Ruthenium N-heterocyclic Carbene Complexes Research Articles

Diastereoselective Synthesis of Sulfoxide-Functionalized N-Heterocyclic Carbene Ruthenium Complexes: An Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. Using these salts, a series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of complexes 4 b, 4 c, 4dBArF and 4 e unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomer. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the β-alkylation of secondary alcohols. Complex 4dPF6 bearing an NHC-functionalised S-Ad group has been further studied with different primary and secondary alcohols as substrates, showing high reactivity and high to moderate β-ol-selectivities.

Novel ruthenium(ii) N-heterocyclic carbene complexes: Synthesis, characterization, and evaluation of their biological activities

Abstract A series of ruthenium(ii) complexes with N-heterocyclic carbene (NHC) ligands of the general type (arene)(NHC)Ru(ii)X2 (where X = halide) (3a–3d) were synthesized and characterized in order to compare their antibacterial activities with benzimidazolium salts 2. Our comparison revealed that ruthenium(ii) NHC complexes 3 were more active than benzimidazolium salts 2. Furthermore, the two complexes 3b and 3d had a potent inhibitory effect against acetylcholinesterase with an IC50 of 4.52 and 4.04 g·mL−1 and against tyrosinase with an IC50 of 20.77 and 25.84 g·mL−1, respectively. In addition, screening of benzimidazolium salts (2a–2d) and their ruthenium(ii) complexes (3a–3d) against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2) were studied. The obtained results revealed that complex 3a is the most active against vinblastines.

Ru-NHC-Catalyzed Asymmetric, Complete Hydrogenation of Indoles and Benzofurans: One Catalyst with Dual Function.

The highly enantioselective and complete hydrogenation of protected indoles and benzofurans has been developed, affording facile access to a range of chiral three-dimensional octahydroindoles and octahydrobenzofurans, which are prevalent in many bioactive molecules and organocatalysts. Remarkably, we are in control of the nature of the ruthenium N-heterocyclic carbene complex and employed the complex as both homogeneous and heterogeneous catalysts, providing new avenues for its potential applications in the asymmetric hydrogenation of more challenging aromatic compounds.

Synthesis of Novel N-Heterocyclic Carbene-Ruthenium (II) Complexes, "Precious" Tools with Antibacterial, Anticancer and Antioxidant Properties.

Ruthenium N-heterocyclic carbene (Ru-NHC) complexes show interesting physico-chemical properties as catalysts and potential in medicinal chemistry, exhibiting multiple biological activities, among them anticancer, antimicrobial, antioxidant, and anti-inflammatory. Herein, we designed and synthesized a new series of Ru-NHC complexes and evaluated their biological activities as anticancer, antibacterial, and antioxidant agents. Among the newly synthesized complexes, RANHC-V and RANHC-VI are the most active against triple-negative human breast cancer cell lines MDA-MB-231. These compounds were selective in vitro inhibitors of the human topoisomerase I activity and triggered cell death by apoptosis. Furthermore, the Ru-NHC complexes' antimicrobial activity was studied against Gram-positive and -negative bacteria, revealing that all the complexes possessed the best antibacterial activity against the Gram-positive Staphylococcus aureus, at a concentration of 25 µg/mL. Finally, the antioxidant effect was assessed by DPPH and ABTS radicals scavenging assays, resulting in a higher ability for inhibiting the ABTS•+, with respect to the well-known antioxidant Trolox. Thus, this work provides encouraging insights for further development of novel Ru-NHC complexes as potent chemotherapeutic agents endowed with multiple biological properties.

Biological Activities of Ruthenium NHC Complexes: An Update

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds.

Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Enzymatic Inhibitory Agents with Antioxidant, Antimicrobial, Antiparasitical and Antiproliferative Activity.

