Differential reactivity of α and β 2′-deoxyribonucleosides towards protonation and metalation

The reactivity of artificial 2′-deoxyribonucleosides, designed as nucleoside surrogates in metal-mediated base pairs, towards protonation and metalation has been shown to be dependent on the choice of the anomer. The α nucleosides comprising the aglycones imidazole, 1,2,4-triazole, benzimidazole and imidazo[4,5-b]pyridine are more basic than the respective β nucleosides as was shown by a combined experimental and theoretical approach. The ΔpKa values observed experimentally are in the range of 0.19 ± 0.03 to 0.41 ± 0.07 (with the error representing three times the standard deviation of the mean value). An independent confirmation of this differential reactivity was obtained from density functional theory (DFT) calculations using 1,2,4-triazole nucleoside as an example. The result of these calculations is in good agreement with the experimental data (ΔpKa = 0.16 vs. 0.21 ± 0.07). The stability of the respective metal ion complexes of the anomeric 1,2,4-triazole nucleosides follows the same trend as that of the respective protonated nucleosides: Those of the α nucleoside are more stable than those of the β nucleoside (Δlog β2 = 0.6 ± 0.2 for the 2:1 complex with Ag+; Δlog β1 = 0.51 ± 0.07 for the 1:1 complex with Hg2+). These slightly different reactivities will be useful for fine-tuning the metal-ion binding behavior of oligonucleotides containing metal-mediated base pairs.