Search

International audience; Potential inversion refers to the situation where a protein cofactor or a synthetic molecule can be oxidized or reduced twice in a cooperative manner, that is the second electron transfer (ET) is easier than the first. This property is very important regarding the catalytic mechanism of enzymes that bifurcate electrons and the properties of bidirectional redox molecular catalysts that function in either direction of the reaction with no overpotential. Cyclic voltammetry is the most common technique for characterizing the thermodynamics and kinetics of ET to or from these molecules. However, a gap in the literature is the absence of analytical predictions to help interpret the values of the voltammetric peak potentials when potential inversion occurs ; the cyclic voltammograms are therefore often analyzed by simulating the data, with no discussion of the possibility of overfitting and often no estimation of the error on the determined parameters. Here we formulate the theory for the voltammetry of freely-diffusing or surface-confined two-electron redox species in the experimentally relevant irreversible limit where the peak separation depends on scan rate. We explain why the model is intrinsically underdetermined, and we illustrate this conclusion by the analysis of the voltammetry of a Ni complex with redox-active iminosemiquinone ligands. Being able to characterize the thermodynamics of two-electron transfer reactions will be crucial for designing more efficient catalysts.

Copper catalysis finds applications in various synthetic fields by utilizing the ability of copper to sustain mono- and bielectronic elementary steps. Further to the development of well-defined copper complexes with classical ligands such as phosphines and N-heterocyclic carbenes, a new and fast-expanding area of research is exploring the possibility of a complementing metal-centered reactivity with electronic participation by the coordination sphere. To achieve this electronic flexibility, redox-active ligands can be used to engage in a fruitful “electronic dialogue” with the metal center, and provide additional venues for electron transfer. This review aims to present the latest results in the area of copper-based cooperative catalysis with redox-active ligands.

We report the design of a unique bioinspired ligand merging redox-active catechol and flavin-related alloxazine substructures. Upon coordination with a Ni(II) salt, this hybrid ligand forms a trinuclear complex containing three NiII centers and three redox-active ligands. This air-stable metallic triangle stabilizing protons and electrons was studied by X-ray crystallography, infra-red (IR) and UV-vis spectroscopy, SQUID magnetometry (Superconducting QUantum Interference Device), MAS-NMR (Magic Angle Spinning-Nuclear Magnetic Resonance), EPR (Electron Paramagnetic Resonance), electrochemistry and DFT (Density Functional Theory). This multidisciplinary approach supports the presence of protons located on the organic ligands, and an electronic structure involving three high spin Ni(II) ions strongly ferromagnetically coupled with radicals. Both ligand and complex provide a new design for molecular bricks and bioinspired energy storage devices.

Biological systems provide attractive reactivity blueprints for the design of challenging chemical transformations. Emulating the operating mode of natural systems may however not be so easy and direct translation of structural observations does not always afford the anticipated efficiency. Metalloenzymes rely on earth-abundant metals to perform an incredibly wide range of chemical transformations. To do so, enzymes in general have evolved tools and tricks to enable control of such reactivity. The underlying concepts related to these tools are usually well-known to enzymologists and bio(inorganic) chemists but may be a little less familiar to organometallic chemists. So far, the field of bioinspired catalysis has greatly focused on the coordination sphere and electronic effects for the design of functional enzyme models but might benefit from a paradigm shift related to recent findings in biological systems. The goal of this review is to bring these fields closer together as this could likely result in the development of a new generation of highly efficient bioinspired systems. This contribution covers the fields of redox-active ligands, entatic state reactivity, energy conservation through electron bifurcation, and quantum tunneling for C-H activation.

