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Considering as a lead molecule the chemokine CXCR4 receptor antagonist AMD-3100, which shows significant anti-HIV activity in vitro and in vivo, we investigated a series of structurally related macrocyclic polyamines incorporating o,o'-phenanthroline or 2,2'-bipyridyl scaffolds as potential antiviral agents with lower toxicity and increased activity against both wild type X4-tropic and dual tropic HIV strains. The antiviral activity of these compounds was evaluated by susceptibility assays in PBMC (Peripheral Blood Mononuclear Cells) and compared to that of AMD-3100. The newly investigated compounds showed IC(50)s values in the low micromolar range and significantly inhibited the viral replication of wild type X4-tropic isolate and dual tropic strains. These macrocyclic polyamines constitute a promising class of HIV entry inhibitors.

The synthesis of the macrocyclic ligand 4,4′-(2,6,10,13,18-pentaaza26)-2,2′-bipyridylcylophane (L), which contains a penta-amine chain linking the 4,4′ positions of a 2,2′-bipyridyl moiety, is reported. The heteroaromatic nitrogens of L are located outside the macrocyclic cavity. Ligand protonation, as well as Cu(II) and Ni(II) complexation by L, were studied by potentiometric and UV-Vis techniques in aqueous solution. Only mononuclear complexes are formed. In [CuL]2+, the metal is encapsulated inside the cavity, not coordinated by the bipyridyl unit. Protonation of the complex occurs on the aliphatic polyamine chain and gives rise to translocation of the metal outside the cavity, bound to the heteroaromatic nitrogens. Conversely, Ni(II) is always bound to the bipyridyl nitrogens in both protonated and unprotonated complexes.

ATP binding to ligands L1 and L3 and to their Zn(II) complexes has been examined by means of potentiometric and 1 H and 31 P NMR measurements in aqueous solution. Their coordination features have been compared to those of ligand L2 and its Zn(II) complex. In all the three cases, the Zn(II) complexes proved to be better receptors than free ligands, due to the synergetic action of metal ion and ammonium functions in ATP binding. Among the three complexes, Zn(II) complex with L1 shows the highest equilibrium constant, which can be ascribed to the fact that, being coordinated by the dipyridine nitrogens outside the macrocyclic cavity, it is less saturated by ligand donors. The 31 P NMR investigation showed that the nucleotide interacts via the P γ and P β phosphate groups with both free ligands and complexes, while the 1 H spectra revealed that the binding is reinforced by the presence of π–π interactions. Photophysical studies showed that the fluorescence emission intensity of the Zn(II) complexes is enhanced upon interaction with ATP.

Two new mixed aza-thia crowns 5-aza-2,8-dithia[9]-(2,9)-1,10-phenanthrolinophane (L(4)) and 2,8-diaza-5-thia[9]-(2,9)-1,10-phenanthrolinophane (L(7)) have been synthesized and characterized. The coordination behavior of L(4) and L(7) toward the metal ions Cu(II), Zn(II), Pb(II), Cd(II), Hg(II), and Ag(I) was studied in aqueous solution by potentiometric methods, in CD3CN/D2O 4:1 (v/v) by (1)H NMR titrations and in the solid state. The data obtained were compared with those available for the coordination behavior toward the same metal ions of structurally analogous mixed donor macrocyclic ligands L(1)-L(3), L(5), L(6): all these contain a phenanthroline subunit but have only S/O/N(aromatic) donor groups in the remaining portion of the ring and are, therefore, less water-soluble than L(4) and L(7). The complexes [Cd(NO3)2(L(5))], [Pb(L(7))](ClO4)2 x 1/2MeCN, [Pb(L(4))](ClO4)2 x MeCN, and [Cu(L(7))](ClO4)2 x 3/2MeNO2 were characterized by X-ray crystallography. The efficacy of L(1)-L(7) in competitive liquid-liquid metal ion extraction of Cu(II), Zn(II), Cd(II), Pb(II), Ag(I), and Hg(II) was assessed. In the absence of Hg(II), a clear extraction selectivity for Ag(I) was observed in all systems investigated.

The synthesis and characterization of two new open-chain ligands, L1 and L2, containing two 2,2'-dipyridine units connected respectively by a pentaethylenhexamine and a pentapropylenhexamine chain, is reported. Zn(II) com- plexation has been studied by means of potentiometric and UV-vis spectrophotometric measurements in aqueous solution. Both ligands form stable mono- and dinuclear complexes, the metal ions being coordinated by a single dipyridine unit and by the adjacent amine groups. The ability of the binuclear Zn(II) complexes as nucleophilic agents in hydrolytic processes has been tested by using bis(p-nitrophenyl) phosphate (BNPP) as substrate. Both complexes display high rate enhance- ments in BNPP cleavage in aqueous solution. The study outlines that different mechanisms are operative in BNPP cleav- age in the presence of the L1 and L2 complexes.

The synthesis and characterization of a new bis([9]aneN3) ligand (H2L) containing two [9]aneN3 macrocyclic moieties separated by a 2,2'-methylene-bis-cresol (cresol = 4-methyl-phenol) unit is reported. A potentiometric and (1)H NMR study in aqueous solution reveals that H2L is in a zwitterionic form, and protonation of the cresolate oxygens occurs only with the formation of the highly charged (H5L)(3+) and (H6L)(4+) species at acidic pH values. The coordination properties of H2L toward Cu(II), Zn(II), Cd(II), and Pb(II) were studied by means of potentiometric and UV spectrophotometric measurements. The ligand gives both mono- and binuclear complexes in aqueous solution. At acidic pH values the ligand forms stable binuclear [M2H2L](4+) complexes, where each metal is coordinated by two amine groups of [9]aneN3 and the deprotonated oxygen of the adjacent cresol unit; the remaining amine group is protonated. Deprotonation of the [M2H2L](4+) species at alkaline pH values affords [M2L](2+) complexes, where all amine groups of the [9]aneN3 moieties are involved in metal coordination. Binding of mono-, di- and triphosphate, and adenosine triphosphate (ATP) was studied by means of potentiometric, (1)H and (31)P NMR measurements and by molecular dynamics simulations. The receptor forms stable 1:1 adducts with di-, triphosphate, and ATP, while the interaction with monophosphate is too low to be detected. In the complexes both the [9]aneN3 moieties act cooperatively in the substrate binding process. The stability of the adducts increases in the order diphosphatetriphosphateATP. This trend is explained in terms of increasing number of charge-charge interactions between the phosphate chains and the protonated [9]aneN3 subunits and, in the case of ATP, of stacking interactions between the adenine and cresol units.

The insertion of 2,2′:6′,2″-terpyridine groups into macrocyclic polyamine structures gives rise to a considerable enhancement of molecular rigidity which affects their coordination properties. This review concerns some examples of both very rigid, shape-persistent Schiff-base macrocycles and less rigid polyamine-macrocycles in which the rigidity of terpyridine is associated with the flexibility of aliphatic polyamine chains. Structural, thermodynamic, electrochemical, and spectroscopic properties of transition metal complexes with these ligands are presented and correlated with the ligand structures. The ability of some complexes to bind and activate substrate molecules, in particular CO 2 uptake and conversion into carbonate/carbamate, and ATPase mimicking, is also described. The review includes an introductive overview of the relevant terpyridine properties.

