Bis- and tris-(methylphosphonic) acid derivatives of a 14-membered tetraazamacrocycle containing pyridine: synthesis, protonation and complexation studies

Abstract

Two N-methylphosphonic acid derivatives of a 14-membered tetraazamacrocycle containing pyridine have been synthesized, H(4)L(1) and H(6)L(2). The protonation constants of these compounds and the stability constants of complexes of both ligands with Ni(2+), Cu(2+) and Zn(2+) were determined by potentiometric methods at 298 K and ionic strength 0.10 mol dm(-3) in NMe(4)NO(3). The high overall basicity of both compounds is ascribed to the presence of the phosphonate arms. (1)H and (31)P NMR spectroscopic titrations were performed to elucidate the sequence of protonation, which were complemented by conformational analysis studies. The complexes of these ligands have stability constants of the order of or higher than those formed with ligands having the same macrocyclic backbone but acetate arms. At pH = 7 the highest pM values were found for solutions containing the compound with three acetate groups, followed immediately by those of H(6)L(2), however, as expected, the increasing pH favours the complexes of ligands containing phosphonate groups. The single-crystal structure of Na(2)[Cu(HL(1))]NO(3)x8H(2)O has shown that the coordination geometry around the copper atom is a distorted square pyramid. Three nitrogen atoms of the macrocyclic backbone and one oxygen atom from one methylphosphonate arm define the basal plane, and the apical coordination is accomplished via the nitrogen atom trans to the pyridine ring of the macrocycle. To achieve this geometric arrangement, the macrocycle adopts a folded conformation. This structure seems consistent with Uv-vis-NIR spectroscopy for the Ni(2+) and the Cu(2+) complexes and with the EPR for the latter.

Lanthanide complexes of macrocyclic derivatives useful for medical applications

“…DELGADO et al The overall basicity of the compounds having methylphosphonate arms is very high compared with that of the N-acetate derivative, ac 3 py14 [6,8]. This is explained by electrostatic effects and hydrogen-bonding formation [6]. Indeed, the electrostatic effect of the double negative charge on the phosphonate groups prevails over the inductive electron-withdrawal effect of these groups, making the nearby amine more basic [6,7].…”

“…DELGADO et al The overall basicity of the compounds having methylphosphonate arms is very high compared with that of the N-acetate derivative, ac 3 py14 [6,8]. This is explained by electrostatic effects and hydrogen-bonding formation [6].…”

“…This is explained by electrostatic effects and hydrogen-bonding formation [6]. Indeed, the electrostatic effect of the double negative charge on the phosphonate groups prevails over the inductive electron-withdrawal effect of these groups, making the nearby amine more basic [6,7]. The different overall basicity of the studied ligands has direct repercussion in their complexation properties and in their biological applications [7].…”

“…The later ligands exhibit larger K ML values for the complexes with lanthanide ions than the corresponding acetate derivative [6][7][8]. Differently, the Ni 2+ , Cu 2+ , and Zn 2+ complexes of the same ligands present K ML of the same order for the acetate and methylphosphonate derivatives, see in Table 2 the values for the Cu(II) complexes [6][7][8]. However, as the direct comparison of stability constants involving ligands with rather different overall basicity can lead to erroneous conclusions, because the competition of metals and proton for ligands is not taken into account, the pM val-…”

“…Table 1 shows the protonation constants of the first series of compounds studied, represented in Fig. 1, determined in aqueous solutions of tetramethylammonium nitrate (NMe 4 NO 3 ) at 298.0 K [6,7].…”