The Difluoromethyl Bioisoster. Is it Always a “Lipophilic Hydrogen Bond Donor”?

The fluorine atom plays an important role in many fields due to its unique combination of small size, high electronegativity, low polarizability and hydrophobicity. Advances in synthetic methods, has made the less abundant CF₂H group more accessible. This group is especially interesting because of its attenuated lipophilicity increase and H-bonding ability. Just how significant is the tendency of CF₂H to donate its a-hydrogen and is it sensitive to other functions in the molecule? Also, how is the lipophilicity induced by this group, affected by the molecular structure of specific compounds? Can it really be used as a lipophilic bioisoster of OH as suggested? In this work we prepared a series of difluoromethyl anisoles and thioanisoles, and studied their drug-like properties; hydrogen bonding and lipophilicity. Using the Abraham`s solute ¹H NMR analysis we have determined their hydrogen bond acidity parameter A (0.085-0.126) and 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 the hydroxyl one. The measured A values were found to correlate with the Hammett s constants of different substituents, with EWG causing an increase in the hydrogen bond acidity. Although the difluoromethyl group is considered a lipophilicity enhancing group, we found that the range of the experimental ∆logP depends on the aryl substituents. Here too, a linear correlation was found between the observed ∆logP and Hammett σ constants, with EWG leading to a decrease in lipophilicity. These findings will enable rational design of fluorinated drug candidates with added metabolic stability or higher binding affinity obtained without an increase in lipophilicity using more precise design rules.