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The coordination behaviour of tris(aminomethyl)phosphine oxide ( tampo ) to selected transition metal ions was studied. In the case of Co(III), Ni(II) and Cu(II) complexes with metal-to-ligand 1:2 stoichiometry, bis(tripodal) tampo coordinations forming octahedral coordination spheres (in the case of Cu(II) complex with significant Jahn-Teller distortion) were found by X-ray diffraction analysis. Based on the potentiometric study, the tripodal coordination of the title ligand is also expected in solution. The stability of the metal complexes follows the Irving-Williams trend. Compared with the structurally “parent” 1,1,1-tris(aminomethyl)ethane ( tame ) ligand, the complexation of tampo occurs at a lower pH as the consequence of low ligand basicity [log K 1 = 6.72(1), log K 2 = 5.34(1) and log K 3 = 3.82(1)], although the values of the stability constants of the metal complexes are relatively low.

A new facile synthetic strategy was developed to prepare bifunctional monophosphinic acid Ln-DOTA derivatives, Gd-DO2AGAPNBn and Gd- DO2AGAPABn. The relaxivities of the Gd-complexes are enhanced compared to Gd-DOTA. Monophosphinic acid arm of these Gd-complexes affords enhancement of inner sphere water exchange rate due to its steric bulkiness. The different functionalities of DO2AGAPNBn were appended in trans positions and are designed to conjugate identical or different vectors according to the potential applications. The conjugation of Gd-DO2AGAPABn with E3 peptide known to target apoptosis was successfully performed and in vivo MRI allowed cell death detection in a mouse model.

The interaction of aminomethylphosphonic acid (H2amp) with the Zn(II)–cyclen complex and the formation of ternary complexes was studied by potentiometry and 31P NMR titrations. Data evaluation of each of the methods separately was found to be insufficient. Thus, data obtained from the both methods were simultaneously treated with the computer program OPIUM. The determined stability constants indicated only weak (log K ∼ 3) coordination of aminomethylphosphonic acid through the phosphonate group. The chelating coordination mode with the participation of the amine group was not confirmed. In excess of Zn(II)–cyclen, the formation of dinuclear complexes, in which two Zn(II)–cyclen units are bridged by a phosphonate group, was observed and their presence was confirmed by mass spectrometry. Such a coordination motif is typical for phosphonates in the solid state and also for phosphatases.

Four geminal bis(phosphinic acids), namely, aminomethylbis(H-phosphinic acid) (H2L1) and 4-aminobutyl-1-hydroxy-1,1-bis(R-phosphinic acid) with R = H (H2L2), Me (H2L3) and CH2CH2COOH (H4L4), were studied. Their acid–base properties and coordination ability towards Cu2+, Ni2+ and Zn2+ ions were studied by potentiometry, UV/Vis spectroscopy and NMR spectroscopy. The amine group in H2L1 has a lower protonation constant (log Ka = 6.79) than those found for other studied bisphosphinates (log Ka = 10.75–11.05) with distant amine groups. The structure of [Ca(H2L2-O,O′)(HL2-O,O′)]Cl revealed an octahedral arrangement of the metal coordination sphere and a linear polymeric structure, which forms through eight-membered Ca(–O–P–O–)2Ca rings. The structure of [Cu(HL3-O,O′)2(H2O)]·5H2O shows two chelating bisphosphinate groups in an equatorial O4 environment. The structure of [Cu(H0.5L3-O,O′)(NO3)0.5]·2.25H2O shows two different coordination environments, one is an elongated tetragonal pyramid, and the other is a trigonal bipyramid with a bidentate nitrate ion.

Preparation of two benzylic bis(phosphonic acids) modified with primary amine or carboxylic acid groups on the benzene ring is described. These compounds were prepared and characterized in the form of both bis(phosphonate) tetraesters and corresponding free acids. The phosphonic acid esters are suitable for further derivation, mainly for conjugation through the amide bond. Mild conversion of the bis(phosphonate) esters to free acids using trimethylsilylbromide allowed to work with functional groups sensitive to conditions of acidic and/or alkaline hydrolysis. Three bis(phosphonate)-containing fluorescent probes were prepared from the building blocks, utilizing amide and sulfamide bonds as spacers. Dyes containing the dansyl group, rhodamine B, and fluorescein were chosen due to their common availability and low cost. The prepared bis(phosphonate)-building blocks and modified fluorescent probes were used for adsorption studies with hydroxyapatite, the commonly used model of bone tissue. Sorption ability of the prepared bis(phosphonate) compounds was similar to that of pamidronate.

Three magnetic resonance (MR)/fluorescence imaging probes were tested for visualization, cellular distribution, and survival of labeled pancreatic islets in vitro and following transplantation. As T(1) contrast agents (CAs), gadolinium(III) complexes linked to β-cyclodextrin (Gd-F-βCD) or bound to titanium dioxide (TiO2 @RhdGd) were tested. As a T(2) CA, perovskite manganite nanoparticles (LSMO@siF@si) were examined. Fluorescein or rhodamine was incorporated as a fluorescent marker in all probes. Islets labeled with gadolinium(III) CAs were visible as hyperintense spots on MR in vitro, but detection in vivo was inconclusive. Islets labeled with LSMO@siF@si CA were clearly visible as hypointense spots or areas on MR scans in vitro as well as in vivo. All CAs were detected inside the islet cells by fluorescence. Although the vitality and function of the labeled islets was not impaired by any of the tested CAs, results indicate that LSMO@siF@si CA is a superior marker for islet labeling, as it provides better contrast enhancement within a shorter scan time.

A synthesis of 1-hydroxy-1,1-bis(H-phosphinates) from acylchlorides is described. Solid-state structures of two bis(phosphinates) determined by X-ray diffraction showed variations in the PC distances. The compounds show negligible sorption on hydroxyapatite and an intermediate chemical stability in aqueous solution. The hydrolysis occurs in acidic as well as alkaline media. Hydrolysis rates of four derivatives show the lowest stability for aromatic derivatives as a result of the electron-withdrawing effect. Main products of hydrolysis are 1-hydroxy-(H-phosphinates) and phosphorous acid. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:195–201, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21003

Multimodal imaging-therapeutic nanoprobe TiO(2)@RhdGd was prepared and successfully used for in vitro and in vivo cell tracking as well as for killing of cancer cells in vitro. TiO(2) nanoparticles were used as a core for phosphonic acid modified functionalities, responsible for contrast in MRI and optical imaging. The probe shows high (1)H relaxivity and relaxivity density values. Presence of fluorescent dye allows for visualization by means of fluorescence microscopy. The applicability of the probe was studied, using mesenchymal stem cells, cancer HeLa cells, and T-lymphocytes. The probe did not exhibit toxicity in any of these systems. Labeled cells were successfully visualized in vitro by means of fluorescence microscopy and MRI. Furthermore, it was shown that the probe TiO(2)@RhdGd can be changed into a cancer cell killer upon UV light irradiation. The above stated results represent a valuable proof of a principle showing applicability of the probe design for diagnosis and therapy.

