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The role of metalloproteinases (MMPs) on the migration and invasion of cancer cells has been correlated with tumor aggressiveness, namely with the up-regulation of MMP-2 and 9. Herein, two pyridine-containing macrocyclic compounds, [15]pyN5 and [16]pyN5, were synthesized, chemically characterized and evaluated as potential MMP inhibitors for breast cancer therapy using 3D and 2D cellular models. [15]pyN5 and [16]pyN5 (5&ndash, 20 &micro, M) showed a marked inhibition of MMPs activity (100% at concentrations &ge, 7.5 &mu, M) when compared to ARP-100, a known MMP inhibitor. The inhibitory activity of [15]pyN5 and [16]pyN5 was further supported through in silico docking studies using Goldscore and ChemPLP scoring functions. Moreover, although no significant differences were observed in the invasion studies in the presence of all MMPs inhibitors, cell migration was significantly inhibited by both pyridine-containing macrocycles at concentrations above 5 &mu, M in 2D cells (p &lt, 0.05). In spheroids, the same effect was observed, but only with [16]pyN5 at 20 &mu, M and ARP-100 at 40 &mu, M. Overall, [15]pyN5 and [16]pyN5 led to impaired breast cancer cell migration and revealed to be potential inhibitors of MMPs 2 and 9.

The purpose of this work was to synthesize and characterize the thiatetraaza macrocycle 1-thia-4,7,10,13-tetraazacyclopentadecane ([15]aneN4S). Its acid-base behaviour was studied by potentiometry at 25 °C and ionic strength 0.10 M in KNO3. The protonation sequence of this ligand was investigated by 1H-NMR titration that also allowed the determination of protonation constants in D2O. Binding studies of [15]aneN4S with Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ metal ions were further performed under the same experimental conditions. The results demonstrated that this compound has a higher selectivity and thermodynamic stability for Hg2+ and Cu2+, followed by Ni2+. The UV-visible-near IR spectroscopies and magnetic moment data for the Co(II) and Ni(II) complexes indicated a tetragonal distorted coordination geometry for both metal centres. The value of magnetic moment and the X-band EPR spectra of the Cu(II) complex are consistent with a distorted square pyramidal geometry.

The rigid [6]ferrocenophane, L-1, was synthesised by condensation of 1,1'-ferrocene dicarbaldehyde with trans-1,2-diaminocyclohexane in high dilution at r.t. followed by reduction. When other experimental conditions were employed, the [6,6,6]ferrocenephane (L-2) was also obtained. Both compounds were characterised by single crystal X-ray crystallography. The protonation of L-1 and its metal complexation were evaluated by the effect on the electron-transfer process of the ferrocene (fc) unit of L-1 using cyclic voltammetry (CV) and square wave voltammetry (SWV) in anhydrous CH3CN solution and in 0.1 M (Bu4NPF6)-Bu-n as the supporting electrolyte. The electrochemical process of L-1 between 300 and 900 mV is complicated by amine oxidation. On the other hand, an anodic shift from the fc/fc(+) wave of L-1 of 249, 225, 81 and 61 mV was observed by formation of Zn2+, Ni2+, Pd2+ and Cu2+ complexes, respectively. Whereas Mg2+ and Ca2+ only have with L-1 weak interactions and they promote the acid-base equilibrium of L-1. This reveals that L-1 is an interesting molecular redox sensor for detection of Zn2+ and Ni2+, although the kinetics of the Zn2+ complex formation is much faster than that of the Ni2+ one. The X-ray crystal structure of [(PdLCl2)-Cl-1] was determined and showed a square-planar environment with Pd(II) and Fe(II) centres separated by 3.781(1) angstrom. The experimental anodic shifts were elucidated by DFT calculations on the [(MLCl2)-Cl-1] series and they are related to the nature of the HOMO of these complexes and a four-electron, two-orbital interaction.

