Ramunas J. Motekaitis

Factors affecting stabilities of chelate, macrocyclic and macrobicyclic complexes in solution

Abstract The factors which contribute to the chelate, macrocyclic and cryptate effects are described. These include the dilution effect, translational entropy, intrinsic basicities of donor atoms, coulombic attractions and repulsions of charged ions and groups, and covalent character of the coordinate bonds. The reduction in hydration/solvation energies and the related coulombic repulsions of the donor atoms of multidentate ligands are related to preorganization of the ligands for complexation of metal ions. A not insignificant part of the chelate and macrocyclic effects is due to increase in the basicities of the donor atoms that occurs on ring formation, as well as to reduction of the steric repulsions of alkyl groups. The effects of ring size on stabilities are described. These factors are illustrated with stabilities of chelates, macrocyclic complexes and cryptates taken from the literature.

Stabilities of the iron(III) chelates of 1,2-dimethyl-3-hydroxy-4-pyridinone and related ligands

Abstract The protonation constants and iron(III) binding constants of 1,2-dimethyl-3-hydroxy-4-pyridinone, DMHP, are reported and the effectiveness of this ligand in the complexation of iron(III) is compared with those of other iron(III) chelators at moderate and high dilution. The ligand is highly effective for Fe(III) in moderately dilute solution (∼10 −3 M), but because of its 3:1 stoichiometry, the most stable complex FeL 3 dissociates extensively in very dilute solution (∼10 −6 M). The relative effectiveness of DMHP for iron(III) binding is compared with those of the bidentate ligands, acethydroxamic acid and catechol, and with the multidentate ligands desferriferrioxamine, diethylenetriaminepentaacetic acid, racemic ethylenebis( o -hydroxyphenylglycine), N,N′ -bis( o -hydroxybenzyl)ethylenediamine- N,N′ -diacetic acid, with the triscatechols MECAMS and enterobactin, as well as with the physiological iron(III) transport protein transferrin.

Metal chelate formation by N-phosphonomethylglycine and related ligands

Abstract Thirteen selected divalent and trivalent metal ions were equilibrated with N-phosphonomethylglycine(PMG) at 1:1 and 1:2 molar ratios of metal ion to ligand at 25.0° and ionic strength μ=0.100 M. Similarly, the same metal ions were also studied with iminobismethylenephosphonic acid (IDP), which has not been previously investigated, as well as the well known ligand, iminodiacetic acid (IDA) (to obtain equilibrium data for the latter not available in the literature). The complexes formed were studied as a function of −log[H+]. All of the appropriate equilibrium stability constants were calculated with the aid of the interactive computer program BEST. The constants obtained generally reproduce the entire experimental potentiometric equilibrium curves to within 0.01 log[H+] units. The protonation constants 10.142, 5.460, 2.229 reproduce the potentiometric equilibrium curve of free PMG to within a σ value of 0.004 log[H+] units while 10.79.6.08, 5.04 and 0.86 are the protonation constants for IDP.

Molecular interaction of pyrophosphate with 1, 13-dioxa-4,7,10,16,20,24-hexaazacyclohexacosane (OBISDIPEN) and its mononuclear and dinuclear copper(II) complexes

Abstract The unsymmetrical hexabasic macrocyclic ligand 1,13-dioxa-4,7,10,16,20,24-hexaazacyclohexacosane ([26]aneN 6 O 2 , OBISDIPEN) forms an assortment of cationic species including mono- through hexaprotonated forms of ther macrocyclic ligand in the absence of metal ions as well as mononuclear and dinuclear Cu(II) complexes. These mononuclear and dinuclear Cu(II) complexes also form protonated and hydroxylated species. The cationic hosts combine with certain molecules and anions (guests) which have the requisite size, shape and donor groups. A bidentate guest molecule or anion can bridge the two metal ions and coordinate them simultaneously. This paper describes the reactions of OBISDIPEN and of its six mononuclear and four dinuclear Cu(II) complexes with the pyrophosphate bridging group to form complexes which exist in a variety of protonated conformations. The binding in these complexes consists of coulombic forces, hydrogen bonds and coordinate metal-donor bonds. The equilibrium constants were obtained by potentiometric titration at 25.0 ± 0.1°C and μ = 0.1 M KCl. These constants are compared to those of the analogous ligand 4,7,10,16,19,22-hexaaza-1,13-dioxacyclotetracosane (OBISDIEN).

