CF₂H, A hydrogen bond donor group: Is it more or less lipophilic bioisoster for OH and SH?

Many papers published in recent years on compounds containing the CF₂H moiety, frequently define this group as a lipophilic bioisoster for OH and SH, due to its ability to act as a hydrogen bond donor and the known lipophilicity the fluorine atom carries.^1-3 Recently, we reported on the lipophilicity and the H-bond acidity (A, the ability of a molecule to act as a hydrogen-bond donor) of various difluoroanisoles and thioanisoles,² and found that the differences in these drug-like properties, relative to the parent anisole/thioanisole, are strongly depended on the aromatic substituents. In the present study, we addressed the question of whether these phenomena would apply when the difluoromethyl group is attached directly to the aromatic ring or to other functions such as aliphatic or electron withdrawing groups (EWG). We compared the effect of the CH₃/CHF₂ exchange (since F is considered a bioisoster for H) on lipophilicity. We found that for all compounds examined, the CF₂H group acts as a relatively weak hydrogen bond donor (A = 0.035-0.151), depending on the attached function. An even more pronounced effect of the attached function was observed for the lipophilicity. Regarding this drug-like properties, we have found that in aromatic compounds the logP of ArCF₂H relative to ArOH is always higher and the DlogP (CF₂H-OH) is significant for EDG, while log P of ArCF₂H relative to ArSH, is lower, with DlogP(CF₂H-SH) most significantly for EWG. These results clearly show that CF₂H may act as a more lipophilic bioisoster for OH but less lipophilic bioisoster for SH, and therefore, may aid in the rational design of drugs containing this moiety.

1. Recent review: Yerien et al. Eur. J. 2017, 23, 14676.
2. Zafrani et al. Med. Chem. 2017, 60, 797.
3. Sessler et al. Am. Chem. Soc. 2017, 139, 9325.