Diruthenium Complexes Research Articles

Steric hindrance and charge influence on the cytotoxic activity and protein binding properties of diruthenium complexes

Paddlewheel diruthenium complexes are being used as metal-based drugs. It has been proposed that their charge and steric properties determine their selectivity towards proteins. Here, we explore these parameters using the first water-soluble diruthenium complex bearing two formamidinate ligands, [Ru2Cl(DPhF)2(O2CCH3)2], and two derivatives, [Ru2Cl(DPhF)(O2CCH3)3] and K2[Ru2(DPhF)(CO3)3] (DPhF− = N,N′-diphenylformamidinate), with one formamidinate. Their protein binding properties have been assessed employing hen egg white lysozyme (HEWL). The results confirm the relationship between the type of interaction (coordinate/non-coordinate bonds) and the charge of diruthenium complexes. The crystallization medium is also a key factor. In all cases, diruthenium species maintain the M–M bond and produce stable adducts. The antiproliferative properties of these diruthenium complexes have been evaluated on an eukaryotic cell-based model. Our data show a correlation between the number of the formamidinate ligands and the anticancer activity of the diruthenium derivatives against human epithelial carcinoma cells. Increased cytotoxicity may be related to increased steric hindrance and Ru25+ core electronic density. However, the effect of increasing the lipophilicity of diruthenium species by introducing a second N,N′-diphenylformamidinate must be also considered. This work illustrates a systematic approach to shed light on the relevant properties of diruthenium compounds to design metal-based metallodrugs and diruthenium metalloenzymes.

Diruthenium Catalyst for Hydrogen Production from Aqueous Formic Acid

Diruthenium complexes [{(η6-arene)RuCl}2(μ-κ2:κ2-benztetraimd)]2+ containing the bridging bis-imidazole methane-based ligand {1,4-bis(bis(2-ethyl-5-methyl-1H-imidazol-4-yl)methyl)benzene} (benztetraimd) are synthesized for catalytic formic acid dehydrogenation in water at 90 °C. Catalyst [{(η6-p-cymene)RuCl}2(μ-κ2:κ2-benztetraimd)]2+ [1-Cl2] exhibited a remarkably high turnover frequency (1993 h-1 per Ru atom) and long-term stability over 60 days for formic acid dehydrogenation, while the analogous (η6-benzene)diruthenium and mononuclear catalysts displayed low activity with poor long-term stability. Notably, catalyst [1-Cl2] also displayed an appreciably high turnover number of 93 200 for the bulk-scale reaction. In addition, the in-depth mass and nuclear magnetic resonance investigations under the catalytic and control experimental conditions revealed the active involvement of several crucial catalytic intermediate species, such as Ru-aqua species [{(η6-p-cymene)Ru(H2O)}2(μ-L)]2+ [1-(OH2)2], Ru-formato species [{(η6-p-cymene)Ru(HCOO)}2(μ-L)] [1-(HCOO)2], and Ru-hydrido species [{(η6-p-cymene)Ru(H)}2(μ-L)] [1-(H)2], in the catalytic formic acid dehydrogenation reaction.

Catalytic Enantioselective Amination of Enol Silyl Ethers Using a Chiral Paddle-Wheel Diruthenium Complex

A chiral paddle-wheel dinuclear ruthenium catalyst was applied to a catalytic asymmetric nitrene-transfer reaction with enol silyl ethers. The ruthenium catalyst was applicable to aliphatic enol silyl ethers as well as aryl-containing enol silyl ethers. The substrate scope of the ruthenium catalyst was superior to that of analogous chiral paddle-wheel rhodium catalysts. α-Amino ketones derived from aliphatic substrates were obtained in up to 97% ee with the ruthenium catalyst, while analogous rhodium catalysts resulted in only moderate enantioselectivity.