Synthetic superoxide dismutase mimetics have emerged as a potential novel class of drugs for the treatment of oxidative stress related diseases. Among these agents, metal complexes with macrocyclic ligands constitute an important group. In this work we synthesized five macrocyclic copper(II) complexes and evaluated their ability to scavenge the superoxide anions generated by the xanthine-xanthine oxidase system. Two different endpoints were used, the nitro blue tetrazolium (NBT) reduction assay (colorimetric method) and the dihydroethidium (DHE) oxidation assay (fluorimetric method). IC(50) values in the low micromolar range were found in four out of five macrocyclic complexes studied, demonstrating their effective ability to scavenge the superoxide anion. The IC(50) values obtained with the NBT assay for the macrocyclic copper(II) complexes, were consistently higher, approximately threefold, than those obtained with the DHE assay. Spectroscopic and electrochemical studies were performed in order to correlate the structural features of the complexes with their superoxide scavenger activity. Cytotoxicity assays were also performed using the MTT method in V79 mammalian cells and we found that the complexes, in the range of concentrations tested in the superoxide scavenging assays were not considerably toxic. In summary, some of the presented macrocyclic copper(II) complexes, specially those with a high stability constant and low IC(50), appear to be promising superoxide scavenger agents, and should be considered for further biological assays.

The stability constants of La 3+ , Sm 3+ and Ho 3+ complexes with 13- and 14-membered macrocycles having methylcarboxylate (trita and teta) or methylphosphonate (tritp and tetp) arms were determined. All the ligands were labelled with 153 Sm and 166 Ho in order to evaluate the effect of the macrocyclic cavity size and type of appended arms on their in vitro and in vivo behaviour. The radiolabelling efficiency was found to be higher than 98% for all the complexes, except for those of tetp. All radiocomplexes studied are hydrophilic with an overall negative charge and low plasmatic protein binding. Good in vitro stability in physiological media and human serum was found for all complexes, except the 153 Sm/ 166 Ho–teta, which are unstable in phosphate buffer (pH 7.4). In vitro hydroxyapatite (HA) adsorption studies indicated that 153 Sm/ 166 Ho–tritp complexes bind to HA having the 166 Ho complex the highest degree of adsorption (>80%, 10 mg). Biodistribution studies in mice demonstrated that 153 Sm/ 166 Ho–trita complexes have a fast tissue clearance with more than 95% of the injected activity excreted after 2 h, value that is comparable to the corresponding dota complexes. In contrast, the 153 Sm–teta complex has a significantly lower total excretion. 153 Sm/ 166 Ho–tritp complexes are retained by the bone, particularly 166 Ho–tritp that has 5–6% (% I.D./g) bone uptake and also a high rate of total excretion. Thus, these studies support the potential interest of 153 Sm/ 166 Ho–trita complexes for therapy when conjugated to a biomolecule and the potential usefulness of the 166 Ho–tritp complex in bone pain palliation.

A set of tetraaza macrocycles containing pyridine and methylcarboxylate (ac(3)py14) or methylphosphonate (MeP(2)py14 and P(3)py14) pendant arms were prepared and their stability constants with La(3+), Sm(3+), Gd(3+) and Ho(3+) determined by potentiometry at 25 degrees C and 0.10 M ionic strength in NMe(4)NO(3). The metal:ligand ratio for (153)Sm and (166)Ho and for ac(3)py14, MeP(2)py14 and P(3)py14, as well as the pH of the reaction mixtures, were optimized to achieve a chelation efficiency higher than 98%. These radiocomplexes are hydrophilic and have a significant plasmatic protein binding. In vitro stability was studied in physiological solutions and in human serum. All complexes are stable in saline and PBS, but 20% of radiochemical impurities were detected after 24 h of incubation in serum. Biodistribution studies in mice indicated a slow rate of clearance from blood and muscle, a high and rapid liver uptake and a very slow rate of total radioactivity excretion. Some bone uptake was observed for complexes with MeP(2)py14 and P(3)py14, which was enhanced with time and the number of methylphosphonate groups. This biological profile supports the in vitro instability found in serum and is consistent with the thermodynamic stability constants found for these complexes.

A new 14-membered oxatriaza macrocycle containing pyridine has been synthesized, 7-oxa-3,11,17-triazabicyclo[11.3.1]heptadeca-1(17),13,15-triene, L1. The protonation constants of this compound and stability constants of its complexes with the Mn2+ to Zn2+, Cd2+, and Pb2+ were determined by potentiometric methods at 25°C and ionic strength 0.10 Mol dm−3 in KNO3. L1 presents two high values of protonation constants, and the third is very low. Its overall basicity is low because the three basic centres are in close proximity. Only mononuclear complexes were found, and the stability constants with all the metal ions studied are of the same order as those of the corresponding complexes of the oxatriaza macrocycle L2 (1-oxa-4,8,12-triazacyclotetradecane), but lower than those of tetraaza macrocycles of similar or lower cavity size. The electronic spectra together with the values of magnetic moments of the cobalt(II) and nickel(II) complexes of L1 suggest that five co-ordinate species are formed in aque...

