Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

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