The influence of amine/amide versus bisamide coordination in nickel superoxide dismutase

Nickel superoxide dismutase (NiSOD) is a mononuclear nickel-containing metalloenzyme that catalyzes the disproportionation of superoxide by cycling between NiII and NiIII oxidation states. In the reduced NiII oxidation state, the metal center is ligated by two cysteinate sulfurs, one amide nitrogen, and one amine nitrogen (from the N-terminus), while in the oxidized NiIII state, an imidazole nitrogen coordinates to the metal center. Herein, we expand on a previous report in which we described a functional metallopeptide-based NiSOD model compound [NiII(SODM1)] (SODM1 = H2N-HCDLPCGVYDPA-COOH) by exploring how acylation of the N-terminus (producing [NiII(SODM1-Ac)]) influences the properties of the metallopeptide. Titration results, GPC data, and mass-spectrometry data demonstrate that NiII coordinates to SODM1-Ac in a 1:1 ratio, while variable pH studies show that NiII coordination is strong at a pH of 7.5 and above but not observed below a pH of 6.2. This is higher than [NiII(SODM1)] by approximately 1.0 pH unit consistent with bisamide ligation. Ni K-edge XAS demonstrates that the NiII center is coordinated in a square-planar NiN2S2 coordination environment with Ni-N distances of 1.846(4) A and Ni-S distances of 2.174(3) A. Comparison of the electronic absorption and CD spectrum of [NiII(SODM1)] versus [NiII(SODM1-Ac)] in conjunction with time-dependent DFT calculations suggests a decrease in Ni covalency in the acylated versus unacylated metallopeptide. This decrease in covalency was also supported by DFT calculations and Ni L-edge XAS. [NiII(SODM1-Ac)] has a quasireversible NiII/NiIII redox couple of 0.49(1) V vs Ag/AgCl, which represents a -0.2 V shift compared with [NiII(SODM1)], while the peak separation suggests a change in the coordination environment upon oxidation (i.e., axial imidazole ligation). Using the xanthine/xanthine oxidase assay, we determine that [NiII(SODM1-Ac)] is less active than [NiII(SODM1)] by over 2 orders of magnitude (IC50 = 3(1) x 10-5 vs 2(1) x 10-7 M). Possible reasons for the decrease in activity are discussed.     

pH-controlled fluorescent emission in the nickel(II) complex of a bifunctional tetramine macrocycle

In the Ni(II) complex of a reinforced tetramine macrocycle, equipped with both a sulfonamide pendant arm and a naphthalene fragment, light emission of the fluorophore is pH-controlled, as a result of a change of the geometry of the complex.     

Synthesis, relaxometric and photophysical properties of a new pH-responsive MRI contrast agent: the effect of other ligating groups on dissociation of a p-nitrophenolic pendant arm

Two gadolinium(III) chelates, GdNP-DO3A (1-methlyene-(p-NitroPhenol)-1,4,7,10-tetraazacycloDOdecane-4,7,10-triAcetate) and GdNP-DO3AM (1-methlyene(p-NitroPhenol)-1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide), containing a single nitrophenolic pendant arm plus either three acetate or three amide pendant arms were synthesized and characterized. The properties of the gadolinium, terbium, and dysprosium complexes of these ligands were examined as a function of pH. The extent and mechanism of the changes in water relaxivity with pH of each gadolinium complex was found to differ substantially for the two complexes. The water relaxivity of Gd(NP-DO3A) increases from 4.1 mM(-1) s(-1) at pH 9 to 7.0 mM(-1) s(-1) at pH 5 as a result of acid-catalyzed dissociation of the nitrophenol from the lanthanide. The nitrophenol group in Gd(NP-DO3AM) does not dissociate from the metal center even at pH 5; therefore, the very modest increase in relaxivity in this complex must be ascribed to an increase in prototropic exchange rate of the bound water and/or phenolic protons.     