The coordination features of a polyaza macrocycle, containing the diverse bipyridine unit 4,4′-(2,5,6,11,14-pentaaza[15]-[15](2,2′)-bipyridylophane (L3), with Co(II) and Cd(II) have been studied in aqueous solution and in the aprotic solvent dimethylsulfoxide (DMSO). The study was carried out at 298 K by means of potentiometric, spectrophotometric and calorimetric techniques. The formation of the dinuclear species M2 L3 is observed for Co(II) both in water and in DMSO, whereas Cd(II) is able to form this type of dinuclear complex only in DMSO. The FT-IR spectra of the mononuclear species ML3, formed in both solvents, provide evidence that the rigid structure of the polyaminic chain prevents metal ions from being coordinated by all of the nitrogens of the macrocyclic cavity, in good agreement with the behavior suggested by the thermodynamic parameters. The results are compared with those for the complexation of Co(II) and Cd(II) with similar polyazamacrocycles containing a bipyridine unit directly inside the cavity. Semi-empirical calculations were also performed to obtain structural information.

Two new fluorescent chemosensors for metal ions have been synthesized and characterized, and their photophysical properties have been explored; they are the macrocycles 5-(2-quinolinylmethyl)-2,8-dithia-5-aza-2,6-pyridinophane (L5) and 5-(5-chloro-8-hydroxyquinolinylmethyl)-2,8-dithia-5-aza-2,6-pyridinophane (L6). Both systems have a pyridyl-thioether-containing 12-membered macrocycle as a binding site. The coordination properties of these two ligands toward CuII, ZnII, CdII, HgII, and PbII have been studied in MeCN/H2O (1:1 v/v) and MeCN solutions and in the solid state. The stoichiometry of the species formed at 25 degrees C have been determined from absorption, fluorescence, and potentiometric titrations. The complexes [CuL5](ClO4)(2).1/2MeCN, [ZnL5(H2O)](ClO4)2, [HgL5(MeCN)](ClO4)2, [PbL5(ClO4)2], [Cu3(5-Cl-8-HDQH-1)(L6H-1)2](ClO4)(3).7.5H2O (HDQ=hydroxyquinoline), and [Cu(L6)2](BF4)(2).2MeNO2 have also been characterized by X-ray crystallography. A specific CHEF-type response of L5 and L6 to the presence of ZnII and CdII, respectively, has been observed at about pH 7.0 in MeCN/H2O (1:1 v/v) solutions.

The chemosensing properties of the polyaza-macrocycle 1-(6,7)-acridine-3,6,9,12-tetraaza-tridecaphane have been investigated by means of emission fluorescence spectroscopy, considering halide ions as substrates. As in the case of the free ligand, the fluorescence emission of the complexes is due to the acridinium species which are formed after photoinduced proton transfer reaction. The complexation constants have been obtained for the bi- and tri-protonated ligands in deoxygenated aqueous solutions. Two different emission behaviours have been observed varying the anion. Fluoride and chloride give rise to fluorescence enhancement whereas bromide and iodide strongly quench the emission. The macrocycle shows an unusual higher selectivity towards the chloride anion rather than fluoride. The fluorescence emission has been modelled considering a modified Stern–Volmer equation, taking into account the quenching effects of the largest anions, which can be considered negligible for fluoride and chloride anions. Ab initio calculations allow us to interpret the fluorescence emission of the complexes in terms of activation energy related to the proton transfer reaction responsible for the emission process.

In this work we have investigated the binding properties of a new synthetic receptor for phosphate anions that combines metal ion coordination with electrostatic and H-bonding interactions. The described receptor is obtained by assembling an iminodiacetic (IDA) fragment, as a Zn(II) binding site, with a polyamine macrocyclic portion containing two trans-1,2-diaminocyclohexane (DAC) units and a pyrrole ring, as a cationic binding site, into an adaptive structure appropriately spanning the length of di- and tridentate phosphates. Potentiometric measurements together with (1)H and (31)P NMR investigation showed that, in a wide pH range including values of physiological interest, the Zn(II) complex of the receptor binds di- and triphosphates, such as ADP, ATP, pyrophosphate (PP) and triphosphate (TP), far better than monophosphate (MP), and that TP is poorly bound by methyliminodiacetate (MIDA) as a model for the Zn(II) binding site. Besides the excellent selectivity over other phosphates, the affinity for TP is the largest reported to date for Zn(II) complexes in water.

The interaction of F−, Cl− and Br− with protonated forms of the cage-like macrobicyclic ligands L1 and L2, containing, respectively, N7 and N6O sets of donor atoms, was studied by means of potentiometric titrations in aqueous solution, achieving the determination of the stability constants of the complex species formed. While L1 forms halogenide complexes [L1HnX](n−1)+ in various protonation states (n = 2–5 for F− and Cl−, n = 1–5 for Br−), only [L2H4X]3+ (X = F−, Cl−, Br−) complexes are formed by L2. For a given anion, the complex stability increases with the ligand charge, in agreement with a fundamental electrostatic character of the anion–receptor interaction. On the contrary, contrasting stability trends are observed when the stability constants of anion complexes with the ligands in a given protonation state are considered. Only in the case of [L1H5X]4+ complexes the stability follows the trend F− > Cl− > Br−, while for less protonated L1 species the trend is Cl− > Br− > F−. In the case of [L2H4X]3+ complexes the stability trend is F− > Br− > Cl−. Despite the fact that [L2H4]4+ forms a largely more stable F− complex than [L1H4]4+, L1 shows clear selectivity in halogenide binding with respect to L2 over all the pH range. L2 displays a marked selectivity in the binding of F− over Cl− and Br− while in the case of L1 inversion of binding selectivity is found upon pH variations, the F− complexes being favoured in very acidic media. Molecular modelling calculations performed in the gas phase and/or by adopting minimal solvation shells, furnished useful information for the interpretation of these stability trends. Anion size and anion desolvation upon coordination are the main factors determining the stability of halogenide complexes with L1 and L2.

The voltammetry of hexavalent chromium (ammonium dichromate) at the interface between two immiscible electrolyte solutions is reported. Detection of Cr(VI) by ion transfer voltammetry is possible by use of an organic phase ionophore, which facilitates the transfer of Cr(VI) from the aqueous into the organic phase. The ionophore was the penta protonated form of polyamine macrocycle 2,5,8,11,14-pentaaza[15]-16,29-phenanthrolinophane (NeoTT). Cyclic voltammetry showed an increase of the peak current on increasing the concentration of Cr(VI). Square wave voltammetry with background subtraction was employed for low level concentration detection. The lowest concentration detected was 0.25 parts per million of Cr(VI). Keywords: Liquid|liquid interface, ITIES, Hexavalent chromium, Facilitated ion transfer, Ammonium dichromate

Reaction pathways have been investigated by quantum-mechanical procedures on gas phase models for the hydrolysis of methyl acetate catalyzed by a monohydroxo-Zn(II) complex formed by a phenanthroline-containing polyamine macrocycle. Based on consideration of energy barrier heights, the hydrolysis process is predicted to be bimolecular, consistently with kinetic data obtained for the hydrolysis of p -nitrophenyl acetate promoted by the modelled catalyst. Differences with respect to results of theoretical studies on the more extensively investigated hydrolysis processes catalyzed by the OH − anion are discussed and appear to be mostly due to the presence of the metal centre close to the OH function in the system now investigated. The pervasive presence and path-controlling role of hydrogen bonds are also discussed.

