Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

Abstract

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 <i>P</i> 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. <i>Ortho-</i>substituted compounds generally display a reduced difference in log <i>P</i> compared to <i>para-</i> and <i>meta</i>-substituted compounds, particularly if an <i>ortho</i>-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 <i>P</i> between oxygen- and fluorine-substituted compounds.