A new redox-responsive receptor, 3,11-bis(ferrocenylmethyl)-7-methyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene, L-1, has been synthesized. The protonation constants of this compound and the stability constants of its complexes with Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+ were determined at 25.0 degrees C, in methanol-water (1:1, v/v), and at ionic strength 0.10 mol dm(-3) in KNO3. The values of the protonation constants of L-1 are similar to those of the parent macrocycle, 7-methyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene L-2, except for K-2 which is 1.82 log units lower than that of L-2. Structural reasons are proposed to explain this behaviour. The stability constants of the metal complexes of L-1 are lower than those of L-2 as expected on the basis of its lower overall basicity, but the Cd2+ complex is exceptional exhibiting a higher stability for L-1. The complexation of L-1 with different metals shifts anodically the ferrocene-ferrocenium half-wave potential in relation to that of the free compound, the largest shift being observed for Cu2+, followed by Ni2+, and then Zn2+ and Cd2+. No shift was observed for Pb2+. It was verified that L-1 is a copper-selective sensor in the presence of Ni2+, Zn2+, Cd2+ and Pb2+ and although it is not the first compound for which this property is claimed it is probably the easiest to synthesize. The electronic spectra of [CuL1](2+) reveal that the four nitrogen atoms of the macrocycle form a square-planar arrangement with a pronounced tetrahedral distortion. The single crystal structures of [(CuLCl)-Cl-1][(CuLI)-I-1]Cl-2. 1.25H(2)O 1 and [(ZnLI)-I-1]Cl . 2H(2)O 2 have shown that these complex cations have distorted square pyramidal co-ordination spheres, the basal being planes formed by the four nitrogen atoms of the macrocyclic framework in 1a(+) and 1b(+) while in 2(+) it is defined by three nitrogen atoms of L-1 and one iodine atom. The apical positions are occupied by a chlorine atom in 1a(+) and by an iodine atom in 1b(+), and by the nitrogen donor atom of the macrocycle trans to the pyridine ring in complex 2(+). To achieve the geometric arrangement described for 2(+) the macrocycle folds considerably through the line defined by the two nitrogen atoms contiguous to the pyridine group. It was also found that the intramolecular distances between the ferrocene groups and transition metal receptor centres studied play an important role in the redox behaviour of these complexes.

Potentiometric titrations showed that the sum of the first three protonation constants of diethylene-triaminepentaacetate N,N″-bis(butylamide)(L1) decreases by units when compared to the diethylenetriaminepentaacetate (dtpa), and that the complexes of Ga3+ and In3+ of L1 have stability constants 6.1–6.3 long units lower than those of dtpa. The decreased basicity of the bis (amide) derivative thus correlates with the lower stability of its complexes. However, at pH 7.4 the lower overall basicity of L1 compared to dtpa partly compensates the lower stability of its complexes. thus causing their conditional stability constants to be comparable to those of the dtpa complexes. The efficacy of L1 in binding Ga3+ and In3+ under physiological conditions is discussed by comparing pM values at pH 7.4, showing That this compound can withstand the competition of transferring for biological media relevant to medical applications. The 13C and 1H N M R shifts were measured for the complexes of Al,3+, Ga3+, and Y3+ with L1and compared with 13C and are hexadentate, possibly of octahedral geometry, and form various structuraly isomers, whereas those of In3+ and Y3+, with a single structural isomer of eight-co-ordination, are very similar to the lanthanide complexes. The complexes of Al3+ and Ga3+ of L1 have considerable populations of isomers with bound amide groups, whereas the single structural isomer of the complexes of In3+ and Y3+ with both amide groups co-ordinated yield a variety of enantimoers in solution.

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.