The synthesis of the novel macrocycle 2,6,9,12,16-pentaaza[17](2,9)(1,10)phenanthrolinophane (L3) is reported. Speciation studies on the systems ZnII−L3 and ZnII−L2 (L2 =2,6,10,13,17,21-hexaaza[22]metacyclophane) performed in aqueous solution show the formation of mono- and dinuclear ZnII complexes. In the two systems, the dinuclear complexes readily hydroxylate, with the hydroxo species being the main ones in solution at relatively low pH values. This feature makes these complexes promising hydrolytic agents for carboxy and phosphate esters. The hydrolytic ability of the L1−L3 dinuclear complexes toward the carboxy and phosphate ester bond was tested by addition of p-nitrophenyl acetate (NA) and bis(p-nitrophenyl)phosphate (BNP). While in the case of NA the cleavage takes place through a simple bimolecular mechanism and the hydrolysis rate depends on the nucleophilicity of the ZnII−OH functions, in the case of BNP the hydrolytic mechanism involves substrate interaction with the metal ions and nucleophilic attack of a ZnII-bound hydroxide ion at the phosphorus atom. The L3 complex gives rise to the highest hydrolysis rate constant {k = 62 × 10−5M−1·s−1 vs. k = 8 × 10−5 and 4 × 10−5M−1·s−1 for [Zn2L2(OH)2]2+ and [Zn2L1(OH)2]2+, respectively}. This may be related to a stronger interaction with the substrate due to the synergetic role in BNP binding played by the phenanthroline unit, which can give π-stacking and hydrophobic interactions with the aromatic units of the substrate, and by the two ZnII ions, which can act cooperatively in BNP coordination. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Zn(II) binding by the dipyridine-containing macrocycles L1-L3 has been analyzed by means of potentiometric measurements in aqueous solutions. These ligands contain one (L1, L2) or two (L3) 2,2'-dipyridine units as an integral part of a polyamine macrocyclic framework having different dimensions and numbers of nitrogen donors. Depending on the number of donors, L1-L3 can form stable mono- and/or dinuclear Zn(II) complexes in a wide pH range. Facile deprotonation of Zn(II)-coordinated water molecules gives mono- and dihydroxo-complexes from neutral to alkaline pH values. The ability of these complexes as nucleophilic agents in hydrolytic processes has been tested by using bis(p-nitrophenyl) phosphate (BNPP) as a substrate. In the dinuclear complexes the two metals play a cooperative role in BNPP cleavage. In the case of the L2 dinuclear complex [Zn(2)L2(OH)(2)](2+), the two metals act cooperatively through a hydrolytic process involving a bridging interaction of the substrate with the two Zn(II) ions and a simultaneous nucleophilic attack of a Zn-OH function at phosphorus; in the case of the dizinc complex with the largest macrocycle L3, only the monohydroxo complex [Zn(2)L3(OH)](3+) promotes BNPP hydrolysis. BNPP interacts with a single metal, while the hydroxide anion may operate a nucleophilic attack. Both complexes display high rate enhancements in BNPP cleavage with respect to previously reported dizinc complexes, due to hydrophobic and pi-stacking interactions between the nitrophenyl groups of BNPP and the dipyridine units of the complexes.

The synthesis of the new terpyridine-containing macrocycle 2,5,8,11,14-pentaaza[15](6,6' ')cyclo(2,2':6',2' ')terpyridinophane (L) is reported. The ligand contains a pentaamine chain linking the 6,6' ' positions of a terpyridine unit. A potentiometric, (1)H NMR, UV-vis spectrophotometric and fluorescence emission study on the acid-base properties of L in aqueous solutions shows that the first four protonation steps occur on the polyamine chain, whereas the terpyridine nitrogens are involved in proton binding only at strongly acidic pH values. L can form both mono- and dinuclear Cu(II), Zn(II), Cd(II), and Pb(II) complexes in aqueous solution. The crystal structures of the Zn(II) and Cd(II) complexes ([ZnLH](2)(micro-OH))(ClO(4))(5) (6) and ([CdLH](2)(micro-Br))(ClO(4))(5).4H(2)O (7) show that two mononuclear [MLH](3+) units are coupled by a bridging anion (OH(-) in 6 and Br(-) in 7) and pi-stacking interactions between the terpyridine moieties. A potentiometric and spectrophotometric study shows that in the case of Cu(II) and Zn(II) the dimeric assemblies are also formed in aqueous solution containing the ligand and the metals in a 1:1 molar ratio. Protonation of the complexes or the addition of a second metal ion leads to the disruption of the dimers due to the increased electrostatic repulsions between the two monomeric units.

The binding properties of 1,4,7-triazacyclononane ([9]aneN3) to metal cations can be adapted through sequential functionalisation of the secondary amines with aminoethyl or aminopropyl pendant arms to generate ligands with increasing numbers of donor atoms. The new amino functionalised pendant arm derivative of 1,4,7-triazacyclononane ([9]aneN3), L1, has been synthesised and its salt [H2L1]Cl2 characterised by X-ray diffraction. The protonation constants of the ligands L1-L4 having one, two or three aminoethyl or three aminopropyl pendant arms, respectively, on the [9]aneN3 framework, and the thermodynamic stabilities of their mononuclear complexes with CuII and ZnII have been investigated by potentiometric measurements in aqueous solutions. In order to discern the protonation sites of ligands L1-L4, 1H NMR spectroscopic studies were performed in D2O as a function of pH. While the stability constants of the CuII complexes increase on going from L1 to L2 and then decrease on going from L2 to L3 and L4, those for ZnII complexes increase from L1 to L3 and then decrease for L4. The X-ray crystal structures of the complexes [Cu(L1)(Br)]Br, [Zn(L1)(NO3)]NO3, [Cu(L2)](ClO4)2, [Ni(L2)(MeCN)](BF4)2, [Zn(L4)](BF4)2.MeCN and [Mn(L4)](NO3)2.1/2H2O have been determined. In both [Cu(L1)(Br)]Br and [Zn(L1)(NO3)]NO3 the metal ion is five co-ordinate and bound by four N-donors of the macrocyclic ligand and by one of the two counter-anions. The crystal structures of [Cu(L2)](ClO4)2 and [Ni(L2)(MeCN)](BF4)2 show the metal centre in slightly distorted square-based pyramidal and octahedral geometry, respectively, with a MeCN molecule completing the co-ordination sphere around NiII in the latter. In both [Zn(L4)](BF4)2.MeCN and [Mn(L4)](NO3)2.1/2H2O the metal ion is bound by all six N-donors of the macrocyclic ligand in a distorted octahedral geometry. Interestingly, and in agreement with the solution studies and with the marked preference of CuII to assume a square-based pyramidal geometry with these types of ligands, the reaction of L4 with one equivalent of Cu(BF4)2.4H2O in MeOH at room temperature yields a square-based pyramidal five co-ordinate CuII complex [Cu(L6)](BF4)2 where one of the three propylamino pendant arms of the starting ligand has been cleaved to give L6.

Synthesis and characterisation of a new macrobicycle containing two dipyridine units (L) is reported. Protonated forms of L are efficient receptors for inorganic phosphate and nucleotide anions. The binding properties of L toward these substrates have been investigated in aqueous solution by means of potentiometric, microcalorimetric and 1H NMR measurements. Only 1:1 receptor–anion complexes have been found in solution. The stability of the adducts with inorganic phosphates anions is higher than that found for the nucleotides complexes. The complexation reactions are endothermic, and promoted by invariably favourable entropic contributions, indicating that these pairing processes are mostly determined by the desolvation of the interacting species that occurs upon charge neutralisation.