The reactivity of a stable copper(II) complex bearing fully oxidized iminobenzoquinone redox ligands towards nucleophiles is described. In sharp contrast with its genuine low-valent counterpart bearing reduced ligands, this complex performs high-yielding C−N bond formations. Mechanistic studies suggest that this behavior could stem from a mechanism akin to reductive elimination occurring at the metal center but facilitated by the ligand: it is proposed that a masked high oxidation state of the metal can be stabilized as a lower copper(II) oxidation state by the redox ligands without forfeiting its ability to behave as a high-valent copper(III) center. These observations are substantiated by a combination of advanced EPR spectroscopy techniques with DFT studies. This work sheds light on the potential of redox ligands as promoters of unusual reactivities at metal centers and illustrates the concept of masked high-valent metallic species. 55;36

Small-molecule catalysts as mimics of biological systems illustrate the chemists' attempts at emulating the tantalizing abilities displayed by nature's metalloenzymes. Among these innate behaviors, spin multistate reactivity is used by biological systems as it offers thermodynamic leverage towards challenging chemical reactivity but this concept is difficult to translate into the realm of synthetic organometallic catalysis. Here, we report a rare example of molecular spin catalysis involving multistate reactivity in a small-molecule biomimetic copper catalyst applied to aziridination. This behavior is supported by spin state flexibility enabled by the redox-active ligand.

International audience; Nickel complexes have gained sustained attention as efficient catalysts in cross‐coupling reactions and co‐catalysts in dual systems due to their ability to react with radical species. Central to this reactivity is nickel's propensity to shuttle through several accessible redox states from Ni0 to NiIV. Here, we report the catalytic generation of trifluoromethyl radicals from a nickel complex bearing redox‐active iminosemiquinone ligands. This unprecedented reactivity is enabled through ligand‐based oxidation performing electron transfer to an electrophilic CF3+ source while the nickel oxidation state is preserved. Additionally, extension of this reactivity to a copper complex bearing a single redox equivalent is reported, thus providing a unified reactivity scheme. These results open new pathways in radical chemistry with redox‐active ligands.

This account describes some advances we have made in the field of iron catalysis. Two types of reactivity have been uncovered. Based on the use of an iron(II) precatalyst in the presence of NaBH4, the first one consists in a SET which can be useful for the reductive dehalogenation of iodide and bromide derivatives. Switching to the non-innocent bis-iminopyridine ligands promotes a previously undescribed Csp2−H activation reaction leading to biaryl derivatives. First clues into the intricate nature of the mechanism were obtained and suggested that the redox-active bis-iminopyridine ligand acts as an electron reservoir. The resulting buildup of electron density triggers the C−H bond breaking. All these findings are discussed in light of the existing literature and perspectives are given.

There is an obvious need to develop efficient countermeasure agents for use in emergency situations or as adjuncts to radiotherapy to protect healthy tissues from the consequences of an irradiation. To this end, we have investigated the capacity of norbadione A, a polyphenol extracted from the edible mushroom Bay boletus to reduce the toxicity of ionizing radiation towards cultured cells and whole-body exposed mice. Results indicate that this compound could slightly enhance the resistance of TK6 lymphoid cells to radiation and increase the survival rate in lethally irradiated mice. However, norbadione A was found to be cytotoxic at concentrations over 30 &μυ;M in vitro. The acute toxicity of this compound also precluded its use at higher doses for enhanced in vivo radioprotection. Norbadione A may nevertheless serve as lead for development of less toxic analogs with potentially cytoprotective/ radioprotective activities. © 2012 Bentham Science Publishers.

International audience; Introduced in the late sixties, non-innocent (or redox) ligands have been extensively studied for their unusual and intriguing chemical behavior. Their ability to delocalize and/or provide electrons to the metal center of organometallic complexes confers them undisputable chemical interest and has proved valuable in the development of novel synthetic methodologies. This review will focus on the chemistry and applications of low-valent iron complexes bearing potentially non-innocent ligands. Because of the elusive nature of these ligands, and whenever possible, theoretical calculations and analysis of spectroscopic data will be presented in an effort to provide insights into the catalytic activity of the complexes.

Complexes of triaryl- and trialkylboranes with N-heterocyclic carbenes (NHCs) participate in Suzuki-Miyaura cross-coupling reactions and provide coupled products in good yields under base-free conditions. The reaction can be applied to Csp(2)-Csp(2) and Csp(2)-Csp(3) carbon-carbon bond formation with triflates, iodides, bromides, and chlorides. These results enrich the utility of NHC-borane complexes, which can be added to the toolkit of Suzuki-Miyaura cross-couplings, along with boronic acids and organotrifluoroborates.