The first systematic study of chemical adsorption/desorption of phosphonic acid and geminal bis(phosphonic acid) on/from the surface of anatase nanoparticles is reported. Stable TiO2 colloidal nanodispersions were used in the study. The colloidal stability is preserved upon nanoparticle modification. A macrocyclic lanthanide(III) complex, attached through a phosphonic/bis(phosphonic) group to the TiO2 surface allowed precise quantification of sorption parameters by means of inductively coupled plasma atomic emission spectroscopy (ICP-AES). Results show different behavior of phosphonate and bis(phosphonate) groups. For phosphonate, a monomolecular layer formation was observed, and the desorption rate depends on the sorption conditions. It is probably caused by different phosphonate binding modes on the surface. Excess amounts of phosphate in the washing media accelerates the desorption rate of the phosphonate. The bis(phosphonate) is adsorbed on the surface in large quantities forming multilayers that resist desorption even in the presence of phosphate ions and, thus, the bis(phosphonate) moiety is a suitable group for anchoring other molecules on the TiO2 particle surface.

Potentiometric titrations and 1H NMR spectroscopic studies of amino acids binding to the [ZnL]2+-complex where L = cyclen in aqueous solution provide information concerning complexing species identity, their stability, and coordination mode declaration. The amino acids form stable ternary [ZnL(HLn)]2+ and [ZnL(Ln)]+ complexes. The observations indicate bidentate coordination mode of the deprotonated amino acids, involving both the amine and the carboxylate functions to the [ZnL]2+ complex in pH region of about 7.5–9.5. The determined stability constants indicate that [ZnL]2+ complex is a very efficient receptor for simple amino acids such as glycine and alanine. Copyright © 2010 John Wiley & Sons, Ltd.

The present study reveals the potential of magnetic nanoparticles based on the La0.75Sr0.25MnO3 perovskite manganite for magnetic resonance imaging (MRI). Moreover, it describes the development of the dual imaging probe where the magnetic cores are combined with a fluorescent moiety while the improved colloidal stability is achieved by a two-ply silica shell. At first, the magnetic cores of La0.75Sr0.25MnO3 are coated with a hybrid silica layer, comprising a covalently attached fluorescein moiety that is subsequently covered by a pure silica layer providing the enhanced stability. The detailed characterization of the intermediate and the final product reveals the importance of the complex two-ply shell. Viability tests show that the complete particles are suitable for biological studies. Internalization of the particles and their presence in intracellular vesicles are observed by fluorescence microscopy in different cell types. Further experiments prove no fatal interference with the vitality and insulin releasing ability of labeled pancreatic islets. Relaxometric measurements confirm high spin–spin relaxivities at magnetic fields of B0 = 0.5–3 T, while visualisation of in vitro labeled pancreatic islets by MRI is successfully tested.

99mTc-phosphonate structures are well established tracers for bone tumour imaging. Our objective was to investigate different 68Ga-labelled phosphonate ligands concerning labelling kinetics, binding to hydroxyapatite and bone imaging using μ-PET. Seven macrocyclic phosphorus-containing ligands and EDTMP were labelled in nanomolar scale with n.c.a. 68Ga in Na-HEPES buffer at pH∼4. Except for DOTP, all ligands were labelled with >92% yield. Binding of the 68Ga-ligand complexes on hydroxyapatite was analysed to evaluate the effect of the number of the phosphorus acid groups on adsorption parameters. Adsorption of 68Ga-EDTMP and 68Ga-DOTP was >83%. For the 68Ga-NOTA-phosphonates an increasing binding with increasing number of phosphonate groups was observed but was still lower than 68Ga-DOTP and 68Ga-EDTMP. μ-PET studies in vivo were performed with 68Ga-EDTMP and 68Ga-DOTP with Wistar rats. While 68Ga-EDTMP-PET showed uptake on bone structures, an excess amount of the ligand (>1.5 mg EDTMP/kg body weight) had to be used, otherwise the 68Ga3+ is released from the complex and forms gallium hydroxide or it is transchelated to 68Ga-transferrin. As a result, the main focus of further phosphonate structures has to be on complex formation in high radiochemical yields with macrocyclic ligands with phosphonate groups that are not required for complexing 68Ga.

Core–shell nanoparticles consisting of La 0.75 Sr 0.25 MnO 3 cores covered by silica were synthesized by a procedure consisting of several steps, including the sol–gel method in the presence of citric acid and ethylene glycol, thermal and mechanical treatment, encapsulation employing tetraethoxysilane and final separation by centrifugation in order to get the required size fraction. Morphological studies revealed well-separated particles that form a stable water suspension. Magnetic studies include magnetization measurements and investigation of the ferromagnetic–superparamagnetic–paramagnetic transition. Magnetic heating experiments in ‘calorimetric mode’ were used to determine the heating efficiency of the particles in water suspension and further employed for biological studies of extracellular and intracellular effects analysed by tests of viability.

International audience; A pyridine-N-oxide functionalized DOTA analogue has been conjugated to a calix[4]arene and the corresponding Gd-complex was characterized with respect to its suitability as MRI contrast agent. The compound forms spherical micelles in water with a cmc of 35 mu M and a radius of 8.2 nm. The relaxivity of these aggregates is 31.2 s(-1) mM(-1) at 25 degrees C and 20 MHz, which corresponds to a molecular relaxivity of 125 s(-1) mM(-1). The high relaxivity mainly originates from the short tau(M) (72.7 ns) and the size of the micelles. The interaction with bovine serum albumin (BSA) was studied and an observed relaxivity of up to 40.8 s(-1) mM(-1) (163.2 s(-1) mM(-1) per binding place) at 20 MHz and 37 degrees C was found in the presence of 2.0 mM protein.