Aluminium complexes of hydroxyaliphatic and hydroxyaromatic ligands in aqueous systems—some problems and solutions

Abstract The stabilities of aluminium(III) complexes of ligands with hard oxygen donors are analysed and an up-to-date compilation of critical stability constants of aluminium(III) complexes of hydroxyaliphatic and hydroxyaromatic chelating agents is presented. The interferences with complex formation caused by hydrolysis of the metal ion to form soluble mononuclear and polynuclear hydroxo complexes, and by aluminium(III) hydroxide precipitation, are illustrated. In view of contradictory reports in the literature, a unified treatment of aluminium(III) citrate complexes is presented, and the formation of stable and metastable forms of mononuclear and ternuclear hydroxo citrate complexes is illustrated. The limitations in the use of normal formation constants for representing equilibrium data involving ligands with very high pKs is explained, and the use of hydrogen ion displacement equilibrium constants for such systems is recommended. Comparison of the effectiveness of several ligands for aluminium(III) complexation shows that desferriferrioxamine B (Desferal®), recommended for the treatment of aluminium(III) overload is by far the superior ligand over a very broad pH range.

Development of iron chelators for Cooley's anemia

Abstract The rationale employed in the design of new chelating ligands for strong binding of Fe(III) at physiological pH for the treatment of iron overload disease such as Cooleys anemia is explained and the preparation and evaluation of forty new iron(III) chelators are described. The new ligands investigated include the following classifications: five analogs of ethylenediaminetetraacetic acid (EDTA) with amino and carboxylate donor groups; ten ligands with phenolic (or potential phenolic) donor groups in addition to amino and carboxylate donors: five ligands containing phenolic groups substituted on pyridine rings in addition to amino and carboxylate donors; six aminophosphonic acid or ester groups with additional phenolate and amino donors; eight macrocyclic polyamines containing auxiliary carboxylate and/or phenolate donor groups; three trishydroxamic acids; two triscatechols; and one multi- dentate ligand with coordinating amide groups. These chelating agents were administered to male BDF 1 hybrid mice overloaded with iron by blood transfusion. Fecal and urinary elimination of iron were measured, as well as the retention of iron in the spleen and liver. The results are compared with the action of desferriferrioxamine B (DFB). Potencies relative to a Desferal® dose of 250 mg/kg tested simultaneously and assigned a potency of 1.0 are reported, and relative toxicities ( LD 50s and toxic signs) are also described. Nine of the ligands tested showed sufficient potency to warrant further development as iron chelating drugs, while six of them have potencies comparable to or greater than that of DFB.

Coordination of Al(III) in the environment and in biological systems

Abstract The tendencies of donor atoms and donor groups to form stable Al(III) complexes are described, and ligands with very basic oxygen donors are compared with chelating ligands having less basic donor atoms. Deprotonated forms of aliphatic α-hydroxy acids, and aromatic hydroxyl or polyhydroxy ligands, have the highest affinities for Al(III). Critical (selected) stability constants, and related protonation and deprotonation constants are given for Al(III) complexes of oxygen donor ligands and aminocarboxylates, including ligands that undergo deprotonation in the presence of metal ions to produce very basic donor oxygens. The hydrolysis of Al(III) leaves a small but appreciable concentration of Al(OH)3 in solution, which may account for transport of Al(III) ion the environment. The presence of fluoride ion causes increased solubility and transport of AI(III). Desferriferrioxamine-B forms a very stable complex of Al(III) and the ligand has been suggested for the treatment of aluminum overload. Also, 1,2-dimethyl-3-hydroxy-4-pyridinone (DMHP, L1) forms a very stable aluminum(III) chelate and may also find application for the removal of Al(III) from the body.

