Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms

A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper(II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper(II) ion within each macrocycle's cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with (64)Cu at room temperature in less than 1 h with specific activities >1 mCi μg(-1). The in vivo behavior of both (64)Cu-CB-TE2P and (64)Cu-CB-TE1A1P were investigated through biodistribution studies using healthy male Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copper chelators including CB-TE2A, NOTA and Diamsar.     

The long and short of it: the influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles

A cross-bridged cyclam ligand bearing two N-carboxymethyl pendant arms (1) has been found to form a copper(II) complex that exhibits significantly improved biological behavior in recent research towards (64)Cu-based radiopharmaceuticals. Both the kinetic inertness and resistance to reduction of Cu-1 are believed to be relevant to its enhanced performance. To explore the influence of pendant arm length on these properties, new cross-bridged cyclam and cyclen ligands with longer N-carboxyethyl pendant arms, 2 and 4, and their respective copper(II) complexes have been synthesized. Both mono- as well as di-O-protonated forms of Cu-2 have also been isolated and structurally characterized. The spectral and structural properties of Cu-2 and Cu-4, their kinetic inertness in 5 M HCl, and electrochemical behavior have been obtained and compared to those of their N-carboxymethyl-armed homologs, Cu-1 and Cu-3. Only the cyclam-based Cu-1 and Cu-2 showed unusually high kinetic inertness towards acid decomplexation. While both of these complexes also exhibited quasi-reversible Cu(II)/Cu(I) reductions, Cu-2 is easier to reduce by a substantial margin of +400 mV, bringing it within the realm of physiological reductants. Similarly, of the cyclen-based complexes, Cu-4 is also easier to reduce than Cu-3 though both reductions are irreversible. Biodistribution studies of (64)Cu-labeled 2 and 4 were performed in Sprague Dawley rats. Despite comparable acid inertness to their shorter-armed congeners, both longer-armed ligand complexes have poorer bio-clearance properties. This inferior in vivo behavior may be a consequence of their higher reduction potentials.     

trans-Methylpyridine cyclen versus cross-bridged trans-methylpyridine cyclen. Synthesis, acid-base and metal complexation studies (metal = Co2+, Cu2+, and Zn2+)

The synthesis of the cross-bridged cyclen CRpy(2) {4,10-bis((pyridin-2-yl)methyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane}, a constrained analogue of the previously described trans-methylpyridine cyclen Cpy(2) is reported. The additional ethylene bridge confers to CRpy(2) proton-sponge type behaviour which was explored by NMR and potentiometric studies. Transition metal complexes have been synthesized (by complexation of both ligands with Co(2+), Cu(2+) and Zn(2+)) and characterized in solution and in the solid state. The single crystal X-ray structures of [CoCpy(2)](2+), [CuCpy(2)](2+) and [ZnCpy(2)](2+) complexes were determined. Stability constants of the complexes, including those of the cross-bridged derivative, were determined using potentiometric titration data and the kinetic inertness of the [CuCRpy(2)](2+) complex in an acidic medium (half-life values) was evaluated by spectrophotometry. The pre-organized structure of the cross-bridged ligand imposes an additional strain for the complexation leading to complexes with smaller thermodynamic stability in comparison with the related non-bridged ligand. The electrochemical study involving cyclic voltammetry underlines the importance of the ethylene cross-bridge on the redox properties of the transition metal complexes.     

Investigation of copper-azamacrocyclic complexes by high-performance liquid chromatography

The use of copper radioisotopes in imaging and therapy has prompted an increased interest in chelators which form stable copper complexes, such as Cu(II)-azamacrocyclic complexes. The effects of charge, stability and the size of the macrocyclic backbone of the Cu(II)-azamacrocyclic complexes on biological behavior have been evaluated. Here we report a reversed-phase high-performance liquid chromatography (HPLC) method to separate several Cu(II)-azamacrocyclic complexes, including Cu(II) complexes of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) and 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A). Absorbance at 280 nm was used to monitor the complexes as they eluted from the reversed-phase column. The effects of the concentration of the buffer, the pH of the buffered mobile phase and the concentration of the organic modifier, methanol, on the separation were investigated. Separation of these copper complexes by ion-pair HPLC with the use of a mass spectrometry-compatible ion-pair reagent, triethylammonium acetate, in the mobile phase at pH 6.3 is also presented. The reversed-phase chromatographic conditions utilized also allow the pK(a)s of Cu-TETA and the log(k'w) values of Cu-CB-TE2A, Cu-TETA and Cu-CB-DO2A to be estimated.     