Molybdenum(VI) Dioxo Complexes Employing Schiff Base Ligands with an Intramolecular Donor for Highly Selective Olefin Epoxidation

Reaction of [MoO(2)(η(2)-tBu(2)pz)(2)] with Schiff base ligands HL(X) (X = 1-5) gave molybdenum(VI) dioxo complexes of the type cis-[MoO(2)(L(X))(2)] as yellow to light brown solids in moderate to good yields. All ligands coordinate via its phenolic O atom and the imine N atom in a bidentate manner to the metal center. The third donor atom (R(2) = OMe or NMe(2)) in the side chain in complexes 1-4 is not involved in coordination and remains pendant. This was confirmed by X-ray diffraction analyses of complexes 1 and 3. Complexes 1, 3, and 5 exist as a mixture of two isomers in solution, whereas complexes 2 and 4 with sterically less demanding substituents on the aromatics only show one isomer in solution. All complexes are active catalysts in the epoxidation of various internal and terminal alkenes, and epoxides in moderate to good yields with high selectivities are obtained. In the challenging epoxidation of styrene, complexes 1 and 2 prove to be very active and selective. The selectivity seems to be influenced by the pendant donor arm, as complex 5 without additional donor in the side chain is less selective. Experiments prove that the addition of n-butyl methyl ether as intermolecular donor per se has no influence on the selectivity. The basic conditions induced by the NMe(2) groups in complexes 3 and 4 lead to lower activity.     

Metal Complexes with Macrocyclic Ligands. Part XLI. Nickel(II) and copper(II) complexes with mono-N-functionalized dithiadiazamacrocycles

Three N₂S₂ macrocycles ( 3, 10, 12 ) carrying an amino group as a pendant arm have been synthesized and their complexation properties towards Ni²⁺ and Cu²⁺ studied. The crystal structures of the Cu²⁺ complexes with 10-methyl-1,4-dithia-7,10-diazacyclododecane-7-ethanamine ( 3 ) and 11-methyl-1,4-dithia-8,11-diazacyclotetradecane-8-ethanamine ( 10 ) show that, in both cases, the Cu²⁺ is pentacoordinated by the four donor atoms of the macrocycle and the amino group of the side chain. In aqueous solution, however, two forms of the complexes with stoichiometries [MLH] and [ML] (M = Cu²⁺ or Ni²⁺) have been observed. In [MLH], the amino group is protonated and does not bind to the metal ion, whereas in [ML] the amino group is bound, and a pentacoordinated geometry results. The pK_a values for the equilibrium [ML] + H⁺?[MLH]⁺ decrease in the order 12 > 10 > 3 , indicating that the 2-aminoethyl side chain binds better to the Cu²⁺ than the 3-aminopropyl side chain. Cyclic voltammetry for the Cu²⁺/Cu⁺ pair shows that the 2-aminoethyl pendant arm stabilizes the Cu²⁺ oxidation state, when the metal ion is in the 14-membered ring ( 10 ), whereas it stabilizes Cu⁺ for the 12-membered macrocycle ( 3 ).     

Development of Macrocyclic Mn(II)−Bispyridine Complexes as pH-Responsive Magnetic Resonance Imaging Contrast Agents

In this study, macrocyclic complexes of Mn (II) with pH-responsive relaxivities were developed. The ligands were based on the rigid MPi platform, which was composed of a triazacyclononane (TACN) macrocycle and two picolyl pendant arms. An aryl sulfonamide moiety introduced in the skeleton of MPi endowed the final Mn complex (Mn−MPA) with pH-sensitive relaxivities. Mn−MPA showed a ∼3-fold increase in longitudinal relaxivity associated with the protonation and decoordination of the sulfonamide group in an acidic environment. We found that it was feasible to tune the pH window of the complexes by choosing proper substituents on the aromatic ring or modifying on the picolyl pendants. Considering the good kinetic inertness, rapid and efficient response to pH stimuli, and easy modulation characteristics, Mn−MPAs can be considered ideal candidates for use as acidic microenvironment-specific MRI contrast agents.     

Coordination properties of cyclam (1,4,8,11-tetraazacyclotetradecane) endowed with two methylphosphonic acid pendant arms in the 1,4-positions

The title ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-diyl-bis(methylphosphonic acid) (H4te2p1,4, H4L), was prepared by an optimized synthetic approach and its complexing properties towards selected metal ions were studied by means of potentiometry. The ligand forms a very stable complex with copper(II) (log beta(CuL) = 27.21), with a high selectivity over binding of other metal ions (e.g. log beta(ZnL) = 20.16, log beta(NiL) = 21.92). The crystal structures of two intermediates in the ligand synthesis and two forms of the nickel(II) complex (obtained by crystallization at different pH) were determined. From acid solution, the crystals of trans-O,O-[Ni(H3L)]Cl.H2O were isolated. In such complex species, one phosphonate pendant arm is double- and the second arm is monoprotonated. The isolation of such species demonstrates a high kinetic inertness of the complex. The central metal ion is surrounded by four in-plane nitrogen atoms (in the ring configuration III) and two oxygen atoms of pendant moieties in the apical positions of octahedral coordination sphere. From neutral solution, the crystals of (trans-O,O-[Ni(H2L)])3.5H2O were isolated. The molecular structures of the complex units found in this structure are analogous to that found in trans-O,O-[Ni(H3L)]Cl.H2O.     