A series of [RuCl2(p-cymene)(NHC)] complexes were obtained by reacting [RuCl2(p-cymene)]2 with in situ generated Ag-N-heterocyclic carbene (NHC) complexes. The structure of the obtained complexes was determined by the appropriate spectroscopy and elemental analysis. In addition, we evaluated the biological activities of these compounds as antienzymatic, antioxidant, antibacterial, anticancer, and antiparasitic agents. The results revealed that complexes 3b and 3d were the most potent inhibitors against AchE with IC50 values of 2.52 and 5.06 μM mL-1. Additionally, 3d proved very good antimicrobial activity against all examined microorganisms with IZ (inhibition zone) over 25 mm and MIC (minimum inhibitory concentration) < 4 µM. Additionally, the ligand 2a and its corresponding ruthenium (II) complex 3a had good cytotoxic activity against both cancer cells HCT-116 and HepG-2, with IC50 values of (7.76 and 11.76) and (4.12 and 9.21) μM mL-1, respectively. Evaluation of the antiparasitic activity of these complexes against Leishmania major promastigotes and Toxoplasma gondii showed that ruthenium complexes were more potent than the free ligand, with an IC50 values less than 1.5 μM mL-1. However, 3d was found the best one with SI (selectivity index) values greater than 5 so it seems to be the best candidate for antileishmanial drug discovery program, and much future research are recommended for mode of action and in vivo evaluation. In general, Ru-NHC complexes are the most effective against L. major promastigotes.

Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Antibacterial Agents and Inhibitors of Bacterial Thioredoxin Reductase.

A series of ruthenium(II) complexes with N-heterocyclic carbene (NHC) ligands of the general type (arene)(NHC)Ru(II)X2 (where X = halide) was prepared, characterized, and evaluated as antibacterial agents in comparison to the respective metal free benzimidazolium cations. The ruthenium(II) NHC complexes generally triggered stronger bacterial growth inhibition than the metal free benzimidazolium cations. The effects were much stronger against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) than against Gram-negative bacteria (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa), and all complexes were inactive against the fungus Candida albicans. Moderate inhibition of bacterial thioredoxin reductase was confirmed for selected complexes, indicating that inhibition of this enzyme might be a contributing factor to the antibacterial effects.

Highly Efficient Ethenolysis and Propenolysis of Methyl Oleate Catalyzed by Abnormal N-Heterocyclic Carbene Ruthenium Complexes in Combination with a Phosphine–Copper Cocatalyst

Fluorinated imidazo[1,5-a]pyridine abnormal carbene ruthenium complexes (F-aImPy–Ru) with a tricyclohexylphosphine copper chloride (Cy3P–CuCl) cocatalyst were developed for the ethenolysis/propenolysis of methyl oleate. These catalysts showed remarkable catalytic efficiencies (turnover numbers of 100,000 for ethenolysis and 200,000 for propenolysis) and excellent α-olefin selectivity (up to 99%). A computational study indicated that the energy barrier of the β-hydride elimination pathway in the presence of a phosphine–copper cocatalyst is higher than that in the absence of the cocatalyst, which might contribute to the improved longevity of the ruthenium catalyst in the reaction.

Synthesis and Reactivity of Poly(propyleneimine) Dendrimers Functionalized with Cyclopentadienone N-Heterocyclic-Carbene Ruthenium(0) Complexes

Ligand design in metal chemistry is a fundamental step when pursuing compounds with specific reactivity. In this paper, the functionalization of the OH group in the lateral chain of the N-heterocyclic-carbene (NHC) ligand bound to a bis-carbonyl cyclopentadienone NHC ruthenium(0) complex allowed the decoration of five generations of poly(propyleneimine) (PPIs) dendrimers with up to 64 organometallic moieties. The coupling was achieved by employing carbonyldiimidazole and the formation of carbamate linkages between dendritic peripheral NH2 and lateral OH groups on ruthenium complexes. The synthetic procedure, chemical purification, and spectroscopic characterization of the five generations of dendrimers (3g1–5) are here described. The ruthenium-modified dendrimers were activated as catalysts in the transfer hydrogenation of the model compound 4-fluoroacetophenone in the presence of cerium ammonium nitrate as their mononuclear congeners. The catalytic activity, being similar for the five generations, shows a decrease if compared to mononuclear complexes. This detrimental effect might be ascribed to the –CH2NH– functionalization, largely present in dendrimer skeleton and that can compete with the hydrogen transfer mechanism, but also partially to a dendritic effect caused by steric encumbrance.

Rhodium(I) and Iridium(I) N-Heterocyclic carbene complexes of imidazolium functionalized amino acids and peptides