Discrete bridging and terminal copper carbenes in copper-catalyzed cyclopropanation

The Cu(I) beta-diketiminate [Me2NN]Cu(eta2-ethylene) (2) catalyzes the cyclopropanation of styrene with N2CPh2 to give 1,1,2-triphenylcyclopropane in 67% yield. Addition of N2CPh2 to 2 equiv of 2 allows for the isolation of the dicopper carbene [[Me2NN]Cu]2(mu-CPh2) (3) in which the diphenylcarbene moiety is symmetrically bound between two [Me2NN]Cu fragments (Cu-C = 1.922(4) and 1.930(4) A) with a Cu-Cu separation of 2.4635(7) A. In toluene-d8 solution, 3 reversibly dissociates a [Me2NN]Cu fragment to give [Me2NN]Cu(toluene) and the terminal carbene [Me2NN]Cu=CPh2. Dicopper carbene 3 reacts with 3 equiv of styrene to give 1,1,2-triphenylcyclopropane and 2 equiv of [Me2NN]Cu(eta2-styrene) within minutes. DFT studies with simplified ligands indicate a stronger Cu-C pi-back-bonding interaction from two Cu(I) centers to the carbene acceptor orbital in a dicopper carbene than that present in a monocopper carbene. Nonetheless, the terminal carbene [Me3NN]Cu=CPh2 (8) that possesses a p-methyl group on each beta-diketiminato N-aryl ring may be isolated and exhibits a shortened Cu-C distance of 1.834(3) A. The stoichiometric cyclopropanation of styrene by 8 in 1,4-dioxane is first-order in both copper carbene 8 and styrene with activation parameters DeltaH = 10.4(3) kcal/mol and DeltaS = -32.3(9) cal/mol.K. In 1,4-dioxane, 8 decomposes to Ph2C=CPh2 via first-order kinetics with activation parameters DeltaH = 21(1) kcal/mol and DeltaS = -8(3) cal/mol.K. Arene solutions of thermally sensitive terminal carbene 8 decompose to [Me3NN]Cu(arene), which reacts with 8 still present in solution to give the more thermally stable [[Me3NN]Cu]2(mu-CPh2).     

Rapid synthesis of cross-bridged cyclam chelators for copper(II) complex formation

Copper(II) complexes of 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (cross-bridged cyclam) derived chelators show high kinetic stability relative to less rigid non-bridged azamacrocyclic chelators and have applications as radiopharmaceuticals in PET imaging. Rapid synthesis of two novel bis-benzyl cross-bridged cyclam derivatives was achieved in 24 h compared to the typical synthesis times, between 14 and 30 days. The X-ray crystal structures are reported for the copper(II) complexes with 1,3-dibromobenzyl and tolyl derivatives revealing different ligand coordination environments. Both structures show tetradentate coordination of the tetraazamacrocycle with axial elongation along the N–Cu–N axis for the 1,3-dibromobenzyl derivative (Cu–N distances: axial av. 2.48(8) Å, equatorial av. 2.081(7) Å).     

Spectroscopic and electrochemical studies of new copper(II) and nickel(II) N2S2 tetradentate complexes of potential interest to nuclear medicine

The coupling of radionuclides such as copper (67Cu and 64Cu) to antibodies by bifunctional chelating agents (or BCA) requires extremely high stability to avoid in vivo release of metal. Six copper(II) and five nickel(II) complexes with N2S2 tetradentate ligands were synthesised for potential medical applications, and stability studies were conducted. I.r and u.v.-vis. spectra provided structural data on the geometry of the complexes. The redox potentials obtained from cyclic voltammetry allowed us to estimate the stability constants of each complex and then select the more suitable ligand for future applications in radioimmunotherapy.     

