Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

Glyn, Richard J. and Pattison, Graham (2021) Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity. J. Med. Chem., 64 (14). pp. 10246-10259. ISSN 0022-2623

Full content URL: https://doi.org/10.1021/acs.jmedchem.1c00668

Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity
Accepted manuscript
[img] Microsoft Word
GP Richard J Med Chem Oxygen Fluoro Bioisosteres Revision Final.docx - Whole Document

Item Type:Article
Item Status:Live Archive


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.

Keywords:medicinal chemistry, lipophilicity, Physico-chemical, organofluorine
Subjects:F Physical Sciences > F100 Chemistry
Divisions:College of Science > School of Chemistry
ID Code:52236
Deposited On:31 Oct 2022 15:36

Repository Staff Only: item control page