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

TLDR

The difluoromethyl group is increasingly studied as a lipophilic hydrogen‑bond donor that can serve as a bioisostere for hydroxyl, thiol, or amine functionalities. The authors synthesized a series of difluoromethyl anisoles and thioanisoles and evaluated their drug‑like properties, hydrogen‑bond acidity (A = 0.085–0.126) via Abraham’s 1H NMR method, and lipophilicity. The difluoromethyl moiety donates hydrogen bonds comparable to thiophenol, aniline, and amine but not hydroxyl, shows Δlog P values between –0.1 and +0.4, correlates linearly with Hammett σ constants, and thus informs rational drug design.

Abstract

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.