Conformational studies of adenosine 5′-phosphorodiamidates in aqueous solution

CD and nmr studies show that the conformational equilibrium of N(P)‐alkylated adenosine 5′‐phosphorodiamidates 2–4 and, to a much lesser extent, adenosine 5′‐phosphorodiamidate 1 differ at two parts from that of adenosine 5′‐phosphate in water. The glycosidic bond conformation is slightly shifted into the direction of the syn range, and the ribose ring N‐conformer population increases. The conformational changes increase with increasing degree of N(P)‐alkylation and cause a change of the sign of the long‐wavelength CD band for 2–4. The new conformation may be characterized by a stacked arrangement for the adenine ring and the 5′‐substituted phosphate group of 2–4. Hydrophobic attraction between the head and the tail of the molecules, as well as the entropy effect (which promotes the clustering of apolar faces in water), may be jointly responsible for this stacked arrangement. The intramolecular attractive forces stabilizing the stacked conformation may act at the expense of the solubility decreasing intermolecular attractive forces, and may thus be responsible for the increased water solubility of 2–4, which is higher than that of 1 by more than two orders of magnitude.