Synthesis and characterization of a series of novel Zn–cyclen–aminoacid complexes are reported and non-covalent interactions were used for the conformation changes description. In addition to the TRANS-I ++++ (same position of NH hydrogen atoms in both isomers) configuration we observed two different isomers in the case of the [{Zn(Δ-cyclen)(HGly)}{Zn(Λ-cyclen)(HGly)}](ClO4)4 · 2H2O (1), [{Zn(Δ-cyclen)(S-HPhe)}{Zn(Λ-cyclen)(S-HPhe)}](ClO4)4 (2) and [Zn(Δ-cyclen)(S-HAla)](ClO4)2 (3) complexes with pentacoordinated zinc atom. Moreover, work also deals with the correlation between spectral and structural properties of the prepared complexes and their thermal stability.

A bifunctional ligand, DO3A-py(NO-C) (DO3A-py(NO-C) = 10-[(4-carboxy-1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), was attached to different generations (G0, G1, G2, and G4) of ethylenediamine-cored PAMAM dendrimers (PAMAM = polyamidoamine). The gadolinium(III) complex of this ligand possesses one molecule of water in its first coordination sphere and has a unique combination of a short water residence lifetime (tau(M) = 34 ns), a neutral overall charge, and a possibility for rigid attachment to molecules bearing primary amino groups. These favorable properties predestine the ligand for constructions of highly efficient nanosized contrast agents for magnetic resonance imaging (MRI). The coupling reaction between the carboxylic group on the pyridine-N-oxide moiety of the protected ligand molecule and primary amines in the dendrimers was achieved by an active ester method under nonaqueous conditions using the coupling agent TBTU. This reaction afforded conjugates with high loadings (80-100% of the theoretically available primary amines) and of high purity. The gadolinium(III) complexes of the conjugates were studied by variable-temperature 17O NMR and 1H NMRD measurements. The water residence lifetime (tau(M) = 55 ns) found in the largest conjugate G4-[Gd(H2O)(do3a-py(NO-C))]57, though somewhat longer compared to the "monomeric" complex, is still short enough not to limit the relaxivity. Surprisingly, compared with analogous conjugates with negatively charged chelates, the prepared uncharged compounds displayed much faster global rotational correlation times (tau(g)) and lower relaxivities. This phenomenon can be explained on the basis of Coulomb interactions. The motion of the charged chelates is restrained due to interactions with their counterions and the chelates themselves, while the uncharged chelates are not affected. Comparison of the PAMAM-based conjugates bearing uncharged and (1-)-charged chelates based on relaxometric data, 1H DOSY spectra, and SAXS measurements reveals that tau(g) reflects the rotational motion of large segments (dendrons) of the conjugates rather than that of the whole macromolecule.

In this study, the complexation rates of two new phosphinate H 4 dota (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) analogs, H 5 do3ap PrA and H 4 do3ap ABn , and H 4 dota itself were compared under identical conditions (H 5 do3ap PrA =10-{[(2-carboxyethyl)hydroxyphosphoryl]methyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; H 4 do3ap ABn =10-{[(4-aminophenyl)hydroxyphosphoryl]methyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). The biodistribution of their 111 In and 90 Y complexes in healthy rats was also studied. Unlike the observation obtained under “chemical” conditions where differences between the ligands were observed no such differences in complexation rates were found under radiochemical conditions. The ligands bind the radiometals similarly to H 4 dota. So, “chemical” formation kinetic data should be transferred into radiochemical conditions only with high care and “radiochemical” complexation experiments should be run as part of standard in vitro studies with new ligands considered as potential radiopharmaceuticals. Pharmacokinetic studies in rats showed similar distribution characteristics for both phosphinate H 4 dota analogs radiolabelled with 111 In and 90 Y when compared with that of the 111 In–H 4 dota complex. No specific uptake in any organ and tissue of rats was determined. The phosphinate complexes are not accumulated in calcified tissues.

Five DOTA-like ligands lacking a water molecule in the first coordination sphere of their Gd III complexes, namely the phosphinates H 4 DOTP H , H 4 DOTP hm and H 4 DOTP Et , and the phosphonate monoesters H 4 DOTP OEt and H 4 DOTP OBu , were synthesized with the aim of exploring the influence of the second hydration sphere on the relaxivity of Gd III complexes. The H 4 DOTP H , H 4 DOTP hm and H 4 DOTP OEt ligands and their Ln III complexes were characterized by potentiometry and time-resolved luminescence; the Gd III complexes are thermodynamically much less stable than that of H 4 DOTA, and no water is coordinated in the inner sphere. The crystal structures of the free ligand H 4 DOTP OEt and of the Gd III complexes of H 4 DOTP H and H 4 DOTP OEt were determined by X-ray diffraction. The complexes have the expected octadentate coordination mode with an N 4 O 4 arrangement; no water molecule is bound to the Gd III ion. Information on the structures of the Ln III complexes of all five ligands in aqueous solution were obtained from 1 H and 31 P NMR spectra. The NMR spectra of the [Ln(DOTP hm )]- and [Ln(DOTP Et )]- complexes show that these compounds have a clear preference for a specific arrangement of phosphorus atoms which gives rise to the symmetrical RRRR (or SSSS) isomer. However, many diastereoisomers were observed for all other complexes. Ln III -induced 17 O NMR shift data reveal that the spatial location of the second-sphere water molecules for the two groups of complexes differs. The parameters governing the effect of the second hydration sphere on the relaxivity of the Gd III complexes of all ligands were evaluated by EPR, variable-temperature 17 O NMR spectroscopy and 1 H NMRD re-laxometry. The presence of second-sphere water molecules is clearly confirmed, depending on the character of the pendant arms. As the relaxivity does not depend significantly on the nature of the phosphorus substituents and/or on the isomerism present in solution, the second-sphere water molecules should be located close to the phosphorus-oxygen atoms.

A new bifunctional cyclen-based ligand, 3-[hydroxy({4,7,10-tris[( TERT-butoxycarbonyl)methyl]-1,4,7,10-tetraazacyclododecan-1-yl}methyl)phosphoryl]propanoic acid, was synthe-sized by alkylation of tri- TERT-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate ( T-Bu 3 DO3A) by ethyl 3-{ethoxy[(mesyloxy)methyl]phosphoryl}propanoate [MsOCH 2 P(O)(OEt)CH 2 CH 2 CO 2 Et]. The ethyl carboxylate group in the side chain was selectively deprotected to obtain the esterified bifunctional ligand. More efficient syntheses of some phosphinopropanoic acid derivatives were devised and the phosphorus alkylation reagent was prepared starting from hypophosphorus acid or its salt.