International audience; A well-defined copper complex bearing iminosemiquinone ligands performs single electron reduction of an electrophilic CF3+ source into CF˙3 radicals. This redox behavior is enabled by the ligand which shuttles through two different redox states (iminosemiquinone and iminobenzoquinone) while the copper center is preserved as a Cu(II). This system was used in the trifluoromethylation of silyl enol ethers, heteroaromatics and in the hydrotrifluoromethylation of alkynes. This is the first example of cooperative redox catalysis for the controlled generation of CF˙3 radicals.

International audience; Coupling reactions are staples in the synthetic world and their efficiency relies on well-defined, mostly bis-electronic, elementary catalytic steps. An area of great interest currently lies in the taming of radical species and their efficient introduction in catalytic cycles. Among these species bearing radical character, redox-active ligands hold much potential and can be used to sustain synthetically relevant couplings by introducing ligand-based electronic contribution. This minireview aims at presenting the current state of this promising field.

A short, convergent synthesis of the mushroom pigment norbadione A is described. The construction of an appropriately substituted naphtholactone intermediate involved a regioselective Diels-Alder reaction between a bis(triisopropylsilyloxy)diene and 2,6-dichlorobenzo-1,4-quinone. A double Suzuki-Miyaura cross-coupling between a diboronate and two identical enol triflates was another key feature of the synthesis.

Cooperative catalysis involving copper(ii) complex bearing redox ligands allows generation of CF˙3 radicals through ligand-based SET while metallic oxidation state is preserved., A well-defined copper complex bearing iminosemiquinone ligands performs single electron reduction of an electrophilic CF3+ source into CF˙3 radicals. This redox behavior is enabled by the ligand which shuttles through two different redox states (iminosemiquinone and iminobenzoquinone) while the copper center is preserved as a Cu(ii). This system was used in the trifluoromethylation of silyl enol ethers, heteroaromatics and in the hydrotrifluoromethylation of alkynes. This is the first example of cooperative redox catalysis for the controlled generation of CF˙3 radicals.

Pulvinic acid and norbadione A analogues can be prepared by Suzuki–Miyaura cross-coupling of functionalized arylboronic esters with appropriate vinyl triflates, in which the hydroxy functions are protected either with methyl or benzyl groups, the latter being cleaved in a more reliable fashion at the end of the synthetic sequence. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

We present a new high-throughput screening method for the selection of powerful water-soluble antiradiation compounds. This method, which uses conventional immunoassay techniques, allowed the capacity of a given compound to protect thymidine from irradiation to be evaluated. By applying this assay to an antioxidant library, we showed for the first time that norbadione A, a well-known mushroom pigment, has pronounced atypical antiradiation properties.

The reaction is proposed to proceed through a metal-based inner-sphere C-H activation involving concomitant electron transfer from the ligand and the substrate.

The reaction of a copper complex bearing iminosemiquinone ligands with a CF3(+) source provides an unprecedented Cu(II)-CF3 complex through ligand-based oxidation. Reactivity of this complex leads to nucleophilic trifluoromethylation of the ligand, suggesting an electronic interplay that results in a formal umpolung of the initial CF3(+).

International audience; Tandem CH activation/arylation between unactivated arenes and aryl halides catalyzed by iron complexes that bear redox-active non-innocent bisiminopyridine ligands is reported. Similar reactions catalyzed by first-row transition metals have been shown to involve substrate-based aryl radicals, whereas our catalytic system likely involves ligand-centered radicals. Preliminary mechanistic investigations based on spectroscopic and reactivity studies, in conjunction with DFT calculations, led us to propose that the reaction could proceed through an inner-sphere CH activation pathway, which is rarely observed in the case of iron complexes. This bielectronic noble-metal-like behavior could be sustained by the redox-active non-innocent bisiminopyridine ligands.

A versatile new method for the preparation of NHC boranes starting from two stable, readily available reactants-an heterocyclic salt and an amine or phosphine-borane-is reported. It uses a Lewis base exchange at boron and provides easy access to new NHC boranes, in particular B-substituted borane ones.

The reaction of a copper complex bearing iminosemiquinone ligands with a CF3+ source provides an unprecedented CuII-CF3 complex through ligand-based oxidation. Reactivity of this complex leads to nucleophilic trifluoromethylation of the ligand, suggesting an electronic interplay that results in a formal umpolung of the initial CF3+.

Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO(2), OH, OMe or Cl) preferably assisted by microwave irradiation. Conversion of the amino group into a thiol preceded a base-induced intramolecular substitution, also facilitated by microwave heating, to generate the second C-S bond of the target dibenzothiophene. The 1-, 2-, 3- or 4-substituted 6-halodibenzothiophenes obtained were subjected to a palladium-mediated coupling with 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity, whereas substitution at C-7 lowered activity. Substitution with chloro at C-6 was not detrimental to activity, but a chloro group at C-7 or C-8 reduced potency. The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK.

A microwave-assisted protocol is developed for the reaction of the substrates with aryl iodides in a short time.

Complexes of triaryl- and trialkylboranes with N-heterocyclic carbenes (NHCs) participate in Suzuki−Miyaura cross-coupling reactions and provide coupled products in good yields under base-free conditions. The reaction can be applied to Csp2−Csp2 and Csp2−Csp3 carbon−carbon bond formation with triflates, iodides, bromides, and chlorides. These results enrich the utility of NHC−borane complexes, which can be added to the toolkit of Suzuki−Miyaura cross-couplings, along with boronic acids and organotrifluoroborates.

Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 microM. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.

A recently reported high-throughput screening strategy has been applied to the rapid selection of new water-soluble antioxidants that display strong protective activities. Based on a competitive immunoassay, a triple-screening procedure was used to evaluate the ability of different compounds to protect thymidine under different oxidative stresses. The pro-oxidant effect of norbadione A in the presence of iron was observed, while some pulvinic acid derivatives proved strongly protective during gamma radiolysis, UV irradiation, and Fenton-like oxidation.

The microscopic protonation mechanism, at an inframolecular level, of norbadione A, a pigment extracted from mushrooms and known to complex cesium cations, was determined by using 1H NMR titrations and the cluster expansion method. This study revealed a pH dependent Z to E isomer switch that occurs in both pulvinic moieties. As a consequence, norbadione A can exist in solution in four stereomeric forms (E−E, E−Z, Z−E, and Z−Z), which can be of interest in the development of molecular-level devices. In the presence of 0.15 M NaCl, the calculated microconstants showed an unusual apparent cooperativity between the enol groups, which results from the release of the sodium cations upon protonation of norbadione A.

Because of their ability to get involved in redox events, non-innocents ligands have long sparked the interest of spectroscopists, and their potential in catalysis has only later been considered. Iminosemiquinonate radical ligands and their derivatives are well-established non-innocent ligands and have been previously used with several metals, showing their efficiency in specific synthetic applications, such as oxidations and cross-couplings. This thesis work deals with the development of reactivities using iminosemiquinonate copper and nickel complexes. First, the ability of these complexes to induce the controlled generation of CF3 radicals by reduction of a CF3+ source was demonstrated, and key organometallic species resulting from a ligand-centered single electron transfer were identified using UV-vis spectroscopy. Catalytic conditions were developed and applied to the trifluoromethylation of silyl enol ethers, heteroarenes and hydrotrifluoromethylation of alkynes. Then, the synthesis of the first well-defined CuII–CF3 complex bearing fully oxidized iminobenzoquinone ligands was achieved. The study of its reactivity revealed the prominent role of the redox ligands, which stabilize a (+II) oxidation state without preventing its ability to behave as a high-valent CuIII complex. These observations were substantiated by a combination of advanced EPR spectroscopy techniques with DFT calculations. Finally, the influence of iminosemiquinonate ligands on the structure and the reactivity of copper–nitrene species, in catalytic nitrene transfer reactions, is the focus of a last project, which is still in progress.; En raison de leur capacité à intervenir dans les processus rédox, les ligands non-innocents ont depuis longtemps suscité un intérêt chez les spectroscopistes, mais leur potentiel en catalyse n'a été que récemment considéré. Le comportement non-innocent des ligands iminosemiquinonate et de leurs dérivés est bien établi et maîtrisé, et, associés à différents métaux, ces ligands ont démontré leur efficacité dans diverses applications synthétiques, telles que les oxydations et les réactions de couplage. Ce travail de thèse a pour objectif de développer des réactivités induites par des complexes de cuivre et nickel coordinés par des ligands de type iminosemiquinonate. Tout d'abord, la capacité de ces complexes à générer des radicaux CF3 par réduction d'une source électrophile de trifluorométhylation a été démontrée, et les espèces organométalliques résultant de l'oxydation monoélectronique centrée sur le ligand ont été identifiées par spectroscopie UV-visible. Un système catalytique a également été mis au point pour la trifluorométhylation radicalaire d'éthers d'énol silylés, d'hétéroarènes et l'hydrotrifluorométhylation d'alcynes. Les propriétés rédox des ligands iminosemiquinonates ont permis l'accès au premier complexe CuII–CF3 coordiné par des ligands oxydés iminobenzoquinones. L'étude de sa réactivité a mis en évidence le rôle essentiel des ligands oxydés, qui stabilisent le degré d'oxydation +II du cuivre, sans empêcher un comportement de CuIII haute valence. Ces observations ont été attestées par un ensemble de données spectroscopiques et théoriques. Enfin, l'étude de l'influence des ligands iminosemiquinonate sur la structure et la réactivité d'espèces cuivre–nitrène, impliquées dans les réactions de transfert de nitrène catalytique, est au centre d'un projet en cours.

