Fridrich Gregáň

Stability of metal ion complexes formed with methyl phosphate and hydrogen phosphate

Abstract The acidity constants of methyl phosphoric acid, CH3OPO(OH)2, and orthophosphoric acid, HOPO(OH)2, and the stability constants of the 1 : 1 complexes formed between Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+ and methyl phosphate, CH3OPO32–, or hydrogen phosphate, HOPO32–, were determined by potentiometric pH titration in aqueous solution (25  °C;I = 0.1 M, NaNO3). On the basis of previously established log K versus pKa straight-line plots for the complexes of simple phosphate monoesters and phosphonate derivatives, R-PO32–, where R is a noncoordinating residue, it is shown that the stability of the M(CH3OPO3) complexes is solely determined (as one might expect) by the basicity of the –PO32– residue. It is emphasized that the mentioned reference lines may also be used to reveal increased complex stabilities, for example, for certain complexes formed with 8-quinolyl phosphate the occurrence of 7-membered chelates can be proven in this way; the same procedure is also applicable to complexes of nucleotides, etc. The M(HOPO3) complexes are slightly more stable (on average by 0.08 log unit) than it is expected from the basicity of HPO42–; this observation is attributed to a more effective solvation, including hydrogen bonding, than is possible with CH3OPO32– species.

Stability of binary and ternary copper(II) complexes of the diphosphate analogue, methylphosphonylphosphate, in aqueous solution

Abstract The stability constants of the 1:1 complexes formed between Cu 2+ or Cu(Arm) 2+ , where Arm = 2,2′-bipyridyl or 1,10-phenanthroline, and methylphosphonylphosphate (MePP 3− ), CH 3 -P(O) 2 − -O-PO 3 2 , were determined by potentiometric pH titration in aqueous solution (25°C; I = 0.1 M, NaNO 3 ). It is shown that the equilibrium, Cu(Arm) 2+ + Cu(MePP) − Cu(Arm)(MePP) − + Cu 2+ , is considerably displaced to its right-hand side, i.e. Δ log K = log K Cu(Arm)(MePP) Cu(Arm) − log K Cu(MePP) Cu ≅ 0.45. This value is significantly larger than the estimate based on statistical considerations, i.e. Δ log K Cu/statis ≅ −0.9, but it agrees with previous observations made for mixed ligand complexes formed by a divalent transition metal ion, a heteroaromatic N base and an O donor ligand. These results will now allow evaluation of complex stabilities of corresponding complexes formed with nucleoside diphosphates.

Metal ion-binding properties of the diphosphate ester analogue, methylphosphonylphosphate, in aqueous solution.

The stability constants of the 1:1 complexes formed between methylphosphonylphosphate (MePP3-), CH3P(O)-2-O-PO32-, and Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+ (M2+) were determined by potentiometric pH titration in aqueous solution (25 °C; l = 0.1 M, NaNO3). Monoprotonated M(H;MePP) complexes play only a minor role. Based on previously established correlations for M2+-diphosphate monoester complex-stabilities and diphosphate monoester β-group. basicities, it is shown that the M(Mepp)- complexes for Mg2+ and the ions of the second half of the 3d series, including Zn2+ and Cd2+, are on average by about 0.15 log unit more stable than is expected based on the basicity of the terminal phosphate group in MePP3-. In contrast, Ba(Mepp)- and Sr(Mepp)- are slightly less stable, whereas the stability for Ca(Mepp)- is as expected, based on the mentioned correlation. The indicated increased stabilities are explained by an increased basicity of the phosphonyl group compared to that of a phosphoryl one. For the complexes of the alkaline earth ions, especially for Ba2+, it is suggested that outersphere complexation occurs to some extent. However, overall the M(Mepp)- complexes behave rather as expected for a diphosphate monoester ligand.

Ternary Complexes in Solution+ with Phosphonates as Ligands. Intramolecular Equilibria in the Mixed Ligand Cu2+ Complexes Formed by 2,2′-Bipyridyl or 1,10-Phenanthroline and the Dianion of Phosphonylmethoxyethane in Water-Dioxane Mixtures

The stability constants of the mixed ligand complexes formed by Cu2+, 2,2′-bipyridyl or 1,10-phenanthroline (= Arm), and the dianion of phosphonylmethoxyethane (PME2-), ethyl phosphonate (EtP2-), methyl phosphonate (MeP2-), or D-ribose 5′-monophosphate (RibMP2-) (= R–PO32-) were determined by potentiometric pH titrations in water containing 30 or 50% (v/v) 1,4-dioxane (I = 0.1 M, NaNO3; 25°C). The corresponding results regarding water as solvent were taken from our earlier work. Previous measurements with simple phosphate monoesters, together with the present results for RibMP2-, were used to establish log versus straight line plots. With the aid of the equilibrium constants determined for the MeP2- and EtP2- systems it is shown that simple phosphonates, i.e., those without an additional binding site, fit also on the same straight lines. Therefore, it could be demonstrated with these reference lines that the Cu(Arm)(PME) complexes in all solvents have a higher stability than expected for a sole phosphonate Cu2+ coordination. This increased stability is attributed to the formation of 5-membered chelates involving the ether oxygen present in the – CH2– O – CH2–PO32- residue of PME2-. The formation degree of the 5-membered chelates in the Cu(Arm)(PME) systems varies only between about 65 and 85% in the three mentioned solvents, despite the fact that the stabilities of the Cu(Arm)(PME) complexes increase by more than 1.8 log units by going from water to 50% dioxane-water. It is concluded that (i) such 5-membered chelates will also be formed in mixed ligand complexes of other metal ions in solvents with a reduced polarity, and (ii), more importantly, that the same interactions will also occur with the parent compound of PME2-, i.e. the dianion of 9-(2-phosphonylmethoxyethyl)adenine (PMEA2-), a compound which shows antiviral properties and for which the ether oxygen is important.

Why is the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine in its diphosphorylated form (PMEApp4–) initially a better substrate for polymerases than (2′-deoxy)adenosine 5′-triphosphate (dATP4–/ATP4–)? Considerations on the mechanism of nucleic acid polymerases

The observation that the antivirally active PMEA in its diphosphorylated form (PMEApp4–) is initially a better substrate for polymerases than dATP4– (ATP4–) can be rationalized by (i) the increased basicity of the phosphonyl group (compared to a phosphoryl group) and (ii) the participation of the ether O atom of PMEApp4– in metal ion binding; both effects together favor M2+ binding at the α group and thus its nucleophilic attack.