The adsorption on hydroxyapatite of three conjugates of a bisphosphonate and a macrocycle having C1, C2, and C3 spacers and their terbium complexes was studied by the radiotracer method using 160Tb as the label. The radiotracer-containing complex of the conjugate with the C3 spacer was used as a probe for the determination of the adsorption parameters of other bisphosphonates that lack a DOTA unit. A physicochemical model describing the competitive adsorption was successfully applied in the fitting of the obtained data. The maximum adsorption capacity of bisphosphonates containing bulky substituents is determined mainly by their size. For bisphosphonates having no DOTA moiety, the maximum adsorption capacity is determined by the electrostatic repulsion between negatively charged bisphosphonate groups. Compounds with a hydroxy or amino group attached to the alpha-carbon atom show higher affinities. Macrocyclic compounds containing a short spacer between the different bisphosphonic acid groups and the macrocyclic unit exhibit high affinities, indicating a synergic effect of the bisphosphonic and the macrocyclic groups during adsorption. The competition method described uses a well-characterized complex and allows a simple evaluation of the adsorption behavior of bisphosphonates. The application of the macrocycle-bisphosphonate conjugates allows easy radiolabeling via complexation of a suitable metal isotope.

A series of new compounds built up on the skeleton of 1,5,8,12-tetraazabicyclo[10.2.2]hexadecane (1,4-ethylene-bridged cyclam, 1,4-en-cyclam) were synthesized and characterized by means of NMR and MS spectroscopy and a single-crystal X-ray structure determination. The attempts to substitute the secondary amino group of the p-nitrobenzyl-1,4-en-cyclam 3, using acetic acid derivatives as the alkylating agents, led to unexpected substitution of one of the piperazine ring nitrogen atoms, yielding the monoquaternary derivatives 4BrBr and 5BrBr, respectively. In order to explain this reaction behaviour, the solution structure of the starting compound 3 was established using 2D-NMR techniques. The acid–base behaviour of the ligands and thermodynamic stability constants of their copper(II) and zinc(II) complexes were determined using potentiometric titrations. Stability constants of the investigated metal complexes are significantly lower than those of the cyclam complexes and comparable to those of the Me4cyclam complexes. A copper(II) complex of amine 3 was prepared and characterized. In the solid state, this complex has the central copper atom surrounded by five donor atoms forming a coordination sphere with geometry between trigonal bipyramid and square pyramid.

Binary and ternary systems containing Zn2+, cyclen and/or pyridinecarboxylic acids and amides [picolinic (HL1), nicotinic (HL2) and dipicolinic (H2L3) acids and nicotinamide (L4)] have been investigated in solution and in the solid state. Dissociation and stability constants for the ligands and binary systems, respectively, are in accordance with literature results. Both picolinic and dipicolinic acids form stable ternary complexes with the [Zn(cyclen)]2+ species; a weak interaction is observed for nicotinic acid and nicotinamide. The formation of ternary complexes stabilizes the products of protonation at the cyclen nitrogen atom, and these protonated complexes are found even up to pH = 7. The structures of the complexes in solution correlate well with those found in the solid state and by molecular modelling calculations. The solid-state structures of several complexes are determined. The zinc atom in the [Zn(cyclen)(NO3)]+ complex is bound in an N4O tetragonal-pyramidal environment. The nicotinic acid anion forms a bridge in the [{Zn(cyclen)}2(μ-L2-N,O)]3+ cation, and both [Zn(cyclen)]2+ units exhibit tetragonal-pyramidal arrangements. An unusual coordination mode is found in the [{Zn(cyclen)}2(μ-L1-O:N,O′)]3+ cation, where the picolinic acid anion also bridges two [Zn(cyclen)]2+ units but is coordinated monodentately through one oxygen atom to one unit (N4O tetragonal pyramid) and chelates through the other pyridine nitrogen and carboxylate oxygen atoms. Nicotinamide in the [Zn(cyclen)(L4-N)]2+ cation is bound to the [Zn(cyclen)]2+ unit through the pyridine nitrogen atom in the axial position of the tetragonal pyramid. This is the first fully quantitative assessment of Zn2+-cyclen-ligand ternary systems, and the results, namely the presence of protonated cyclen in the ternary species even at high pH, are relevant for evaluation of the [Zn(cyclen)]2+ unit as a model complex for zinc-containing enzymes.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Two new tetraamine ligands, bis[N-(2-aminoethyl)aminomethyl]phosphinic acid (Hen2p) and bis[N-(3-aminopropyl)aminomethyl]phosphinic acid (Hpn2p), were synthesized from the corresponding diaminoalkanes and bis(chloromethyl)phosphinic acid. Their acid–base properties and complexation with Cu2+, Ni2+, and Zn2+ ions were studied by potentiometric titrations. Different chain lengths of the ligands result in significantly different coordination abilities. The five-membered chelate ring of Hen2p leads to a higher stability of its complexes. In comparison with tetraamines having the same number of the bridging atoms separating the amino groups, the presence of the phosphinic acid moiety decreases the basicity of the amine groups, and consequently, the stability of their complexes. Several solid-state structures were determined by X-ray diffraction analysis. Four nitrogen atoms coordinate the Cu2+ or Zn2+ ion in a square-planar fashion, whereas the phosphinic acid group is not coordinated or acts as a bridging unit between neighboring metal ions. The unexpectedly high stability of the Ni2+/Hpn2p complex can be explained by the possible presence of a tetramer in solution as was found in the solid state.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The complex formation of the bifunctional monophosphinic acid DOTA analogue DO3APABn (1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl] phosphinic acid}) with 111In at a tracer level was analyzed. Formation of a complex between 111In and DO3APABn was very rapid even at room temperature and high radiolabeling yields were achieved. As introducing the methylphosphinic acid arm to the DOTA structure generated a chiral centre, more than one peak (probably corresponding to various diastereoisomers) of 111In-DO3APABn were separated on HPLC. Four peaks were separated by HPLC, they probably correspond to four diastereoisomers of 111In-DO3APABn originating from combination of chirality of complexes of DOTA-like ligands with chirality of coordinated phosphorus atom. Studies in rats showed rapid elimination of radioactivity from the blood and other organs and tissues. The results indicate that DO3APABn represents a promising ligand for radiolabeling of target-specific biomolecules with radiometals.