Synthesis and catalysis of diruthenium hydride complexes with bidentate dimethylsulfoxide ligand

A new, simple and controllable synthetic route is established to one-step synthesize diruthenium complexes with μ -H, μ -Cl halogen and μ -S,O-dmso bridges, namely (Bu4N)[Ru2(μ -H)(μ -X)(μ -S,O-dmso)(S-dmso)3(Cl)3] (Bu4N·1, where dmso = dimethyl sulfoxide) in one step. This complex is obtained by treating [Ru(dmso)4Cl2] with Bu4NCl in presence of excess Et3N in refluxing methanol. Advantages over prior routes to these analogous complexes lie in one-step controllable synthesis, and the short reaction times under experimentally convenient conditions. The properties of Bu4N·1 in solution and in solid-state are investigated. In addition, the catalytic performance of Bu4N·1 for CO2 + H2 / HCOO– interconversion in aqueous solution is also described.

1,4-Divinylphenylene-bridged diruthenium complexes with 2-hydroxypyridine- and 2- or 8-hydroxyquinoline-olate ligands

Abstract Four divinylphenylene-bridged diruthenium complexes [{Ru(CO)(P i Pr3)2(L-κ 2 [N,O] – )}2(μ-CH=CH-C6H4-CH=CH-1,4)] (2a–2d) with N,O-chelating 2-hydroxypyridine and 2-hydroxy- or 8-hydroxyquinoline ligands are presented. They were studied by NMR spectroscopy, electrochemical methods and, in their neutral and oxidized states, by IR, UV/Vis/NIR and, if applicable, by EPR spectroscopy. The experimental studies are complimented by (TD-)DFT calculations. Our results indicate that the pyridine-olate complexes 2a,b exist as three isomers with a ratio of about 78:20:2 that differ with respect to the orientation of the N and O donors relative to the CO and alkenyl ligands in the equatorial coordination plane. Only the isomer with both imine N donors trans to the alkenyl ligand is observed for complexes 2c,d with quinolinato ligands. All complexes undergo two consecutive, chemically and electrochemically reversible one-electron oxidations at low potentials. Our results indicate strong contributions of the divinylphenylene bridge to the redox processes and an even delocalization of the electron hole and the unpaired spin density over the entire π-conjugated divinylphenylene diruthenium backbone with only minor involvement of the peripherally attached κ 2 [N,O] – donor ligands.

Trithiolato-bridged dinuclear ruthenium(II)-arene conjugates tethered with lipophilic units: Synthesis and Toxoplasma gondii antiparasitic activity

Trithiolato-bridged dinuclear ruthenium(II)-arene complexes are active against various parasites including Toxoplasma gondii. Lipids, isoprenoids and lipoate are metabolites scavenged by T. gondii from the host cell but also synthesized by the parasite, and these molecules can be appended to the diruthenium moiety in a conjugate approach aiming at compounds with improved antiparasitic activity and selectivity. The synthesis and in vitro T. gondii activity evaluation of 23 new trithiolato diruthenium complexes bearing various lipophilic units are reported. The influence of several structural elements as the nature of the lipophilic pendant and the type of the connecting bond between the two units on the conjugates’ biological properties were examined. In a primary screening, the antiparasitic efficacy and cytotoxicity were assessed at 0.1 and 1 µM against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase and on human foreskin fibroblasts (HFF) host cells. For 14 selected conjugates the half-maximal inhibitory concentration (IC50) on T. gondii and their effect on HFF viability at 2.5 µM were determined. The decanoic, oleic and elaidic ester conjugates 13a, 16a and 17a efficiently inhibited parasite proliferation (IC50 values of 0.065, 0.127 and 0.123 µM, respectively) with no effect on HFF viability at 2.5 µM and deserve further attention.

Synthesis and Antiparasitic Activity of New Trithiolato-Bridged Dinuclear Ruthenium(II)-arene-carbohydrate Conjugates.

Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC ‘click’ (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions, and there in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) and in non-infected human foreskin fibroblasts, HFF, was determined at 0.1 and 1 µM. When evaluated at 1 µM, seven diruthenium-carbohydrate conjugates strongly impaired parasite proliferation by >90%, while HFF viability was retained at 50% or more, and they were further subjected to the half-maximal inhibitory concentration (IC50) measurement on T. gondii β-gal. Results revealed that the biological activity of the hybrids was influenced both by the nature of the carbohydrate (glucose vs. galactose) appended on ruthenium complex and the type/length of the linker between the two units. 23 and 26, two galactose-based diruthenium conjugates, exhibited low IC50 values and reduced effect on HFF viability when applied at 2.5 µM (23: IC50 = 0.032 µM/HFF viability 92% and 26: IC50 = 0.153 µM/HFF viability 97%). Remarkably, compounds 23 and 26 performed significantly better than the corresponding carbohydrate non-modified diruthenium complexes, showing that this type of conjugates are a promising approach for obtaining new antiparasitic compounds with reduced toxicity.

Effect of Equatorial Ligand Substitution on the Reactivity with Proteins of Paddlewheel Diruthenium Complexes: Structural Studies

The paddlewheel [Ru2Cl(O2CCH3)4] complex was previously reported to react with the model protein hen egg white lysozyme (HEWL), forming adducts with two diruthenium moieties bound to Asp101 and Asp119 side chains upon the release of one acetate. To study the effect of the equatorial ligands on the reactivity with proteins of diruthenium compounds, X-ray structures of the adducts formed when HEWL reacts with [Ru2Cl(D-p-FPhF)(O2CCH3)3] [D-p-FPhF = N,N'-bis(4-fluorophenyl)formamidinate] under different conditions were solved. [Ru2Cl(D-p-FPhF)(O2CCH3)3] is bonded through their equatorial positions to the Asp side chains. Protein binding occurs cis or trans to D-p-FPhF. Lys or Arg side chains or even main-chain carbonyl groups can coordinate to the diruthenium core at the axial site. Data help to understand the reactivity of paddlewheel diruthenium complexes with proteins, providing useful information for the design of new artificial diruthenium-containing metalloenzymes with potential applications in the fields of catalysis, biomedicine, and biotechnology.

Diruthenium complexes as pH-responsive delivery systems: a quantitative assessment

The study of the release of carboxylate ligands from diruthenium compounds is crucial for designing drug delivery systems based on such complexes. The influence of different key parameters on the release process was evaluated throughin vivoassays.

Charge effect in protein metalation reactions by diruthenium complexes

A study of the protein binding properties of diruthenium compounds depending on the charge of the complexes generated in solution.

Di-ruthenium complexes of 1,4-diazabutadiene ligands: synthesis, characterization and utilization as catalyst precursors for the oxidative coupling of amines to imines in air

A group of tri-chloro bridged di-ruthenium(ii) complexes, bearing chelated 1,4-diazabutadienes, served as efficient catalyst-precursors for the oxidative and deaminative C–N coupling of primary amines to imines using aerial oxygen as the oxidant.

Synthesis, Photophysical Properties and Biological Evaluation of New Conjugates BODIPY: Dinuclear Trithiolato-Bridged Ruthenium(II)-Arene Complexes.

The synthesis, photophysical properties and antiparasitic efficacy against Toxoplasma gondii β-gal (RH strain tachyzoites expressing β-galactosidase) grown in human foreskin fibroblast monolayers (HFF) of a series of 15 new conjugates BODIPY-trithiolato-bridged dinuclear ruthenium(II)-arene complexes are reported (BODIPY=4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, derivatives used as fluorescent markers). The influence of the bond type (amide vs. ester), as well as that of the length and nature (alkyl vs. aryl) of the spacer between the dye and the diruthenium(II) complex moiety, on fluorescence and biological activity were evaluated. The assessed photophysical properties revealed that despite an important fluorescence quenching effect observed after conjugating the BODIPY to the diruthenium unit, the hybrids could nevertheless be used as fluorescent tracers. Although the antiparasitic activity of this series of conjugates appears limited, the compounds demonstrate potential as fluorescent probes for investigating the intracellular trafficking of trithiolato-bridged dinuclear Ru(II)-arene complexes in vitro.

Catalytic N-H Bond Formation Promoted by a Ruthenium Hydride Complex Bearing a Redox-Active Pyrimidine-Imine Ligand.