Because of their ability to get involved in redox events, non-innocents ligands have long sparked the interest of spectroscopists, and their potential in catalysis has only later been considered. Iminosemiquinonate radical ligands and their derivatives are well-established non-innocent ligands and have been previously used with several metals, showing their efficiency in specific synthetic applications, such as oxidations and cross-couplings. This thesis work deals with the development of reactivities using iminosemiquinonate copper and nickel complexes. First, the ability of these complexes to induce the controlled generation of CF3 radicals by reduction of a CF3+ source was demonstrated, and key organometallic species resulting from a ligand-centered single electron transfer were identified using UV-vis spectroscopy. Catalytic conditions were developed and applied to the trifluoromethylation of silyl enol ethers, heteroarenes and hydrotrifluoromethylation of alkynes. Then, the synthesis of the first well-defined CuII–CF3 complex bearing fully oxidized iminobenzoquinone ligands was achieved. The study of its reactivity revealed the prominent role of the redox ligands, which stabilize a (+II) oxidation state without preventing its ability to behave as a high-valent CuIII complex. These observations were substantiated by a combination of advanced EPR spectroscopy techniques with DFT calculations. Finally, the influence of iminosemiquinonate ligands on the structure and the reactivity of copper–nitrene species, in catalytic nitrene transfer reactions, is the focus of a last project, which is still in progress.; En raison de leur capacité à intervenir dans les processus rédox, les ligands non-innocents ont depuis longtemps suscité un intérêt chez les spectroscopistes, mais leur potentiel en catalyse n'a été que récemment considéré. Le comportement non-innocent des ligands iminosemiquinonate et de leurs dérivés est bien établi et maîtrisé, et, associés à différents métaux, ces ligands ont démontré leur efficacité dans diverses applications synthétiques, telles que les oxydations et les réactions de couplage. Ce travail de thèse a pour objectif de développer des réactivités induites par des complexes de cuivre et nickel coordinés par des ligands de type iminosemiquinonate. Tout d'abord, la capacité de ces complexes à générer des radicaux CF3 par réduction d'une source électrophile de trifluorométhylation a été démontrée, et les espèces organométalliques résultant de l'oxydation monoélectronique centrée sur le ligand ont été identifiées par spectroscopie UV-visible. Un système catalytique a également été mis au point pour la trifluorométhylation radicalaire d'éthers d'énol silylés, d'hétéroarènes et l'hydrotrifluorométhylation d'alcynes. Les propriétés rédox des ligands iminosemiquinonates ont permis l'accès au premier complexe CuII–CF3 coordiné par des ligands oxydés iminobenzoquinones. L'étude de sa réactivité a mis en évidence le rôle essentiel des ligands oxydés, qui stabilisent le degré d'oxydation +II du cuivre, sans empêcher un comportement de CuIII haute valence. Ces observations ont été attestées par un ensemble de données spectroscopiques et théoriques. Enfin, l'étude de l'influence des ligands iminosemiquinonate sur la structure et la réactivité d'espèces cuivre–nitrène, impliquées dans les réactions de transfert de nitrène catalytique, est au centre d'un projet en cours.