Acid-base and metal-ion-binding properties of 9-[2-(2-phosphonoethoxy)ethyl]adenine (PEEA), a relative of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). An exercise on the quantification of isomeric complex equilibria in solution.

The acidity constants of 3-fold protonated 9-[2-(2-phosphonoethoxy)ethyl]adenine, H 3 (PEEA) + , and of 2-fold protonated (2-phosphonoethoxy)ethane, H 2 (PEE), and the stability constants of the M(H;PEEA) + , M(PEEA), and M(PEE) complexes with M 2 + = Mg 2 + , Ca 2 + , Sr 2 + , Ba 2 + , Mn 2 + , Co 2 + , Ni 2 + , Cu 2 + , Zn 2 + , or Cd 2 + have been determined (potentiometric pH titrations; aqueous solution; 25 °C; I = 0.1 M, NaNO 3 ). It is concluded that in the M(H;PEEA) + species, the proton is at the phosphonate group and the metal ion at the adenine residue. The application of previously determined straight-line plots of log K M M ( R - P O 3 ) versus pK H H ( R - P O 3 ) for simple phosph(on)ate ligands, R-PO 3 2 - , where R represents a residue that does not affect metal-ion binding, proves that the M(PEEA) complexes of Co 2 + , Ni 2 + , Cu 2 + , Zn 2 + , and Cd 2 + as well as the M(PEE) complexes of Co 2 + , Cu 2 + , and Zn 2 + have larger stabilities than is expected for a sole phosphonate coordination of M 2 + . For the M 2 + complexes without an enhanced stability (e.g., Mg 2 + or Mn 2 + ), it is concluded that M 2 + binds in a monodentate fashion to the phosphonate group of the two ligands. Combination of all of the results allows the following conclusions: (i) The increased stability of the Co(PEE), Cu(PEE), Zn(PEE), and Co(PEEA) complexes is due to the formation of six-membered chelates involving the ether-oxygen atom of the aliphatic residue (-CH 2 -O-CH 2 CH 2 -PO 3 2 - ) of the ligands with formation degrees of about 15-30%. (ii) Cd(PEEA) forms a macrochelate with N7 of the adenine residue (formation degree about 30%); Ni(PEEA) has similar properties. (iii) With Zn(PEEA), both mentioned types of chelates are observed, that is, Zn(PEEA) c l / O and Zn(PEEA) c l / N 7 , with formation degrees of about 13 and 41%, respectively; the remaining 46% is due to the "open" isomer Zn(PEEA) o p in which the metal ion binds only to the PO 3 2 - group. (iv) Most remarkable is Cu(PEEA) because a fourth isomer, Cu(PEEA) c l / O / N 3 , is formed that contains a six-membered ring involving the ether oxygen next to the phosphonate group and also a seven-membered ring involving N3 of the adenine residue with a very significant formation degree of about 50%. Hence, PEEA 2 - is a truly ambivalent ligand, its properties being strongly dependent on the kind of metal ion involved. Comparisons with M 2 + complexes formed by the dianions of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and related ligands reveal that five-membered chelates involving an ether-oxygen atom are considerably more stable than the corresponding six-membered ones. This observation offers an explanation of why PMEA is a nucleotide analogue with excellent antiviral properties and PEEA is not.