We have prepared and characterized a new phenol-based compartmental ligand (H(2)L) incorporating 1,4,7-triazacyclononane ([9]aneN(3)), and we have investigated its coordination behavior with Cu(II), Zn(II), Cd(II), and Pb(II). The protonation constants of the ligand and the thermodynamic stabilities of the 1:1 and 2:1 (metal/ligand) complexes with these metal ions have been investigated by means of potentiometric measurements in aqueous solutions. The mononuclear [M(L)] complexes show remarkably high stability suggesting that, along with the large number of nitrogen donors available for metal binding, deprotonated phenolic functions are also involved in binding the metal ion. The mononuclear complexes [M(L)] show a marked tendency to add a second metal ion to afford binuclear species. The formation of complexes [M(2)(H(2)L)](4+) occurs at neutral or slightly acidic pH and is generally followed by metal-assisted deprotonation of the phenolic groups to give [M(2)(HL)](3+) and [M(2)(L)](2+) in weakly basic solutions. The complexation properties of H(2)L have also been investigated in the solid state. Crystals suitable for X-ray structural analysis were obtained for the binuclear complexes [Cu(2)(L)](BF(4))(2).(1)/(2)MeCN (1), [Zn(2)(HL)](ClO(4))(3).(1)/(2)MeCN (2), and [Pb(2)(L)](ClO(4))(2).2MeCN (4). In 1 and 2, the phenolate O-donors do not bridge the two metal centers, which are, therefore, segregated each within an N(5)O-donor compartment. However, in the case of the binuclear complex [Pb(2)(L)](ClO(4))(2).2MeCN (4), the two Pb(II) centers are bridged by the phenolate oxygen atoms with each metal ion sited within an N(5)O(2)-donor compartment of L(2)(-), with a Pb.Pb distance of 3.9427(5) A.

The interaction between several L-amino acids and dipeptides and the ZnII complex with ligand L, a macrocycle containing a triamine chain linking the 2,9 positions of a phenanthroline moiety, has been studied by means of potentiometric and 1H NMR spectroscopic measurements in aqueous solutions. In the [ZnL]2+ complex, the metal ion displays an unsaturated coordination environment and the metal can act as a binding site for these substrates. Amino acids and dipeptides in their neutral (zwitterionic) form bind to ZnII through the carboxylate function and, when in their anionic form, through the amine group. In this case the carbonyl of the amide function is probably also involved in metal coordination. Amino acids containing aromatic pendants form the most stable complexes, due to hydrophobic and/or π-stacking interactions between the aromatic subunits of the substrates and the phenanthroline moiety of the metal receptor. The hydrolytic properties of the ZnII complex with L, involving the cleavage of the peptide bond, have been tested by using L-leucine-p-nitroanilide (LNA), which contains an activated peptide bond. This substrate forms stable [ZnL(LNA)]2+ and [ZnL(OH)(LNA)]+ complexes. The formation of the [ZnL(OH)(LNA)]+ complex is followed by LNA hydrolysis, through a nucleophilic attack of the Zn−OH function on the peptide bond. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The coordination features of the two dipyridine-containing polyamine macrocycles 2,5,8,11,14-pentaaza[15]-[15](2,2′)[1,15]-bipyridylophane (L1) and 4,4′-(2,5,8,11,14-pentaaza[15]-[15](2,2′)-bipyridylophane) (L2) toward Cu(II) and Ni(II) have been studied by means of potentiometric and spectrophotometric UV-vis titrations in aqueous solutions. While in L1 all the nitrogen donor atoms are convergent inside the macrocyclic cavity, in L2 the heteroaromatic nitrogen atoms are located outside. Ligands L1 and L2 form stable mono- and dinuclear complexes with Cu(II). In the case of Ni(II) coordination, only L1 gives dinuclear complexes, while L2 can form only mononuclear species. In the Cu(II) or Ni(II) complexes with L1 the metal(s) are lodged inside the macrocyclic cavity, coordinated to the heteroaromatic nitrogens. As shown by the crystal structure of the [CuL1]2+ and [NiL1]2+ cations, at least one of the two benzylic nitrogens is not coordinated and facile protonation of the complex takes place at neutral or slightly acidic pH values. The particular molecular architecture of L2, which displays two well-separated binding moieties, strongly affects its coordination behavior. In the mononuclear [CuL2]2+ complex, the metal is encapsulated inside the cavity, not coordinated by the dipyridine unit. Protonation of the complex, however, occurs on the aliphatic polyamine chain and gives rise to translocation of the metal outside the cavity, bound to the heteroaromatic nitrogens. In the [NiL2]2+ complex the metal is coordinated by the dipyridine nitrogens, outside the macrocyclic cavity. Thermodynamic and/or kinetic considerations may explain the different behavior with respect to the corresponding Cu(II) complex.

The coordination chemistry of the mixed donor 12-membered macrocyclic ligand 1-aza-4,10-dithia-7-oxacyclododecane ([12]aneNS2O) with CuII, ZnII, CdII, HgII, and PbII has been investigated both in water solution and in the solid state. The protonation constant for [12]aneNS2O and stability constants with the aforementioned metal ions have been determined potentiometrically and compared with those reported for other mixed N/S/O-donor tetradentate 12-membered macrocycles. The measured values are consistent with trends observed previously for aza macrocycles as secondary N-donors are replaced by O- and S-donors. In particular our results show that HgII in water has the highest affinity for [12]aneNS2O followed by CuII, CdII, PbII, and ZnII. For each considered metal ion, 1 ∶ 1 complexes of [12]aneNS2O have been isolated in the solid state; those of CuII, HgII, and CdII have also been characterised by X-ray crystallography. In the cases of copper(II) and cadmium(II) complexes the ligand adopts a folded [2424] conformation, whereas a more planar [3333] conformation is observed in the case of the mercury(II) complex. The macrocycle [12]aneNS2O and its structural analogue [12]aneNS3 have then been used as receptor units in the design and synthesis of the new ferrocene-containing redox-active ionophores N-ferrocenylmethyl 1-aza-4,10-dithia-7-oxacyclododecane (L1) and N-ferrocenylmethyl 1-aza-4,10,7-trithiacyclododecane (L2). Electrochemical studies carried out in MeCN in the presence of increasing amounts of CuII, ZnII, CdII, HgII, and PbII showed that the wave corresponding to the Fc/Fc+ couple of the uncomplexed ionophores L1 and L2 is gradually replaced by a new reversible wave at more positive potentials and corresponding to the Fc/Fc+ couple of the complexed ionophores. The maximum shift of the ferrocene oxidation wave was found for L1 in the presence of ZnII (230 mV) and PbII (220 mV), whereas for L2 a selective sensing response for CuII over the other guest metal cations was observed with an oxidation peak shift of 230 mV.