The conjugation of organometallic complexes to peptides is generally achieved through covalent organic linkages of the metal’s ligand to the peptide. Examples of direct coordination to metal centers by amino acid side chain residues remain rare. In one such example, side chain methylation of the natural amino acid histidine (His) resulted in an imidazolium functionalized amino acid which was used for the synthesis of rhodium(I), iridium(I), iridium(III), palladium(II) and ruthenium(III) N-heterocyclic carbene (NHC) complexes of the single amino acid and peptides containing this amino acid. Here, we have synthesized two new, non-natural imidazolium functionalized amino acid derivatives, which were used for solid phase peptide synthesis and for the synthesis of [M(COD)(NHC)Cl] (COD = 1,5 cyclooctadiene) complexes of Rh(I) and Ir(I). In total, six new complexes of the single amino acids and four complexes where the amino acids are present in a peptide environment were synthesized. Their characterization provides convincing evidence of conversion of the imidazolium moiety to an NHC ligand and thus the presence of a direct metal-carbon bond between the metal center and the amino acid side chain. Therefore, our compounds represent unique examples of peptide-conjugated complexes that bear the potential to be used for the synthesis of N-heterocyclic carbene complexes conjugated to cancer cell targeting peptides.

Polymer supported N-heterocyclic carbene ruthenium complex catalyzed transfer hydrogenation of ketones

Polymer supported N-heterocyclic carbene ruthenium complex (Poly-Ru-1) was synthesized by free radical polymerization of Ru complex monomer and divinylbenzene. The structure of Poly-Ru-1 was characterized by 13C solid-state NMR spectroscopy, N2 adsorption-desorption, X-ray photoelectron spectroscopy (XPS). 13C solid-state NMR spectra indicated the complete polymerization of Ru complex monomer. Poly-Ru-1 had the high specific surface area of 286.7 m2 g−1 and ruthenium was in +2 oxidation state. Poly-Ru-1 showed higher catalytic activity than the corresponding homogenous catalyst in transfer hydrogenation of ketones, which was attributed to the high dispersion of the active sites.

Synthesis, characterization, biological determination and catalytic evaluation of ruthenium(ii) complexes bearing benzimidazole-based NHC ligands in transfer hydrogenation catalysis

A new series of ruthenium (ii) N-heterocyclic carbene complexes has been synthesized via transmetalation. The obtained complexes were applied to transfer hydrogenation of ketone derivatives.

Transformations of biomass-based levulinate ester into γ-valerolactone and pyrrolidones using carbon nanotubes-grafted N-heterocyclic carbene ruthenium complexes

Abstract As a renewable biomass-based compound with wide applications in food additives, fine chemical synthesis and fuels, γ-valerolactone (GVL) has attached much attention. While, pyrrolidones are widely used in pharmaceutical, agrochemical, material industrial and other chemical production. In this research, we demonstrated transformations of biomass-based ethyl levulinate (EL) into GVL and pyrrolidones by using heterogeneous catalysts (CNT-Ru-1) with N-heterocyclic carbene ruthenium (NHC-Ru) complex grafted on multi-walled carbon nanotube (CNT). The Ru catalyst showed high efficiency on EL hydrogenation to GVL with both EL conversion and GVL yield exceeding 99%. Moreover, the Ru catalyst readily promoted reductive amination of EL in the presence of various amines for pyrrolidone synthesis. Finally, the Ru catalyst was also applicable to hydrogenation of various carbonyl compounds for the synthesis of the corresponding alcohols with excellent catalytic performance. The research provides insight for heterogenizing the homogeneous noble metal-based catalysts with high catalytic active for biomass-based transformations.

Heterobimetallic ruthenium-zinc complexes with bulky N-heterocyclic carbenes: syntheses, structures and reactivity.

The ruthenium-zinc heterobimetallic complexes, [Ru(IPr)2(CO)ZnMe][BArF4] (7), [Ru(IBiox6)2(CO)(THF)ZnMe][BArF4] (12) and [Ru(IMes)'(PPh3)(CO)ZnMe] (15), have been prepared by reaction of ZnMe2 with the ruthenium N-heterocyclic carbene complexes [Ru(IPr)2(CO)H][BArF4] (1), [Ru(IBiox6)2(CO)(THF)H][BArF4] (11) and [Ru(IMes)(PPh3)(CO)HCl] respectively. 7 shows clean reactivity towards H2, yielding [Ru(IPr)2(CO)(η2-H2)(H)2ZnMe][BArF4] (8), which undergoes loss of the coordinated dihydrogen ligand upon application of vacuum to form [Ru(IPr)2(CO)(H)2ZnMe][BArF4] (9). In contrast, addition of H2 to 12 gave only a mixture of products. The tetramethyl IBiox complex [Ru(IBioxMe4)2(CO)(THF)H][BArF4] (14) failed to give any isolable Ru-Zn containing species upon reaction with ZnMe2. The cyclometallated NHC complex [Ru(IMes)'(PPh3)(CO)ZnMe] (15) added H2 across the Ru-Zn bond both in solution and in the solid-state to afford [Ru(IMes)'(PPh3)(CO)(H)2ZnMe] (17), with retention of the cyclometallation.

