Experimental evidence for intramolecular attractive nonbonded C-F center dot center dot center dot H-C interactions in 2 ',3 '-dideoxy-4 '-(fluoromethyl)nucleosides - Through-space J(CF) and J(HF) NMR coupling constants, correlation with empirical parameters of solvent polarity and single-crystal X-ray structures

A collection of 5'-O-benzyl-2',3'-dideoxy-4'-(fluoromethyl)-nucleosides car rying both purinic and pyrimidinic nucleobases (uracil, 5-Br-uracil, 5-O2N- uracil, B-Cl-purine and inosine) were synthesized in both the alpha and the beta form. Through-space-transmitted 6J(CF) NMR coupling constants between F and C-6 (pyrimidinic base) or C-8 (purinic base) were observed for all o f the a anomers of the compounds examined, whilst the corresponding (7)J(HF ) coupling constants were resolved only for the 5-substituted uracil deriva tives. The absolute values of all the through-space couplings were found to decrease monotonically with increasing solvent polarity (CDCl3, MeOD, [D-6 ]lacetone, [D-6]DMSO). This trend suggests that the through-space interacti on is mediated by an intramolecular (sp(3))C-F H-C(sp(2)) hydrogen bond. Th e possibility of any relevant solvent-induced conformational change influen cing the F/base mutual spatial relationship in the molecules investigated w as ruled out by heteronuclear steady-state H-1{F-19}-NOE experiments. A Lin ear correlation was observed between (6)J(CF) and (7)J(HF) coupling constan ts and the Kamlet-Tait's hydrogen bond basicity parameter beta. The crystal structures of the alpha and beta anomers of the 5-nitrouracil nucleoside s how evidence that the H-6 of the nucleobase forms hydrogen-bond-like intera ctions involving the O-benzyl oxygen atom in the beta anomer, and that in t he case of the alpha anomer this is replaced by the F atom of the fluoromet hyl group.