Gating the electron transfer at a monocopper centre through the supramolecular coordination of water molecules within a protein chamber mimic.

Functionality of enzymes is strongly related to water dynamic processes. The control of the redox potential for metallo-enzymes is intimately linked to the mediation of water molecules in the first and second coordination spheres. Here, we report a unique example of supramolecular control of the redox properties of a biomimetic monocopper complex by water molecules. It is shown that the copper complex based on a calix[6]arene covalently capped with a tetradentate [tris(2-methylpyridyl)amine] (tmpa) core, embedding the metal ion in a hydrophobic cavity, can exist in three different states. The first system displays a totally irreversible redox behaviour. It corresponds to the reduction of the 5-coordinate mono-aqua-CuII complex, which is the thermodynamic species in the +II state. The second system is detected at a high redox potential. It is ascribed to an "empty cavity" or "water-free" state, where the CuI ion sits in a 4-coordinate trigonal environment provided by the tmpa cap. This complex is the thermodynamic species in the +I state under "dry conditions". Surprisingly, a third redox system appears as the water concentration is increased. Under water-saturation conditions, it displays a pseudo-reversible behaviour at a low scan rate at the mid-point from the water-free and aqua species. This third system is not observed with the Cu-tmpa complex deprived of a cavity. In the calix[6]cavity environment, it is ascribed to a species where a pair of water molecules is hosted by the calixarene cavity. A molecular mechanism for the CuII/CuI redox process with an interplay of (H2O) x (x = 0, 1, 2) hosting is proposed on the basis of computational studies. Such an unusual behaviour is ascribed to the unexpected stabilization of the CuI state by inclusion of the pair of water molecules. This phenomenon strongly evidences the drastic influence of the interaction between water molecules and a hydrophobic cavity on controlling the thermodynamics and kinetics of the CuII/CuI electron transfer process.

Mononuclear iron(ii) complexes containing a tripodal and macrocyclic nitrogen ligand: synthesis, reactivity and application in cyclohexane oxidation catalysis.

Two novel tripodal ligands L1 and L2 based on a tris(methylpyridyl)amine (TPA) motif have been prepared and reacted with two different iron(ii) salts. The ligand L1 contains a bis(amino-phenyl)-TPA group whereas the macrocyclic ligand L2 displays two different coordinating cores, namely TPA and pyridine-dicarboxamide. The resulting mononuclear complexes 1-4 have been characterized in the solid state and in solution by spectroscopic and electrochemical methods. All complexes are high spin and mainly pentacoordinated. X-ray diffraction analyses of the crystals of complexes 2 and 3 demonstrate that the coordination sphere of the iron(ii) centre adopts either a distorted bipyramidal-trigonal or square pyramidal geometry. In the absence of an exogenous substrate, oxidation of complex 2 by H2O2 induces an intramolecular aromatic hydroxylation, as shown by the X-ray structure of the resulting dinuclear complex 2'. Catalytic studies in the presence of a substrate (cyclohexane) show that the reaction process is strongly impacted by the macrocyclic topology of the ligand and the nature of the counter-ion.

Effect of Monoelectronic Oxidation of an Unsymmetrical Phenoxido-Hydroxido Bridged Dicopper(II) Complex.

A (µ-hydroxido, µ-phenoxido)CuIICuII complex 1 has been synthesized using an unsymmetrical ligand bearing an N, N-bis(2-pyridyl)methylamine (BPA) moiety coordinating one copper and a dianionic bis-amide moiety coordinating the other copper(II) ion. Electrochemical mono-oxidation of the complex in DMF occurs reversibly at 213 K at E1/2 = 0.12 V vs Fc+/Fc through a metal-centered process. The resulting species (complex 1+) is only stable at low temperature and has been spectroscopically characterized by UV-vis-NIR cryo-spectroelectrochemical and EPR methods. DFT and TD-DFT calculations, consistent with experimental data, support the formation of a CuIICuIII phenoxido-hydroxido complex. Low-temperature chemical oxidation of 1 by NOSbF6 yields a tetranuclear complex 2(SbF6)(NO2) which displays two binuclear CuIICuII subunits. The X-ray crystal structure of 2(SbF6)(NO2) evidences that the nitrogen of the terminal amide group is protonated and the coordination of the amide occurs via the O atom. The bis-amide moiety appears to be a non-innocent proton acceptor along the redox process. Alternatively, protonation of complex 1 leads to the complex 2(ClO4)2, as evidenced by X-ray crystallography, cyclic voltammetry, and 1H NMR.