Five geminal bis(phosphonates) containing an amino group in the α, γ or δ position of the carbon chain have been synthesised and their acid–base and complexation properties with Cu2+, Zn2+, Ca2+, Mg2+ and Na+ ions studied by potentiometry. Determination of the stability constants of the complexes with divalent metal ions is complicated by the formation of precipitates. The results of these studies show a negligible effect of the hydroxo group in the α position on the acid–base and complexation properties of the ligands. The presence of an amino group in the α position, however, decreases the basicity, which results in a lower complexation ability of the bis(phosphonates). The crystal structures of the three ligands with different degrees of protonation have also been determined. The structure of the triammonium salt of aminomethylbis(phosphonic acid) shows that the proton is bound to the nitrogen atom in monoprotonated species. The structure of the Cu2+ complex of pamidronate [{Cu2(H2pam)2}·H2O]n shows the presence of dimeric units with a relatively short distance (2.99 A) between the metal centres. These units form a coordination polymeric chain. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

International audience; Novel synthetic approaches for the development of multimodal imaging agents with high chemical stability are demonstrated. The magnetic cores are based on La0.63Sr0.37MnO3 manganite prepared as individual grains using a flux method followed by additional thermal treatment in a protective silica shell allowing to enhance their magnetic properties. The cores are then isolated and covered de novo with a hybrid silica layer formed through the hydrolysis and polycondensation of tetraethoxysilane and a fluorescent silane synthesized from rhodamine, piperazine spacer, and 3-iodopropyltrimethoxysilane. The aminoalkyltrialkoxysilanes are strictly avoided and the resulting particles are hydrolytically stable and do not release dye. The high colloidal stability of the material and the long durability of the fluorescence are reinforced by an additional silica layer on the surface of the particles. Structural and magnetic studies of the products using XRD, TEM, and SQUID magnetometry confirm the importance of the thermal treatment and demonstrate that no mechanical treatment is required for the flux-synthesized manganite. Detailed cell viability tests show negligible or very low toxicity at concentrations at which excellent labeling is achieved. Predominant localization of nanoparticles in lysosomes is confirmed by immunofluorescence staining. Relaxometric and biological studies suggest that the functionalized nanoparticles are suitable for imaging applications.

The thermodynamic and kinetic stabilities of the complexes of phosphonate and phenylphosphinate analogues of H5dtpa with selected transition- and lanthanide-metal ions are presented. Both phosphorus-containing ligands form thermodynamically very stable complexes, with stability constants comparable with or even higher than those reported for the parent H5dtpa. However, the kinetic inertness of their gadolinium(III) complexes against acid- and metal-assisted decomplexations is surprisingly much lower. The half-life times of gadolinium(III) complexes of the new ligands in the pres

Two triphenylphosphine derivatives, diethyl [4-(diphenylphosphanyl)benzyl]phosphonate (3a) and tetraethyl {[5-(diphenylphosphanyl)-1,3-phenylene]dimethylene}bis(phosphonate) (3b), and also the corresponding free acids 4a and 4b were prepared. These ligands were characterized by 1H, 13C and 31P NMR spectroscopy and mass spectrometry. A full set of their Pd(II) and Pt(II) complexes of the general formula [MCl2L2] and one dinuclear complex trans-[Pd2Cl4(3a)2] were synthesized and their isomerization behaviour in solution was studied. The complexes were characterized by 1H, 13C, 31P and 195Pt NMR spectroscopy, mass spectrometry and far-IR spectroscopy. The X-ray structures of all complexes with 3a or 3b have usual slightly distorted square-planar geometry on the metal ion. Salts of phosphonic acids 4a and 4b and their complexes are freely soluble in aqueous solution; therefore, they can be potentially useful in aqueous or biphasic catalysis.

Compound [Y(Hdo3aP(ABn))(H2O)][Y(Hdo3aP(ABn))].6H2O.iPrOH, where H4do3aP(ABn) is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-methyl(4-aminobenzylphosphinic) acid, a monophosphinate analogue of H4dota, was prepared in the solid state and studied using X-ray crystallography. In contrast to all single-crystal structures of complexes of H4dota-like ligands published before, three distinct units were found in one cell: two species adopting a twisted-square-antiprismatic configuration with (TSA) and without (TSA') a coordinated water molecule and one isomer with a square-antiprismatic configuration (SA). In addition, this is the first complex with the H4dota-like ligand for which the structures of three possible species were determined in the solid state.

A new cyclam-based ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-bis(methylphosphonic acid) (1,4-H4te2p), was synthesized. Cyclam was protected by the reaction with PhP(S)Cl2 to form exclusively five-membered cyclic phenylphosphonothioic diamide 2 in a moderate yield. The solid-state structures of 2 and several by-products were determined. Compound 2 was isolated as two stable conformers differing in a mutual position of benzene ring and sulfur atom with respect to the cyclam ring. Compound 2 was used for the synthesis of 1,4-dibenzylcyclam. However, the deprotection of the thiophosphoryl-protected bis(methylphosphonate diester) with aqueous HCl under non-optimized conditions led to a mixture of cyclam derivatives differently substituted with methylphosphonic acid groups. The crystal structures of the target product, 1,4-H4te2p, and also 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrakis(methylphosphonic acid) (H8tetp) were determined. A similar reaction with cyclen (1,4,7,10-tetraazacyclododecane) led only to hardly purifiable mixtures.

The luminescence lifetimes of europium(III) complexes with new monophosphorus acid derivatives of H(4)dota were measured by means of time-resolved laser-induced luminescence spectroscopy in H(2)O and D(2)O. The hydration numbers of these complexes were estimated using different empirical equations [Horrocks and Sudnick (1979) J. Am. Chem. Soc. 101 (1979) 334; Choppin and Barthelemy(1989) Inorg. Chem. 28, 3354-3357; Choppin and Bünzli Lanthanide probes in life, chemical and earth sciences. Theory and practice (1989); Kimura and Kato J. Alloys Comp. 275-277 (1998) 806; Parker (1999) J. Chem. Soc., Perkin Trans. 2, 493-503; Supkowski and Horroks (2002) Inorg. Chim. Acta. 340, 44-48]. It was shown that all the relationships gave similar results with a satisfactory precision. The hydration numbers of complexes of H(3)do3a and H(4)dota agreed with the literature values. One water molecule is coordinated in complexes of the new ligands. The results showed that the Choppin formula based on measurements only in H(2)O can be satisfactorily used for estimation of the hydration numbers.

