Ruthenium Pincer Complex Research Articles

Bioelectrocatalytic Conversion of N2: From Chemically Inert Gas to Chiral Chemicals

Dinitrogen molecule (N2) is the most abundant natural gas and also the ultimate source of nitrogen for nitrogenated industrial and natural compounds. So far, the fully hydrogenated product, ammonia (NH3), is the most common product of N2 fixation.1 However, NH3, the regular end-product of N2 fixation, is a bulk chemical with low added-value. The conversion of NH3 to nitrogenous compounds with high added-value and complicated structure still requires further tedious chemical synthesis with the use of precious metal catalysts.2 In our study, an upgraded N2 fixation system was firstly designed and constructed based on a bioelectrocatalytic N2 reduction architecture.3 The NH3 generated via N2 reduction catalyzed by nitrogenase was in situ utilized by L-alanine dehydrogenase to realize the reductive amination of pyruvate and the generation of alanine. The reduced equivalent to support the N2 reduction and reductive amination of pyruvate was regenerated by the electrochemical method. ω-TA transferred the amino group from alanine to ketone substrates and finally produced desired chiral amine intermediates.4 On this basis, an H2 fuel cell module was integrated into the upgraded N2 fixation system to construct a self-powered H2/α-keto acid fuel cell. In the new system, the upgraded N2 fixation was powered by the oxidation of H2 with high Faradaic efficiency and without the requirement of external electrical energy input.5 Finally, the end-product of N2 fixation in our study successfully went beyond NH3 and reached high-value-added chiral amine intermediates and chiral amino acids. The produced chiral amine intermediates and chiral amino acids have wild application in pharmaceuticals production and biotechnology research. References (1) Foster, S. L.; Bakovic, S. I. P.; Duda, R. D.; Maheshwari, S.; Milton, R. D.; Minteer, S. D.; Janik, M. J.; Renner, J. N.; Greenlee, L. F. Catalysts for nitrogen reduction to ammonia. Nat. Catal. 2018, 1, 490.(2) Balaraman, E.; Srimani, D.; Diskin-Posner, Y.; Milstein, D. Direct synthesis of secondary amines from alcohols and ammonia catalyzed by a ruthenium pincer complex. Catal. Lett. 2015, 145, 139-144.(3) Milton, R. D.; Cai, R.; Abdellaoui, S.; Leech, D.; De Lacey, A. L.; Pita, M.; Minteer, S. D. Bioelectrochemical Haber-Bosch Process: An Ammonia-Producing H2/N2 Fuel Cell. Angew. Chem. Int. Ed. 2017, 56, 2680-2683.(4) Chen, H.; Cai, R.; Patel, J.; Dong, F.; Chen, H.; Minteer, S. D. Upgraded Bioelectrocatalytic N2 Fixation: From N2 to Chiral Amine Intermediates. J. Am. Chem. Soc. 2019, 141, 4963-4971.(5) Chen, H.; Prater, M. B.; Cai, R.; Dong, F.; Chen, H.; Minteer, S. D., Bioelectrocatalytic Conversion from N2 to Chiral Amino Acids in a H2/α-Keto Acid Enzymatic Fuel Cell. J. Am. Chem. Soc. 2020, 142 (8), 4028-4036.

Cationic ruthenium(II)–NHC pincer complexes: Synthesis, characterisation and catalytic activity for transfer hydrogenation of ketones

Cationic ruthenium pincer complexes, [Ru(CNC)(CO)(PPh3)Cl]X (CNC = 2,6‐bis(1‐methylimidazol‐2‐ylidene)‐pyridine, X = Cl− [1a], PF6− [1b]), [Ru(CNC)(PPh3)2Cl]X (X = Cl− [2a], PF6− [2b]) and [Ru(CNC)(PPh3)2(H)]X (X = Cl− [3a], PF6− [3b]) with triphenylphosphine, CO and halides as coligands have been synthesised and characterised by 1H, 13C, 31P NMR, mass and single‐crystal X‐ray crystallography. The application of Ru complexes in the transfer hydrogenation of a wide range of ketones with 2‐propanol as the hydrogen source is explored. The in situ transformations observed during the synthesis help understand and suggest a plausible mechanism via the hydride complex 3b. All complexes appear to be efficient catalyst precursors for transfer hydrogenation of ketones.

