(15N5)-Labeled adenine derivatives: synthesis and studies of tautomerism by 15N NMR spectroscopy and theoretical calculations

A Laxer, D. T Major, H. E Gottlieb, B Fischer

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Since the nitrogens of nucleosides and nucleotides play an important role in the molecular recognition of these compounds, 15N NMR became a method of choice in this field. Fully 15N-labeled adenine, required in the latter studies, was obtained in four synthetic steps, in a good yield. Likewise, (15N5)-2-hexylthioether-adenine and (15N5)-8-Br-adenine were obtained in five synthetic steps from the relatively inexpensive 15N sources:  15N-NH4Cl, 15N-NH4OH, 15N-NaNO2. Full 15N labeling of these adenine prototypes enabled to obtain high-resolution 15N NMR spectra of these bases at 60.8 MHz. Furthermore, the spectra suggested the existence of the N3-H species in the tautomeric mixtures of these compounds in solution, in addition to the well-reported N9-H (major) and N7-H (minor) tautomers. These observations were also supported by quantum mechanical calculations of the tautomeric equilibria in the gas phase and in solution of the above-mentioned adenine compounds. The gas-phase tautomeric equilibria were estimated using density functional theory and second-order perturbation theory methods. Solvent effects were included by means of both continuum and discrete solvation models. The observation of the existence of the N3-H tautomer has a clear impact on the possible H-bonding patterns of these adenine prototypes and on their molecular recognition by various biological macromolecules. The above15N-labeled analogues are expected to find use as 15N NMR probes for numerous biochemical studies.
Original languageAmerican English
Pages (from-to)5463-5481
JournalThe Journal of Organic Chemistry
Issue number16
StatePublished - 2001


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