Fluorine as a Hydrogen-Bond Acceptor: Experimental Evidence and Computational Calculations

• Published in: Chemistry : a European journal Vol. 20; no. 35; pp. 11058 - 11068
• Main Authors: Dalvit, Claudio, Invernizzi, Christian, Vulpetti, Anna
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 25.08.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Bonding; Chemical bonds; Computation; Computer Simulation; Correlation; Drug Design; Fluorine; Fluorine - chemistry; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Magnetic Resonance Spectroscopy; molecular electrostatic potential; NMR spectroscopy; noncovalent interactions; Nuclear magnetic resonance; Thermodynamics; Topology; molecular electrostatic potential; NMR spectroscopy; noncovalent interactions; hydrogen bonds; fluorine
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201402858

Hydrogen‐bonding interactions play an important role in many chemical and biological systems. Fluorine acting as a hydrogen‐bond acceptor in intermolecular and intramolecular interactions has been the subject of many controversial discussions and there are different opinions about it. Recently, we have proposed a correlation between the propensity of fluorine to be involved in hydrogen bonds and its 19F NMR chemical shift. We now provide additional experimental and computational evidence for this correlation. The strength of hydrogen‐bond complexes involving the fluorine moieties CH2F, CHF2, and CF3 was measured and characterized in simple systems by using established and novel NMR methods and compared to the known hydrogen‐bond complex formed between acetophenone and p‐fluorophenol. Implications of these results for 19F NMR screening are analyzed in detail. Computed values of the molecular electrostatic potential at the different fluorine atoms and the analysis of the electron density topology at bond critical points correlate well with the NMR results. Who is strongest? Hydrogen bonds involving the fluorine moieties CH2F, CHF2, and CF3 were measured and characterized by using different NMR parameters and compared to a known hydrogen‐bond complex. Computed values of the molecular electrostatic potential at the different fluorine atoms and the analysis of the electron‐density topology at bond critical points correlate well with the NMR findings (see figure).