Synthesis of NNN Chiral Ruthenium Complexes and Their Cytotoxicity Studies.

The synthesis and characterization of chiral pincer-ruthenium complexes of the type (R2NNN)RuCl2 (PPh3) (R = 3-methylbutyl and 3,3-dimethylbutyl) is reported here. The cytotoxicity studies of these complexes were studied and compared with the corresponding activity of achiral complexes. The cytotoxic effect of pincer-ruthenium complexes on human dermal fibroblasts and human tongue carcinoma cells assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay displayed an inhibition of normal and cancer cell growth in a dose-dependent manner. Intracellular reactive oxygen species (ROS) level measurement, lactate dehydrogenase assay, DNA fragmentation, and necrosis studies revealed that treatment with pincer-ruthenium complexes induced a redox imbalance in SAS cells by upregulating ROS generation and caused necrotic cell death by disrupting the cellular membrane integrity.

Transfer Hydrogenation of Flavanones and ortho‐Hydroxychalcones to 1,3‐Diarylpropanols Catalyzed by CNN Pincer Ruthenium Complexes

AbstractThe transfer hydrogenation of flavanones and ortho‐hydroxychalcones catalyzed by ruthenium pincer complexes RuCl(CNNPh)(disphosphine) has allowed the synthesis of ortho‐hydroxy 1,3‐diarypropanols in 80–88 % yield, under mild reaction conditions and short reaction times (1 h) in 2‐propanol. The amount of the co‐catalyst NaOiPr has been found crucial for the selective reduction of flavanones to ortho‐hydroxy 1,3‐diarypropanols vs. flavan‐4‐ols. Preliminary results show that with pincer catalysts bearing (S,R)‐Josiphos, flavanone is reduced to the corresponding (S)‐alcohol in moderate conversion (36 %) and up to 92 % ee.

Mechanistic Investigations of Ruthenium Catalyzed Dehydrogenative Thioester Synthesis and Thioester Hydrogenation.

We have recently reported the previously unknown synthesis of thioesters by coupling thiols and alcohols (or aldehydes) with liberation of H2, as well as the reverse hydrogenation of thioesters, catalyzed by a well-defined ruthenium acridine-9H based pincer complex. These reactions are highly selective and are not deactivated by the strongly coordinating thiols. Herein, the mechanism of this reversible transformation is investigated in detail by a combined experimental and computational (DFT) approach. We elucidate the likely pathway of the reactions, and demonstrate experimentally how hydrogen gas pressure governs selectivity toward hydrogenation or dehydrogenation. With respect to the dehydrogenative process, we discuss a competing mechanism for ester formation, which despite being thermodynamically preferable, it is kinetically inhibited due to the relatively high acidity of thiol compared to alcohol and, accordingly, the substantial difference in the relative stabilities of a ruthenium thiolate intermediate as opposed to a ruthenium alkoxide intermediate. Accordingly, various additional reaction pathways were considered and are discussed herein, including the dehydrogenative coupling of alcohol to ester and the Tischenko reaction coupling aldehyde to ester. This study should inform future green, (de)hydrogenative catalysis with thiols and other transformations catalyzed by related ruthenium pincer complexes.

A new bis-pyrazolylpyridine ruthenium(III) complex as a potential anticancer drug: in vitro and in vivo activity in murine colon cancer.

