Radical Complexes of Nickel(II)/Copper(II) and Redox Non-innocent MB-DIPY Ligands: Unusual Stability and Strong Near-Infrared Absorption at λmax ∼1300†nm.

The preparation of radicals with intense and redox-switchable absorption beyond 1000 nm is a long-standing challenge in the chemistry of functional dyes. Here we report the preparation of a series of unprecedented stable neutral nickel(II) and copper(II) complexes of "Manitoba dipyrromethenes" (MB-DIPYs) in which the organic chromophore is present in the radical-anion state. The new stable radicals have an intense absorption at λmax ∼1300 nm and can be either oxidized to regular [MII (MB-DIPY)]+ (M=Cu or Ni) or reduced to [MII (MB-DIPY)]- compounds. The radical nature of the stable [MII (MB-DIPY)] complexes was confirmed by EPR spectroscopy with additional insight into their electronic structure obtained by UV-Vis spectroscopy, electro- and spectroelectrochemistry, magnetic measurements, and X-ray crystallography. The electronic structures and spectroscopic properties of the radical-based chromophores were also probed by density functional theory (DFT) and time-dependent DFT (TDDFT) calculations. These nickel(II) and copper(II) complexes represent the first stable radical compounds with a MB-DIPY ligand.

Stable M(II)-Radicals and Nickel(III) Complexes of a Bis(phenol) N-Heterocyclic Carbene Chelated to Group 10 Metal Ions.

The tetradentate ligand based on (1-imidazolium-3,5-di tert-butylphenol) units was prepared and chelated to group 10 metal ions (Ni(II), Pd(II), and Pt(II)), affording complexes 1, 2, and 3, respectively. The X-ray crystal structures of 1-3 show a square planar metal ion coordinated to two N-heterocyclic carbenes and two phenolate moieties. The cyclic voltammetry curves of complexes 1-3 show two reversible oxidation waves in the range 0.11-0.21 V ( E1/21) and 0.55-0.65 V ( E1/22) vs Fc+/Fc, which are assigned to the successive oxidations of the phenolate moieties. One-electron oxidation affords mononuclear ( S = 1/2) systems. Complex 1+·SbF6- was remarkably stable, and its structure was characterized. The coordination sphere is slightly dissymmetric, while the typical patterns of phenoxyl radicals were observed within the ligand framework. Complex 1+ exhibits a rhombic signal at g = 2.087, 2.016, and 1.992, confirming its predominant phenoxyl radical character. The g-values are slightly smaller for 2+ (2.021, 2.008, and 1.983) and larger for 3+ (2.140, 1.999, and 1.885) yet consistent with phenoxyl radical species. The electronic spectra of 1+-3+ display an intervalence charge-transfer (IVCT) transition at 2396, 2600, and 2294 nm, respectively. Its intensity supports the description of cations 1+ and 3+ as mixed-valent (Class II/III) compounds according to the Robin Day classification. Complex 2+ behaves as a mixed-valent class II radical compound. In the presence of pyridine, radical species 1+ is successively converted into stable mono and bis(adducts), which are both Ni(III) complexes. Dications 1+2-3+2 were prepared electrochemically. They are electron paramagnetic resonance (EPR)-silent and do not show IVCT transition in their NIR spectra, consistent with a bis(radical) formulation. The proposed electronic structures are fully supported by density functional theory calculations.

Copper(II) complexes of N3O tripodal ligands appended with pyrene and polyamine groups: Anti-proliferative and nuclease activities.

A series of tripodal ligands based on the 2-tert-butyl-4-R-6-phenol was synthesized, where R=aldehyde (HL1), R=putrescine-pyrene (HL2) and R=putrescine (HL3). A dinucleating ligand wherein a putrescine group connects two tripodal moieties was also prepared (H2L4). The corresponding copper complexes (1, 2, 3, and 4, respectively) were prepared and characterized. We determined the phenol's pKas in the range 2.47-3.93. The DNA binding constants were determined at 6×106, 5.5×105 and 2.7×106 for 2, 3 and 4, respectively. The complexes display a metal-centered reduction wave at Epc,red=-0.45 to -0.5V vs. saturated calomel electrode, as well as a ligand-centered oxidation wave above 0.57V at pH7. In the presence of ascorbate they promote an efficient cleavage of DNA, with for example a concentration required to cleave 50% of supercoiled DNA of 1.7µM for 2. The nuclease activity is affected by the nature of the R group: putrescine-pyrene≈bis-ligating>putrescine>aldehyde. The species responsible for strand scission is the hydroxyl radical. The cytotoxicity of the complexes was evaluated on bladder cancer cell lines sensitive or resistant to cis-platin. The IC50 of complexes 2 and 4 span over a short range (1.3-2µM) for the two cell lines. They are lower than those of the other complexes (3.1-9.7µM) and cis-platin. The most active compounds block the cell cycle at the G0/1 phase and promote apoptosis.