Ru(ii)-N-heterocyclic carbene complexes: synthesis, characterization, transfer hydrogenation reactions and biological determination.

A series of ruthenium(ii) complexes with N-heterocyclic carbene ligands were successfully synthesized by transmetalation reactions between silver(i) N-heterocyclic carbene complexes and [RuCl2(p-cymene)]2 in dichloromethane under Ar conditions. All new compounds were characterized by spectroscopic and analytical methods. These ruthenium(ii)–NHC complexes were found to be efficient precatalysts for the transfer hydrogenation of ketones by using 2-propanol as the hydrogen source in the presence of KOH as a co-catalyst. The antibacterial activity of ruthenium N-heterocyclic carbene complexes 3a–f was measured by disc diffusion method against Gram positive and Gram-negative bacteria. Compounds 3d exhibited potential antibacterial activity against five bacterial species among the six used as indicator cells. The product 3e inhibits the growth of all the six tested microorganisms. Moreover, the antioxidant activity determination of these complexes 3a–f, using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azinobis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) as reagent, showed that compounds 3b and 3d possess DPPH and ABTS antiradical activities. From a concentration of 1 mg ml−1, these two complexes presented a similar scavenging activity to that of the two used controls gallic acid (GA) and butylated hydroxytoluene (BHT). From a concentration of 10 mg ml−1, the percentage inhibition of complexes 3b and 3d was respectively 70% and 90%. In addition, these two Ru–NHC complexes exhibited antifungal activity against Candida albicans. Investigation of the anti-acetylcholinesterase activity of the studied complexes showed that compounds 3a, 3b, 3d and 3e exhibited good activity at 100 μg ml−1 and product 3d is the most active. In a cytotoxicity study the complexes 3 were evaluated against two human cancer cell lines MDA-MB-231 and MCF-7. Both 3d and 3e complexes were found to be active against the tested cell lines showing comparable activity with examples in the literature.

Cationic abnormal N-heterocyclic carbene ruthenium complexes as suitable precursors for the synthesis of heterobimetallic compounds.

The cationic abnormal N-heterocyclic carbene complex [Ru(OAc)(dppe)(PC)]Br (2b) (PC = bidentate phosphine-carbene ligand) has been obtained by treatment of the neutral derivative RuBr(OAc)(PPh3)(PC) (2a) with dppe in THF. Reaction of 2b with Ag2O afforded the heterobimetallic complex Ru(OAc)(dppe)(PC)AgBr (2c) which can be easily transmetallated with [Ir(cod)Cl]2 giving Ru(OAc)(dppe)(PC)IrCl(cod) (2d). Similarly, [{Ru(OAc)(PC)(PC')}2Ag][AgBr2] (1b) reacts with [Ir(cod)Cl]2 with formation of Ru(OAc)(PC)(PC')IrCl(cod) (1e). All complexes were characterized by NMR in solution and by single crystal X-ray diffraction studies in solid state. For the cationic complexes the 1H NMR resonance of the carbene-proton is considerably down-field shifted (δ > 9 ppm) with respect to that of the neutral derivatives. Cyclic voltammetry and differential pulse voltammetry studies show that the Ru-centered redox process occurs at lower potential (ΔE > 100 mV) after transmetallation with iridium, suggesting an interaction of the two metals along the π-system of the heterocycle ligand. These complexes display catalytic activity in transfer hydrogenation of acetophenone in 2-propanol with a significant influence of Ir and Ag centers on the Ru moiety. The synthesis of the imidazolyl-based N-heterocyclic dicarbene Ru-Ir complexes, which entails the easy metallation of the reactive cationic abnormal N-heterocyclic carbene Ru complexes with Ag2O, represents a suitable pathway for the preparation of heterometallic ruthenium complexes.

A Ruthenium(II) N-Heterocyclic Carbene (NHC) Complex with Naphthalimide Ligand Triggers Apoptosis in Colorectal Cancer Cells via Activating the ROS-p38 MAPK Pathway.

