Exploring Atypical Fluorine–Hydrogen Bonds and Their Effects on Nucleoside Conformations

• Published in: Chemistry : a European journal Vol. 24; no. 61; pp. 16432 - 16439
• Main Authors: O'Reilly, Daniel, Stein, Robin S., Patrascu, Mihai Burai, Jana, Sunit Kumar, Kurian, Jerry, Moitessier, Nicolas, Damha, Masad J.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 02.11.2018
• Subjects: Chemistry; Computer applications; Computer simulation; Conformational analysis; Critical point; Fluorination; Fluorine; Hydrogen; Hydrogen bonding; Hydrogen bonds; Magnetic resonance spectroscopy; NMR spectroscopy; Nucleosides; Protons; Quantum mechanics; nucleosides; conformational analysis; NMR spectroscopy; hydrogen bonds; fluorine
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201803940

The ability of fluorine to serve as a hydrogen‐bond acceptor has been debated for many years. Short fluorine–hydrogen contacts are thought to play a key role in stabilizing some complex supramolecular systems. To directly probe the existence of fluorine–hydrogen bonds, we have performed NMR spectroscopy and computational modeling on a series of C2′‐fluorinated nucleosides. Specifically, quantum mechanics/molecular mechanics (QM/MM) analysis and [19F,1H] HMBC NMR experiments provided direct evidence for a C−H⋅⋅⋅F hydrogen bond in a 2′‐F,4′‐C‐α‐alkyl‐ribonucleoside analogue. This interaction was also supported by QTAIM and NBO analyses, which confirmed a bond critical point for the C−H⋅⋅⋅F interaction (0.74 kcal mol−1). In contrast, although conformational analysis and NMR experiments of 2′‐deoxy‐2′‐fluoro‐arabinonucleosides indicated a close proximity between the 2′‐fluorine and the H6/8 protons of the nucleobase, molecular simulations did not provide evidence for a C−H⋅⋅⋅F hydrogen bond. Detecting the atypical: Direct evidence for δ+C−H⋅⋅⋅Fδ− bonds that play a subtle but important role in conformational stability (see picture).