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 7.4×10(5) to 4×10(7) m(-1) for G4 -DNA models. Complex 4 exhibits an IC50 value of 70 nm for telomerase inhibition.

Geometric and Electronic Structures of Nickel(II) Complexes of Redox Noninnocent Tetradentate Phenylenediamine Ligands.

Five tetradentate ligands based on the N,N'-bis(2-amino-3,5-di-tert-butylphenyl)-o-phenylenediamine backbone were prepared, with different substituents at positions 4 and 5 (CH3 (3a), p-CH3O-C6H4 (3b), H (3c), Cl (3d), F (3e)). Their reaction with a nickel(II) salt in air affords the neutral species 4(a-e), which were isolated as single crystals. 4(a-e) feature two antiferromagnetically exchange-coupled diiminosemiquinonate moieties, both located on peripheral rings, and a diamidobenzene bridging unit. Oxidation of 4(a-e) with 1 equiv of AgSbF6 yields the cations 4(a-e)(+), which harbor a single diiminosemiquinonate radical. Significant structural differences were observed within the series. 4b(+) is mononuclear and contains a localized diiminosemiquinonate moiety. In contrast, 4c(+) is a dimer wherein the diiminosemiquinonate radical is rather delocalized over both peripheral rings. 4d(+) represents an intermediate case where the complex is mononuclear, but the radical is fully delocalized. Oxidation of 4(a-e) with 2 equiv of AgSbF6 produces the corresponding mononuclear dications. X-ray diffraction data on 4(b-d)(2+) reveals that the bridging ring retains its diamidobenzene character, whereas both peripheral rings have been oxidized into diiminobenzoquinone moieties. All the complexes were characterized by electrochemistry, EPR, and UV-vis-NIR spectroscopy. Remarkably, the electronic structures of the complexes differ from those reported by Wieghardt et al. for copper and zinc complexes of a related ligand involving a mixed N2O2 donor set (J. Am. Chem. Soc. 1999, 121, 9599). The easier oxidation of phenylenediamine moieties in comparison to aminophenols is proposed to account for the difference.

Nickel(ii) radical complexes of thiosemicarbazone ligands appended by salicylidene, aminophenol and aminothiophenol moieties.

The nickel(ii) complexes of three unsymmetrical thiosemicarbazone-based ligands featuring a sterically hindered salicylidene (1), aminophenol (2) or thiophenol (3) moiety were synthesized and structurally characterized. The metal ion lies in an almost square planar geometry in all the complexes. The cyclic voltammetry (CV) curve of 1 shows an irreversible oxidation wave at E = 0.49 V, which is assigned to the phenoxyl/phenolate redox couple. The CV curves of 2 and 3 display a reversible one-electron oxidation wave (E1/2 = 0.26 and 0.22 V vs. Fc(+)/Fc, respectively) and an one-electron reduction wave (E1/2 = -1.55 and -1.46 V, respectively). The cations 2(+) and 3(+) as well as the anions 2(-) and 3(-) were generated. The EPR spectra of the cations in THF show a rhombic signal at g1 = 2.034, g2 = 2.010 and g3 = 1.992 (2(+)) and g1 = 2.069, g2 = 2.018, g3 = 1.986 (3(+)) that is consistent with a main radical character of the complexes. The difference in anisotropy is assigned to the different nature of the radical, iminosemiquinonate vs. iminothiosemiquinonate. The anions display an isotropic EPR signal at giso = 2.003 (2(+)) and 2.006 (3(+)), which is indicative of a main α-diimine radical character of the compounds. Both the anions and cations exhibit charge transfer transitions of low to moderate intensity in their visible spectrum. Quantum chemical calculations (B3LYP) reproduce both the g-values and Vis-NIR spectra of the complexes. The radical anions readily react with dioxygen to give the radical cations. 2(+) catalyzes the aerobic oxidation of benzyl alcohol into benzaldehyde.

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.

Nuclease and anti-proliferative activities of copper(II) complexes of N3O tripodal ligands involving a sterically hindered phenolate.