New materials for dye-sensitized solar cells were incorporated and tested with success in sandwich type regenerative photoelectrochemical modules. A transition metal complex with two terpy ligands previously synthesized in our laboratory, [(2,2′:6′,2″-terpyridine-4′-iodophenyl)(2,2′:6′,2″-terpyridine-4′-phenylphosphonic acid)-ruthenium(II)]dichloride, has sensitized transparent thin nanostructured SnO2 film electrodes obtained by a doctor blade technique. A solvent-free composite polymer electrolyte consisting of high-molecular mass poly(ethylene) oxide filled with titania and containing LiI and I2 was introduced in order to transport the current of the cell at the counter electrode. Under white light illumination, the cell produced a continuous photocurrent as high as 0.63 mA cm−2 and a photovoltage of about 290 mV. The obtained IPCE (16%) and energy conversion values (0.1%) were similar to the corresponding values found with the standard N3 dye under the same conditions.

Solution properties of complexes of a new H4dota-like ligand containing three acetate and one methylphosphonate pendant arms (H5do3ap, H5L) were studied. The ligand exhibits a high last dissociation constant (pKA = 13.83) as a consequence of the presence of phosphonate moiety. In solution, successive attachment of protons leads to several reorganizations of protonation sites and the neutral zwitterionic species H5do3ap has the same solution structure as in the solid state, where the nitrogen atom binding methylphosphonate and the opposite nitrogen atoms are protonated. Stability constants with Na+ and trivalent lanthanide ions (La3+, Ce3+, Eu3+, Gd3+, Lu3+) and Y3+ have been determined. The constants are comparable or higher than those of H4dota due to the higher overall basicity of H5do3ap. Formation of the stable protonated complexes, as well as complexes with the L:M = 1:2 stoichiometry, was proved. Formation and decomplexation kinetics of the Ce3+ and Gd3+ complexes were investigated. The mechanism of formation of the H5do3ap complexes is similar to that observed for H4dota complexes and the complex species with mono- or diprotonated ligand on the cyclen ring are considered as the reaction intermediates. Acid-assisted decomplexation of H5do3ap complexes is faster in comparison with those of H4dota. This is caused by higher basicity of the phosphonate pendant arm and the ring nitrogen atoms, which facilitates the proton transfer from the bulk solution to the nitrogen atoms of cyclen ring.

A novel conjugate of a polysaccharide and a Gd(III) chelate with potential as contrast agent for magnetic resonance imaging (MRI) was synthesized. The structure of the chelate was derived from H5DTPA by replacing the central pendant arm by a phosphinic acid functional group, which was covalently bound to the polysaccharide inulin. On the average, each monosaccharide unit of the inulin was attached to approximately one (0.9) chelate moiety. The average molecular weight is 23110 and the average number of Gd3+ ions per molecule is 24. The ligand binds the Gd3+ ion in an octadentate fashion via three nitrogen atoms, four carboxylate oxygen atoms, and one P-O oxygen atom, and its first coordination sphere is completed by a water molecule. This compound shows promising properties for application as a contrast agent for MRI thanks to a favorable residence lifetime of this water molecule (170 ns at 298 K), a relatively long rotational correlation time (866 ps at 298 K), and the presence of two water molecules in the second coordination sphere of the Gd3+ ion. Furthermore, its stability toward transmetalation with Zn(II) is as high as that of the clinically used [Gd(DTPA)(H2O)]2-.

In an aqueous solution at room temperature, 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H(4)L(1)) and Cu(I) (I) form a pentacoordinated (pc) complex, pc-[Cu(L(1))](2-), exhibiting conformation I of the cyclam ring. At high temperature, the complex isomerises to a hexacoordinated isomer, trans-O,O-[Cu(L(1))](2-), with a trans-III conformation of the cyclam ring. In pc-[Cu(L(1))](2-), four ring nitrogen atoms and one phosphonate oxygen atom are arranged around Cu(I) (I) in a structure that is half-way between a trigonal bipyramid and a tetragonal pyramid, with one phosphonic acid group uncoordinated. In the trans-O,O-[Cu(L(1))](2-) isomer, the nitrogen atoms form a plane and the phosphonic acid groups are in a mutually trans configuration. A structurally very similar ligand, 4-methyl-1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H(4)L(2)), forms an analogous pentacoordinated complex, pc-[Cu(L(2))](2-), at room temperature. However, the complex does not isomerise to the octahedral complex analogous to trans-O,O-[Cu(L(1))](2-). Because of the high thermodynamic stability of pc-[Cu(L(1))](2-), (logbeta=25.40(4), 25 degrees C, I=0.1 mol dm(-3) KNO(3)) and the formation of protonated species, Cu(I) (I) is fully complexed in acidic solution (-log [H(+)] approximately 3). Acid-assisted decomplexation of both of the isomers of [Cu(H(2)L(1))] takes place only after protonation of both uncoordinated oxygen atoms of each phosphonate moiety and at least one nitrogen atom of the cycle. The exceptional kinetic inertness of both isomers is illustrated by their half-lives tau(1/2)=19.7 min for pc-[Cu(H(2)L(1))] and tau(1/2) about seven months for trans-O,O-[Cu(H(2)L(1))] for decomplexation in 5 M HClO(4) at 25 degrees C. The mechanism of formation of pc-[Cu(L(1))](2-) is similar to those observed for other macrocyclic complexes.

Bis(aminomethyl)phosphinic acid, (NH2CH2)2PO2H (HL), was synthesized using a new procedure. Its coordination ability towards Co(II)/(III), Ni(II), Cu(II) and Zn(II) was studied both in solution and in the solid state. Because of the presence of two nitrogen atoms the ligand exhibits a higher overall basicity than common (aminoalkyl)phosphinic acids. Consequently, the values of the determined stability constants are comparable with those found for (aminoalkyl)phosphonic acids. NMR titrations of Zn(II) point to the interaction of phosphinate with the metal ion in a strong acid solution. The X-ray structures show several coordination modes in the solid state. All-trans-[MCl2(H2L-O)2(H2O)2]Cl2, where M(II) are Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Ca(II), and Cd(II), crystallized from acid solutions. The central ion is octahedrally coordinated with two phosphinate oxygen atoms, two molecules of water and two chlorides in all-trans arrangement. Amine groups are protonated and non-coordinated. Participation of the donor groups in crystals isolated from neutral solutions depends on the metal ion. All donor atoms are coordinated in monomeric fac-N,N,O-trans-O,O′-[Co(L-N,N,O)2]+. On the other hand, in the zinc(II) complex, two phosphinate oxygen atoms and two amine nitrogen atoms (trans to each other) of two different ligand molecules are coordinated in an equatorial plane and two amino groups of the two other ligand molecules are bound in axial positions. Thus, each molecule of the amino acid forms a five-membered N,O-chelate to one zinc(II) ion and the other amino group is bound to the neighbouring ion creating an infinite chain. Nickel(II) forms a trans-O,O′-[Ni(H2O)2(L-N,N)2] complex in which the metal ion is chelated by four amine nitrogen atoms forming two six-membered chelates in an equatorial plane and the octahedron is completed with two water molecules at the apical positions. The phosphinate group is not coordinated. The above results point to a relatively low coordination ability of the phosphinate group; however, due to its low pKA, it is able to bind metal ions at lower pH than other coordinating groups do.