The synthesis of a piano-stool ruthenium hydride, [(η5-C5Me5)Ru(PmIm)H] (PmIm = (N-(1,3,5-trimethylphenyl)-1-(pyrimidin-2-yl)ethan-1-imine), for the dual purpose of catalytic dihydrogen activation and subsequent hydrogen atom transfer for the formation of weak chemical bonds is described. The introduction of a neutral, potentially redox-active PmIm supporting ligand was designed to eliminate the possibility of deleterious C(sp2)-H reductive coupling and elimination that has been identified as a deactivation pathway with related rhodium and iridium catalysts. Treatment of [(η5-C5Me5)RuCl2]n with one equivalent PmIm ligand in the presence of zinc and sodium methoxide resulted in the isolation of the diruthenium complex, [(η5-C5Me5)Ru(PmIm)]2, arising from the C-C bond formation between two PmIm chelates. Addition of H2 to the ruthenium dimer under both thermal and blue light irradiation conditions furnished the targeted hydride, [(η5-C5Me5)Ru(PmIm)H], which has a relatively weak DFT-calculated Ru-H bond dissociation free energy (BDFE) of 47.9 kcal/mol. Addition of TEMPO to [(η5-C5Me5)Ru(PmIm)H] generated the 17-electron metalloradical, [(η5-C5Me5)Ru(PmIm)], which was characterized by EPR spectroscopy. The C-C bond forming process was reversible as the irradiation of [(η5-C5Me5)Ru(PmIm)]2 generated [(η5-C5Me5)Ru(PmIm)H] and a piano-stool ruthenium complex containing an enamide ligand derived from H-atom abstraction from the PmIm chelate. Equilibration studies were used to establish an experimental estimate of the effective Ru-H BDFE, and a value of 50.8 kcal/mol was obtained, in agreement with the observed loss of H2 and the DFT-computed value. The ruthenium hydride was an effective catalyst for the thermal catalytic hydrogenation of TEMPO, acridine, and a cobalt-imido complex and for the selective reduction of azobenzene to diphenylhydrazine, highlighting the role of this complex in catalytic weak bond formation using H2 as the stoichiometric reductant.

Effect of Propargylic Substituents on Enantioselectivity and Reactivity in Ruthenium-Catalyzed Propargylic Substitution Reactions: A DFT Study.

We recently proposed a transition-state model for asymmetric propargylic substitution reactions of propargylic alcohols catalyzed by optically active thiolate-bridged diruthenium complexes [Chem. – Asian J.2021, 16, 3760−376634549529]. In the present study, we further examined the effects of propargylic substituents on both enantioselectivity and reactivity in the propargylic substitution reactions via ωB97X-D-level density functional theory (DFT) calculations. When the propargylic alcohol bears a methyl group at the propargylic position, we obtained results that contrast with the result of our previous study on propargylic alcohols without methyl groups. This result indicates that methyl group substitution at the propargylic position reverses the stereoselectivity. Substitution of a trifluoromethyl group for a methyl group was suggested to result in higher enantioselectivity. The obtained results are consistent with the experimental study on enantioselective propargylic phosphinylation reactions reported by our group.

Indazole-Derived Mono-/Diruthenium and Heterotrinuclear Complexes: Switchable Binding Mode, Electronic Form, and Anion Sensing Events.

