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Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening
Author(s) -
Dalvit Claudio,
Vulpetti Anna
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201600446
Subject(s) - hydrogen bond , chemistry , intermolecular force , intramolecular force , fluorine , low barrier hydrogen bond , chemical shift , hydrogen , chemical bond , ligand (biochemistry) , acceptor , photochemistry , computational chemistry , molecule , organic chemistry , biochemistry , receptor , physics , condensed matter physics
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 CH 2 F, CHF 2 , and CF 3 , 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.