Some macrocyclic compounds containing pyridinc have been synthetized: 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene(1), 3,7,10,16-tetraazabicyclo[10.3.1]hexadeca-1(16),12,14-triene(2), 3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (3), and 7-methyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15 trienc (4). The protonation reactions of these ligands were studied by potentiometric and 1 H NMR techniques

Two pentaaza macrocycles containing pyridine in the backbone, namely 3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene ([15]pyN(5)), and 3,6,10,13,19-pentaazabicyclo[13.3.1]nonadeca-1(19),15,17-triene ([16]pyN(5)), were synthesized in good yields. The acid-base behaviour of these compounds was studied by potentiometry at 298.2K in aqueous solution and ionic strength 0.10 M in KNO(3). The protonation sequence of [15]pyN(5) was investigated by (1)H NMR titration that also allowed the determination of protonation constants in D(2)O. Binding studies of the two ligands with Ca(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) metal ions were performed under the same experimental conditions. The results showed that all the complexes formed with the 15-membered ligand, particularly those of Cu(2+) and especially Ni(2+), are thermodynamically more stable than with the larger macrocycle. Cyclic voltammetric data showed that the copper(II) complexes of the two macrocycles exhibited analogous behaviour, with a single quasi-reversible one-electron transfer reduction process assigned to the Cu(II)/Cu(I) couple. The UV-visible-near IR spectroscopic and magnetic moment data of the nickel(II) complexes in solution indicated a tetragonal distorted coordination geometry for the metal centre. X-band EPR spectra of the copper(II) complexes are consistent with distorted square pyramidal geometries. The crystal structure of [Cu([15]pyN(5))](2+) determined by X-ray diffraction showed the copper(II) centre coordinated to all five macrocyclic nitrogen donors in a distorted square pyramidal environment.

A new bis-N,N'-(5-methylimidazol-4-ylmethyl) derivative of a 14-membered tetraazamacrocycle, L-1, has been synthesized. The protonation constants of this compound and the stability constants of its complexes with divalent first-row transition metal ions and Fe3+ were determined at 298.2 K in aqueous 0.10 mol dm(-3) KNO3. Compound L-1 exhibits high overall basicity, which is mainly conferred by theimidazolyl groups. The complexes of the divalent first row-transition metal ions of L-1 follow the Irving-Williams order of stability with the maximum for Cu2+ as expected, but a steep fall of constants is verified for the Mn2+, Fe2+ and Co2+, in one side, and for the Zn2+ complexes, in the other side. Additionally, L-1 shows a large affinity for Fe3+, and the relative stability constants for its Cd2+ and Pb2+ complexes indicate that L-1 may be useful for the complexometric determination of these two toxic metal ions in solutions containing both metal ions. These studies together with NMR, UV-vis and EPR spectroscopic data indicated the presence of mononuclear complexes, which adopt distorted pyramidal or octahedral geometries depending on the metal centre. The X-ray crystal structure of [ Cu(HL1)](PF6)(2)(NO3) center dot H2O showed that the coordination sphere of the copper centre can be described as a distorted square pyramid with the basal plane defined by three nitrogen donors of the macrocycle backbone and one nitrogen atom from one imidazolyl pendant arm. The apical position is occupied by the nitrogen atom of the macrocycle trans to the pyridine ring. To achieve this coordination environment, the macrocycle is folded along the axis defined by the two N atoms contiguous to the pyridine ring. The free methylimidazolyl arm points away from the metal centre leading to an intramolecular Cu center dot center dot center dot N distance of 5.155( 1) angstrom.

Structural studies of metal complexes of five ditopic hexaazamacrocycles containing two pyridine rings ([n]py2N4 n= 18, 20, 22, 24 and 26) have been carried out. The synthesis of macrocycles [22]- to [26]-py2N4 are also reported. The protonation constants of the last three compounds and the stability constants of their complexes with Ni2+, Cu2+, Zn2+, and Pb2+ were determined at 25 degrees C in 0.10 mol dm(-3) KNO3 in aqueous solution. Our results with [22]py2N4 show significant differences from those described previously, while [24]py2N4 has not been studied before and [26]py2N4 is a new compound. Mononuclear and dinuclear complexes of the divalent metal ions studied with [22]- to [26]-py2N4 were found in solution. The stability constants for the ML complexes of the three ligands follow the Irving-Williams order: NiL2+ > ZnL2+ > PbL2+, however for the dinuclear complexes the values for Pb2+ complexes are higher than the corresponding values for the Ni2+ and the Zn2+ complexes. The X-ray single crystal structures of the supramolecular aggregates [Cu2([20]py2N4)(H2O)4][Cu(H2O)6](SO4)3 x 3H2O and [Cu(2)([20]py(2)N4)(CH3CN)4][Ni([20]py2N4)]2(ClO4)8 x H2O, which are composed of homodinuclear [Cu2([20]py2N4])(H2O)4]4+ and [Cu2([20]py2N4])(CH3CN))4]4+, and mononuclear species, [Cu(H2O)6]2+ and [Ni([20]py2N4)]2+, respectively, assembled by an extensive network of hydrogen bonds, are also reported. In both homodinuclear complexes the copper centres are located at the end of the macrocycle and display distorted square pyramidal coordination environments with the basal plane defined by three consecutive nitrogen donors and one solvent molecule, water in and acetonitrile in . The macrocycle adopts a concertina-type conformation leading to the formation of macrocyclic cavities with the two copper centres separated by intramolecular distances of 5.526(1) and 5.508(7) A in 1a and 2a, respectively. The mononuclear complex [Ni([20]py2N4])]2+ displays a distorted octahedral co-ordination environment with the macrocycle wrapping the metal centre in a helical shape. EPR spectroscopy of the copper complexes indicated the presence of mono- and dinuclear species.