We synthesized and characterized the ruthenium(iii) pincer-type complex [RuCl3(H2Lt-Bu] (H2Lt-Bu = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine, 1) by elemental analysis, IR and UV-Vis spectroscopy, and the mass spectrometry (MS) method ESI Q-TOF. For comparison reasons, we also studied ruthenium(iii) terpyridine complexes of the general formula [Ru(N-N-N)Cl3], where N-N-N = 4'-chloro-terpyridine (Cl-tpy; 2) or 4'-chlorophenyl-terpyridine (Cl-Ph-tpy; 3). A kinetic study of the substitution reactions of 1-3 with biomolecules showed that the rate constants depend on the properties of the spectator ligand and the nature of the entering nucleophile. The DNA/HSA binding study showed that in comparison to complex 1 (bis-pyrazolylpyridine), the other two (2 and 3) terpyridine complexes had a slightly better binding affinity to calf thymus DNA (CT DNA), while in the case of human serum albumin (HSA), complex 1 exhibited the strongest quenching ability. We demonstrated that 1 possesses significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells and in vivo antitumor activity in murine heterotopic colon carcinoma. Complex 1 induced G0/G1 cell cycle arrest and apoptotic death in CT26 cells. Additionally, 1 showed antiproliferative activity, as evaluated by the detection of the expression levels of the Ki67 protein. Furthermore, the in vivo results showed that 1 reduced primary tumour growth and the number and growth of lung and liver metastases, significantly prolonging the treated mice's survival rate. This study highlighted that 1 does not show hepato- and nephrotoxicity. Our data demonstrated the considerable antitumor activity of the ruthenium(iii) pincer complex against CT26 tumour cells and implicated further investigations of its role as a potential chemotherapeutic agent for colon carcinoma.

Catalytic Oxidative Deamination by Water with H2 Liberation.

Selective oxidative deamination has long been considered to be an important but challenging transformation, although it is a common critical process in the metabolism of bioactive amino compounds. Most of the synthetic methods developed so far rely on the use of stoichiometric amounts of strong and toxic oxidants. Here we present a green and efficient method for oxidative deamination, using water as the oxidant, catalyzed by a ruthenium pincer complex. This unprecedented reaction protocol liberates hydrogen gas and avoids the use of sacrificial oxidants. A wide variety of primary amines are selectively transformed to carboxylates or ketones in good to high yields. It is noteworthy that mechanistic experiments and DFT calculations indicate that in addition to serving as the oxidant, water also plays an important role in assisting the hydrogen liberation steps involved in amine dehydrogenation.

Ruthenium-Catalyzed Ester Reductions Applied to Pharmaceutical Intermediates

Ruthenium pincer complexes were synthesized and used for catalytic ester reductions under mild conditions (∼5 bar of hydrogen). An experimental design approach was used to optimize the conditions f...

Dynamic Kinetic Resolution of Alcohols by Enantioselective Silylation Enabled by Two Orthogonal Transition-Metal Catalysts.

A nonenzymatic dynamic kinetic resolution of acyclic and cyclic benzylic alcohols is reported. The approach merges rapid transition‐metal‐catalyzed alcohol racemization and enantioselective Cu‐H‐catalyzed dehydrogenative Si‐O coupling of alcohols and hydrosilanes. The catalytic processes are orthogonal, and the racemization catalyst does not promote any background reactions such as the racemization of the silyl ether and its unselective formation. Often‐used ruthenium half‐sandwich complexes are not suitable but a bifunctional ruthenium pincer complex perfectly fulfills this purpose. By this, enantioselective silylation of racemic alcohol mixtures is achieved in high yields and with good levels of enantioselection.

