Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept

There
is a growing interest in organic compounds containing the
difluoromethyl group, as it is considered a lipophilic hydrogen bond
donor that may act as a bioisostere of hydroxyl, thiol, or amine groups.
A series of difluoromethyl anisoles and thioanisoles was prepared
and their druglike properties, hydrogen bonding, and lipophilicity
were studied. The hydrogen bond acidity parameters A (0.085–0.126) were determined using Abraham’s solute 1H NMR analysis. It was found that the difluoromethyl group
acts as a hydrogen bond donor on a scale similar to that of thiophenol,
aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl
is considered a lipophilicity enhancing group, the range of the experimental
Δlog P(water–octanol) values (log P(XCF2H) – log P(XCH3)) spanned from −0.1 to +0.4. For both parameters,
a linear correlation was found between the measured values and Hammett
σ constants. These results may aid in the rational design of
drugs containing the difluoromethyl moiety.