The p38 MAPK pathway is known to influence the anti-tumor effects of several chemotherapeutics, including that of organometallic drugs. Previous studies have demonstrated the important role of p38 both as a regulator and a sensor of cellular reactive oxygen species (ROS) levels. Investigating the anti-cancer properties of novel 1,8-naphthalimide derivatives containing Rh(I) and Ru(II) N-heterocyclic carbene (NHC) ligands, we observed a profound induction of ROS by the complexes, which is most likely generated from mitochondria (mtROS). Further analyses revealed a rapid and consistent activation of p38 signaling by the naphthalimide-NHC conjugates, with the Ru(II) analogue—termed MC6—showing the strongest effect. In view of this, genetic as well as pharmacological inhibition of p38α, attenuated the anti-proliferative and pro-apoptotic effects of MC6 in HCT116 colon cancer cells, highlighting the involvement of this signaling molecule in the compound’s toxicity. Furthermore, the influence of MC6 on p38 signaling appeared to be dependent on ROS levels as treatment with general- and mitochondria-targeted anti-oxidants abrogated p38 activation in response to MC6 as well as the molecule’s cytotoxic- and apoptogenic response in HCT116 cells. Altogether, our results provide new insight into the molecular mechanisms of naphthalimide-metal NHC analogues via the ROS-induced activation of p38 MAPK, which may have therapeutic interest for the treatment of various cancer types.

Enhanced Tumor Diagnostic and Therapeutic Effect of Mesoporous Silica Nanoparticle-Mediated Pre-targeted Strategy.

Improving the targeting efficiency of imaging agents or anticancer drugs has become essential in the current primary mission to enhance the diagnostic or therapeutic effects. To improve the tumor diagnosis and therapy effect, a promising drug-delivery and targeting strategy was established based on the bioorthogonal chemistry. The delivery system was composed of the pre-targeting carrier Biotin-MSNs-DBCO nanoparticles and the azido cargoes. The fluorescence probe 1-(3-azidopropyl) fluorescein (FITC-N3) and ruthenium N-heterocyclic carbene complex N3-S-S-NHC-Ru were synthesized and served as the tumor imaging and therapy probes, respectively. The cell imaging and viability was investigated by the Biotin-MSNs-DBCO pre-targeted for 4h in colonic carcinoma (HeLa) cells. For the tumor cell imaging, Biotin-MSNs-DBCO could react with FITC-N3 rapidly and completely in 20min with 93% yields. The fluorescence intensity of tumor cells was obviously increased by the Biotin-MSNs-DBCO pre-targeted. The cytotoxicity of the ruthenium complex N3-S-S-NHC-Ru was significantly improved appropriately three times with the IC50 (half inhibitory concentration) value of 6.68 ± 1.29μM and enhancement of the mitochondrial dysfunction. The pre-targeting nanoparticle Biotin-MSNs-DBCO could selectively capture the azido compounds in tumor cells, which provided a site-specific target for the cargoes and then resulted in an enhancement of diagnostic or therapeutic effects.

Deactivation of a ruthenium(II) N-heterocyclic carbene p-cymene complex during transfer hydrogenation catalysis

A ruthenium (II) N-heterocyclic carbene (NHC) complex was synthesized to investigate ligand dissociation as a possible deactivation pathway for the catalytic cycle of a transfer hydrogenation reaction. Diiodo(1,3-dimethylbenzimidazole-2-ylidene)(p-cymene)ruthenium(II) was synthesized for use as the catalytic species and characterized using physico-chemical, spectroscopic methods, and single crystal X-ray diffraction. The transfer of hydrogen from isopropanol to acetophenone was followed using 1H NMR. We observed 94% conversion of the substrate to the alcohol product after 1 h. We also found that the p-cymene complex decomposed during the catalytic reaction to the extent of 80% deactivation after 1 h, based on 1H NMR spectrometry. From Gaussian calculations, an ultraviolet–visible spectrum that is in excellent agreement with the actual spectrum was computed, giving insight into the nature of the absorptions observed experimentally.

Ruthenium(II) Bipyridyl Complexes with Cyclometalated NHC Ligands.

We present the synthesis and characterization of novel cyclometalated ruthenium N-heterocyclic carbene (NHC) complexes of the general formula [Ru(C^C*)(bpy)2]PF6 (bpy = 2,2'-bipyridine), with the C^C* ligand being based on different 1-phenylimidazoles. They were synthesized in a one-pot procedure starting from the corresponding p-cymene NHC complexes [Ru(C^C*)(p-cymene)Cl]. Their structural, spectroscopic, and electrochemical properties were investigated by NMR, X-ray, UV/vis, and CV, as well as density functional theory methods. Because of the stronger electron-donating carbene ligands, these complexes represent a new class of bisheteroleptic dyes with improved photophysical and electrochemical properties.