Olivier Jarjayes

X‐Ray Structures of Copper(II) and Nickel(II) Radical Salen Complexes: The Preference of Galactose Oxidase for Copper(II)

Organic radicals are normally extremely reactive, and often nonselective and toxic species. They are found in a number of proteins, some of which are involved in essential processes such as photosynthesis and DNA synthesis. Nature has therefore nicely succeeded in domesticating them and taking advantage of their high reactivity. Galactose oxidase (GO, Scheme 1), which catalyzes aerobic oxidation of primary

Intramolecularly hydrogen-bonded versus copper(II) coordinated mono- and bis-phenoxyl radicals.

Ligands bearing two salicylidene imine moieties substituted in ortho and para positions by tert-butyl groups have been electrochemically oxidized into mono- and bis-phenoxyl radicals. The process involves an intramolecular proton coupled to electron transfer and affords a radical in which the oxygen atom is hydrogen-bonded to a protonated ammonium or iminium group. A weak intramolecular dipolar interaction exists between the two phenoxyl moieties in the bis-radical species. The copper(II) complexes of these ligands have been characterized and electrochemically oxidized. The mono-phenoxyl radical species are X-band EPR silent. The bis-phenoxyl radical species exhibits a (S= 3/2) ground state: it arises from a ferromagnetic exchange coupling between the two spins of the radicals and that of the copper(II) when the spacer is rigid enough; a flexible spacer such as ethylidene induces decomplexation of at least one phenoxyl group. Metal coordination is more efficient than hydrogen-bonding to enhance the chemical stability of the mono-phenoxyl radicals.

Interaction of polycationic Ni(II)-salophen complexes with G-quadruplex DNA.

A series of nine Ni(II) salophen complexes involving one, two, or three alkyl-imidazolium side-chains was prepared. The lengths of the side-chains were varied from one to three carbons. The crystal structure of one complex revealed a square planar geometry of the nickel ion. Fluorescence resonance energy transfer melting of G-quadruplex structures in the presence of salophen complex were performed. The G-quadruplex DNA structures were stabilized in the presence of the complexes, but a duplex DNA was not. The binding constants of the complexes for parallel and antiparallel G-quadruplex DNA, as well as hairpin DNA, were measured by surface plasmon resonance. The compounds were selective for G-quadruplex DNA, as reflected by equilibrium dissociation constant KD values in the region 0.1-1 μM for G-quadruplexes and greater than 2 μM for duplex DNA. Complexes with more and shorter side-chains had the highest binding constants. The structural basis for the interaction of the complexes with the human telomeric G-quadruplex DNA was investigated by computational studies: the aromatic core of the complex stacked over the last tetrad of the G-quadruplex with peripherical cationic side chains inserted into opposite grooves. Biochemical studies (telomeric repeat amplification protocol assays) indicated that the complexes significantly inhibited telomerase activity with IC50 values as low as 700 nM; the complexes did not significantly inhibit polymerase activity.

Ligand‐Centered Redox Activity in Cobalt(II) and Nickel(II) Bis(phenolate)–Dipyrrin Complexes

One for all: a trianionic ligand containing the biologically relevant moieties phenolate and porphyrin was designed and synthesized. One-electron oxidation of the nickel and cobalt complexes of these ligands affords an unprecedented and highly stable hybrid porphyrinyl-phenoxyl radical bound to the metal center. Two-electron oxidation of these complexes leads to the M(2+) -(close-shell two-electron oxidized ligand) species.

Stable Anilinyl Radicals Coordinated to Nickel: X-ray Crystal Structure and Characterization

Two anilinosalen and a mixed phenol-anilinosalen ligands involving sterically hindered anilines moieties were synthesized. Their nickel(II) complexes 1, 2, and 3 were prepared and characterized. They could be readily one-electron oxidized (E(1/2)=-0.30, -0.26 and 0.10 V vs. Fc(+)/Fc, respectively) into anilinyl radicals species [1](+), [2](+), and [3](+), respectively. The radical complexes are extremely stable and were isolated as single crystals. X-ray crystallographic structures reveal that the changes in bond length resulting from oxidation do not exceed 0.02 Å within the ligand framework in the symmetrical [1](+) and [2](+). No quinoid bond pattern was present. In contrast, larger structural rearrangements were evidenced for the unsymmetrical [3](+), with shortening of one C(ortho)-C(meta) bond. Radical species [1](+) and [2](+) exhibit a strong absorption band at around 6000 cm(-1) (class III mixed valence compounds). This band is significantly less intense than [3](+), consistent with a rather localized anilinyl radical character, and thus a classification of this species as class II mixed-valence compound. Magnetic and electronic properties, as well as structural parameters, have been computed by DFT methods.

Structural and spectroscopic investigation of an anilinosalen cobalt complex with relevance to hydrogen production.

A Co(II) anilinosalen catalyst containing proton relays in the first coordination sphere has been synthesized that catalyzes the electrochemical production of hydrogen from acid in dichloromethane and acetonitrile solutions. The complex has been spectroscopically and theoretically characterized in different protonation and redox states. We show that both coordinated anilido groups of the neutral Co(II) complex can be protonated into aniline form. Protonation induces an anodic shift of more than 1 V of the reduction wave, which concomitantly becomes irreversible. Hydrogen evolution that originates from the aniline protons located in the first coordination sphere is observed upon bulk electrolysis at -1.5 V of the protonated complex in absence of external acid. Structures for intermediates in the catalytic reaction have been identified based on this data.