Electrochemical Water Oxidation and Stereoselective Oxygen Atom Transfer Mediated by a Copper Complex.

Water oxidation by copper-based complexes to form dioxygen has attracted attention in recent years, with the aim of developing efficient and cheap catalysts for chemical energy storage. In addition, high-valent metal-oxo species produced by the oxidation of metal complexes in the presence of water can be used to achieve substrate oxygenation with the use of H2 O as an oxygen source. To date, this strategy has not been reported for copper complexes. Herein, a copper(II) complex, [(RPY2)Cu(OTf)2 ] (RPY2=N-substituted bis[2-pyridyl(ethylamine)] ligands; R=indane; OTf=triflate), is used. This complex, which contains an oxidizable substrate moiety (indane), is used as a tool to monitor an intramolecular oxygen atom transfer reaction. Electrochemical properties were investigated and, upon electrolysis at 1.30 V versus a normal hydrogen electrode (NHE), both dioxygen production and oxygenation of the indane moiety were observed. The ligand was oxidized in a highly diastereoselective manner, which indicated that the observed reactivity was mediated by metal-centered reactive species. The pH dependence of the reactivity was monitored and correlated with speciation deduced from different techniques, ranging from potentiometric titrations to spectroscopic studies and DFT calculations. Water oxidation for dioxygen production occurs at neutral pH and is probably mediated by the oxidation of a mononuclear copper(II) precursor. It is achieved with a rather low overpotential (280 mV at pH 7), although with limited efficiency. On the other hand, oxygenation is maximum at pH 8-8.5 and is probably mediated by the electrochemical oxidation of an antiferromagnetically coupled dinuclear bis(µ-hydroxo) copper(II) precursor. This constitutes the first example of copper-centered oxidative water activation for a selective oxygenation reaction.

Chemoselective guest-triggered shaping of a polynuclear CuII calix[6]complex into a molecular host.

A new calix[6]arene scaffold bearing a tris-imidazole binding site at the small rim and three tetradentate aza ligands at the large rim was synthesized. The system binds three CuII ions at the large rim sites and is unable to bind a fourth one, which remains in solution. The charge repulsion between the complexes, together with the flexibility of the scaffold, disorganizes the small rim site for binding and prevents its use for host-guest studies. Although the presence of MeCN or DMF guests does not alter this state, the addition of a heptylamine guest, which further displays Brønsted basicity, restores its receptor ability by stabilizing the extra CuII ion at the tris-imidazole site with concomitant guest encapsulation and binding of an exo hydroxo ligand. This chemoselective nuclearity switch yields a tetranuclear complex in which the guest backbone is preorganized in front of three potentially reactive Cu(ii) complexes, reminiscent of polynuclear CuII enzyme active sites.

"Two-Story" Calix[6]arene-Based Zinc and Copper Complexes: Structure, Properties, and O2 Binding.

A new "two-story" calix[6]arene-based ligand was synthesized, and its coordination chemistry was explored. It presents a tren cap connected to the calixarene small rim through three amido spacers. X-ray diffraction studies of its metal complexes revealed a six-coordinate ZnII complex with all of the carbonyl groups of the amido arms bound and a five-coordinate CuII complex with only one amido arm bound. These dicationic complexes were poorly responsive toward exogenous neutral donors, but the amido arms were readily displaced by small anions or deprotonated with a base to give the corresponding monocationic complexes. Cyclic voltammetry in various solvents showed a reversible wave for the CuII/CuI couple at very negative potentials, denoting an electron-rich environment. The reversibility of the system was attributed to the amido arms, which can coordinate the metal center in both its +II and +I redox states. The reversibility was lost upon anion binding to Cu. Upon exposure of the CuI complex to O2 at low temperature, a green species was obtained with a UV-vis signature typical of an end-on superoxide CuII complex. Such a species was proposed to be responsible for oxygen insertion reactions onto the ligand according to the unusual and selective four-electron oxidative pathway previously described with a "one-story" calix[6]tren ligand.