Copper(II) complexes 1(2+)-6 of a series of tripodal ligands involving a N3O donor set, namely 2-[(bis-pyridin-2-ylmethyl-amino)-methyl]-4-methoxy-phenol (1L), 2-tert-butyl-4-methoxy-6-[bis-pyridin-2-ylmethyl-amino)-methyl]-phenol (2L), 2-tert-butyl-4-methoxy-6-{[(2-pyridin-2-yl-ethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (3L), 2-tert-butyl-4-methoxy-6-{[(6-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (4L), 2-tert-butyl-4-fluoro-6-{[(6-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (5L) and 2-tert-butyl-4-methoxy-6-{bis[(6-methyl-pyridin-2-ylmethyl)-amino]-methyl}-phenol (6L), respectively, were synthesized. Complexes 1(2+), 3(+) and 4(+) were structurally characterized by X-ray diffraction. The structure of 1(2+) is dimeric, with an essentially trigonal bipyramidal geometry around the copper(II) ions and two bridging deprotonated phenolate moieties. The mononuclear complexes 3(+) and 4(+) contain a square pyramidal copper ion, coordinated in axial position by the phenol moiety. In the water-DMF (90 : 10) mixture at pH 7.3 all the copper(II) complexes are mononuclear, mainly under their phenolate neutral form (except 3(+)), with a coordinated solvent molecule. The DNA cleavage activity of the complexes was tested towards the ϕX174 DNA plasmid. In the absence of an exogenous agent 1(2+) does not show any cleavage activity, 2(+) and 3(+) are moderately active, while 4(+), 5(+) and 6(+) exhibit a high nuclease activity. Experiments in the presence of various scavengers reveal that reactive oxygen species (ROS) are not involved in the strand scission mechanism. The cytotoxicity of the complexes was evaluated on bladder cancer cell lines sensitive or resistant to cisplatin. The IC50 values of the complexes 2(+), 4(+), 5(+) and 6(+) are lower than that of cisplatin (range from 6.3 to 3.1 µM against 9.1 µM for cisplatin). Furthermore, complexes 2(+), 4(+), 5(+) and 6(+) are able to circumvent cisplatin cellular resistance.

Reversible double oxidation and protonation of the non-innocent bridge in a nickel(II) salophen complex.

Substitution on the aromatic bridge of a nickel(II) salophen complex with electron-donating dimethylamino substituents creates a ligand with three stable, easily and reversibly accessible oxidation states. The one-electron-oxidized product is characterized as a nickel(II) radical complex with the radical bore by the central substituted aromatic ring, in contrast to other nickel(II) salen or salophen complexes that oxidize on the phenolate moieties. The doubly oxidized product, a singlet species, is best described as having an iminobenzoquinone bridge with a vinylogous distribution of bond lengths between the dimethylamino substituents. Protonation of the dimethylamino substituents inhibits these redox processes on the time scale of cyclovoltammetry, but electrolysis and chemical oxidation are consistent with deprotonation occurring concomitantly with electron transfer to yield the mono- and dioxidized species described above.

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.

One-electron oxidized nickel(II) complexes of bis and tetra(salicylidene) phenylenediamine Schiff bases: from monoradical to interacting Ni(III) ions.

The nickel(II) complexes of the mono and di-nucleating Schiff base ligands H(2)L(OMe), H(2)L(NO2) and H(4)L(bis) respectively were synthesized and characterized. H(2)L(OMe) and H(2)L(NO2) differ from one another by the substituents of the phenylene spacer, electron-donating methoxy or electron-withdrawing nitro groups respectively. X-Ray crystal structure analysis shows that the nickel(II) ion(s) resides within a square planar geometry in each complex. Cyclic voltammetry curves reveal that the electrochemical communication is strongly influenced by the substituent and the solvent. The one-electron oxidized species [Ni(L(OMe))](+) in CH(2)Cl(2) is a phenoxyl radical with partial delocalization of the spin density on a metal orbital (contribution of 6.8%), whereas [Ni(L(NO2))](+) was found to disproportionate once it is generated. A shift of electronic hole is observed in the presence of pyridine: both [Ni(L(OMe))](+) and the one-electron oxidation product of [Ni(L(NO2))] are converted into mononuclear octahedral nickel(III) complexes involving two axially bound pyridines. In the dinickel(II) complex of H(4)L(bis), namely [Ni(2)(L(bis))], the phenylene spacer mediates an electronic communication between the two metallic sites. Single oxidation of [Ni(2)(L(bis))] affords the delocalized phenoxyl radical [Ni(2)(L(bis))](+), whose EPR signature is close to that of [Ni(L(OMe))](+). Double oxidation affords the bis-{Ni(II)-delocalized radical} species [Ni(2)(L(bis))](2+). Each radical is located at a distinct metallic site and a weak but appreciable magnetic interaction exists between the paramagnetic centres. In the presence of pyridine, a complex involving two ferromagnetically coupled nickel(III) ions is obtained. The magnetic coupling has been estimated to 3.7 cm(-1), while the zero field splitting parameters are |D| = 0.012 cm(-1) and E = 0. They are weak, in agreement with the large intermetallic distance (7.7 A) observed in the neutral precursor [Ni(2)(L(bis))].