64Cu放射性药物化学

64Cu半衰期为12.7 h,其衰变过程既发射β+粒子(β+,0.655 MeV,17.8%),又发射β-粒子(β-,0.573 MeV,38.4%)。近20年来,随着铜配位化学的发展,新型配体不断出现(如DOTA、TETA、NOTA、CB-TE2A、C3B-DO2A等)。Cu(Ⅱ)的络合物在生物体内/外的稳定性不断提高,64Cu已经成功标记在氨基酸、多肽、蛋白、核酸等分子以及纳米颗粒上。64Cu可制成正电子显像药物用作诊断,同时也有发展为放射性治疗药物的潜力。新型铜配体和标记方法以及新的药物靶标的研究已经成为64Cu放射性药物研究的热点,至今已研制出了多种64Cu标记的放射性药物,如64Cu-ATSM是有效的肿瘤乏氧显像剂,64Cu-PTSM是优良的血流示踪剂等。本文旨在介绍64Cu(Ⅱ)几种主要类型的含氮配体以及64Cu标记的放射性药物在显像和治疗方面的最新研究进展,并展望其发展趋势。     

The exocyclic functionalisation of bis(thiosemicarbazonate) complexes of zinc and copper: the synthesis of monomeric and dimeric species

This paper reports the synthesis of bimetallic zinc thiosemicarbazone complexes with rigid aromatic linkers, using either 1,3- or 1,4- benzenediamines or 1,3- or 1,4- benzenedialdehydes as the basis of the linking groups. Non-rigid aliphatic diamines and dialdehydes were also used to link the zinc chelating units. Reaction of a bis(thiosemicarbazone) with a pendant NHNH(2) group with monoaldehydes or ketones gives a range of monomeric complexes with exocylic imine groups bearing a range of substituents. The zinc complexes can be quantitatively and rapidly transmetallated to the corresponding copper complexes and this route or direct reaction with the free ligand can be used to radiolabel the monomeric species with (64)Cu. In vivo and in vitro studies of one of the (64)Cu imine complexes shows substantial hypoxic selectivity and high tumour uptake in a murine model.     

Inside or outside a ligand cleft? Synthetic, structural, and kinetic inertness studies of zinc, cadmium, and mercury complexes of cross-bridged cyclam and cyclen

Ethylene cross-bridging of the popular tetraazamacrocyclic ligand cyclam has led to metal complexes with enhanced kinetic inertness. The synthesis and spectral characterization of zinc(II), cadmium(II), and mercury(II) complexes of cross-bridged cyclam (L1) as well as cross-bridged cyclen (L2) are reported along with the details of our synthetic route to L2. X-ray structural studies revealed that all Zn(II) and Cd(II) cations are fully kappa(4)N-coordinated inside the respective ligand's molecular cleft with L1 providing the better fit for Zn(II). While Hg(II) is similarly coordinated to L2, it has been found to complex L1 outside the ligand cleft in a novel exo-kappa(2)N-mode. Solution NMR data of the kappa(4)N complexes are consistent with the presence of only a single cis-folded isomer in each case. Ligand (1)H and (13)C coupling to both (111,113)Cd and (199)Hg in their complexes can be clearly discerned. The relative kinetic inertness of representative cross-bridged complexes in acidic aqueous solution has been assessed and found to be in the following order: Zn(II) > Cd(II)[dbl greater-than] Hg(II). The data also reaffirm that cross-bridged cyclam ligand L1 forms a substantially more inert complex with zinc(II) than either the smaller cyclen analogue L2 or the unbridged 1,4,8,11-tetramethyl-cyclam L3.     

Synthesis of four novel pendant armed macrocyclic ligands and their interaction with lanthanide(III) cations

The ability of La³⁺ ions to form stable complexes with four novel pendant-armed N_xO_y-macrocycles derived from 2,6-bis(2-formylphenoxymethyl)pyridine, L¹, L², L³, and L⁴, has been studied. The corresponding (unsubstituted) parent ligands were prepared by the reaction between 2,6-bis(2-formylphenoxymethyl)pyridine and three different amines: 1,2-bis(2-aminophenoxy)propane (L¹), diethylenetriamine (L²), and 3,6-dioxa-1,8-octanediamine (L³ and L⁴). This was followed for the parent ligands of L¹, L³, and L⁴ by in situ reduction with sodium borohydride. The pendant-armed ligands were then synthesized by the alkylation of the free-NH groups with p-(L¹ and L³) and o-nitrobenzyl bromide (L⁴), and 2-chloromethylpyridine chlorohydrate (L²). A series of Ln(III) complexes were prepared for the four ligands by the direct synthesis between the corresponding macrocycle and Ln(III) hydrated nitrates and perchlorates. The number of complexes obtained from the pendant-armed macrocycles is lower than that of the (unsubstituted) parent ones, suggesting that the introduction of pendant arms in the macrocyclic skeletons increases the selectivity of the ligands. More complexes were synthesized when using nitrate as the counterion, showing the important role of the counterion in the complexation reaction. The text was submitted by the authors in English.     

