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 [19 F,1 H] 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.