Proton binding by the two tren-based tris-macrocycles L1 and L2, composed, respectively, by three 1,4,7,10-tetrazacyclododecane ([12]aneN4) and three 1-oxa-4,7,10-triazacyclododecane ([12]aneN3O) macrocyclic moieties appended to a “tren” unit (tren = tris(2-aminoethyl)amine), has been analyzed by means of potentiometric and 1H and 13C NMR measurements in aqueous solutions. This study reveals that the ligands form highly charged polyammonium cations at neutral pH, containing six acidic protons equally distributed among the three macrocyclic units. A potentiometric and UV-vis spectrophotometric study shows that both ligands can form stable trinuclear Cu(II) complexes in a wide pH range. In the polynuclear complexes each metal is coordinated to a single macrocyclic unit. While the Cu(II) complexes with L1 do not show any tendency to form hydroxylated complexes, the mono-, di- and trinuclear L2 complexes give stable hydroxo-complexes, present in aqueous solutions from slightly acidic to alkaline pH values. Melting point studies indicate that the new tris-macrocyles and their Cu(II) complexes lead to stronger stabilization of double-stranded nucleic acids than those observed earlier with analogous ditopic macrocyclic ligands, again with preference for RNA-type polymers compared to DNA. The copper complexes promote cleavage of plasmid DNA and of bis-p-nitrophenyl phosphate (BNPP). Particular rate enhancements for BNPP with some complexes are attributed to the simultaneous action of three metal ions and partially to the formation of hydroxo complexes at neutral pH.

Zn(II) coordination by the phenanthroline-containing macrocycle 2,6,10,14-tetraaza[15](2,9)cyclo(1,10)phenanthrolinophane (L4) has been studied by means of potentiometric measurements in aqueous solution. Its coordination properties have been compared with those of other phenanthroline- or dipyridine-containing open-chain (L1, L2) or cyclic (L3) ligands. ATP binding to the Zn(II) complexes with L1–L4 has been examined by means of potentiometric and 1H and 31P NMR measurements in aqueous solution. In the ATP adducts with the [ZnL]2+ complexes, the nucleotide interacts with the metal via the terminal Pγ phosphate group; the equilibrium constants for the addition of ATP to the complexes depend on the number and arrangement of the nitrogen donors coordinated to the metal ion. Protonation of the [ZnL]2+ complexes gives [ZnHxL](x + 2)+ species, which contain two binding sites for the phosphate chain of ATP; while the Pγ phosphate group gives a coordination bond with the metal, the Pβ one interacts via P–O−⋯H–N+ salt bridges with the ammonium functions of the complex. In consequence, protonated complexes are better ATP receptors than the simple [ZnL]2+ species and even than the protonated forms [HxL]x+ of the ligands, due to the synergetic action of the metal ion and of ammonium functions in ATP binding.

Zn(II) binding by two tren-based tris-macrocycles has been analysed by means of potentiometric measurements in aqueous solutions. Both ligands form stable trinuclear Zn(II) complexes. Deprotonation of Zn(II)-coordinated water molecules gives mono-, di- and tri-hydroxo complexes. The ability of these trinuclear complexes as hydrolytic agents has been tested by using p-nitrophenyl acetate and bis(p-nitrophenyl) phosphate (BNPP) as substrates. BNPP cleavage takes place through a bridging interaction of the substrate with at least two metals and simultaneous nucleophilic attack of a Zn–OH function at phosphorus. A significant increase of the hydrolysis rate with respect to the mononuclear Zn(II) complex with [12]aneN4 is observed.

A terpyridine-based receptor featuring two [9]aneN(3) units is able to selectively bind and sense diphosphate over mono- and triphosphate in aqueous solution at pH 7, thanks to the conformational change of its structure induced by Zn(2+) coordination to the polypyridyl moiety.

The mixed oxa-aza macrocycle [15]aneN 3 O 2 with cyanomethyl pendant arms on all three N-centres, 1,4,7-tris(cyanomethyl)-1,4,7 triaza-10,13-dioxacyclopentadecane (L), and its complexes with Cu(II), Ni(II), Zn(II), Cd(II) and Pb(II) have been prepared. The protonation constants of the ligand and the thermodynamic stabilities of the 1:1 metal:ligand complexes with Cu(II), Zn(II), Cd(II) and Pb(II) have been investigated by means of potentiometric measurements in aqueous solutions. These metal ions form only mononuclear complexes with unusually low stability constants, compared with those found for other cyclic or acyclic triamine compounds due to the relatively poor σ-donating properties of tertiary nitrogens and to the stiffening of the macrocyclic framework imposed by the cyanomethyl side arms, which are unable to co-ordinate to the metal ion sitting within the macrocyclic cavity. The single crystal X-ray structures of 1:1 complexes with Cu(II), Ni(II), Cd(II) and Pb(II) have been determined. The structures of [Cu(L)(CH 3 CN)](ClO 4 ) 2 and [Ni(L)(CH 3 CN)](ClO 4 ) 2 show slightly distorted octahedral co-ordination geometries with the metal cation bound to all the donor atoms of the macrocyclic ring and to a MeCN molecule. The structure of [Cd(L)(NO 3 ) 2 ] confirms binding of all the donor atoms of the ring, but in this case the metal ion is also co-ordinated to two nitrate anions, one of them in a bidentate fashion. In the case of Cu(II), Ni(II) and Cd(II) complexes, the nitrile arms do not take part in co-ordination to the metal ion and are directed away from its co-ordination sphere. Interestingly, the structure of the Pb(II) complex [Pb(L)(ClO 4 )] 2 2 + confirms the formation of a binuclear species with binding of a nitrile pendant arm from an adjacent molecule. Two ClO 4 - anions bridge within the binuclear units in a bidentate fashion. NMR spectroscopic studies on the Zn(II), Cd(II) and Pb(II) complexes have revealed a rigidity in the complexes which is lost on increasing temperature.

The coordination features toward Cd(II) of four phenanthroline-containing and three dipyridine-containing macrocyclic polyamines have been studied by means of potentiometric and spectrophotometric UV–Vis measurements in aqueous solutions. All ligands form stable 1:1 metal complexes. The stability constants of the Cd(II) are generally lower than those reported for Cd(II) complexes with aliphatic macrocyclic polyamines containing the same number of nitrogen donors. This effect is mainly related to the stiffening of the ligands, due to the insertion of a large and rigid heteroaromatic moiety within the aliphatic polyamine framework. This structural feature does not allow the nitrogen donor to achieve an optimal arrangement around the metal ion. The decreased stability is often accompanied by facile protonation of the complexes, suggesting that some amine groups are not involved in metal binding.

The synthesis of the two new linear hexa-amines, 3,7,10,14-tetraazahexadecane-l,16-diamine (L 1 ) and 5,9,12,16-tetraazaicosane-l,20-diamine (L 2 ) has been reported. Ligand protonation and Cu(II) and Zn(II) coordination have been studied in aqueous solution by means of potentiometric, microcalorimetric (298.1 K, I =0.1 mol dm −3 ) and spectrophotometric (UV–Vis, 1 H and 13 C NMR) measurements. The species present in solution and their stability constants have been determined. L 1 forms mono- and binuclear complexes in aqueous solution with Cu(II). In the [ML 1 ] 2+ complexes, the metal ion is coordinated by five nitrogen atoms, while in the [ML 2 ] 2+ complexes the metal ion is four-coordinate. This different behavior is explained in terms of the different numbers of methylene groups between adjacent nitrogen atoms.