Structural relationships between dicopper diacetylide (Cu-C≡C-C≡C-Cu) and dicopper acetylide (Cu-C≡C-Cu)

Dicopper diacetylide Cu-C≡C-C≡C-Cu, prepared from butadiyne has been studied by FT-IR spectroscopy in comparison to dicopper acetylide Cu-C≡C-Cu. Upon ageing by exposure to air at room temperature, Cu-C≡C-Cu has been transformed into Cu-C≡C-C≡C-Cu as demonstrated by FT-IR spectroscopy and this compound is further transformed on standing in air. A special kind of solid state oxidative coupling reaction occurs so that polyynes chains are formed in these aged solids. It is shown that the FT-IR spectrum of copper acetylide prepared from ammonia solutions of Cu⁺ and Cu²⁺ ions is comparable to that of air oxidized Cu-C≡C-Cu (and Cu-C≡C-C≡C-Cu) prepared exclusively from Cu⁺ ions in presence of a reducing agent demonstrating that Cu²⁺ ions display the same oxidizing effect as oxygen causing coupling reactions in solution and producing Cu-C≡C-C≡C-Cu.Cu-C≡C-Cu oxidized at 60–70°C with CuCl₂ produces a product which could be formulated as Cu(C≡C)₂₀Cu; FT-IR absorption at 1950 cm⁻¹ could suggest the presence of cumulenic carbon chain although acetylenic carbon chains cannot be excluded completely.     

New 64Cu PET imaging agents for personalised medicine and drug development using the hexa-aza cage, SarAr

The success of positron emission tomography (PET) in personalised medicine and drug development requires radioisotopes that provide high quality images and flexible chemistry for a broad application. 64Cu is arguably one of the most suitable PET isotopes for imaging with the evolving target agents, but there are not many appropriate chelating agents for 64Cu and this has limited its wider application. The bi-functional chelator, SarAr is known to bind 64Cu2+ quantitatively (i.e. one metal per ligand present) and rapidly (<2 min) at 10(-6) M over a range of pH (4-9). In this paper the conjugation of SarAr to the whole and fragmented antibody is described. Conjugation of the SarAr to the protein does not impair its coordination of the 64Cu. It complexes the 64Cu2+ rapidly, quantitatively and essentially irreversibly at pH 5. Animal studies show that the 64Cu-SarAr-immunoconjugates maintain their specificity for the target and are stable in vivo. Also, SarAr is a platform technology, is easy to use in a kit formulation and is readily adaptable for the wider application in 64Cu PET imaging.     

Experimental and theoretical study on the structure and formation mechanism of [C6H5Cu(m)]- (m = 1-3)

The important intermediate phenyl-copper metal complexes [C(6)H(5)Cu(m)]- (m = 1-3), which are produced from the reactions between copper metal clusters formed by laser ablation and the benzene molecules seeded in argon carrier gas, are studied by photoelectron spectroscopy(PES) and density functional theory (DFT). Their structures and bonding patterns are investigated, which results in the conclusion that C(6)H(5) groups bond perpendicularly on copper clusters through Cu-C sigma bond. The formation mechanism of these complexes has been studied at B3LYP//6-311G(d, p)/Lanl2dz level. Direct insertion reaction between [Cu(m)]- and C(6)H(6) yields intermediate complex [C(6)H(5)Cu(m)H]-, and then eliminates the H atom, or releases the H atom to other neutral Cu atoms or anionic Cu ions via H abstraction reaction. The first step is the rate-limiting step with C-H activation and cleavage, and H abstraction by neutral Cu atom is the most energetically favorable pathway for the final step. Moreover, the complex [C(6)H(5)Cu(2)]- is ascertained to be easier to be generated than [C(6)H(5)Cu(3)]- and [C(6)H(5)Cu]-, which are in excellent agreement with the experimental results.     

