Elsevier

Polyhedron

Volume 160, 1 March 2019, Pages 180-188
Polyhedron

A new series of lanthanide complexes with the trans-disubstituted Py2[18]aneN6 macrocyclic ligand: synthesis, structures and properties

https://doi.org/10.1016/j.poly.2018.12.006Get rights and content

Abstract

New lanthanide complexes with the trans-disubstituted macrocyclic ligand Py2[18]aneN6 (denoted as L1) were successfully synthesized. The coordination properties of compound L1 towards different lanthanide metal ions (Ln = La–Yb, except Lu) were explored, and structural studies have been carried out both in the solid state and in aqueous solution. In all cases, complexes with a 1:1 metal:ligand molar ratio were obtained. The crystalline structures of the following compounds: [H4L1](NO3)4, [CeL1(NO3)2](NO3) and [SmL1(NO3)2](NO3) have been characterized by single crystal X-ray diffraction. In both complexes, the asymmetric unit contains the cation complex [LnL1(NO3)2]+ (Ln = Ce3+, Sm3+) which consist of a mononuclear endomacrocyclic backbone whilst the ten coordination environment is completed by two bidentade nitrate ions. The two five membered chelate rings formed by the ethylenediamine moieties adopt (δδ) [or (λλ)] conformations and also presented a C2 symmetry (as observed in solution by NMR).

Graphical abstract

The coordination properties of a novel trans-disubstituted macrocyclic ligand Py2[18]aneN6 (denoted as L1) towards different lanthanide metal ions (Ln = La–Yb, except Lu) were explored, and structural studies have been carried out both in the solid state and in aqueous solution. The crystalline structures of the following compounds: [H4L1](NO3)4, [CeL1(NO3)2](NO3) and [SmL1(NO3)2](NO3) have been characterized by single crystal X-ray diffraction.

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Introduction

Magnetic resonance imaging (MRI) is a medical imaging technique consisting of magnetizing body atom nuclei, generally hydrogen nuclei of water molecules, using a very strong magnetic field. This technique measures the random motion of water molecules in tissues, revealing their microarchitecture. For this reason, MRI is frequently used in clinical diagnosis [1].

Gd3+ metal complexes are able of catalytically reducing the time of relaxation of water molecules that are in the vicinity, allowing the obtaining of higher quality images. For this reason, complexes of the element gadolinium (Gd) are the most widely used of all MR contrast agents [2]. However, this metal presents a high toxicity. The ionic radius of Gd3+ and Ca2+ are similar, and as a result it can disrupt Ca2+ mediated signaling, forming strong complexes that can accumulate within the body.

For this reason, it is really important to develop novel compounds to be used as contrast agents. They must satisfy the following conditions: contain an effective organic ligand that selectively forms metal complexes, thermodynamically stable and kinetic inertia. Furthermore, fast renal excretion, stability in aqueous conditions, water solubility, and a low osmotic potential would be also necessary for the clinical application of these compounds in solution [3], [4], [5].

On the other hand, macrocyclic derivatives based on 1,4,7,10-tetraazcyclodecane (cyclen) are among the most broadly used ligands for stable lanthanide complexation in water [1], [2], [3], [4], [5]. The easiest synthetic approach is the per substitution, in which all four N-atoms of the macrocycle are alkylated or acylated [1].

The most important representative of this family of ligands is H4DOTA [1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid, Chart 1], which forms lanthanide complexes of remarkably high thermodynamic stability and kinetic inertness [6], [7].

From the synthetic point of view there is an important challenge, the preparation of mono-, di- or trisubstituted derivatives. The metallic complexes formed between various lanthanide ions and the heptadentate ligand H3DO3A [1,4,7,10-tetraazacyclodecane 1,4,7-triacetic acid, Chart 1] and their derivatives have been also widely studied [8], [9], [10], [11], [12], [13].

A feature of the coordination chemistry of lanthanide ions is that it has high coordination rates. In the case of metal complexes with Gd3+ that are used in MRI, they tend to present a coordination index of nine. Typically, the Ln3+ cation occupies the center of the structure of the complex, and is linked to eight heteroatoms of a ligand, while the last coordinating position that remains free is occupied by a molecule of water solvent.

