title: Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" Concept.
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 solute1H 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.
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Yossi
authors.initials: Y
authors.lastname: Zafrani
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Yeffet
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Sod-Moriah
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Berliner
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Dafna
authors.initials: D
authors.lastname: Amir
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Daniele
authors.initials: D
authors.lastname: Marciano
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Gershonov
authors.affiliation: The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
authors.forename: Sigal
authors.identifier: 0000-0002-1784-3827
authors.initials: S
authors.lastname: Saphier
mesh_terms: D000840:Anisoles / Q000138:chemical synthesis / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D058116:Lewis Acids / Q000138:chemical synthesis / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000840:Anisoles; D006845:Hydrocarbons, Fluorinated; D058116:Lewis Acids; D013440:Sulfides