A systematic evaluation of molecular recognition phenomena. 2. Interaction between phosphates and nucleotides with hexaazamacrocyclic ligands containing diethylic ether spacers.

The host-guest interactions between ortho- (Ph), pyro- (Pp), and tripolyphosphate (Tr) anions together with ATP (At), ADP (Ad), and AMP (Am) nucleotides and the two hexaazamacrocyclic ligands 1,15-dioxa-4,8,12,18,22,26-hexaazacyclooctacosane (Pn) and 1,13-dioxa-4,7,10,16,20,24-hexaazacyclohexacosane (Op) have been investigated by potentiometric equilibrium methods. Ternary complexes are formed in aqueous solution as a result of hydrogen bond formation and Coulombic attraction between the host and the guest. Formation constants for all the species obtained are reported. The selectivity of the Pn and Op ligands with regard to the different phosphate and nucleotide substrates is discussed and illustrated with total species distribution diagrams. A comparison is also carried out, with the results obtained in this work and those obtained previously with three other closely related hexaazamacrocyclic ligands. This comparison manifests the importance of ligand basicity, rigidity, and pi-stacking capability in order to understand their binding and selectivity.

Prediction of stability constants. I: Protonation constants of carboxylates and formation constants of their complexes with class A metal ions

Abstract Methods recently developed for the estimation of stability and protonation constants of ligands for which no data currently exist are now applied to aliphatic organic mono-, di-, and tricarboxylic acids and their complexes with basic metal ions such as the alkali(I) and alkaline earth(II) metal ions, the lanthanide(III) ions, the actinide(III and IV) ions, and the dioxoactinide(VI) ions. The results consist of selected measures values, and estimated values, of the protonation and formation constants of 18 structural types of carboxylate ligands. Variations of stability constants with ionic strength are determined for various charge types, extending the data for potential application to environment systems, sea water, and biological fluids. The complexes of the alkali metal ions and of the alkaline earth ions showed variations in stability constants that are interpreted with the aid of ionic models of these complexes. The lanthanide complexes showed increases in stability constant increments through the first half of the series, followed by a change to a lower slope, and in some cases to a negative slope, at or just before gadolinium(III). Data currently available for the actinides are limited, but a few estimated constants are presented. More data are needed to establish definite trends.

Speciation of metals in the oceans. I. Inorganic complexes in seawater, and influence of added chelating agents

Abstract The speciation of the metal ions in the surface waters of the open ocean has been computed by using critical stability constants describing all of the inorganic complexes that can be formed by the metal ions and inorganic ligands present. The stability constants used were adjusted to change the literature values from 0.10 M ionic strength to the 0.70 M ionic strength of seawater by using a new empirical technique involving experimentally observed variations of stability constants with ionic strength for complexes of similar charge types. For stability constants not listed in Critical Stability Constant compilations, values were estimated by using known trends of stability constants of similar complexes. The speciation determinations made include equilibria with suspended solid phases such as hydroxides, carbonates, and basic carbonates of the metal ions present. Perturbation of metal speciation resulting from the addition of some common chelating agents is determined and the results obtained are discussed in terms of the effects on seawater by the introduction of these chelating agents into the environment. In the 10 −9 to 10 −7 range of added chelant, EDTA (ethylenediaminetetraacetate), NTA (nitrilotriacetate), TPP (tripolyphosphate) and CIT (citrate) exist in the ocean primarily as their Ca(II) and Mg(II) chelates. EDTA and NTA are the dominant ligands for Cu(II) and Ni(II), while TPP is extensively complexed to Fe(III). CIT strongly influences Cu(II) speciation, while SSA (sulfosalicylate, a well-known Fe(III) reagent) has no influence on any of these metal ions or their complexes.