Placing CF₂ in the Center: Major Physicochemical Changes Upon a Minor Structural Alteration in Gem‐Difunctional Compounds

Abstract

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.

Biocatalytic asymmetric reduction of fluoroalkyl ketones to access enantiopure fluoroalkyl secondary alcohols

“…The introduction of the CF 2 group into organic compounds can significantly enhance their lipophilicity and metabolic stability, and change their bioavailability, and hence, has become a common strategy for new drug development. 18 In 2014, Rodrígue's group 19 used LBADH from Lactobacillus brevis to reduce α,α-difluoroacetophenone to get the corresponding ( S )-alcohol with an excellent enantiomeric excess (>99%) and good conversion (>90%). However, this protocol features a limited substrate scope for difluoroalkylated ketones.…”

Diphosphoryl‐functionalized Polyoxometalates: Structurally and Electronically Tunable Hybrid Molecular Materials

“…11 With POM 4 displaying excellent hydrolytic stability and the lowest LUMO energy, diphosphonate-hybridized POMs are valuable targets for further modulation of the redox properties of the Wells-Dawson POM. Difluoromethylenediphosphonate is known to be an isopolar analogue of pyrophosphate, [12] and its incorporation into POM 5 (E 1/2 = À 0.66 V vs. Fc + j Fc) mimicked the behavior of 2 with a negative shift in the first redox event with respect to 4 (À 30 mV), albeit to a lesser degree. Alkyl substitution at the…”

Diphosphoryl‐functionalized Polyoxometalates: Structurally and Electronically Tunable Hybrid Molecular Materials

“…11 With POM 4 displaying excellent hydrolytic stability and the lowest LUMO energy, diphosphonate-hybridized POMs are valuable targets for further modulation of the redox properties of the Wells-Dawson POM. Difluoromethylenediphosphonate is known to be an isopolar analogue of pyrophosphate, [12] and its incorporation into POM 5 (E 1/2 = À 0.66 V vs. Fc + j Fc) mimicked the behavior of 2 with a negative shift in the first redox event with respect to 4 (À 30 mV), albeit to a lesser degree. Alkyl substitution at the carbon bridge resulted in a marginally shifted E 1/2 of the first redox event as seen for the α-monosubstituted diphosphonates 8 and 9 (E 1/2 = À 0.61 V vs. Fc + j Fc), as well as the α,αdisubstituted disphosphonate 6 (E 1/2 = À 0.62 V vs. Fc + j Fc).…”