Influence of Asymmetry on the Redox Properties of Phenoxo- and Hydroxo-Bridged Dicopper Complexes: Spectroelectrochemical and Theoretical Studies.

The redox properties and electronic structures of a series of phenoxo- and hydroxo-bridged dicopper(II) complexes have been explored. Complexes (1a-c)2+ are based on symmetrical ligands with bis(2-methylpyridyl)aminomethyl as complexing arms bearing different substituting R groups (CH3, OCH3, or CF3) in the para position of the phenol moiety. Complex 2a2+ is based on a symmetrical ligand with bis(2-ethylpyridyl)aminomethyl arms and R = CH3, while complex 3a2+ involves an unsymmetrical ligand with two different complexing arms (namely bis(2-ethylpyridyl)aminomethyl and bis(2-methylpyridyl)aminomethyl). Investigations have been done by electrochemical and spectroelectrochemical means and correlated to theoretical calculations as this series of complexes offers a unique opportunity of an in-depth comparative analysis. The voltammetric studies have shown that the redox behavior of the dicopper complexes is not influenced by the nature of the solvent. However, the increase of the spacer chain length and the unsymmetrical design induce significant modifications of the voltammetric responses for both oxidation and reduction processes. DFT calculations of the redox potentials using a computational reference redox couple calculated at the same level of theory to reduce systematic errors confirm these results. Ligand contributions to the electronic structure of the different species have been analyzed in detail. The good agreement between experimental and theoretical results has validated the developed calculation method, which would be used in the following to design new dinuclear copper complexes. These studies demonstrate that subtle modification of the ligand topology can significantly affect the redox and spectroscopic properties. In particular, the unsymmetrical design allows the formation of a transient mixed-valent Cu(II)-Cu(III) phenoxo complex detected upon spectroelectrochemical experiments at room temperature, which evolves toward a dicopper (II,II) phenoxyl complex. The latter displays an intense π → π* transition band at 393 nm in the UV-vis spectrum compared to the less intense ligand to metal charge transfer band at 518 nm observed for the mixed-valent Cu(II)-Cu(III) phenoxo complex.

Characterization of a Dinuclear Copper(II) Complex and Its Fleeting Mixed-Valent Copper(II)/Copper(III) Counterpart.

The synthesis of a dinuclear copper(II) complex, supported by a 1,3-diamino-2-propanol-based tetraamide ligand, is reported. Structural properties in the solid state and in solution, by means of XRD analysis and NMR spectroscopy, respectively, provide evidence of a highly flexible complex that can display several conformations, leading to the image of the wings of a butterfly. The complex was fully characterized and the redox properties were investigated. Room-temperature spectro-electrochemistry was used to monitor the formation of a metastable mono-oxidized product that displayed an absorption band centered at λ=463 nm. EPR investigation of the low-temperature, chemically generated, mono-oxidized product reveals the presence of an intermediate described as a mixed-valent CuII CuIII species, which is a model of the possible highly oxidizing intermediate in particulate methane monooxygenase.

Immobilization of Monolayers Incorporating Cu Funnel Complexes onto Gold Electrodes. Application to the Selective Electrochemical Recognition of Primary Alkylamines in Water.

The immobilization of a copper calix[6]azacryptand funnel complex on gold-modified electrodes is reported. Two different methodologies are described. One is based on alkyne-terminated thiol self-assembled monolayers. The other relies on the electrografting of a calix[4]arene platform bearing diazonium functionalities at its large rim and carboxylic functions at its small rim, which is post-functionalized with alkyne moieties. In both cases, the CuAAC electroclick methodology proved to be the method of choice for grafting the calix[6]azacryptand onto the monolayers. The surface-immobilized complex was fully characterized by surface spectroscopies and electrochemistry in organic and aqueous solvents. The Cu complex displays a well-defined quasi-reversible system in cyclic voltammetry associated with the Cu(II)/Cu(I) redox process. Remarkably, this redox process triggers a powerful selective detection of primary alkylamines in water at a micromolar level, based on a cavitary recognition process.

Room-Temperature Characterization of a Mixed-Valent µ-Hydroxodicopper(II,III) Complex.

Bis(µ-hydroxo)dicopper(II,II) bearing a naphthyridine-based ligand has been synthesized and characterized in the solid state and solution. Cyclic voltammetry at room temperature displays a reversible redox system that corresponds to the monoelectronic oxidation of the complex. Spectroscopic and time-resolved spectroelectrochemical data coupled to theoretical results support the formation of a charge-localized mixed-valent Cu(II,III)2 species.

