Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

Graham Pattison, Richard J. Glyn

Research output: Contribution to journalArticlepeer-review


The replacement of oxygenated functionality (hydroxy and alkoxy) with a fluorine atom is a commonly used bioisosteric replacement in medicinal chemistry. In this paper, we use molecular matched-pair analysis to better understand the effects of this replacement on lipophilicity. It seems that the reduced log P of the oxygenated compound is normally dominant in determining the size of this difference. We observe that the presence of additional electron-donating groups on an aromatic ring generally increases the difference in lipophilicity between an oxygenated compound and its fluorinated analogue, while electron-withdrawing groups lead to smaller differences. Ortho-substituted compounds generally display a reduced difference in log P compared to para- and meta-substituted compounds, particularly if an ortho-substituent can form an intramolecular hydrogen bond. Hydrogen-bond acceptors remote to an aromatic ring containing fluorine/oxygen can also reduce the difference in log P between oxygen- and fluorine-substituted compounds.
Original languageEnglish
Pages (from-to)10246-10259
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - 2 Jul 2021

Bibliographical note

Funding Information:
We thank the University of Brighton for funding of consumables toward the MRes project of R.J.G.

Publisher Copyright:
© 2021 American Chemical Society


  • Hydrocarbons
  • Fluorine
  • Halogenation
  • Aromatic compounds
  • Substituents
  • Lipophilicity
  • Bioisosteres


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