Controllable Intramolecular Motions That Generate Fluorescent Signals for a Metal Scorpionate Complex

Simply by changing the pH value, the side chain of complex 1 can be reversibly moved between two positions. Coordination to the metal center through the nitrogen atom of the side chain at moderate pH values is accompanied by a decrease in fluorescence intensity (from I_F=100% to I_F=60%). A further decrease is observed upon deprotonation of the bound water molecule at higher pH (I_F≤2%). Therefore, 1 can be seen as a molecular three-position switch.     

Dynamic Ligand Reactivity in a Rhodium Pincer Complex

Ligand cooperativity provides (transition) metal complexes with new reactivities in substrate activation and catalytic reactions, but usually the ligand acts as an internal (Brønsted) base, while the metal acts as a (Lewis) acid. We describe the synthesis and stepwise activation of a new phosphane‐pyridine‐amide ligand PNN^H2 in combination with Rh^I. The ligand is susceptible to stepwise proton and hydride loss from the nitrogen arm (imine formation) and deprotonation at the pyridylphosphine arm (dearomatization), giving rise to amine complex 1 , amido species 2 , imine complex 3 and dearomatized compound 4 . Complex 4 bears a dual‐mode cooperative PNN′ ligand containing both a (nucleophilic) basic methine fragment and a reactive (electrophilic) imine moiety. The basic ligand arm enables substrate deprotonation while the imine ligand arm enables reversible “storage” of the activated (nucleophilic) form of a sulfonamide substrate at the ligand. In combination with metal‐based reactivity, this allows for the mono‐alkylation of o‐toluenesulfonamide with iodomethane. Compounds 1 , 3 and 4 are structurally characterized. We also report the first structurally characterized example of an aminal in the coordination sphere of rhodium, complex 5 , [Rh(CO)( PNN′′ )], formed by sequential N?H activation of sulfonamide by the dearomatized ligand PNN′ and follow‐up nucleophilic attack of anionic sulfonamide onto the imine fragment.     

Dramatically enhanced carbon acidity of the nitrobenzyl fragment in a nickel(II) scorpionate complex

The -CH(2)- group of the 2-nitrobenzyl pendant arm of the scorpionate complex I deprotonates in basic aqueous solution (pK(a) = 10.6), due to the coordination of the nitronate group to the nickel(II) center. Metal coordination enhances 2-nitrobenzene acidity by 10 orders of magnitude. [reaction: see text]     

Scorpiands: Quinquedentate Ligands that Couple the Rigidity of Cyclam and the Flexibility of a Coordinating Side Chain

This review tells the story of scorpiands, polyamine ligands which, when specifically stimulated, act as scorpions, and of their metal complexes, scorpiates. Scorpiands consist of a tetramine macrocycle (typically cyclam) capable of firmly including a transition metal and of a side chain ending with a nitrogen containing coordinating group: under unperturbed conditions the coordinating group is bound to the metal (ON), but on addition of acid the nitrogen is protonated and comes off the metal (OFF). Alternating acid/base addition makes the side chain move imitating the tail of a scorpion that bites a prey firmly immobilized by the claws. Occurrence of the ON-OFF motion is monitored by the colour change of the scorpiate complexes associated to the change of coordination or by fluorescence quenching/restoring when a light-emitting substituent is linked to the side arm. Scorpiate complexes can be considered optical molecular switches and, from a different standpoint, molecular machines able to convert chemical energy into mechanical work.     

Highly localized charges control electrostriction: reaction volumes for the reduction of mononuclear and bridged ruthenium complexes

Changes in electrostriction caused by the reduction of metal centers in monomeric Ru and bridged Ru/Fe complexes reported in this work are highly localized in a polar solvent such as water. In mononuclear complexes, such as [(edta-H)Ru(III)(H2O)], where the pendant carboxylate is protonated or not depending on pH, the charge that determines electrostricted solvent behavior is defined within distances encompassed by the first coordination sphere of the redox center (DeltaV(complex) = 1.4 +/- 0.6 cm3 mol(-1) (pH 4) or 0.9 +/- 0.6 cm3 mol(-1) (pH 1.1)). Furthermore, in dinuclear complexes, even differences in the ligand charge around the second metal center have insignificant effects on electrostrictive interaction with the solvent. Reduction of the Fe center in the systems [(NH3)5Ru(III)(mu-NC)Fe(III)(CN)5] and [(edta)Ru(III)(mu-NC)Fe(III)(CN)5]4- is virtually unaffected (-21.8 +/- 1.8 cm3 mol(-1) and -21.7 +/- 2.8 cm3 mol(-1), respectively) when the Ru center is changed from formally cationic (3+) to anionic (1-).     

