Metal Complexes of 4,11‐Dimethyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐bis(methylphosphonic acid) – Thermodynamic and Formation/Decomplexation Kinetic Studies

Abstract

The macrocyclic ligand with two methylphosphonic acid pendant arms, 4,11‐dimethyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐bis(methylphosphonic acid) (1,8‐H4Me2te2p, H4L3), was synthesized by a new simple approach. The product of the reaction of quarternized formaldehyde cyclam aminal with the sodium salt of diethyl phosphite was hydrolyzed to give a very high yield of the title ligand. The (H6L3)2+ cation in the solid state is protonated on all ring nitrogen atoms and on each phosphonate group. In the solid‐state structure of [Cu(H3L3)][Cu(H2L3)]PF6·3H2O, neutral as well as positively charged complex species are present. Molecular structures of both species are very similar having the copper(II) ion in a coordination environment between square‐pyramidal and trigonal‐bipyramidal arrangements (τ = 0.43 and 0.48) with one pendant arm non‐coordinated. The ligand forms stable complexes with transition‐metal ions showing a high selectivity for divalent copper atoms. The formation of complexes of the ligand with CuII, ZnII and CdII is fast, confirming the acceleration of complexation due to the presence of the strongly coordinating pendant arms. Acid‐assisted decomplexation is fast for all three metal ions. Therefore, the copper(II) complex is not suitable for medicinal applications employing copper radioisotopes, but the title ligand motive can be employed in copper(II) separation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Bifunctional Cyclam‐Based Ligands with Phosphorus Acid Pendant Moieties for Radiocopper Separation: Thermodynamic and Kinetic Studies

“…Figure 3 shows that phosphonate ligand H 4 L2 binds copper(II) faster than phosphinate ligand H 2 L1 by 1–2 order(s) of magnitude, with increasing difference on going to higher pH. Compared to other related systems reported in the literature, the overall reaction rate of the phosphonate ligand H 4 L2 is comparable to those of other ligands with two phosphonate pendant arms (H 4 te2p26 and parent H 4 te2p‐Me 2 ,35 Supporting Information, Figure S12). The complexation proceeds via analogous protonated species with similar reactivities of the individual species (Table 4).…”

“…The doubly protonated cyclam skeleton is locked in a stable conformation due to the presence of intramolecular hydrogen bonds 1. In cyclam itself and in several of its derivatives, such hydrogen bonds even lead to a reverse order of consecutive protonation constants 35. The first deprotonation of H 2 L species stabilised by intramolecular hydrogen bonds opens the locked macrocycle conformation, and the second deprotonation proceeds much more easily due to the greater flexibility of the HL species.…”

“…For complexes of the phosphonate ligand H 4 L2 , the first two protonations of the complexes should take place on phosphonate groups 26. 34, 35 The resulting doubly protonated species are very probably “in‐cage” complexes for all three metal ions (a PO 3 H − group can be firmly bound to central metal ions),26, 30, 35 as almost all corresponding log K h values (5.0–7.6, Table 2) are lower than the analogous ones found for the free ligand (7.46 and 6.25, Table 1). Such a decrease is attributable to the electron‐withdrawing effect of the coordinated metal ion and it indirectly confirms the expected coordination of a phosphonate pendant arm.…”

“…According to distribution diagrams (Figure 2), protonation of the distant amino group of the aminobenzyl unit is expected for systems with both ligands, and thus probably mono‐ ( n =1, d k 0 ) and diprotonated ( d k 1 ) species are kinetically important for the Cu II –H 2 L1 complex, and tri‐ ( n =3, d k 0 ) and tetraprotonated ( d k 1 ) are kinetically decisive for the Cu II –H 4 L2 complex. Although a simplified equation with d k 0 =0 is commonly sufficient for good fit of experimental data (e.g., as was used for the Cu II –H 4 te2p‐Me 2 complex),35 inclusion of this particular rate constant significantly improved fits by lowering the observed sum of squared deviations by 20–30 %. However, this rate constant was calculated with relatively large uncertainty (Table 5).…”

“…It has been observed that fully N ‐substituted cyclam derivatives (i.e., only tertiary amino groups are present) have significantly different properties; in particular, their complexes show significantly lower kinetic inertness than those of ligands having one or more secondary amino groups. Previously, we have shown that the ligand 1,8‐H 4 te2p‐Me 2 (Scheme ) forms a copper(II) complex with very high selectivity, and acid‐assisted dissociation of the complex is faster than that observed for non‐methylated derivative 1,8‐H 4 te2p 35…”