Ln3+ complexes with different tetrasubstituted heaazamacrocycles derived from L [Chart 1] have been previously synthesized and studied [14], [15], [16]. These ligands are potentially decadentade and for large Ln3+ ions the metal is endomacrocyclic coordinated to all donor atoms, while for the smaller ones, coordination number is in some cases reduced to nine, as in LAc4 [17] [Chart 1]. However, the high number of donor atoms present in these tetrasubstituted macrocycles prevents a water molecule can be incorporated into the first coordination sphere of the Ln3+ ion.

In an attempt to obtain a new dipyridine receptor able to form stable Ln3+ complexes with one water molecule in the inner sphere of the ions, we have recently synthesized the new trans-N,N′-methylated hexaazamacrocycle L1 [18], derived from L. This new macrocyclic ligand shows two methylated trans amine groups, and it has been prepared using a similar procedures described for trans-disubstituted cyclen macrocycles [13]. The synthesis of the macrocyclic precursors was achieved following the previously described method [19].

As an extension of our work we report here structural studies, in solid and in solution, of the lanthanide complexes with the ligand trans-N,N-methylated hexaazamacrocycle L1, derived from L. This macrocyclic receptor L1 could provide a convenient platform for the design of stable Ln3+ complexes for biological applications. Starting from it, a new receptor can be synthesized by alkylation of the trans secondary amine groups presents in the ligand.

Some Ln3+ complexes of L1 have been synthesized and characterized by means of analytical and spectroscopic techniques. The crystal structures of the compound salt [H4L1](NO3)4 showing two trans methyl groups and the metal complexes [CeL1(NO3)2](NO3) and [SmL1(NO3)2](NO3) have also been characterized by single crystal X-ray crystallography.

Also, the structure of the complexes in solution has been studied by NMR. Alkylation of the two remaining secondary amine groups leads to potentially octadentade macrocyclic receptors as in cyclen derivatives.

Section snippets

Chemical and starting materials

Pyridine-2,6-dicarbaldehyde [20] and L [21], were achieved following the literature. L1 has been synthesized following the previously mentioned methodology developed in the research group [13]. The remaining reagents employed in the synthesis were purchased from Aldrich/Panreac and were used without further purification. The solvents used were of reagent grade and purified by usual methods.

Measurements

Elemental analyses were performed on a Fisons Instruments EA1108 microanalyzer. Infra-red spectra were

Synthesis and characterization of complexes derived from L1

The lanthanide complexes of L1 were synthesized in a 1:1 metal:ligand ratio in acetonitrile, giving rise to compounds of formula [ML1](NO3)3·xH2O (M = La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+ and Yb3+) in good yield. All compounds are soluble in DMSO, CH3CN and acetone. The compounds are also soluble in a mixture of DMSO and H2O at 10%.

The IR spectra were recorded as KBr discs. The bands due to ν(Cdouble bondN) and ν(Cdouble bondC) stretching modes of the pyridine rings on the complexes

Conclusions

A new trans-disubstituted macrocyclic ligand L1 has been obtained in satisfactory yield and purity. The complexation capability of L1 in a 1:1 metal:ligand molar ratio towards the lanthanide metal ions has been investigated. The ligand L1 probably does not have a large enough cavity to give rise to dinuclear endomacrocyclic complexes with these ions, therefore compounds containing cationic and anionic species were obtained. The crystalline structures of [H4L1](NO3)4, [CeL1(NO3)2](NO3) and [SmL1

Acknowledgments

This work was made possible thanks to the financial support received from the Xunta de Galicia (Galicia, Spain) under the “Grupos de Referencia Competitiva” Programme (Project GRC2015/009). The authors are indebted to CACTUS (Universidad de Santiago de Compostela) for the X-ray measurements. C. Núñez acknowledges Miguel Servet I Programme (CP16/00139) from the “Instituto de Salud Carlos III” (Plan Estatal de I + D + i 2013-2016 and European Development Regional Fund) of the Spanish Ministry of

Conflicts of interest

The authors declare no competing interests.

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