The ditopic macrocyclic ligand 1,4,7,10,19,22,25,28-octaaza-13,16,31,34-tetraoxa-cyclohexatriacontane (L) forms very stable mono- and bi-nuclear Cu2+ complexes in aqueous solution. The stability constants determined for these complexes are reported. In the solid state, the binuclear complex gives rise to the {[(Cu2L)Cl]⊃Cl(H2O)}(ClO4)2 compound in which both direct and indirect activation of anion binding promoted by Cu2+, as well as the structuring effect of this metal cation on anion binding, synergistically participate in the assembly of a polymeric inclusion compound.

Reperfusion injury after oxygen starvation is a key pathogenic step in ischemic diseases. It mainly consists in oxidative stress, related to mitochondrial derangement and enhanced generation of reactive oxygen species (ROS), mainly superoxide anion (O2(•2)), and peroxynitrite by cells exposed to hypoxia. This in vitro study evaluates whether Mn(II)(4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate).2H2O, or Mn(II)(Me2DO2A), a new low molecular weight, Mn(II)-containing O2(•) scavenger, has a direct protective action on H9c2 rat cardiac muscle cells subjected to hypoxia and reoxygenation. Mn(II)(Me2DO2A) (1 and 10 μmol/l) was added to the culture medium at reoxygenation and maintained for 2 h. In parallel experiments, the inactive congener Zn(II)(Me2DO2A), in which Zn(II) replaced the functional Mn(II) center in the same organic scaffold, was used as negative control. Mn(II)(Me2DO2A) (10 μmol/l) significantly increased cardiac muscle cell viability (trypan blue assay), improved mitochondrial activity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test, membrane potential Δψ), reduced apoptosis (mitochondrial permeability transition pore opening, caspase-3, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay), decreased intracellular ROS levels (2',7'-dichlorodihydrofluorescein diacetate and MitoSOX assays), and decreased protein nitroxidation (nitrotyrosine [NT] expression) and DNA oxidation (8-hydroxy-deoxyguanosine levels). Of note, Zn(II)(Me2DO2A) had no protective effect. The mechanism of Mn(II)(Me2DO2A) relies on concentration-dependent removal of harmful O2(•) generated at reoxygenation from dysfunctional mitochondria in hypoxia-induced cells, as indicated by the MitoSOX assay. This study suggests that Mn(II)(Me2DO2A) is a promising antioxidant drug capable of reducing O2(•)-mediated cell oxidative stress which occurs at reoxygenation after hypoxia. In perspective, Mn(II)(Me2DO2A) might be used to reduce ischemia-reperfusion organ damage in acute vascular diseases, as well as to extend the viability of explanted organs before transplantation.

This study was carried out to evaluate whether high-frequency ultrasounds, a commonly used aesthetic medicine treatment for skin rejuvenation, may enhance the penetration of the Mn-containing compound Mn II (Me 2 DO2A) (manganese II 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) biologically active as a superoxide anion scavenger, in the cutaneous layers of ex vivo human skin explants. Although its antioxidant properties are well known and the compound is basically not toxic in animal models, its trans-cutaneous permeation and its toxicological profile at a systemic level have not yet fully analyzed. Therefore, its possible penetration in the deep cutaneous layers was also evaluated. To this purpose, Mn II (Me 2 DO2A) was formulated as emulsion-gel, lipogel and hydrogel. These different formulations were also tested in combination with high-frequency ultrasounds (10–3500 Hz frequency modulation on a 5 MHz main frequency) used as physical permeation enhancers, delivered by a MedVisage™ device (General Project, Montespertoli, Italy) currently used for aesthetic medicine purposes. The permeation of the Mn-containing compound from the formulations was evaluated by inductively coupled plasma atomic emission spectrometry (ICP-AES) measurements of Mn in horizontal cryosections of the skin samples cut at different depths to separate the epidermis, papillary and reticular dermis, as well as by vertical Franz diffusion cells. The results show that the hydrogel formulation yielded the highest transepidermal delivery of Mn II (Me 2 DO2A) and that the application of ultrasounds (3 W, FM 100 Hz, 2 × 10 s) significantly enhanced its penetration into the epidermis and upper dermal layers. Of note, nearly undetectable amounts of Mn II (Me 2 DO2A) were detected in the reticular dermis and the Franz cell fluid. Although an in vivo confirmation of these results will be necessary, this method may allow to minimize undesired drug passage to the bloodstream and undesired delivery to non-target internal organs and avoiding its renal excretion and release into the environment.

Protonation and alkali- and alkaline-earth-metal coordination by the dipyridine-containing cryptand L have been studied by means of potentiometric and spectroscopic (UV-vis, (1)H NMR) measurements in aqueous solutions. This ligand is constituted by an aliphatic polyamine chain and a coordinating cleft, delimited by two dipyridine units, where the metal ion is lodged. The resulting complexes are characterized by an unusually high stability. The polyamine chain is not involved, or weakly involved, in metal coordination, and facile protonation can occur on the nitrogen atoms of this moiety. Similar coordination features are found in the Eu(III) complex. A fluorescence emission study reveals that the Eu(III) cryptate shows the characteristic visible emission of the metal, due to the intramolecular energy transfer to the metal ion mainly from the lower energy triplet state of the cryptand. On the other hand, the emission intensity is modulated by pH, giving a maximum at neutral pH and decreasing at both acidic and alkaline pH values.

The interaction of cytosine (CyH), thymine (TH) and uracil (UH) with the dinuclear Zn(II) complexes of ligand 1,4,7,16,19,22hexaza-10,13,25,28-tetraoxacyclotriacontane (L) has been studied by means of potentiometric titrations (0.1 mol dm −3 NMe4NO3, 298.1 K), and 1 H NMR measurements. The equilibrium constants for the formation of the ternary complexes with the nucleobases indicate that the [Zn2L] 4 + complex displays similar binding features towards thymine and uracil. The dizinc complex forms stable 1:1 and 1:2 complexes with both deprotonated thymine and uracil at neutral or slightly alkaline pH values. The constants for the addition of first and second substrate molecules are almost equal indicating that each nucleobase is coordinated, almost independently, by one metal ion of [Zn2L] 4 + . This feature is confirmed by the crystal structures of [Zn2LT2] 2 + and [Zn2LU2] 2 + . In the [Zn2LA2] 2 + (A − =T − ,U − ) complexes the two metal ions have almost the same coordination environment and each Zn(II) is coordinated to three nitrogens of the macrocycle and to a deprotonated nitrogen of the nucleobases. In the crystal packing the dinuclear clusters give rise to a supramolecular architecture based on infinite pillars of [Zn2LA2] 2 + (A − =T − , U − ) assembled via hydrogen bonding. Cytosine forms only 1:1 adducts with the dizinc complex and the stability constants values suggest that the deprotonated nucleobase bridges the two metal ions. © 2001 Published by Elsevier Science B.V.

A binuclear ZnII complex with an oxa-aza macrocyclic ligand can bind two deprotonated thymine or uracil moieties, giving versatile building blocks for the assembly of supramolecolar structures, by hydrogen bond pairing of the nucleobases.

The basicity and the coordination properties of several polyamine macrocycles containing phenanthroline or dipyridine moieties as integral part of the cyclic framework are reported. The ligands behaves as fluorescent chemosensors for both H+ and metal ions. The use of such ligands in the preparation of simple molecular machines, of chemosensors for metallo-hexacyanide anions, and of catalysts for photoinduced redoxreactions is also described. The paper is a brief review of recent works performed by the authors.