Improving the stability and inertness of Cu(ii) and Cu(i) complexes with methylthiazolyl ligands by tuning the macrocyclic structure.

A tacn based ligand bearing two methylthiazolyl arms (no2th) was synthesized with the aim to find ligands forming very stable and inert complexes with Cu(ii) and Cu(i) in aqueous medium for radiopharmaceutical applications. The no2th ligand was efficiently prepared following the orthoamide intermediate synthesis. The complexes with Cu(2+) and Zn(2+) were obtained and analyzed by X-ray diffraction. The [Cu(no2th)](2+) complex presents a pentacoordinated distorted square pyramidal coordination geometry, while the metal ion in [Zn(no2th)](2+) adopts a hexacoordinated distorted trigonal prismatic geometry involving the coordination of a perchlorate counter ion. The acid-base properties of no2th have been studied using potentiometric titrations, and the stability constants of Cu(2+) and Zn(2+) complexes were determined by potentiometric and UV-vis titrations using H4edta as a competitor ligand. The stability constant determined for the Cu(2+) complex is rather high (log KCuL = 20.77 and pCu = 17.15), and moreover no2th exhibits a high selectivity for copper(ii) in relation to zinc(ii). The kinetics of the copper(ii) complexation process is very fast even in acidic medium. In addition, the [Cu(no2th)](2+) complex was found to be inert under rather harsh conditions (up to 2 M HCl and 60 °C), displaying a very high half-life time of about 15 days in 2 M HCl at 90 °C. The electrochemical reduction of the copper(ii) complex in water leads to the reversible formation of a stable copper(i) species. Spectroscopic studies performed by NMR, UV-vis and EPR, assisted by theoretical calculations, show that the [Cu(no2th)](2+) complex presents a structure in solution similar to that observed in the solid state. When compared to its cyclam di-N-methylthiazolyl counterpart, the results reported in this paper unambiguously show that replacing the cyclam unit by a tacn moiety improves the stability and inertness of its Cu(ii) and Cu(i) complexes.

Supramolecular modeling of mono-copper enzyme active sites with calix[6]arene-based funnel complexes.

Supramolecular bioinorganic chemistry is a natural evolution in biomimetic metallic systems since it constitutes a further degree of complexity in modeling. The traditional approach consisting of mimicking the first coordination sphere of metal sites proved to be very efficient, because valuable data are extracted from these examples to gain insight in natural systems mechanisms. But it does not reproduce several specific aspects of enzymes that can be mimicked by the implementation of a cavity embedding the labile active site and thus controlling the properties of the metal ion by noncovalent interactions. This Account reports on a strategy aimed at reproducing some supramolecular aspects encountered in the natural systems. The cavity complexes described herein display a coordination site constructed on a macrocycle. Thanks to a careful design of the cavity-based ligands, complexes orienting their labile site specifically toward the inside of the macrocycle were obtained. The supramolecular systems are based on the flexible calix[6]arene core that surrounds the metal ion labile site, thereby constraining exogenous molecules to pass through the conic funnel to reach the metal center. Such an architecture confers to the metal ion very unusual properties and behaviors, which in many aspects are biologically relevant. Three generations of calix[6]-based ligands are presented and discussed in the context of modeling the monocopper sites encountered in some enzymes. A wide range of phenomena are highlighted such as the impact that the size and shape of the access channel to the metal center have on the selectivity and rate of the binding process, the possible remote control of the electronics through small modifications operated on the cavity edges, induced-fit behavior associated with host-guest association (shoe-tree effect) that affects the redox properties of the metal ion and the electron exchange pathway, consequences of forbidden associative ligand exchange allowing a redox switch to drive an "antithermodynamic" ligand exchange, drastic effects of the full control of the second coordination sphere, and dioxygen activation in a confined chamber conducted to a selective and unusual four-electron redox process. All these findings bring new clues for better understanding the control exerted by the proteic environment on a metal center, allow the identification of new reaction pathways, and lead to new proposals for enzymatic catalytic cycle (such as the formation of an alkylhydroperoxide intermediate for mononuclear Cu-hydroxylases). The supramolecular systems may also be exploited for designing highly selective and sensitive probes for molecules of particular function and shape or to design new selective catalysts.