A chelator-free multifunctional [64Cu]CuS nanoparticle platform for simultaneous micro-PET/CT imaging and photothermal ablation therapy

We synthesized and evaluated a novel class of chelator-free [(64)Cu]CuS nanoparticles (NPs) suitable both for PET imaging and as photothermal coupling agents for photothermal ablation. These [(64)Cu]CuS NPs are simple to make, possess excellent stability, and allow robust noninvasive micro-PET imaging. Furthermore, the CuS NPs display strong absorption in the near-infrared (NIR) region (peak at 930 nm); passive targeting prefers the tumor site, and mediated ablation of U87 tumor cells occurs upon exposure to NIR light both in vitro and in vivo after either intratumoral or intravenous injection. The combination of small diameter (～11 nm), strong NIR absorption, and integration of (64)Cu as a structural component makes these [(64)Cu]CuS NPs ideally suited for multifunctional molecular imaging and therapy.     

Polycarbonate microspheres containing mitomycin C and magnetic powders as potential hepatic carcinoma therapeutics

The polycarbonate copolymer poly(trimethylene carbonate-co-5,5-dimethyl trimethylene carbonate) (P(TMC-co-DTC)) was synthesized by the polymerization of trimethylene carbonate (TMC) and 5,5-dimethyl trimethylene carbonate (DTC) using tin (II) 2-ethylhexanoate [Sn(Oct)(2)] as a catalyst. In vitro degradation tests indicated this polycarbonate copolymer degraded slowly in phosphate buffer saline solution (PBS, 0.1 mol/L, at 37°C). Magnetic polymer microspheres (MMC-PC-M) generated from the P(TMC-co-DTC) copolymer and containing Fe(3)O(4) magnetic ultrafine powders and an anticancer drug, mitomycin C (MMC) were prepared by a solvent evaporation technique. These anticancer magnetic polycarbonate microspheres showed strong magnetic responsiveness and high MMC loading capacity. In vitro drug release studies indicated that these microspheres sustained steady release rates of MMC in PBS. In vitro cytotoxicity assays demonstrated the microspheres were strongly inhibitory to human hepatic carcinoma (Bel-7204) cells. In vivo site-specific therapy in nude mice with human hepatic carcinoma indicated that the microspheres possessed markedly high antitumor activity against human hepatic carcinoma (Bel-7204).     

Optimized preparation and preliminary evaluation of [64Cu]–DOTA–trastuzumab for targeting ErbB2/Neu expression

Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. Trastuzumab is a monoclonal antibody that binds with high affinity to HER2/neu, which is over expressed on breast and other tumors. Developing new tracers for the detection of this cancer is of great interest. In this study, trastuzumab was successively labeled with [⁶⁴Cu]CuCl₂ after conjugation with DOTA-NHS-ester. The conjugate was purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA–trastuzumab was labeled with ⁶⁴Cu produced by ⁶⁸Zn(p,αn)⁶⁴Cu nuclear reaction (30 MeV protons at 180 μA). Radiochemical purity, integrity of protein after radiolabeling and immunoreactivity of radiolabeled mAb trastuzumab with HER2/neu antigen and SkBr3 cell line were performed by RIA. In vitro stability of radiolabeled mAb in human serum was determined by thin layer chromatography. In vitro internalization studies were performed with the SkBr3 cell line and the tissue biodistribution of the ⁶⁴Cu–DOTA–trastuzumab was evaluated in wild-type rat (90 ± 5.5 μCi, 2, 6, 12, 24 h p.i.). The radioimmunoconjugate was prepared with a radiochemical purity of higher than 96 ± 0.5 % (ITLC) and specific activity as high as 5.3 μCi/μg. The average number of chelators per antibody for the conjugate used in this study was 5.8/1. The sample was showed to have similar patterns of migration in the gel electrophoresis. The ⁶⁴Cu–DOTA–trastuzumab showed high immunoreactivity towards HER2/neu antigen and SkBr3 cell line. In vitro stability of the labeled product was found to be more than 94 % in PBS and 82 ± 0.5 % in human serum over 48 h. In vitro internalization studies of the ⁶⁴Cu–DOTA–trastuzumab showed that up to 11.5 % of the radioimmunoconjugate internalized after 10 h. The accumulation of the radiolabeled mAb in liver, skin, intestine, lung, spleen, kidney and other tissues demonstrates a similar pattern to the other radiolabeled anti-HER2 immunoconjugates. ⁶⁴Cu–DOTA–trastuzumab is a potential compound for molecular imaging of PET for diagnosis and treatment studies and follow-up of HER2 expression in oncology.     

