The Strength of the Anomeric Effect in Adenosine, Guanosine, and in Their 2‘-Deoxy Counterparts is Medium-Dependent

In nucleosides, the anomeric effect (AE) (i.e. stereoelectronic n(O4‘)→σ* C1‘-N9 interactions) places the aglycon in the pseudoaxial orientation in the N-type conformation (2‘- exo -3‘- endo ), whereas the inherent steric effect of the nucleobase opposes the AE by its tendency to take up pseudoequatorial orientation in the S-type conformation (2‘- endo -3‘- exo ). This means that the actual energetic contribution of the AE of an N - or a C -aglycon in a nucleoside can be determined by subtracting the steric effect of the N - or C -aglycon from the total effect of the aglycon on the drive of N ⇄ S pseudorotational equilibrium. The Δ G ° of N ⇄ S pseudorotational equilibrium among a set of various neutral C - and N -nucleosides showed that the relatively most thermodynamically stabilized S-type conformer is found in 9-deazaadenosine in which 9-deazaadenin-9-yl at C1‘ takes up the relatively most favored pseudoequatorial orientation between pH 8.8−12.0 (Δ H ° = −14.2 kJ/mol) as a result of the exclusive steric control for the drive (Δ H °) of N ⇄ S pseudorotational equilibrium. 9-Deazaadenin-9-yl at C1‘ therefore serves as the best reference point for subtraction of the steric effect of the adenin-9-yl or guanin-9-yl in adenosine (A), guanosine (G), and in their 2‘-deoxy counterparts (dA and dG). Since the electronic character of adenin-9-yl or guanin-9-yl changes from the neutral to the protonated (or deprotonated in case of guanin-9-yl) state as the pH of the medium changes (refs 1p, 1s), the work reported here shows for the first time that the intrinsic AE of A, G, dA, and dG are indeed pD-dependent. The tunable strength of the AE can vary from 23.4 to 17.7 kJ/mol in A from pD 1.2 to 7.0, 37.5 to 15.6 kJ/mol in G from pD 0.6 to 11.6, 18.0 to 14.8 kJ/mol in dA from pD 0.9 to 7.0, 20.7 to 13.8 kJ/mol in dG from pD 0.9 to 11.6.