Magnetic nanoparticles of the La1−x Sr x MnO3 perovskite phase (x = 0.20–0.45) were synthesized by a sol–gel method followed by thermal and mechanical treatments. The particles were coated with a uniform silica shell, and differential centrifugation yielded a product with high colloidal stability in water. X-ray powder diffraction (XRD) data showed that the mechanical processing did not affect the lattice parameters of the magnetic cores but only reduced their mean size d XRD. The magnetic properties of the bare particles were mainly controlled by the chemical composition and were also affected by the size of the particles. Subsequent silica coating led to an effective decrease in magnetization. Relaxometry measurements were focused primarily on colloids using magnetic cores of the same size (d XRD ≈ 20 nm) and different compositions, and coated with a shell measuring approximately 20 nm in thickness. The exceedingly high transverse relaxivities [r 2(20 °C) = 290–430 s−1 mmol−1 L at B 0 = 0.5 T] of the samples exhibited pronounced temperature dependence and correlated very well with the magnetic data. Additional samples differing in the size of the cores and silica shell thickness were prepared as well to analyze the effect of the particles on 1H transverse relaxation. The results suggest that the dominant regime of transverse relaxation is the static dephasing regime.

New calixarene derivatives bearing two phosphonic acid groups, 25,27-dimethoxy-26,28-dihydroxycalix[4]arene-11,23-diphosphonic acid 3 and its tetraethyl ester 2 were synthesized. Their X-ray structures confirmed cone conformation of the molecules, more deformed for the ester due to bulky ethyl groups. Complexes [CaH2L(MeOH)2]·4 MeOH (4) and [LnH2L(NO3)(H2O)2]·2 H2O 2 MeOH (Ln=La(III), Pr(III), Nd(III), H4L=26,28-dihydroxy-25,27-dimethoxycalix[4]arene-11,23-diphosphonic acid) were also prepared. Structures of the Ca(II) complex 4 and Nd(III) complex 5 were determined by X-ray analysis. The structural motif of 4 is similar to that found for the free acid 3. The calixarenes are linked by coordination of phosphonates to Ca(II) in a polymeric structure instead of a network of hydrogen bonds in 3. Structure of 5 is different: four calixarene molecules are linked through coordination to Nd(III) in a supramolecular macroring, which forms a pore (approximately 17 A in diameter) penetrating through the structure.

Three new bis(phosphonic) acids were prepared by derivatization of p-tert-butylcalix[4]arene on the lower rim by –(CH2)xPO3H2 groups and were fully characterized by NMR spectroscopy; some of them were further investigated by X-ray analysis. The compounds obtained were tested as extractants for La3+, Eu3+, Yb3+ and Th4+ in 0.1–1 M HNO3. Structural details of the complex HLn(H2L1)2 where Ln = Y, La, Eu were elucidated by NMR techniques in solution. The extraction efficiencies decrease with increasing length of the CH2 spacer; the dependence is not monotonic, and an extraordinary selectivity was observed for Yb. The extraction efficiency of Ln3+ for all of the ligands studied increased significantly with decreasing ionic radius.

A comparison of complexing properties of cyclen and cyclam derivatives containing acetic acid pendant arms on one hand and their methylphosphonic or methylphosphinic acid analogues on the other is made mainly with complexes of copper and lanthanides due to their applications in medicine. The stability constant values of Cu(II) complexes are determined mainly by the basicity of amine groups. The influence of other possible effects, such as the macrocyclic effect in tetraazacycle in contrast to linear amines or the number of additional donor atoms in or outside of pendant arms and their basicity, seems to be very small. The stability constants for Gd(III), in addition to the basicity of amines, are also influenced by the basicity of the pendants and their number. The values of cyclam derivatives are lower than those of cyclen and it corresponds to the ring size effect as was found for zinc(II) complexes. In contrast to Cu(II), the Gd(III) stability constants of the phosphonic acid ligands are also lower than those with H4dota derivatives. A comparison of co-ordination polyhedra of the carboxylic and phosphonic or phosphinic derivatives shows similar motifs that are more determined by the macrocyclic effect than by the kind of donor groups in pendant arms. The differences between the polyhedra observed result from longer C–P(O) bond in the phosphorus derivatives than that C–C(O) in the acetate pendants. Consequently, the lanthanide(III) complexes with phosphorus acid derivatives are more sterically hindered; oxygen atoms in the O4 plane are close to one another and there is insufficient room for co-ordination of a water molecule, which is crucial in MRI applications.

The X-ray structure determinations show that 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic) acid H4L forms both cis- and trans-O,O isomeric complexes with Co(III). Orientation of the other donor atoms indicates the formation of cis-O1,O2-trans-N1,N8-cis-O1,N4-[Co(HL)]. The kinetically preferred cis-isomer is easily formed due to the strong hydrogen bond between the neighboring phosphonic acid groups. The presence of the hydrogen bond in aqueous solution is confirmed by the value of pKa which increases by four orders of magnitude in comparison with the trans-isomer. Formation of the trans-[Co(HL)] occurs only after long heating of a Co(II) solution with the ligand under inert atmosphere before oxidation, which is explained by insertion of the Co(II) ion in the plane of nitrogen atoms of 1,4,8,11-tetraazacyclotetradecane.