Water‐soluble Schiff base Cu(II) and Zn(II) complexes: Synthesis,DNA targeting ability and chemotherapeutic potential of Cu(II) complex for hepatocellular carcinoma – in vitro and in vivo approach

Reliable compounds with low toxicity are tempting potential chemotherapeutics. With an aim of achieving less toxic but more potent metallodrugs, four new‐generation hydrophilic Cu(II) and Zn(II) complexes with DNA‐targeting properties were synthesized and characterized using various physicochemical data. The excellent DNA binding and cleavage results confirmed the mode of binding of DNA with the complexes and their ability to denature it. The profound in vitro cytotoxicity exhibited by complex 3 against a panel of cell lines (HeLa, MCF‐7 and HepG‐2) along with NHDF (normal human dermal fibroblasts) with distinct activity towards HepG‐2 and low toxicity to NHDF prompted in vivo studies of induced hepatocellular carcinoma‐affected Swiss albino rats. On evaluating various serum hepatic, biological and histopathological parameters, complex 3 showed excellent activity in restoring the damaged liver to normal. As a means of identifying the pathway of DNA damage, flow cytometric evaluation of cell cycle analysis was performed, which revealed S phase arrest‐induced apoptosis in HepG‐2 cells by complex 3 , making it a cell cycle‐specific drug.     

Structural and spectroscopic studies of some copper(I) halide tert-butyl isocyanide adducts

Single-crystal structural characterizations confirm the existence of the unusual 1 : 4 copper(I) halide : unidentate ligand adducts [Cu(CNt-Bu)4]X for X = Cl, Br (two forms), I (the chloride and one form of the bromide being solvated) with crystal packing dominated by stacks of interleaving cations. Cu-C range between 1.941(2) and 1.972(4) A. The structure of the 1 : 2 chloride complex is also recorded, being [ClCu(CNt-Bu)2], with the copper(I) atom environment trigonal planar, while CuCN : (CNt-Bu) (1 : 1) is a single-stranded polymer which spirals about a crystallographic 3-axis (CN scrambled), the ligands being pendant from the ...CuCNCuCN... string. The (5Cu static broadline NMR spectra of [Cu(CNt-Bu)4]I and [Cu(CNt-Bu)4]Br.H2O in the solid state exhibit dominant, narrow -1/2 <--> +1/2 central transition resonances and associated +/-1/2 <--> +/-3/2 satellite transition resonances which are characteristic of first-order quadrupole broadened systems, while associated high-resolution 65Cu MAS NMR data provide accurate measurement of the 65Cu isotropic chemical shifts. Both approaches provide complete data on the quadrupole and chemical shift interactions which contribute to these spectra. Far-IR spectra of products of reactions involving a range of CuX : t-BuNC ratios reveal the existence of 1 : 1.5 adducts for X = Br, I. Metal-carbon and metal-halogen bands are assigned in the far-IR spectra, which indicate a binuclear double halogen-bridged structure for the 1 : 1.5 complexes.     

Homo- and heteropolynuclear Ni2+ and Cu2+ complexes of polytopic ligands, consisting of a tren unit substituted with three 12-membered tetraazamacrocycles

Two new polytopic ligands L1 and L2 have been synthesized. They consist of a central tren unit to which three 1,4,7,10-tetraazacyclododecane rings are attached via an ethylene and a trimethylene bridge, respectively. The complexation properties of L1 and L2 towards Cu(2+) and Ni(2+) were studied by potentiometric pH titration, UV-Vis, EPR spectroscopy and kinetic techniques. As a comparison, the Cu(2+) and Ni(2+) complexes with L3 (1-(N-methyl-2-aminoethyl-1,4,7,10-tetraazacyclododecane)) were also investigated. The crystal structures of [CuL3H(H(2)O)](ClO(4))(3) and [NiL3Cl](ClO(4)) were solved and show that the side chain in its protonated form is not involved in coordination, whereas deprotonated it binds to the metal ion. The thermodynamically stable 3:1 complexes of L1 or L2 have a metal ion in the three macrocyclic units. However, when three equivalents of Cu(2+) are added to L1 or L2 the metal ion first binds to the tren unit and only then to the macrocycles. The kinetics of the different steps of complexation have been studied and a mechanism is proposed.