The Effects on Lipophilicity of Replacing Oxygenated Functionality with Their Fluorinated Bioisosteres

The replacement of oxygenated functionality (hydroxy, alkoxy) with a fluorine atom is a very commonly used bioisosteric replacement in medicinal chemistry. In this paper we use a Molecular Matched Pair Analysis approach to better understand the effects of this bioisosteric replacement on the physicochemical properties of compounds, particularly in terms of lipophilicity. We observe that the presence of electron-donating groups on an aromatic ring generally increase the difference in lipophilicity between an oxygenated compound and its fluorinated analogue.