Ligands L1 and L2 contain two ethylenediamine chains linked to the 2,9 and 6,6′ positions of phenanthroline and bipyridyl, respectively. Their molecular architecture defines a coordinative ‘cleft,’ a potential binding site for metals and anionic species. Their coordination properties toward Zn(II), Cd(II) and Pb(II) were studied by means of potentiometric, microcalorimetric and UV–vis spectrophotometric measurements. In the [ML]2+ complexes (L = L1 or L2), the metal is enveloped inside the ligand cleft, as shown by the crystal structure of the [ZnL2]2+ cation. On the other hand, the analysis of the thermodynamic data for metal complexation reveals that in the [ML]2+ complexes some nitrogen donors are weakly bound, or not bound, to the metal, owing to the presence of a rigid heteroaromatic unit, which leads to a stiffening of the ligands. Both L1 and L2, in their protonated forms, behave as multifunctional receptors for the nucleotide anions at neutral or slightly acidic pH, giving 1:1 complexes. Binding of diphosphate, triphosphate, ATP and ADP was studied by means of potentiometry and 1H and 31P NMR spectroscopy. Charge–charge and hydrogen bonding interactions take place between the polyphosphate chain of nucleotides and the polyammonium groups of L1 and L2, whereas the adenine moiety shows charge–dipole interactions with the ammonium groups and π-stacking with the heteroaromatic units of the receptors. Copyright © 2001 John Wiley & Sons, Ltd.

The equilibria involving the uptake of dioxygen (O2) to the dicobalt(II) complexes of the macrocyclic ligands [27]aneN9 (1,4,7,10,13,16,19,22,25-nonaazacycloheptacosane) and [30]aneN10 (1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane), and of the acyclic polyamine Me2octaen (1,25-dimethyl-1,4,7,10,13,16,19,22,25-nonaazapentacosane) have been studied by potentiometric measurements in 0.15 mol dm−3 NaClO4 aqueous solution at 298.1±0.1 K, and the relevant equilibrium constants have been reported. All three ligands form stable oxygenated complexes of the type [Co2L(O2)]4+ and [Co2L(O2)OH]3+, in which the O2 molecule is bound in the end-on mode to a single metal ion. In the case of the macrocyclic complexes the coordination of O2 and OH− reveals a cooperativity effect, i.e. a significant stability increase is observed when one of these species coordinates to a dinuclear complex containing the other one, with respect to the same reactions involving (Co2L)4+. This behaviour suggests the interaction via hydrogen bonding between the two species (O2 and OH−) coordinated to different cobalt(II) ions.

The stability constants of CuII complexes that consist of either an oxa-aza macrocycle with two triamine moieties linked by dioxa chains, or two macrocyclic ligands with a polyamine chain which are connecting the 2 and 9 positions of phenanthroline, have been determined by means of potentiometric measurements. The results are compared to those reported for other ligands with a similar molecular architecture. Of the complexes that contain phenanthroline in their macrocycle, the CuII ion of the complex with the smallest and most rigid macrocycle (L3) has an unsaturated coordination sphere, while in the complex with the largest macrocycle (L5) the CuII ion is coordinatively almost saturated. These results are corroborated by the crystal structure of the [CuL5](ClO4)2 complex. The affinity of the ligands and the complexes towards nucleic acids was studied by measuring the changes in the melting temperature, which showed that the affinity of the macrocyclic ligands towards double-stranded DNA or RNA is generally smaller than that of their linear analogues that bear a similar charge, with a strong preference for polyA–polyU, a model for RNA. However, the complexes of two of the changed macrocyclic ligands which contain a phenanthroline unit (L4, L5) showed a distinctly larger increase in their melting temperature ΔTm with DNA (polydA–polydT), which is reversed again in favor of RNA upon metallation to the dinuclear copper complex with L5. Experiments with supercoiled plasmid DNA showed a particularly effective cleavage with a mononuclear CuII complex that contains a phenanthroline unit (L6). Related ligands showed less activity towards DNA, but not so towards the biocidic bis(p-nitrophenyl)phosphate (BNPP). In both cases (with DNA and BNPP) the activity seemed to increase with decrease of coordinative saturation of the CuII ion, with the exception of one particular ligand (L6). Experiments with radical scavengers in the DNA experiments showed some decrease in cleavage, which indicates the participation of redox processes.

Ni(II) and Co(II) coordination with the macrocyclic ligand 1,4-dioxa-7,10,13-triazacyclopentadecane (L) has been investigated in solution (Co(II) and Ni(II)) and in the solid state (Ni(II)). Complexation equilibria have been studied by means of potentiometric titrations in 0.15 mol dm-3 NaCl, at 298.1 ± 0.1 K, evidencing the formation of [ML]2+, [MLOH]+, and [ML(OH)2] (M = Co, Ni) species. Under aerobic conditions, the mononuclear Co(II) complex binds dioxygen, forming the dibridged [Co2L2(O2)OH]3+. This is the unique oxygenated species formed. The importance of the bridging OH- anion for the formation of the oxygenated complex has been evidenced by competitive coordination of SCN-. Structural information has been obtained by resolving the crystal structure of the [NiLCl][NiL(H2O)](ClO4)3 compound. The structure contains [NiLCl]+ and [NiL(H2O)]2+ cations in which the metal ions have octahedral coordination environments determined by five ligand donor atoms and one Cl-/H2O.

It seemed plausible that tri- and tetraamine ligands with a substituent which binds to Cu(I) but not to Cu(II), e.g., an allyl, stabilize Cu(I) in aqueous solutions and shift its redox potential cathodically relative to Cu+(aq). Therefore, the ligands N(CH2CH2NR2)2(CH2CH2NRCH2CHCH2) (R = H or CH3) were synthesized. These ligands indeed stabilize Cu(I) in aqueous solutions and shift the redox potential of the Cu(II)/Cu(I) and Cu(I)/Cu(0) couples cathodically relative to Cu2+/+(aq) and the complexes CuIIL/CuIL where L = R2NCH2CH2NRCH2CH2NR(CH2CHCH2). Therefore, the copper complexes with the new ligands are expected to be better catalysts to processes in which the redox step is the rate-determining step.

The protonation and metal ion (Cu2+, Zn2+, Cd2+, Pb2+) complexation abilities of three heteroditopic cryptands in solution are described and the relevant equilibrium constants are reported. The two distinct binding subunits of the ligands act cooperatively in the coordination of M(H2O)2+ (M = metal ion) species. The cryptand L1 binds five protons in very acidic solution and crystallizes as [(H5L1)(ClO4)5].4 H2O in the monoclinic space group P21ln with a = 14.281(4), b = 14.313(7), c = 24.082(8) A, β = 92.00(2)°, Z = 4, R = 0.079, and wR2 = 0.2010. The molecule shows an endo-endo conformation with a pseudo-threefold symmetry axis passing through the two bridgehead nitrogen atoms. All the cryptands (L1-L3) readily form inclusion complexes with Cu2+, Ni2+, Zn2+, Cd2+, and Pb2+ ions at the tren end of the cavity. The crystal structure of [(NiL2Cl)Cl].5.5 H2O.CH3OH is also reported [C2/c, a = 26.671(6), b = 16.784(4), c = 18.591(8) A, β = 101.006(14)°, Z = 8, R = 0.091, and wR2 = 0.1424]. The NiII ion resides in a trigonal-bipyramidal coordination environment with the equatorial sites occupied by the three secondary nitrogen atoms of the cryptand and the axial sites occupied by a bridgehead nitrogen atom and a Cl- ion.

