Difluoromethylation4.1 Metal-Induced Carbene Difluoromethylation4.2 Non-Metal-Induced Difluoromethyl Carbenes5 Cross-Coupling Difluoromethylation5.1 Palladium-Catalyzed Difluoromethylation5.2 Nickel-Catalyzed Difluoromethylation5.3 Copper-Mediated Difluoromethylation5.4 Iron-Catalyzed Difluoromethylation5.5 Gold-Mediated Difluoromethylation6 Electrophilic Difluoromethylation7 Other Examples7.1 A Difluoromethyl-Borane Complex7.2 A Tellurium Difluoromethyl Derivative8 Summary

A practical, convenient, and general method for the difluoromethylation of tertiary amines, using diethyl bromodifluoromethylphosphonate and fluoride, is described. This commercially available phosphonate smoothly reacts with a fluoride ion to liberate a difluorocarbene intermediate that in the presence of a proton source and a tertiary amine generates the corresponding α-difluoromethylammonium compound in good to excellent yields. Despite the involvement of a difluorocarbene intermediate, this difluoromethylation occurs almost exclusively on the nitrogen atom with diverse molecular structures, including drugs, surfactants, chiral phase transfer catalysts, polymers, ionic liquids, and other fine chemicals. A preliminary assessment of the effects that an α-difluoromethyl groupT has on hydrogen bonding and logP of quaternary ammonium salts is also described.