Supramolecular control of a mononuclear biomimetic copper(II) center: bowl complexes vs funnel complexes.

Modeling the mononuclear site of copper enzymes is important for a better understanding of the factors controlling the reactivity of the metal center. A major difficulty stems from the difficult control of the nuclearity while maintaining free sites open to coordination of exogenous ligands. A supramolecular approach consists in associating a hydrophobic cavity to a tripodal ligand that will define the coordination spheres as well as access to the metal ion. Here, we describe the synthesis of a bowl Cu(II) complex based on the resorcinarene scaffold. This study supplements a previous work on Cu(I) coordination. It provides a complete picture of the cavity-copper system in its two oxidation states. The first XRD structure of such a bowl complex was obtained, evidencing a 5-coordinate Cu(II) ion with the three imidazole donors bound to the metal (two in the base of the pyramid, one in the apical position) and with an acetate anion, completing the base of the pyramid, and deeply included in the bowl. Solution studies conducted by EPR and UV-vis absorption spectroscopies as well as cyclic voltammetry highlighted interaction with coordinating solvents, various carboxylates that can sit either in the endo or in the exo position depending on their size as well as possible stabilization of hydroxo species in a mononuclear state. A comparison of the binding and redox properties of the bowl complex with funnel complexes based on the calix[6]arene core further highlights the importance of supramolecular features defining the first, second, and third coordination sphere for control of the metal ion.

Insights into water coordination associated with the Cu(II)/Cu(I) electron transfer at a biomimetic Cu centre.

The coordination properties of the biomimetic complex [Cu(TMPA)(H2O)](CF3SO3)2 (TMPA = tris(2-pyridylmethyl)amine) have been investigated by electrochemistry combined with UV-Vis and EPR spectroscopy in different non-coordinating media including imidazolium-based room-temperature ionic liquids, for different water contents. The solid-state X-ray diffraction analysis of the complex shows that the cupric centre lies in a N4O coordination environment with a nearly perfect trigonal bipyramidal geometry (TBP), the water ligand being axially coordinated to Cu(II). In solution, the coordination geometry of the complex remains TBP in all media. Neither the triflate ion nor the anions of the ionic liquids were found to coordinate the copper centre. Cyclic voltammetry in all media shows that the decoordination of the water molecule occurs upon monoelectronic reduction of the Cu(II) complex. Back-coordination of the water ligand at the cuprous state can be detected by increasing the water content and/or decreasing the timescale of the experiment. Numerical simulations of the voltammograms allow the determination of kinetics and thermodynamics for the water association-dissociation mechanism. The resulting data suggest that (i) the binding/unbinding of water at the Cu(I) redox state is relatively slow and equilibrated in all media, and (ii) the binding of water at Cu(I) is somewhat faster in the ionic liquids than in the non-coordinating solvents, while the decoordination process is weakly sensitive to the nature of the solvents. These results suggest that ionic liquids favour water exchange without interfering with the coordination sphere of the metal centre. This makes them promising media for studying host-guest reactions with biomimetic complexes.

Locally induced and self-induced "electroclick" onto a self-assembled monolayer: writing and reading with SECM under unbiased conditions.

Localized "electroclick" was achieved on azido-terminated self-assembled monolayers using Scanning Electrochemical Microscopy (SECM) in feedback mode, in which the substrate is not electrically connected (unbiased conditions). The method allows both the local immobilization of diverse functional moieties and the monitoring of each modification step at a micrometer scale. Conditions of the "click" coupling reaction were optimized especially to avoid the deposit of metallic copper by the choice of a specific ligand to stabilize the Cu(I) species. The catalytic efficiency in localized "electroclick" reaction of Cu(II)TMPA (TMPA: tris(2-pyridylmethyl)amine) as the "click" catalyst was compared with a derivative containing an alkyne group Cu(II)6eTMPA, the same molecule playing the role of the catalyst and the substrate. Evidences for surface self-catalysis propagation are demonstrated through SECM imaging showing a random 2D progression of the catalytic modification.

Electrochemically driven cup-and-ball CuI and CuII complexes.

