Fluorinated nucleic acid constituents: a carbon-13 nuclear magnetic resonance study of adenosine, cytidine, uridine, and their fluorinated analogues

Abstract

Adenosine, cytidine, uridine, and their fluorinated analogues 2-fluoroadenosine, 5-fluorocytidine, and 5-fluorouridine have been analyzed by carbon-13 nuclear magnetic resonance (NMR) spectroscopy. All carbon resonances of the sugar and base moieties are assigned. The carbon-fluorine coupling constants of the base and the carbon-proton coupling constants between carbons of the base and protons of the base and the anomeric proton of the sugar have been assigned. Effects of the fluorine atom on carbon chemical shifts of the nucleoside are expressed as delta delta F values [delta delta F = delta (fluorinated nucleoside) - delta (normal nucleoside)]. Theoretical charge density calculations (CNDO/2) of the fluorinated and non-fluorinated base carbons are compared [delta ET = E (fluorinated nucleoside) - E (normal nucleoside)]. The delta delta F and delta ET values are shown to correlate very well, except where a nitrogen atom is situated beta to the fluorine atom. This apparent deviation is attributed to a lone-pair electron (LPE) effect of the nitrogen. Contributions of the LPE effect appear to vary 1JC,H and 1JC,F values in a predictable way. Long-range (four- and five-bond) carbon-fluorine coupling constants are obbserved in the base moiety. At these experimental conditions, indroduction of the fluorine atom has no measurable conformational effect on the sugar-base torsion angle.