Formation of thioesters by dehydrogenative coupling of thiols and alcohols with H2 evolution

Thioesters play important roles in chemistry and biology, but their synthesis generally exhibits a poor atom economy and generates copious waste. We report here the dehydrogenative coupling of alcohols and thiols to yield thioesters and evolve H2. This waste-free reaction is catalysed by an acridine-based ruthenium pincer complex in hexamethyldisiloxane as the optimal solvent without any additives. Various thioesters were formed in good-to-excellent yields using equivalent amounts of alcohols and thiols in excellent selectivity with hydrogen gas as the only by-product. A plausible mechanism, which involves an outer-sphere dehydrogenation process in which the thiol not only serves as a reactant, but also as an assisting ligand, is proposed based on mechanistic studies and the isolation of intermediates. This system provides a facile, efficient and waste-free synthesis of thioesters. Synthetic methods for the green and atom-economical synthesis of thioesters are scarce. Now, a catalytic protocol utilizing a ruthenium pincer complex provides efficient access to thioesters with hydrogen gas as the sole by-product via dehydrogenative coupling of alcohols with thiols.

Highly Efficient Transfer Hydrogenation Catalysis with Tailored Pyridylidene Amide Pincer Ruthenium Complexes.

The rational optimization of homogeneous catalysts requires ligand platforms that are easily tailored to improve catalytic performance. Here, it is demonstrated that pyridylidene amides (PYAs) provide such a platform to custom-shape transfer hydrogenation catalysts with exceptional activity. Specifically, a series of meta-PYA pincer ligands with differently substituted PYA units has been synthezised and coordinated to ruthenium(II) centres to form bench-stable tris-acetonitrile complexes [Ru(R-PYA-pincer)(MeCN)3 ](PF6 )2 (R=OMe, Me, H, Cl, CF3 ). Analytic studies including 1 H NMR spectroscopy, cyclic voltammetry, and X-ray crystallography reveal a direct influence of the substituents on the electronic properties of the ruthenium center. The complexes are active in the catalytic transfer hydrogenation of ketones, with activities directly encoded by the PYA substitution pattern. Their perfomance improves further upon exchange of an ancillary MeCN ligand with PPh3 . While complexes [Ru(R-PYA-pincer)(PPh3 )(MeCN)2 ](PF6 )2 were only isolated for R=H, Me, an in situ protocol was developed to generate these complexes in situ for R=OMe, Cl, CF3 by using a 1:2 ratio of the complexes and PPh3 . This in situ protocol together with a short catalyst pre-activation provided highly active catalytic systems. The most active pre-catalyst featured the methoxy-substituted PYA ligand and reached turnover frenquencies of 210 000 h-1 under an exceptionally low catalyst loading of 25 ppm for the benchmark substrate benzophenone, representing one of the most active transfer hydrogenation systems known to date.

Energy landscape study of water splitting and H2 evolution at a ruthenium(II) pincer complex.

A bird's-eye view of the water splitting and H2 generation at a ruthenium(II) pincer complex is presented. Using a combination of density functional theory and efficient algorithms for exploration of potential energy hypersurface (PES), a total of 197 local minima and 186 transition states are identified, and a new mechanism for water splitting and H2 evolution via hydroxycarbonyl intermediates is presented. Furthermore, a global feature of the reaction PES, so-called potential energy landscape, is discussed on analyzing the obtained structures. As a result, the landscape is characterized by hierarchical structure, namely, PES consists of many "superbasins (SBs)" that are separated by relatively high energy barriers corresponding to bond breaking around Ru(II) center. Each SB involves a set of conformational isomers that can be interchanged with each other through relatively small barriers. To the best of our best knowledge, this is the first report on the quantum chemical computation of the hierarchical structure of PES for a realistic, catalytic reaction system.

Ruthenium Pincer Complex Catalyzed Selective Synthesis of C‐3 Alkylated Indoles and Bisindolylmethanes Directly from Indoles and Alcohols

AbstractHerein, we presented Ru‐SNS complex that serves as a useful catalyst for C‐3 alkylation of 1H‐indoles with various aliphatic primary and secondary alcohols including cyclic alcohols as well as benzylic alcohols. The selective synthesis of bisindolylmethane derivatives is also achieved from the same set of indole and alcohol just by altering the reaction parameters. Furthermore, the sustainable synthesis of C‐3 alkylated indoles directly from 2‐(2‐nitrophenyl)ethan‐1‐ol and alcohols catalysed by a Ru‐complex via “borrowing hydrogen” strategy is reported. This protocol provides an atom‐economical sustainable route to access structurally important compounds like arundine, vibrindole A and tryptamine based derivatives.magnified image

Selective Room-Temperature Hydrogenation of Amides to Amines and Alcohols Catalyzed by a Ruthenium Pincer Complex and Mechanistic Insight.