Nickel(II) ion reacts with 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H4L1) at room temperature with formation of cis-[Ni(L1)]2- complex. The complex was crystallised in several forms in dependence on conditions of isolation (temperature, pH, solvent mixture). Crystal structures of cis-O,O-[Ni(H2L1)] (1), cis-O,O-[Ni(H2L1)]·2H2O (2), cis-O,O-[Ni(H3L1)]Cl·H2O (3) and cis-O,O-[Ni(H4L1)]Cl2·2H2O (4) were determined by X-ray diffraction. In all the compounds, Ni2+ is in octahedral cis-O1,O2-trans-N1,N8-cis-O1,N4-[Ni(L1)]2- (hereafter abbreviated as cis-O,O-[Ni(L1)]2-) arrangement with V conformation of the cyclam ring. Complexes 3 and 4 exhibit very unusual coordination through the phosphoryl group of double-protonated phosphonate moiety. Tetraethylester of H4L1 having only poorly coordinating phosphoryl oxygen atoms also forms nickel(II) complex 5 with cis arrangement. Corresponding trans-O,O-[Ni(L1)]2- complex is formed only in strongly acidic medium through conversion of the cis complex; it was characterised by X-ray diffraction as dihydrochloride dihydrate, trans-O,O-[Ni(H4L1)]Cl2·2H2O (6). The analogous compound (NH4)2(trans-O,O-[Ni(L2)])·H2O (7) is obtained quantitatively by reaction of Ni2+ with 4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H4L2). Formation of this complex 7 in the III cyclam ring conformation is preferred to the cis complex due to steric hindrance of bulky benzyl groups in cis-[Ni(L2)]2- complex with the V cyclam ring conformation.

In magnetic resonance imaging (MRI), paramagnetic complexes are utilized as contrast agents. Much attention has been paid to the development of new contrast agents responsive to pH, temperature or concentration of various components of body liquids. We report a new type of MRI probe sensing the concentrations of calcium and magnesium in biological media. The ligand do3apBP combines a dota-like chelator with a bisphosphonate group. In the complex, the Gd(III) ion is entrapped in the macrocyclic cavity whereas the bisphosphonate group is not coordinated and therefore is available for coordination with endogenous metal ions. In the presence of metal ions, Gd–do3apBP appears to show formation of coordination oligomers leading to an unprecedented increase in r1 up to 200–500%. The extremely high relaxivity response makes this type of compound interesting for further studies as MRI ion-responsive probes for biomedical research. Copyright © 2010 John Wiley & Sons, Ltd.

Perhydro-3,6,9,12-tetraazacyclopenteno[1,3- f,g ]acenaphthylene is readily mono- and dialkylated on nitrogen with alkyl bromides and iodides giving mono- and bis-quarternary ammonium salts. The title compound is a unified starting material for the preparation of cyclene based chelators.

Cyclam derivatives with methylphosphonic acid arms in position 1,8 and substituent R = H, Me, CH2Ph in positions 4 and 11 are synthesised by Mannich reaction of an appropriate cyclam derivative, formaldehyde and phosphonic acid/diethyl phosphite followed by removal of protecting benzyl groups from nitrogen atoms. Mono(methylphosphonic acid) derivative of cyclam can be obtained by a similar route. Crystal structures of four phosphonic acid derivatives show the same ring conformation and orientation pendants due to strong intramolecular hydrogen bonds between phosphonate oxygen atoms and protonated nitrogen atoms adjacent over ethylene chains. The hydrogen bonds are stable even in aqueous solution. Activation parameters for destabilisation of the conformation are estimated from temperature-dependent NMR measurement. The protonation constants determined confirm the expected high basicity of the compounds and its dependence on the nitrogen atom substituents. The enhanced basicity of the nitrogen atoms non-bonded to methylenephosphonic acid moiety, is explained by the presence of the strong hydrogen bonds.

A new macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraylmethyltrimethylenetris(phenylphosphinic acid) H3L1 was synthesised and its complexes with lanthanides were prepared. X-Ray analysis of seven Ln complexes (Ln = La, Ce, Nd, Eu, Tb, Er, Yb) shows a formation of dimers [LnL1]2 with phosphinic acid bridges in the solid state. All complexes are isostructural and the coordination polyhedra are formed by four N atoms and four O atoms of phosphinic acid groups. A water molecule is placed near the O4 base. The LnOw distance is strongly dependent on Ln(III), it varies from 2.815(6) A in the La complex to 4.448(10) A in the Yb complex. The 31P NMR studies show formation of a rather complex mixture of isomers in solution. The dimer stability in solution is verified by reaction with triphenylphosphine oxide (tppo) and with pyridine N-oxide and by cyclic voltammetry.

Addition of compounds with a P-H bond to Schiff bases of both simple and macrocyclic compounds proceeds smoothly as a non catalysed thermally initialised reaction in an inert solvent. For macrocyclic systems and bulky phosphorus substituents a stereoselective formation of the trans isomer was confirmed by X ray analysis. The addition is reversible, and the reverse reaction is catalysed by Lewis acids. The trans orientation of phosphorus substituents on the macrocycle ring, the stereochemical rigidity of molecules and reversibility of the addition limit the use of the compounds formed in such manner as ligands.

Lanthanide complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(phenylphosphinic) acid] (H4L) were found to give a linear correlation of 1H and 31P NMR chemical shifts to temperature in the physiologically relevant temperature range, with dependencies comparable or better than those found for existing complexes; due to the greater hydrophobic character of the ligand the complexes may exhibit a different biodistribution in the body.

5,7,7,12,14,14-Hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (1) (Curtis macrocycle) was synthesized and studied by X-ray diffraction and NMR spectroscopy. In addition, a product of its decomposition 5,7,7-trimethyl-2,3,6,7-tetrahydro-1,4-diazepine (2) was found and identified by NMR spectroscopy. The X-ray structure of 1·H2O and 1·2 HBr·2 H2O is given.

Analogues of iminodiacetic acid (H2IDA) and nitrilotriacetic acid (H3NTA) bearing two (hydroxomethyl)methylphosphinate or (2-carboxyethyl)methylphosphinate groups were synthesized. Their acid-base and coordination properties with divalent metal ions (Cu2+, Ni2+ and Zn2+) were studied by potentiometry. The compounds exhibit very low basicity of the amino groups (pKa = 6.2–7.6) due to presence of two electron-withdrawing methylphosphinate groups and, consequently, a low stability of the complexes. In the case of IDA-analogues, the low complex stability results in precipitation of metal hydroxides in neutral region. As expected, NTA-analogues form more stable complexes and, thus, they were also studied in the alkaline region. Presence of additional carboxylate in the 2-carboxyethylphosphinic acid groups results in the formation of dinuclear complexes. Solid state structures of two compounds were determined by X-ray diffraction analysis. The compounds are protonated on the nitrogen atom and the structures are stabilized by rich hydrogen bond network.Graphical abstract