Potentiometric Selectivities of Dibenzo-16-crown-5 Compounds for Alkali and Alkaline Earth Metal Cations and Ammonium Ions

Potentiometric selectivities toward alkali and alkaline earth metal cations and ammonium ions are utilized to probe the complexation of these cationic species by dibenzo-16-crown-5 lariat ethers. Attachment of one or two pendant groups to the central carbon of the three-carbon bridge in dibenzo-16-crown-5 markedly alters the potentiometric responses of the ionophores when incorporated in solvent polymeric membrane electrodes. Results obtained for dibenzo-16-crown-5 compounds with coordinating side arms containing ether, carboxylic acid, ester, and amide groups provide insight into the role of the side arm in metal ion complexation by lariat ether compounds.     

Co-ordination chemistry of amino pendant arm derivatives of 1,4,7-triazacyclononane

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, photophysical, and anion-sensing properties of quinoxalinebis(sulfonamide) functionalized receptors and their metal complexes

We report the synthesis, characterization, and photophysical properties of a series of organic receptors and their corresponding ReI and RuII metal complexes as anion probes featuring bis(sulfonamide) interacting sites incorporating highly chromophoric pi-conjugated quinoxaline moieties. The interactions with various anions were extensively investigated. These probe molecules are capable of recognizing F-, OAc-, CN-, and H2PO4- with different sensitivities. The probe-anion interactions can be easily visualized via naked-eye colorimetric or luminescent responses. Probe 1 has the weakest acidic sulfonamide N-H protons and therefore simply forms hydrogen-bonding complexes with F-, OAc-, CN-, and H2PO4-. Probe 2 undergoes a stepwise process with the addition of F- and OAc-: formation of a hydrogen-bound complex followed by sulfonamide N-H deprotonation. Direct sulfonamide N-H deprotonation occurs upon the addition of CN-, while only a hydrogen-bound complex forms with the H2PO4- ion for probe 2 in a dimethyl sulfoxide (DMSO) solution. Similar probe-anion interactions occur in probe 3 with the addition of F-, CN-, or H2PO4-. However, only a genuine hydrogen-bound complex forms in the presence of the OAc- ion in a DMSO solution of probe 3 because of the subtle difference in the pKa values of sulfonamide N-H protons when probes 2 and 3 are compared. Coordination of probe 1 to a ReI center or probe 2 to a RuII center increases the intrinsic acidity of sulfonamide N-H protons and results in an enhanced sensitivity to anions.     

Kinetics and Mechanism of the Cu2+ Induced Hydrolysis of Nitrile Groups in the Side Chain of Tetraazamacrocycles. Models for Nitrilases

Abstract

A series of mono-N-functionalized tetraaza macro-cycles having a nitrile group in their side chain have been synthesized and the kinetics and mechanism of the Cu²⁺ induced hydrolysis has been studied. Two factors were systematically varied: the length of the side chain and thus the distance between Cu²⁺ and the nitrile group, as well as the rigidity of the macro-cycle by introducing an additional ethylene bridge.

The mechanism of the hydrolysis proceeds by an intramolecular attack of a coordinated OH^? onto the nitrile group in a five or six center transition state. The intramolecular nature of the reaction has been proven (a) by the pH dependence of the hydrolysis, which in some cases has a plateau at high pH values, (b) by the competitive inhibition with SCN^?, and (c) by the spectral changes observed at high pH.

The sequence of Cu²⁺ induced hydrolysis rates is the following: flexible macrocycle with a short chain > rigid macrocycle with a short chain > flexible macrocycle with a longer chain < rigid macro-cycle with a longer chain. The length of the side chain, which determines whether a five or six center transition state is formed, is the most important factor. The fastest hydrolysis has a half-life time of about 50 ms at pH 12.5 and 25°C and indicates the efficiency of the metal ion. The rigidity of the macrocycle also influences the reactivity since in the rigid complexes on one side the Cu²⁺ ion is less accessible for OH^? to give the reactive intermediate and on the other side the transition state is less reactive because of topological aspects.     