Valence tautomerism in octahedral and square-planar phenoxyl-nickel(II) complexes: are imino nitrogen atoms good friends?

The two tetradentate ligands H(2)L and H(2)L(Me) afford the slightly distorted square-planar low-spin Ni(II) complexes 1 and 2, which comprise two coordinated phenolate groups. Complex 1 has been electrochemically oxidized into 1(+), which contains a coordinated phenoxyl radical, with a contribution from the nickel orbital. In the presence of pyridine, 1(+) is converted into 1(Py) (+), an octahedral phenolate nickel(III) complex with two pyridines axially coordinated: An intramolecular electron transfer (valence tautomerism) is promoted by the geometrical changes, from square planar to octahedral, around the metal center. The tetradentate ligand H(2)L(Me), in the presence of pyridine, and the hexadentate ligand H(2)L(Py) in CH(2)Cl(2) afford, respectively, the octahedral high-spin Ni(II) complexes 2(Py) and 3, which involve two equatorial phenolates and two axially coordinated pyridines. At 100 K, the one-electron-oxidized product 2(Py) (+) comprises a phenoxyl radical ferromagnetically coupled to the high-spin Ni(II) ion, with large zero-field splitting parameters, while 3(+) involves a phenoxyl radical antiferromagnetically coupled to the high-spin Ni(II) ion.

Fine tuning of the oxidation locus, and electron transfer, in nickel complexes of pro-radical ligands.

A large number of complexes of the first-row transition metals with non-innocent ligands has been characterized in the last few years. The localization of the oxidation site in such complexes can lead to discrepancies when electrons can be removed either from the metal center (leading to an M((n+1)+) closed-shell ligand) or from the ligand (leading to an M(n+) open-shell ligand). The influence of the ligand field on the oxidation site in square-planar nickel complexes of redox-active ligands is explored herein. The tetradentate ligands employed herein incorporate two di-tert-butylphenolate (pro-phenoxyl) moieties and one orthophenylenediamine spacer. The links between the spacer and both phenolates are either two imines ([Ni(L1)]), two amidates ([Ni(L3)]2-), or one amidate and one imine ([Ni(L2)]-). The structure of each nickel(II) complex is presented. In the noncoordinating solvent CH2Cl2, the one-electron-oxidized forms are ligand-radical species with a contribution from a singly occupied d orbital of the nickel. In the presence of an exogenous ligand, such as pyridine, a Ni(III) closed-shell ligand form is favored: axial ligation, which stabilizes the trivalent nickel in its octahedral geometry, induces an electron transfer from the metal(II) center to the radical ligand. The affinity of pyridine for the phenoxylnickel(II) species is correlated to the N-donor ability of the linkers.

Hydrophilic and lipophilic iron chelators with the same complexing abilities.

A new series of iron chelators with the same coordination sphere as the water-soluble ligand O-trensox, but featuring a variable hydrophilic-lipophilic balance, have been obtained by grafting oxyethylene chains of variable length on a C-pivot tripodal scaffold. The X-ray structure of a ferric complex exhibiting tris(8-hydroxyquinolinate) coordination and solution thermodynamic properties (pK(a) of the ligands, stability constants of the ferric complexes) have been determined. The complexing ability (pFe(III) values) of the ligands are similar to that of O-trensox. Partition coefficients between water and octanol or chloroform have been measured and transport across a membrane has been mimicked ("shuttle process"). The results of biological assays (iron chelation with free ligands or iron nutrition with ferric complexes) could not be correlated with the partition coefficients. These results call into question the role of distribution coefficients (of the ligands and/or complexes) in the biological activities of iron chelators.

Sulfide oxidation by hydrogen peroxide catalyzed by iron complexes: two metal centers are better than one.

Peroxoiron species have been proposed to be involved in catalytic cycles of iron-dependent oxygenases and in some cases as the active intermediates during oxygen-transfer reactions. The catalytic properties of a mononuclear iron complex, [Fe(II)(pb)(2)(CH(3)CN)(2)] (pb=(-)4,5-pinene-2,2'-bipyridine), have been compared to those of its related dinuclear analogue. Each system generates specific peroxo adducts, which are responsible for the oxidation of sulfides to sulfoxides. The dinuclear catalyst was found to be more reactive and (enantio)selective than its mononuclear counterpart, suggesting that a second metal site affords specific advantages for stereoselective catalysis. These results might help for the design of future enantioselective iron catalysts.