Modulation of the H-Bond Basicity of Functional Groups by α-Fluorine-Containing Functions and its Implications for Lipophilicity and Bioisosterism

Abstract

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.

Relating Conformational Equilibria to Conformer‐Specific Lipophilicities: New Opportunities in Drug Discovery

“…In addition, knowledge of logp values can guide structural modifications to optimize the lipophilicity of the bioactive conformation. The K-p relationship also shows how conformer-specific lipophilicity values can be independently obtained from the macroscopic lipophilicity and the phase-specific conformer equilibrium constants, while for specific cases involving slow chemical exchange of the species in solution, direct, straightforward measurement of conformer specific lipophilicities by our 19 F NMR based method is possible. This is the first time that direct logp measurement has been demon- strated.…”

“…The ρ and K determinations require assignment of each fluorine signal in each phase to a particular rotamer, as it was observed that the relative position of cis-and transamide rotamer resonances in the 19 F NMR spectrum in octanol was not always the same as that in water. Conformer signal assignment in the water phase is easily accomplished by a control experiment using (octanol-saturated) D 2 O by standard NOESY analysis combined with peak integration (see Supporting Information).…”

“…The presence of conformational equilibria distinguishes logp from logP optimization, and on this basis we propose a specific strategy towards optimizing microscopic lipophilicities. This is exemplified with a direct and convenient measurement of conformer-specific lipophilicities using our 19 F NMR based logP determination procedure, [18] which is possible when conformers have observable and different 19 F chemical shift values. Recently, Zafrani et al reported the logP determination of trifluoromethyl ketones and their hydrates using this NMR method, which is based on the same principle.…”

“…Recently, Zafrani et al reported the logP determination of trifluoromethyl ketones and their hydrates using this NMR method, which is based on the same principle. [19] The principle of the strategy for logp optimization, and of the direct logp measurement, is illustrated for amide rotamers (Figure 2) in slow exchange in solution, where each rotamer signal can be integrated directly. This constitutes a system with four coupled equilibria of conformers between (refers to p) and within (refers to K) the two phases (Figure 2A).…”

“…This constitutes a system with four coupled equilibria of conformers between (refers to p) and within (refers to K) the two phases (Figure 2A). Our lipophilicity measurement procedure [18] involves acquiring a 19 F NMR spectrum of each phase after phase separation (Figure 2B), and measuring integration relative to an added internal reference. Three peaks are observed: one corresponding to the reference, and two corresponding to each amide rotamer.…”