We report a room-temperature protocol for the hydrogenation of various amides to produce amines and alcohols. Compared with most previous reports for this transformation, which use high temperatures (typically, 100–200 °C) and H2 pressures (10–100 bar), this system proceeds under extremely mild conditions (RT, 5–10 bar of H2). The hydrogenation is catalyzed by well-defined ruthenium-PNNH pincer complexes (0.5 mol %) with potential dual modes of metal–ligand cooperation. An unusual Ru-amidate complex was formed and crystallographically characterized. Mechanistic investigations indicate that the room-temperature hydrogenation proceeds predominantly via the Ru–N amido/amine metal–ligand cooperation.

Cyclometalated Ruthenium Pincer Complexes as Catalysts for the α-Alkylation of Ketones with Alcohols.

Ruthenium PNP pincer complexes bearing supplementary cyclometalated C,N‐bound ligands have been prepared and fully characterized for the first time. By replacing CO and H− as ancillary ligands in such complexes, additional electronic and steric modifications of this topical class of catalysts are possible. The advantages of the new catalysts are demonstrated in the general α‐alkylation of ketones with alcohols following a hydrogen autotransfer protocol. Herein, various aliphatic and benzylic alcohols were applied as green alkylating agents for ketones bearing aromatic, heteroaromatic or aliphatic substituents as well as cyclic ones. Mechanistic investigations revealed that during catalysis, Ru carboxylate complexes are predominantly formed whereas neither the PNP nor the CN ligand are released from the catalyst in significant amounts.

Determining the Catalyst Properties That Lead to High Activity and Selectivity for Catalytic Hydrodeoxygenation with Ruthenium Pincer Complexes

Ten ruthenium pincer complexes were evaluated as catalysts for the hydrodeoxygenation (HDO) reaction on a lignin monomer surrogate, vanillyl alcohol. Four of these complexes are reported herein with the synthesis and full characterization data for all and single-crystal X-ray diffraction data for three complexes bearing OH/O–, NMe2, and Me substituents on the pincer. A systematic study of these CNC pincer complexes revealed that the π-donor substituent on the pyridine ring plays a key role in enhancing the yield of the desired deoxygenated product. While OMe, OH, and NMe2 are all effective as π-donor substituents on the central pyridine ring in the pincer, the highest conversion to products and the best selectivity was observed with OH substituents and added sodium carbonate as a base. Base serves to deprotonate the OH group and form 1O- as observed spectroscopically. Furthermore, efforts to use other catalysts have revealed that free or labile sites are needed on the ruthenium center and an electronicall...

On the Mechanism of the Ruthenium‐catalyzed β‐methylation of Alcohols with Methanol

AbstractSelective β‐methylation of alcohols with methanol has been recently described using a catalytic system comprising the ruthenium pincer complex [RuH(CO)(BH4)(HN(C2H4PPh2)2)]‐(Ru‐MACHO‐BH) 1 and alcoholate bases as co‐catalysts.1 Here we present a detailed mechanistic analysis for the mono‐methylation of 1‐phenyl‐propane‐1‐ol 2 a as prototypical example. Several experimentally observed intermediates were localized as stable minima on the DFT‐derived energy surface of the entire reaction network. The ruthenium complex [Ru(H)2(CO)(HN(C2H4PPh2)2)] I was inferred as the active species catalyzing the de‐hydrogenation/re‐hydrogenation of substrates and intermediates (“hydrogen borrowing”). The hydrogen‐bonded alcohol adduct of this complex was identified as the lowest lying intermediate (TDI). The C−C bond formation results from a base‐catalyzed aldol reaction comprising the transition state with the highest energy (TDTS). Experimentally determined Gibbs free activation barriers of 26.1 kcal/mol and 26.0 kcal/mol in methanol and toluene as solvents, respectively, are reflected well by the computed energy span of the complex reaction network (29.2 kcal/mol).

