Quantitation of the pD Dependent Thermodynamics of the N ⇄ S Pseudorotational Equilibrium of the Pentofuranose Moiety in Nucleosides Gives a Direct Measurement of the Strength of the Tunable Anomeric Effect and the pKa of the Nucleobase† (original) (raw)

1996, The Journal of Organic Chemistry

The anomeric and the gauche effects are two competing stereoelectronic forces that drive the North (N) (C2′-exo-C3′-endo) a South (S) (C2′-endo-C3′-exo) pseudorotational equilibrium in nucleosides. The quantitation of the energetics of pD dependent N a S pseudorotational equilibria of the pentofuranose moiety in 2′-deoxyribonucleosides 1-6, 1′-imidazolyl-2′-deoxy-D-ribofuranose 7, and ribonucleosides 8-13 shows that the strength of the anomeric effect of the constituent heterocyclic moiety at C1′ is dependent upon the unique aromatic nature of the nucleobase, which is tuned by the pD of the medium. The force that drives the protonation a deprotonation equilibrium of the heterocyclic nucleobases in nucleosides is transmitted through the anomeric effect to drive the two-state N a S pseudorotational equilibrium of the constituent furanose: (i) The enhanced strength (∆∆H°(P-N)) of the anomeric effect in the protonated (P) nucleoside compared to the neutral (N) form is experimentally evidenced by the increased preference of sugar for N-type conformation and of the nucleobase in the pseudoaxial orientation in the former by ∆∆H°(P-N) of 3.2 kJ/mol for dA (1), 4.9 kJ/mol for dG (2), 0.7 kJ/mol for dC (3), 2.3 kJ/mol for dImb (7), 4.2 kJ/mol for A (8), 8.7 kJ/mol for G (9), and 2.9 kJ/mol for C (10). (ii) In contrast, the S-type sugar conformer, which places the nucleobase in pseudoequatorial orientation, is considerably more preferred in the alkaline medium owing to the weakening of the anomeric effect in the N1-deprotonated D-guanine and N3deprotonated uracil, 5-fluorouracil, or thymine moieties compared to the neutral counterparts by ∆∆H°(N-D) of 2.1 kJ/mol for dG (2), 0.7 kJ/mol for dU (4), 0.5 kJ/mol for T (5), 0.3 kJ/mol for FdU (6), 4.3 kJ/mol for G (9), 1.7 kJ/mol for U (11), 1.5 kJ/mol for rT (12), and 1.5 kJ/mol for FU (13). This has allowed us to independently measure the pK a of constituent heterocyclic nucleobases by the quantitation of the pD dependent energetics of the two-state N a S pseudorotational equilibrium. † Dedicated to Prof. C. B. Reese on the occasion of his 65th birthday.