Tripodal Iminophenolate Ligand Complexes of Gallium(III), Indium(III), and Thallium(III)

The polydentate tripodal Schiff base ligand H3L has been prepared by treating a methanolic solution of tris(aminoethyl)amine and 5-bromosalicylaldehyde. This ligand, and its complexes with group-13 metal ions (GaIII, InIII, and TlIII) have been characterized by elemental analysis, NMR spectroscopy, FAB+-MS, and X-ray diffraction analysis. The ligand, not preorganized in the solid state, acts as a hexadentate N3O3 ligand in all cases to form octahedral structures, the apical nitrogen not being involved in the chelation even for the [Tl(L)] complex. NMR studies reveal that the intact and rigid structures of the complexes are maintained in solution. For the [Tl(L)] complex, long-range thallium isotope effect on the chemical shift (δH and δC) and on the coupling constants (JTl-H and JTl-C) has been observed, confirming a strong and stable bond between TlIII and H3L.

Efficient Inhibition of Telomerase by Nickel–Salophen Complexes

Four nickel(II)–salophen complexes containing alkyl‐imidazolium chains connected at the ortho or meta positions were prepared: N,N′‐bis(2‐hydroxy‐4‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)phenylenediamine (1), N,N′‐bis(2‐hydroxy‐3‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)phenylenediamine (2), N,N′‐bis(2‐hydroxy‐3‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)methyl‐3H‐imidazol‐1‐iumphenylenediamine (3), and N,N′‐bis(2‐hydroxy‐4‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)methyl‐3H‐imidazol‐1‐iumphenylenediamine (4). They protect G‐quadruplex DNA (G4‐DNA) against thermal denaturation and show KA values in the range of 7.4×105 to 4×107 m−1 for G4‐DNA models. Complex 4 exhibits an IC50 value of 70 nm for telomerase inhibition.

Geometric and Electronic Structures of Phenoxyl Radicals Hydrogen Bonded to Neutral and Cationic Partners

Two di-tert-butylphenols incorporating an N-methylbenzimidazole moiety in the ortho or para position have been synthesised ((Me)OH and (pMe)OH, respectively). Their X-ray structures evidence a hydrogen bond between the phenolic proton and the iminic nitrogen atom, whose nature is intra- and intermolecular, respectively. The present studies demonstrate that (Me)OH is readily oxidised by an intramolecular PET mechanism to form the hydrogen-bonded phenoxyl-N-methylbenzimidazolium system ((Me)OH)(.+) , whereas oxidation of (pMe)OH occurs by intermolecular PET, affording the neutral phenoxyl benzimidazole ((pMe)O)(.) system. The deprotonations of (Me)OH and (pMe)OH yield the corresponding phenolate species ((Me)O)(-) and ((pMe)O)(-), respectively, whilst that of the previously reported (H)OH (analogous to (Me)OH but lacking the N-methyl group) produces an unprecedented hydrogen-bonded phenol benzimidazolate species, as evidenced by its X-ray structure. The latter is believed to be in equilibrium in solution with its tautomeric phenolate form, as suggested by NMR, electrochemistry and DFT studies. The one-electron oxidations of the anions occur by a simple ET process affording phenoxyl radical species, whose electronic structure has been studied by HF-EPR spectroscopy and DFT calculations. In particular, analysis of the g(1) tensor shows the order 2.0079>2.0072>2.0069>2.0067 for ((Me)O)(.), ((H)O)(.), ((Me)OH)(.+) and ((H)OH)(.+), respectively. ((Me)O)(.) exhibits the largest g(1) tensor (2.0079), consistent with the absence of intramolecular hydrogen bond. The g(1) tensor of ((H)O)(.) is intermediate between those of ((Me)OH)(.+) and ((Me)O)(.) (g(1)=2.0072), indicating that the phenoxyl oxygen is hydrogen-bonded with a neutral benzimidazole partner.

Templated Formation of Discrete RNA and DNA:RNA Hybrid G-Quadruplexes and Their Interactions with Targeting Ligands.

G-rich RNA and DNA oligonucleotides derived from the human telomeric sequence were assembled onto addressable cyclopeptide platforms through oxime ligations and copper-catalyzed azide-alkyne cycloaddition (CuAAc) reactions. The resulting conjugates were able to fold into highly stable RNA and DNA:RNA hybrid G-quadruplex (G4) architectures as demonstrated by UV, circular dichroism (CD), and NMR spectroscopic analysis. Whereas rationally designed parallel RNA and DNA:RNA hybrid G4 topologies could be obtained, we could not force the formation of an antiparallel RNA G4 structure, thus supporting the idea that this topology is strongly disfavored. The binding affinities of four representative G4 ligands toward the discrete RNA and DNA:RNA hybrid G4 topologies were compared to the one obtained with the corresponding DNA G4 structure. Surface plasmon resonance (SPR) binding analysis suggests that the accessibility to G4 recognition elements is different among the three structures and supports the idea that G4 ligands might be shaped to achieve structure selectivity in a biological context.