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 CH2/CF2 replacement in various α,α-phenoxy- and 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.
|Journal||Chemistry - A European Journal|
|State||Published - 1 Feb 2023|
Bibliographical noteFunding Information:
Rational modulation of physicochemical properties of organic compounds is an important tool employed in all branches of chemistry. Within the vast toolbox of reagents and molecular moieties used to obtain desired properties, fluorination represents a unique case due to its ability to alter many physicochemical properties at a low ‘cost’ in terms of molecular mass and size, relative to the original, non-fluorinated, compound. As a result, fluorinated compounds have been used for decades in many medicinal and chemical applications. The unique characteristics of fluorine including the highest electronegativity, small van der Waals radius and low polarizability, affect molecules in diverse ways, rendering it difficult to predict these effects. For this reason, fluorination effects on molecular and physicochemical properties in general and in particular on adjacent functional groups, have been studied intensively in the last few years. For example, fluorination can affect the acidity, basicity, H-bond acidity[5,6] and H-bond basicity of nearby groups in addition to its effects on physicochemical properties such as boiling point, solubility and lipophilicity.[10-18] The lipophilicity of compounds is important for many applications in the fields of drug discovery, environmental sciences and agrochemicals. A common method of assessing lipophilicity is by measuring the compound's partition coefficient between water and an organic solvent, with water/octanol being a very popular system for many applications. The partition of a compound between these two phases is mainly affected by molecular volume, polarity and H-bond basicity. The interplay between these three parameters, determines the final outcome of the effect of fluorination on the partition coefficient. There have been many studies on the various effects fluorine atoms may have on aliphatic[24,25] and aromatic systems, as well as on adjacent functional groups. Geminal difunctional systems that are separated by one methylene bridge, are prevalent constructs in many branches of chemistry. Having observed pronounced effects of fluorination next to functional groups, we anticipated that fluorination on the central methylene group of geminal-difunctional systems could show interesting effects on the physicochemical properties of such compounds. However, to the best of our knowledge, to date no systematic study of such effects has been reported. In this work, we report our findings on the effects of difluorination of methylene bridges between various functional groups. In particular, the increase in lipophilicity is quite dramatic, considering that only two fluorine atoms are incorporated. The additivity of this effect was examined to show the full potential of such fluorine incorporation. We show that conformational changes brought about by this fluorination pattern may affect the polarity and the lipophilicity in unpredictable ways. In addition, charge distribution was calculated using natural bond orbital (NBO) analysis, and in particular cases, H-bond basicity (pKHB) was measured. The various effects found, in some cases with surprising magnitude, are herein described and thoroughly discussed.
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- fluorine effects