The conformation of copper "funnel" complexes that contains a coordinating appended arm can be electrochemically switched between endo, which corresponds to the self-coordination of the arm through the cavity, and exo positions. This process, which is reminiscent of a cup-and-ball device, is activated by an exogenous ligand for complexes that contain a hydroxy-terminated arm. The exchange is electrochemically triggered and is operated in either Cu(I) or Cu(II) redox states, depending on the exogenous ligand, that is, CO or n-butylamine, respectively.

Electrochemical behavior and dioxygen reactivity of tripodal dinuclear copper complexes linked by unsaturated rigid spacers.

New dinucleating ligands based on two tripodal tris(2-pyridylmethyl)amine (TMPA) units linked by a series of delocalized π-electrons spacers have been synthesized. Their di-Cu(II) complexes have been prepared and structurally characterized. As compared to the corresponding monotopic complexes, these dinuclear Cu(II) complexes reveal spectroscopic and voltammetric features ascribable to weakly perturbed electronic interactions. In the case of the anthracenyl spacer, observation both in the solid and in solution suggests that the existence of intramolecular π-π stacking interactions influences the geometry of the complex and hence its electronic properties. The bis-Cu(I) complexes were prepared electrochemically. In the specific case of the complex bearing a mono-alkyne spacer, addition of dioxygen in acetonitrile leads to the slow formation of a trans-µ-1,2 peroxo Cu(2) complex which shows good stability at 268 K (t(1/2) = 240 s). Analysis of the kinetics of the peroxo formation by UV-vis spectroscopy suggests that the increased activation barrier for intramolecular binding of dioxygen is due to the rigidity of the spacer.

Synthesis and studies of a water-soluble and air-stable Cu(I)/Cu(II) open-shell funnel complex.

The derivatization of the large rim of a TMPA-capped calix[6]arene (TMPA = tris(2-pyridylmethyl)amine) with three trimethylammonium groups enables the water-solubilization of two air-stable Cu(I)/Cu(II) complexes. These two complexes present a vacant coordination site shielded from the aqueous environment by the calixarene core. The spectroscopic and electrochemical data recorded in pure water indicate that the host-guest properties of the funnel complex are retained in both oxidation states of the copper cation.

A generic platform for the addressable functionalisation of electrode surfaces through self-induced "electroclick".

A novel and general strategy for the immobilisation of functional objects onto electrodes is described. The concept is based on the addition of two pendant ethynyl groups onto a bis(pyridyl)amine derivative, which acts as a molecular platform. This platform is pre-functionalised with an N(3)-tagged object of interest by Huisgen cycloaddition to one of the ethynyl groups in biphasic conditions. Hence, when complexed by Cu(II) , this molecular-object holder can be immobilised, by a "self-induced electroclick", through the second ethynyl group onto N(3)-alkanethiol self-assembled monolayers on a gold electrode. Two different functional groups, a redox innocent ((CH(2))(3)-Ph) and an electrochemical probe (ferrocene), were immobilised by following this strategy. The in situ electrochemical grafting showed, for both systems, that the kinetics of immobilisation is fast. The voltammetric characterisation of the surface-tagged functionalised copper complexes indicated that a good surface coverage was achieved and that a moderately fast electron-transfer reaction occurs. Remarkably, in the case of the redox-active ferrocenyl-immobilised system, the electrochemical response highlighted the involvement of the copper ion of the platform in the kinetics of the electron transfer to the ferrocene moiety. This platform is a promising candidate for applications in surface addressing in areas as diverse as biology and materials.

Tris(triazolyl) calix[6]arene-based zinc and copper funnel complexes: imidazole-like or pyridine-like? A comparative study.

Huisgen dipolar cycloaddition leads straightforwardly to new funnel complexes based on the calix[6]arene macrocycle bearing three functionalized triazoles as coordinating units at the small rim. Coordination to Zn(II) and Cu(I) cations was studied using (1)H NMR and IR spectroscopies and cyclic voltammetry. The nature of the substituents on the triazole ring affects the behavior of the ligands and their coordinating ability and controls the host-guest properties of the metal receptors for exogenous substrates. Depending on their substitution pattern but also on the metal ion and the guest ligand, the triazole-based systems behave either imidazole-like or pyridine-like. The ease of preparation and the versatility of 1,4-disubstituted-1,2,3-triazoles with tunable steric and electronic properties make them promising candidates for further applications from biology to materials.