Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening.
It is known that strong hydrogen-bonding interactions play an important role in many chemical and biological systems. However, weak or very weak hydrogen bonds, which are often difficult to detect and characterize, may also be relevant in many recognition and reaction processes. Fluorine serving as a hydrogen-bond acceptor has been the subject of many controversial discussions and there are different opinions about it. It now appears that there is compelling experimental evidence for the involvement of fluorine in weak intramolecular or intermolecular hydrogen bonds. Using established NMR methods, we have previously characterized and measured the strengths of intermolecular hydrogen-bond complexes involving the fluorine moieties CH2 F, CHF2 , and CF3 , and have compared them with the well-known hydrogen-bond complex formed between acetophenone and the strong hydrogen-bond donor p-fluorophenol. We now report evidence for the formation of hydrogen bonds involving fluorine with significantly weaker donors, namely 5-fluoroindole and water. A simple NMR method is proposed for the simultaneous measurement of the strengths of hydrogen bonds between an acceptor and a donor or water. Important implications of these results for enzymatic/chemical reactions involving fluorine, for chemical and physical properties, and for ligand/protein (19) F NMR screening are analyzed through experiments and theoretical simulations.
Faculty of Science, University of Neuchâtel, 2000, Neuchâtel, Switzerland. claudio.dalvit@sanofi.com.|Sanofi, LG-CR/SDI/SBB, 94403, Vitry-sur-Seine, France. claudio.dalvit@sanofi.com.
Claudio
C
Dalvit
Novartis Institutes for Biomedical Research, Global Discovery Chemistry, CADD, 4002, Basel, Switzerland. anna.vulpetti@novartis.com.
Anna
http://orcid.org/0000-0002-3114-8679
A
Vulpetti
D005461:Fluorine / Q000737:chemistry*; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010636:Phenols / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D014867:Water
D007211:Indoles; D008024:Ligands; D010636:Phenols; D011506:Proteins; D014867:Water; D005461:Fluorine; C106880:4-fluorophenol; C095066:5-fluoroindole
NMR spectroscopy; fluorine; fluorine NMR screening; hydrogen bonds; molecular matched-pairs analysis