The synthesis of the macrocyclic ligand 1,4,7,13-tetramethyl-10,16-bis( o -thiophenylmethyl)-1,4,7,10,13,16-hexaazacyclooctadecane ( L2 ) is reported. This compound presents a hexaaza macrocyclic backbone bearing two thiophenylmethyl side arms. Ligand protonation and Cu(II), Zn(II), Cd(II) and Pb(II) coordination were studied by means of potentiometric measurements. In the metal complexes all nitrogens seem to be involved in metal coordination, while the sulfur atoms of the heteroaromatic subunits do not participate in metal binding, as confirmed by the crystal structure of [Pb L2 Cl]·BPh 4 . In the [Pb L2 Cl] + cation the metal is enveloped by the macrocyclic ligand, coordinated by the six nitrogens and a chloride anion with a distorted monocapped trigonal prismatic geometry. Although L2 forms complexes of lower stability with respect to other N -functionalized hexaazamacrocycles, this ligand displays selective coordination of the larger Cd(II) and Pb(II) over Zn(II). All the metal complexes under investigation are readily extractable from aqueous solutions to organic solvents. Therefore, L2 is a promising selective extracting agent for metal cations.

Two new polyamine ligands 2,9-bis(2-methylaminoethylaminomethyl)phenanthroline (L3) and 6,6′-bis(2-methylaminoethylaminomethyl)-2,2′-bipyridyl (L4) have been synthesized. L3 and L4 contain respectively a phenanthroline and a bipyridyl unit bearing two N-methylethylenediamine side-arms. Their co-ordination properties toward CuII were studied by means of potentiometric, calorimetric, UV-vis spectroscopic and electrochemical measurements and compared with those of macrocyclic ligands with similar molecular architecture (L1 and L2). The macrocyclic ligands give only mononuclear complexes, while the acyclic ligands form mono- and bi-nuclear complexes in aqueous solution, due to their higher flexibility. Considering the mononuclear complexes, the analysis of the thermodynamic parameters for copper(II) co-ordination shows that the complexes with the acyclic ligands are mainly stabilized by the entropic change. On the contrary, the enthalpic term gives a more favourable contribution to the formation of the complexes with the macrocyclic ligands. This different behaviour is discussed in terms of ligand rigidity and ligand and metal desolvation. The crystal structure of the [CuL3]2+ complex shows the metal to be six-co-ordinated, with a rather unusual geometry, enveloped inside the ligand cleft and almost co-ordinatively saturated and shielded from solvent molecules. At the same time the two heteroaromatic nitrogens are weakly bound to the metal.

Ni(II) and Co(II) coordination by the macrocyclic ligand 2,5,8,11-tetraaza[12]-13,26-phenanthrolinophane (L), which contains a tetraamine chain linking the 2,9 positions of phenanthroline, has been studied in anaerobic conditions by means of potentiometric and UV–vis spectrophotometric measurements in aqueous solution. These complexes are far less stable than those with the aliphatic hexaazamacrocycle [18]aneN6. This experimental observation suggests that in the [ML]2+ complexes some amine groups are weakly involved or not involved in metal coordination. This hypothesis is supported by the crystal structure of [NiL(H2O)]2+, which shows the metal hexacoordinated by five nitrogens of the macrocyclic ring and an oxygen of a water molecule, with a distorted octahedral coordination geometry. One of the benzylic amine groups is not bound to the metal. A similar coordination environment is also proposed for the Co(II) complex. The kinetic study of Ni(II) complexation with L, carried out by means of spectrophotometric UV measurements, points out that the rate-determining step for Ni(II) coordination is the formation of the first bond. This involves the metal ion and one of the two nitrogen atoms of the phenanthroline moiety.

A new mixed oxa–aza macrocycle having ethylamino pendant arms on the secondary nitrogens, namely 7,10,13-tris(2-aminoethyl)-1,4-dioxa-7,10,13-triazacyclopentadecane (L), has been synthesized. The co-ordination chemistry of L towards ZnII, CuII, CdII, PbII and BaII has been studied by X-ray crystallography, potentiometry and NMR spectroscopy. The single crystal structures of [Zn(L)][ClO4]2 and [Cu(L)][ClO4]2 confirm that the complexes are isostructural with the metal ion bound to the three pendant arm N-donors and to two N-donors of the macrocyclic core to give a slightly distorted square-pyramidal geometry. The remaining three donors, a tertiary amine and the two oxygens of the ring, remain unco-ordinated leaving one part of the macrocyclic cavity open with the metal ion bound exo to the macrocyclic cavity. The single crystal structures of [Pb(L)][ClO4]2 and [Ba(L)][ClO4]2 show the metal ion co-ordinated to all the donor atoms of the ligand, with BaII co-ordinated additionally to a ClO4− anion in a bidentate fashion to give a 10-co-ordinate metal centre. The binding of L to ZnII, CuII, CdII and PbII was investigated by potentiometric measurements in aqueous solutions. These metals form only mononuclear complexes with unusually low stability constants compared with those found for other hexaamine macrocycles. All the complexes show a marked tendency to protonation. These observations suggest the presence of unco-ordinated or weakly co-ordinated N-donors also in aqueous solution. NMR spectroscopic studies on the complexes of ZnII, CdII, BaII and PbII of L reveal a rigidity which is lost on increasing temperature.

The present article is concerned with proton transfer reactions in aqueous solution of open-chain, macrocyclic and macropolycyclic or cage compounds having nitrogen atoms as protonation sites in the molecular framework, although several compounds with additional different donors will be considered. The main purpose of this review is to collect some significant examples of proton transfer processes in order to show how the electronic properties and molecular topology of polyamines affect the thermodynamic parameters of their protonation equilibria.

The ligands R(2)NCH(2)CH(2)N(R)CH(2)CH(2)N(R)CH(2)CH=CH(2), where R = H, CH(3), were synthesized. The stability constants of their complexes with Cu(II) and Cu(I) in aqueous solutions were determined. Both ligands stabilize Cu(I) in aqueous solutions, though the reduction potentials of both (CuL(i)())(2+/+) couples are shifted cathodically in comparison to the Cu(2+/+)(aq) couple. These properties indicate that these complexes should be good catalysts for a variety of processes that are catalyzed by Cu(I).

The interactions of phosphate and pyrophosphate anions with polyammonium cations deriving from 14 polyamines (five polyazacycloalkanes, four polyazacyclophanes, and five acyclic polyamines) in aqueous solution have been studied by means of potentiometric, microcalorimetric, and NMR measurements in solution. Very stable 1:1 receptor-to-anion complexes are formed. The stability trends of such complexes are not strictly determined by electrostatic forces, hydrogen bond interactions being of considerable importance in the complex formation, the thermodynamic data being consistent with different hydrogen bonding modes. ΔH°−TΔS° compensatory relationships hold for such complexation reactions. The crystal structures of (H4L1)(H2P2O7)2·2H2O and (H4L2)(H2P2O7)2·6H2O (L1 = 1,4,7,10,13,16-hexaazacyclooctadecane, L2 = 1,10-dimethyl-1,4,7,10,13,16-hexaazacyclooctadecane) have been solved by X-ray analysis, evidencing different substrate/anion binding characteristics.