Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

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.