The article deals with the newer classes of mononuclear: [(acac)2RuIII(H-Iz)(Iz-)] 1, [(acac)2RuIII(H-Iz)2]ClO4 [1]ClO4/[1']ClO4, and [(bpy)2RuII(H-Iz)(Iz-)]ClO4 [2]ClO4, mixed-valent unsymmetric dinuclear: [(acac)2RuIII(μ-Iz-)2RuII(bpy)2]ClO4 [3]ClO4, and heterotrinuclear: [(acac)2RuIII(μ-Iz-)2MII(μ-Iz-)2RuIII(acac)2] (M = Co:4a, Ni:4b, Cu:4c, and Zn:4d) complexes (H-Iz = indazole, Iz- = indazolate, acac = acetylacetonate, and bpy = 2,2'-bipyridine). Structural characterization of all the aforestated complexes established their molecular identities including varying binding modes (Na and Nb donors and 1H-indazole versus 2H-indazole) of the heterocyclic H-Iz/Iz- in the complexes. Unlike [1']ClO4 containing two NH protons at the backface of H-Iz units, the corresponding [1]ClO4 was found to be unstable due to the deprotonation of its positively charged quaternary nitrogen center, and this resulted in the eventual formation of the parent complex 1. A combination of experimental and density functional theory calculations indicated the redox noninnocent feature of Iz- in the complexes along the redox chain. The absence of intervalence charge transfer transition in the near-infrared region of the (Iz-)2-bridged unsymmetric mixed-valent RuIIIRuII state in [3]ClO4 suggested negligible intramolecular electronic coupling corresponding to a class I setup (Robin and Day classification). Heterotrinuclear complexes (4a-4d) exhibited varying spin configurations due to spin-spin interactions between the terminal Ru(III) ions and the central M(II) ion. Though both [3]ClO4 and 4a-4d displayed ligand (Iz-/Iz•)-based oxidation, reductions were preferentially taken place at the bpy and metal (RuIII/RuII) centers, respectively. Unlike 1 or [2]ClO4 containing one free NH proton at the backface of H-Iz, [1']ClO4 with two H-Iz units could selectively and effectively recognize F-, OAc-, and CN- among the tested anions: F-, OAc-, CN-, Cl-, Br-, I-, SCN-, HSO4-, and Η2PΟ4- in CH3CN via intermolecular NH···anion hydrogen bonding interaction. The difference in the sensing feature between [1']ClO4 and 1/[2]ClO4 could be rationalized by their pKa values of 8.4 and 11.3/10.8, respectively.

Binuclear metal ruthenium complexes bridged by isomeric bis(ethynyl)pyridine: Syntheses, characterization and electronic coupling properties

Isomeric diruthenium complexes with bis(ethynyl)pyridine as bridge core [2,6-bis(ethynyl)pyridine (1), 3,5-bis(ethynyl)pyridine (2), 2,5-bis(ethynyl)pyridine (3)] were successfully prepared and characterized by 1H NMR, 13C NMR and elemental analysis. The electrochemical properties of complexes 1–3 were investigated by cyclic voltammetry (CV) and square-wave voltammetry (SWV), and different potential difference values were revealed and affected by N atom position and distance between redox metal centers. Electron absorption spectra showed that the absorption of the linear molecule 3 displayed a red shift relative to that of complexes 1 and 2. The broad near-infrared absorption characteristic of the singly-oxidized complex 3+ revealed the existence of a mixed-valence state, which can be classified as a class II mixed-valence system according to the intervalence charge transfer (IVCT) absorption parameter Hab and Г. These results indicated that 3 has higher conjugation and charge delocalization ability than isomers 1 and 2. Density functional theory (DFT) calculations spin density distribution analysis further confirmed the above results, and time-dependent DFT showed the NIR multi-absorption of complex 3+, and effectively attributed to Ru–CC→Ru IVCT absorption characteristics.

Considerations on Gated CO2 Adsorption Behavior in One-Dimensional Porous Coordination Polymers Based on Paddlewheel-Type Dimetal Complexes: What Determines Gate-Opening Temperatures?

Low-dimensional coordination polymers such as one-dimensional chains often exhibit gated guest sorption accompanying structural transition at a temperature (TG), which is associated with an external pressure of the guest (PG) characteristic to the material and guest used. This phenomenon can be evaluated using the Clausius-Clapeyron relationship with the equation d(ln PG)/d(1/TG) = ΔHG/R, where ΔHG and R are the transition enthalpy and gas constant, respectively. In this study, gated CO2 adsorption behavior was investigated in a one-dimensional chain based on a benzoate-bridged paddlewheel diruthenium(II,II) complex with a phenazine (phz) linker, [Ru2(p-MeOPhCO2)4(phz)] (1; p-MeOPhCO2- = p-anisate). Surprisingly, 1 underwent gate opening (GO)/closing (GC) at a much higher TG, e.g., 385 K for GC, under PCO2 = 100 kPa than those previously reported for such chain compounds, which usually appeared in the temperature range of 200-270 K. The transition entropy ΔSG in each system plays a key role in shifting TG; 1 results in a much smaller |ΔSG| in the series. Only 1 produced a CO2-accessible two-dimensional topological pore in its CO2-adsorbed phase 1⊃CO2, whereas the others reported previously produced one-dimensional or discrete topological pores for CO2 accommodation, strongly reflecting the degree of freedom of CO2 molecules in pores, which is related to ΔSG.

