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

Sigal Saphier, Shahaf Katalan, Guy Yacov, Anat Berliner, Orit Redy-Keisar, Gil Fridkin, Lee Ghindes-Azaria, Ishay Columbus, Alexander Pevzner, Eyal Drug, Hagit Prihed, Eytan Gershonov, Yoav Eichen, Shlomi Elias, Galit Parvari, Yossi Zafrani

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 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.

Original languageEnglish
Article numbere202202939
JournalChemistry - A European Journal
Volume29
Issue number7
DOIs
StatePublished - 1 Feb 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 Wiley-VCH GmbH.

Keywords

  • conformations
  • difluoromethylene
  • fluorine effects
  • lipophilicity
  • polarity

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