A new tetraazamacrocycle containing two 5-chloro-8-hydroxyquinoline side arms, L 1 , was synthesized. The protonationconstants of L 1 and the stability constants of its complexes with Cu 2 ,Zn 2 ,Cd and Pb were determined by potentiometric orspectrophotometric methods, at 20 8C in methanol:water (5:1, v/v) and ionic strength 0.10 mol dm 3 in tetrabutylammonium nitrate(TBAN). Compound L 1 has three high protonation constants, the most basic centres being both phenolates of the arms. Mono- anddinuclear complexes were found in solution for all the metal ions, the complexes of copper are thermodynamically very stable, andthe dinuclear complexes of lead(II) are the predominant species even in 1:1 mixtures. UV / Vis spectra of some complexes and EPRof the copper ones confirmed the presence of dinuclear complexes.# 2003 Elsevier B.V. All rights reserved. Keywords: Tetraazamacrocycle; Stability constants; Dinuclear complexes; EPR copper complexes; 8-Hydroxyquinolinyl groups 1. IntroductionMacrocycles containing quinoline side arms havefound many applications as analytical reagents inabsorption spectrophotometry, fluorometry, solvent ex-traction, and partition chromatography [1,2]. Thesecompounds are also used as pesticides [2].The 8-hydroxyquinoline (HQ) forms a stable five-membered chelate ring with metal centres and verystable complexes with divalent transition and post-transition metal ions of the type M(HQ) , M(HQ)

Two N-(2-pyridylmethyl) derivatives of a 14-membered tetraaza macrocycle containing pyridine have been synthesized, L-1 and L-2. The protonation constants of these compounds and the stability constants of complexes of both ligands with Co2+ to Zn2+, Cd2+, Pb2+, Fe3+ and In3+ were determined by potentiometric methods at 25 degrees C and ionic strength 0.10 mol dm(-3) in KNO3. The values of the protonation constants for L-1 and L-2 are quite different. The metal complexes of both ligands present lower values of stability constants than expected. The only exception is the case of the Cd2+ complex with L-2 which exhibits a particularly high stability constant, indicating that this ligand has a remarkable selectivity for this metal ion relative to zinc. The Cd2+ complex seems to be the only one to bond to all the donor atoms of the ligand or at least to more than the other metal ions studied. The pM values determined at physiological pH, which take into account the competition of the protons for the ligand, have shown that L-2 is the most selective compound for cadmium relative to zinc. The single crystal structure of [CuL2][ClO4](2) determined by X-ray diffraction has shown that the co-ordination geometry around the copper atom can be described approximately as a distorted square pyramid. To achieve this geometric arrangement the macrocycle adopts a folded conformation. Furthermore the nitrogen atom of one free pyridylmethyl pendant arm is directed towards the copper centre leading to a distance between these two atoms of 3.304(11) Angstrom, which suggests a weak bonding interaction consistent with a [5+1] co-ordination.