Mixed Valency vs Radical Bridge Formulation in Symmetrically and Asymmetrically Ligated Diruthenium Complexes

Abstract: The asymmetrical dinuclear [{(trpy*)Ru} 2 (µ-adc-Salph)Cl](PF 6 ) 1 (PF 6 ), trpy* = 4,4’,4”-tri- tert -butyl-2,6,2’,6”-terpyridine, adc-Salph = 1-benzoyl-2-salicyloylhydrazido(3-), and the related symmetrical dinuclear [{Cl(trpy*)Ru} 2 (µ,η 2 :η 2 -adc-Ph)](PF 6 ) 2 (PF 6 ), adc-Ph = 1,2-bis(benzoyl)hydrazido(2-), were synthesized and structurally characterized. Both paramagnetic compounds were compared with the previously reported symmetrical [{(trpy*)Ru} 2 (µ,η 3 :η 3 -adc-Sal)](PF 6 ) 3 (PF 6 ) containing the bis-tridentate bridge 1,2-bis(salicyloyl)hydrazido(4-). Molecular structures and magnetic resonance features ( 1 H NMR, EPR) indicate spin density distribution over the metal(s) and the bridging ligand. Reversible one-electron reduction and oxidation were possible in all instances yielding comproportionation constants K c of about 10 9 for the paramagnetic intermediates 1 + - 3 + . Structural results, spin density distribution and UV-Vis-NIR spectroelectrochemistry were analyzed for 1 + with the help of TD-DFT calculations for a model compound ( tert -Bu→Me). Intense absorptions around λ max = 1450-1650 nm for the cations were assigned to mixed metal/ligand transitions with significant inter-valence charge transfer (IVCT) character. For both the symmetrical and asymmetrical arrangements the cationic intermediates can be described as considerably mixed metal/ligand systems.

Synthesis of Triple‐Stranded Diruthenium(II) Compounds

AbstractA series of ligands containing a 1,4‐disubstituted 1,2,3‐triazole unit have been used for the formation of triple‐stranded dinuclear Ru(II) complexes. In contrast to the previously reported complexes of labile metals, the use of inert Ru(II) enabled stereoisomeric mixtures of triple‐stranded diruthenium(II) complexes to be accessed. The chromatographic resolution of the enantiomers of a reported helicate containing a more rigid 1,4‐xylyl spacer was carried out on cellulose. The ligand spacer was modified and as the flexibility increased the production of isomeric mixtures was detected; the mesocate and helicate forms were separated when an n‐propyl spacer was used. This pair of diastereomers was found to exhibit photoconversion, a unique observation for Ru(II) compounds of this type. Partial separation via chromatographic resolution was achieved for compounds containing an n‐butyl spacer, and the presence of a mesocate/helicate pair confirmed.

High Stabilization of Low Valency in a Homoleptic ortho-Hydroxybenzoate-bridged Paddlewheel Diruthenium(II,II) Complex

Abstract A paddlewheel-type homoleptic diruthenium(II,II) complex ([Ru2II,II]), [Ru2(o-OHPhCO2)4(THF)2] (o-OH), bridged by ortho-hydroxybenzoate (o-OHPhCO2−) and tetrahydrofuran (THF) coordinated at the axial position (Lax) was isolated. The use of meta- and para-substituted hydroxybenzoate (x-OHPhCO2−; x = m and p) produced the corresponding [Ru2II,III] species neutralized by deprotonation of one of the x-OHPhCO2− ligands. In the o-OH complex, the formation of intramolecular hydrogen bonds between the o-OH group and carboxylate oxygen atom stabilized the [Ru2II,II] species significantly.