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.

Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on 31P-NMR spectroscopy. The log P values measured ranged between −3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pK HB) measurements of selected compounds. Clear signal separation in 31P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to −250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and 31P-NMR analysis.

Fluorine atoms play an important role in all branches of chemistry and accordingly, it is very important to study their unique and varied effects systematically, in particular, the structure-physicochemical properties relationship. The present study describes exceptional physicochemical effects resulting from a H/F exchange at the methylene bridge of gem-difunctional compounds. The Δlog P (CF2-CH2) values, that is, the change in lipophilicity, observed for the CH 2 /CF 2 replacement in various α,α-phenoxyand thiophenoxy-esters/amides, diketones, benzodioxoles and more, fall in the range of 0.6-1.4 units, which for most cases, is far above the values expected for such a replacement. Moreover, for compounds holding more than one such gem-difunctional moiety, the effect is nearly additive, so one can switch from a hydrophilic compound to a lipophilic one in a limited number of H/F exchanges. DFT studies of some of these systems revealed that polarity, conformational preference as well as charge distributions are strongly affected by such hydrogen to fluorine atom substitution. The pronounced effects described, are a result of the interplay between changes in polarity, H-bond basicity and molecular volume, which were obtained with a very low 'cost' in terms of molecular weight or steric effects and may have a great potential for implementation in various fields of chemical sciences.

The conformation and motions of organic chains bound to the surface of MCM41-type mesoporous silica materials are investigated in molecular detail. 2D heteronuclear correlation measurements in conjunction with relaxation measurements are used to infer both the orientation and the motions of the organic chains on the silica surface. In octyl-MCM41, proximity of octyl tether carbons to silanols is observed with the exception of the terminal carbons, pointing to slight chain bending which positions the center carbons in the chain closer to neighboring silanols. In aminopropyl-MCM41, the carbon directly bound to the amine group is the closest to silanol protons and physisorbed water protons, indicating a tilted orientation of the tail allowing for the amine group to interact with the silanol. Motions in the two chains are characterized by using 13C longitudinal and rotating frame relaxation measurements. Substantial differences in the T 1 and T 1ρ times of the two materials are shown to be the result of differences in activation energy for respective rotation and libration motions between the two materials. The shorter tether in aminopropyl-MCM41, characterized by larger kinetic barriers for libration motions, demonstrates higher chain rigidity. The longer chain in octyl-MCM41 is characterized by faster librations and slower bond rotations in the center carbons. Evidence from structural and dynamical data jointly provides a detailed view of the chain behavior and underscores differences in the physical properties of the two tethers bound to the MCM41-type surface.

The solvolysis of the extremely toxic nerve agent VX and its derivatives ((OEt)MeP(O)LG, LG is leaving group), promoted by nucleophiles such as fluoride, hydroxide/water or methoxide/ methanol, revealed major differences in both reaction rates and products distribution. To rationalize these differences, which are of high relevance for different issues such as toxicity, persistence and decontamination of V-type nerve agents, we conducted a combined experimental and computational (DFT) study on a series of derivatives in which only the LG was varied (O/S, N/C and more replacements). Experimentally, a high dependence of these solvolysis reactions on the LG's nature, mainly its pKa value and the presence of β-amine moiety was observed. The DFT calculations showed that the transition states energies for P-LG bond cleavage, by fluoride or hydroxide are roughly similar for PÀ S scission while for PÀ O cleavage sharp difference was observed in favor of hydroxide. This LG's effect was also found to be an important determinant in biochemical processes as shown by the relative phosphonylation rates and toxicity of the described V-type nerve agents and analogues.