The N,N'-bis(butanamide) derivative of TTHA (TTHA = triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid), and its Ga(3+) and In(3+) complexes were synthesized and characterized. The crystal X-ray diffraction structure of [Ga(2)(OH)(2)(TTHA)][Na(2)(H(2)O)(6)].2H(2)O was determined. The complex crystallizes in the monoclinic space group P2(1)/n with a = 7.179(2) Å, b = 20.334(3) Å, c = 10.902(5) Å, beta = 101.90(2) degrees, and Z = 2. Each gallium atom is bonded to six donor atoms (N(2)O(4)) in a slightly distorted octahedral geometry. The values of the protonation constants and the protonation sequence were determined by potentiometry and NMR. The stability constants of the Al(3+), Ga(3+), Fe(3+), and In(3+) complexes of TTHA-(BuA)(2) and of the Ga(3+) complex of TTHA were determined by potentiometry. The structures, in solution, of the Al(3+), Ga(3+), and In(3+) complexes of TTHA-(BuA)(2) and TTHA were analyzed by (1)H, (13)C, (27)Al, (71)Ga, and (115)In NMR techniques. Derivatization of two terminal carboxylates by butanamide substituents leads to a significant decrease of the total ligand basicity (5.77 log units) and to a change of the solubility of the resulting complexes. The stability constant of the ML complexes of TTHA-(BuA)(2) with Fe(3+) exhibits the highest value of the series (10(23.92)). The In(3+) complex is more stable than that of Ga(3+) and almost as stable as that of the Fe(3+). However, the decrease in indium and iron complex stability is less drastic going from TTHA to TTHA-(BuA)(2) (about 3 log units) than for Al(3+) or Ga(3+) (about 6 log units). pM values calculated under physiological conditions for DTPA, TTHA, and the bis(butanamide) derivatives have shown that while DTPA remains a ligand of choice to chelate Fe(3+) and In(3+) ions in vivo compared to transferrin as competitor ligand, TTHA, surprisingly, appears to be the best of these four ligands (pM = 22.71) to chelate Ga(3+).

The protonation constants of H2L1, 3,11-bis(carboxymethyl)-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene and H3L2, 3,7,11-tris(carboxymethyl)-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene, and stability constants of complexes formed by these macrocycles with Mg2+, Ca2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Pb2+, Ga3+, Fe3+ and In3+ were determined at 25 °C and ionic strength 0.10 mol dm–3 in NMe4NO3. Both compounds are very selective for the divalent first-row transition-metal ions, exhibiting very high stability constants for Cu2+, fairly high values for Ni2+, but sharply decreasing ones for the remaining metal ions of this row. Their complexes with the alkaline-earth or larger metal ions, such as Pb2+, have low stability constants. The crystal structure of [CuL1]·4H2O was determined. The copper atom is encapsulated by the macrocycle in a distorted octahedral environment. The equatorial plane contains the four nitrogen atoms of the tetraaza ring and six-co-ordination is completed via two oxygen atoms of the appended carboxylate groups. The angles at the metal centre are close to the expected values of 90 and 180° for octahedral geometry. Molecular mechanics studies carried out for the cis and the trans octahedral [ML1] complexes were consistent with the structure found in the solid state. For a mean CuII–N distance of 2.01 A the experimentally observed trans isomer is 6.5 kcal mol–1 more stable than the cis one. On the other hand these calculations suggest that larger ions such as Pb2+, Ca2+ or Mn2+ can be accommodated by the macrocycle in a cis-octahedral environment. However, these ions allow co-ordination numbers higher than six and so other structures ought to be also considered. The low stability constants for metal complexes of Co2+ and Zn2+ indicate that these complexes do not have a trans-octahedral structure, while the molecular mechanics calculations reveal that the cis isomer is not the most stable form. Therefore, other structures with co-ordination numbers lower than six should be considered, implying that one or more donor atoms are not co-ordinated. Stability constants of metal complexes of (L2)3– and EPR studies suggest that not all the donor atoms in this macrocycle are co-ordinated when complexes are formed with first-row-transition divalent metal ions.

Some 9- and 10-membered oxa-diaza macrocyclic ligands and their N-acetate derivatives have been synthesized and their protonation patterns studied by 1 H NMR and potentiometric techniques. The stability constants of the complexes formed by these ligands with several alkaline-earth and first-series transition metal ions, zinc, cadmium and lead, were determined by potentiometry and the values were compared with those formed with the analogous 9-membered tri-aza macrocyclic ligands and with 12-membered oxa-triaza ligands. The substitution of one nitrogen by an oxygen atom in the backbone of the macrocyclic ring has pronounced effects both on the kinetics of the complexation reactions (faster equilibration) and on the stability of the metal complexes formed (decreased stability). The differences in this last case are analysed for two pairs of cyclic amines ([9]aneN 3 /[9]aneN 2 O and [12]aneN 4 /[12]aneN 3 O) with the first transition metal ions and for the corresponding N-acetate derivatives with the first transition and alkaline-earth metal ions.