Elsevier

Journal of Inorganic Biochemistry

Volume 189, December 2018, Pages 103-114
Journal of Inorganic Biochemistry

Equilibrium studies of new bis-hydroxypyrone derivatives with Fe3+, Al3+, Cu2+ and Zn2+

https://doi.org/10.1016/j.jinorgbio.2018.09.013Get rights and content

Highlights

  • Easy-low cost synthesis of chelating agents for medical and environmental applications

  • Study of complex formation equilibria of the ligands with Fe3+, Al3+, Cu2+ and Zn2+

  • Trivalent metal ions form stable M2L3 complexes through the oxygen donor atoms.

  • Complexes with divalent metal ions involve also linker nitrogen atoms in coordination.

Abstract

This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe3+, Al3+, Cu2+ and Zn2+. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2. The different anchoring position of the linker, as well as the linker length, can affect both protonation and complex formation equilibria. A thorough study of the protonation and complex formation equilibria of the three ligands toward the metal ions is presented based on combined potentiometric and spectroscopic studies, and 1H NMR. The obtained results allow remarking that the orientation of the oxygen atoms in the kojic acid units, related to the anchoring position of the linker, strongly affects the protonation constants, while the chelating ability is practically unaffected. The trivalent metal ions form stable complexes with a 2:3 metal to ligand stoichiometry through the oxygen donor atoms of the ligands, whereas divalent metal ions form binuclear complexes for which the nitrogen atoms from the linker might be involved in the coordination sphere. The stability of the complexes decreases with linker length, and the selectivity of the ligands toward metal ions grows in the order Zn2+ < Cu2+ < Al3+ < Fe3+.

Graphical abstract

Three new ligands were synthesized joining two kojic acid units through different diamines, their protonation and complex formation toward Fe3+, Al3+, Cu2+ and Zn2+ studied by potentiometry, spectroscopy, and NMR. Trivalent ions form 2:3 metal/ligand complexes through oxygen atoms; divalent ions form binuclear complexes with involved also linker nitrogen atoms.

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Introduction

Metal ion toxicity is nowadays a primary topic in medicinal, environmental and agricultural chemistry, and the research of new metal chelators is still a leading motif in scientific research. Effective metal chelating agents, in addition to their recognized medical uses [[1], [2], [3]], find also an increasing number of applications in environmental remediation [[4], [5], [6]] and in agriculture for supplying essential elements to plants in an easily available form, or making accessible those elements already present in the soil [[7], [8], [9]]. Besides the formation of stable metal complexes, the lack of toxicity, the biodegradability and the low cost are the fundamental requisites of metal chelating agents for these applications. With these aims in mind, we designed and synthesized the three new ligands object of the present paper as iron and aluminium chelating agents. Since 2010, our research group has been studying a number of kojic acid (KA) (Fig. 1) derivatives, formed by two KA units joined through variable linkers always attached in position 6 (Fig. 2) [[10], [11], [12], [13]].

In the same years, other research groups have been working on KA derivatives [[14], [15], [16], [17]]. The main features of these molecules are the low toxicity, the versatility for metal complex formation, and in some cases tyrosinase inhibitory activity. In a recent review regarding these ligands [18], it was reported that the length of the linker plays a basic role in determining the stoichiometry of the formed iron complexes (Fe2L2 and Fe2L3 stoichiometries). In the 2:3 complexes the mode of coordination completely fits that in Fe(KA)3, remarking that no strain is introduced with the length of the linker. The entropic and enthalpic contributions were also qualitatively discussed to explain the gain in pFe1 passing from kojic acid to the bis-kojic derivatives [18]. In the following, when mentioning the KA derivatives linked in position 6, we will refer to them as L ligands.

In the present study, a different strategy in the synthesis is proposed: we preserved kojic acid, a cheap molecule without toxic effects, as the basic unit for the new chelators, but adopted a different synthetic strategy joining the 2 KA units through simple linear diamines of variable length by reacting them with the OH groups in position 2. The simplicity of synthesis allows an easy and low cost preparation. The different mutual position of the binding oxygen groups, related to the anchoring position of the linker, as well as the linker length, can affect both the protonation and complex formation equilibria. In particular, we present a thorough study of the ligands obtained using as a linker the three basic linear ethylene diamine, propylene diamine and butylene diamine. This strategy has the aims of evaluating how the anchoring position and the length of the linker affect both the protonation constants, and the complex formation constants; of introducing coordinating nitrogen atoms in the linker, that could be involved in the coordination to Cu2+ and Zn2+ ions [19], and to use a synthetic method transferable to analogous pyridinone molecules.

The complex formation and coordination mode of S2, S3 and S4 ligands (Fig. 3) toward Fe3+ and Al3+ ions, studied by combined potentiometric and spectroscopic techniques, has been extended to the bivalent essential metal ions Zn2+ and Cu2+. In fact, a recent speciation study showed that iron chelation could imply the depletion or dislocation of essential metal ions, and stated “that a thorough understanding of the copper and zinc complexation models is of paramount importance and must always be presented for any ligand intended to be used in therapy” [19].

Section snippets

Reagents

HCl, NaCl, NaOH, D2O, ethanol, DCl, NaOD, FeCl3, AlCl3, ZnCl2, CuCl2, 5-hydroxy-2-hydroxymethyl-pyran-4-one (kojic acid, KA; purity 99%), ethylene diamine, propane-1,3-diamine, and butane-1,4-diamine were Aldrich products. Carbonate free sodium hydroxide solutions were prepared according to Albert and Serjeant [20].

The metal ion standard solutions were prepared by dissolving the required amount of chloride salts in pure double distilled water and adding a stoichiometric amount of HCl to prevent

Protonation equilibria

The protonation equilibria of the free ligands were studied by combined potentiometric-UV measurements and NMR titrations. The log K values, evaluated from potentiometric data with Hyperquad program, and the absorptivity spectra, calculated with HypSpec program, are presented in Table 1 and in Fig. 4 respectively. Furthermore, the protonation constants of the three amines that constitute the linkers, potentiometrically determined, are presented for comparison in the same Table 1 [29].

As

Conclusion and perspectives

In conclusion, taking into account the whole results obtained both from potentiometric and spectroscopic measurements it is possible to point out all the following facts:

  • The orientation of the oxygen atoms in the KA units, which depends on the size of the linker in position 2, strongly affects the protonation constants. The chelating ability of ligands S2–S4 is instead of the same order of magnitude of those of the ligands with the linker connected in position 6.

  • All the three ligands form

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

VMN and MAZ acknowledge the financial support by MIUR-PRIN 2015 - 2015MP34H3. VMN thanks Fondazione Banco di Sardegna and Regione Autonoma della Sardegna for the financial support “Progetti Biennali di Ateneo Annualità 2016”.

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