A magnetostructural study of linear NiII MnIII NiII, NiII CrIII NiII and triangular Ni(II)3 species containing (pyridine-2-aldoximato)nickel(II) unit as a building block

Three trinuclear complexes, NiII MnIII NiII, NiII CrIII NiII and Ni(II)3 based on (pyridine-2-aldoximato)nickel(II) units are described. Two of them, and , contain metal-centers in linear arrangement, as is revealed by X-ray diffraction. Complex is a homonuclear complex in which the three nickel(II) centers are disposed in a triangular fashion. The compounds were characterized by various physical methods including cyclic voltammetric and variable-temperature (2-290 K) susceptibility measurements. Complexes and display antiferromagnetic exchange coupling of the neighbouring metal centers, while weak ferromagnetic spin exchange between the adjacent Ni II and Cr III ions in is observed. The experimental magnetic data were simulated by using appropriate models.     

The role of pendant amines in the breaking and forming of molecular hydrogen catalyzed by nickel complexes

We present the results of a comprehensive theoretical investigation of the role of pendant amine ligands in the oxidation of H(2) and formation of H(2) by [Ni(P(R)(2)N(R')(2))(2)](2+) electrocatalysts (P(R)(2)N(R')(2) is the 1,5-R'-3,7-R derivative of 1,5-diaza-3,7-diphosphacyclooctane, in which R and R' are aryl or alkyl groups). We focus our analysis on the thermal steps of the catalytic cycle, as they are known to be rate-determining for both H(2) oxidation and production. We find that the presence of pendant amine functional groups greatly facilitates the heterolytic H(2) bond cleavage, resulting in a protonated amine and a Ni hydride. Only one single positioned pendant amine is required to serve this function. The pendant amine can also effectively shuttle protons to the active site, making the redistribution of protons and the H(2) evolution a very facile process. An important requirement for the overall catalytic process is the positioning of at least one amine in close proximity to the metal center. Indeed, only protonation of the pendant amines on the metal center side (endo position) leads to catalytically active intermediates, whereas protonation on the opposite side of the metal center (exo position) leads to a variety of isomers, which are detrimental to catalysis.     

Hydrogen and copper ion-induced molecular reorganizations in scorpionand-like ligands. A potentiometric, mechanistic, and solid-state study

Two aza scorpionand-like macrocycles (L2 and L3) have been prepared. L2 consists of a tren amine with two of its arms cyclizized with a 2,6-bis(bromomethyl)pyridine. In L3, the remaining pendant arm has been further functionalized with a fluorophoric naphthalene group. X-ray data on the compounds [H(L3)]ClO4.H2O (1) and [H3(L3)](H2PO4)3.H2O (2) as well as solution studies (pH-metry, UV-vis, and fluorescence data) show the movement of the pendant arm as a result of the protonation degree of the macrocycles and of the formation of intramolecular hydrogen bonds. X-ray data on the complexes [Cu(L2)](ClO4)2]2.H2O (3) and [Cu(L3)](ClO4)2 (4) and solution studies on Cu2+ coordination show the implication of the nitrogen of the arm in the binding to the metal ion. Kinetic studies on the decomposition and formation of the Cu2+ complexes provide additional information about the pH-dependent molecular reorganizations. Moreover, the obtained information suggests that the kinetics of the tail on/off process is essentially independent of the lability of the metal center.     

Copper coordination by polymers with glycylglycine, phenylalanine or methionine in the side chain: potentiometric and viscosimetric study

The coordination of copper(II) to polymers bearing glycylglycine, phenylalanine or methionine in their side chain was studied by potentiometry and viscosimetry. These polymers, which are not polypeptides, have carboxyl and amide group as potential binding sites in their side chain. They form a 2:1 COO:Cu complex in the lower pH range. The stability of this complex is in the order PPhe > PMet > PGlygly corresponding to the existence and stability of a compact conformation which exists for PPhe and PMet but not for PGlygly. The values of the stability constants decrease while the metal concentration increases. This is linked to the simultaneous viscosity decrease and was explained by increased steric strains in the collapsed polymer complex. At higher pH, potentiometric data indicate that deprotonation of the amide group occurs but the stoichiometry of the corresponding complex(es) cannot be obtained thanks to this technique although one amide group seemed to be deprotonated per copper ion.