Selective and high yield transformation of glycerol to lactic acid using NNN pincer ruthenium catalysts.

The conversion of glycerol selectively to lactic acid has been accomplished in high yields (ca. 90%) by using a NNN pincer-Ru catalyst. DFT explains the role of the Ru-P bond and sterics in favoring the catalysis.

CNN pincer ruthenium complexes for efficient transfer hydrogenation of biomass-derived carbonyl compounds.

The ligand HCNNOMe (6-(4-methoxyphenyl)-2-aminomethylpyridine) is easily prepared from the commercially available 6-(4-methoxyphenyl)pyridine-2-carbaldehyde by the reaction of hydroxylamine and hydrogenation (H2, 1 atm) with Pd/C. The pincer complexes cis-[RuCl(CNNOMe)(PPh3)2] (1) and [RuCl(CNNOMe)(PP)] (PP = dppb, 2; and dppf, 3) are synthesized from [RuCl2(PPh3)3], HCNNOMe and PP (for 2 and 3) in 2-propanol with NEt3 at reflux and are isolated in 85-93% yield. Carbonylation of 1 (CO, 1 atm) gives [RuCl(CNNOMe)(CO)(PPh3)] (4) (79% yield) which cleanly reacts with Na[BArf4] and PCy3, affording the cationic trans-[Ru(CNNOMe)(CO)(PCy3)(PPh3)][BArf4] (5) (92% yield). These robust pincer complexes display remarkably high catalytic activity in the transfer hydrogenation (TH) of lignocellulosic biomass carbonyl compounds, using 2-propanol at reflux in a basic medium (NaOiPr or K2CO3). Thus, furfural, 5-(hydroxymethyl)furfural and Cyrene are reduced to the corresponding alcohols with 2 and 3, at S/C in the range of 10 000-100 000, within minutes or hours (TOF up to 1 500 000 h-1). The monocarbonyl complex 5 was found to be extremely active in the TH of cinnamaldehyde, vanillin derivatives and ethyl levulinate at S/C in the range of 10 000-50 000. Vanillyl alcohol is also obtained by the TH of vanillin with 5 (S/C = 500) in 2-propanol in the presence of K2CO3.

N–Alkylation of Amines Catalyzed by a Ruthenium–Pincer Complex in the Presence of in situ Generated Sodium Alkoxide

We report the use of ruthenium–NNN‐pincer complexes of the type (R2NNN)RuCl2(PPh3) (R = tBu, iPr, Cy and Ph) for the catalytic N‐alkylation of primary amines under solvent‐free conditions. For the first time, the base that is required to promote these reactions is generated in situ from the alcohol by the use of sodium. The resulting sodium alkoxide regenerates the alcohol substrate while acting as the water scavenger thus mitigating the need of an additional base. Among the catalysts screened, (tBu2NNN)RuCl2(PPh3) (0.02 mol‐%) gives very high turnovers and good yields at 140 °C. The (tBu2NNN)RuCl2(PPh3) catalyzed N‐alkylation tolerates a variety of amine and alcohol substrates. While excellent turnover (29000) was obtained for the (tBu2NNN)RuCl2(PPh3) (0.002 mol‐%) catalyzed alkylation of aniline with cyclohexyl methanol, the turnovers obtained in the corresponding catalytic methylation of p‐anisidine was also very high (12000). The (tBu2NNN)RuCl2(PPh3) catalyzed reactions have also been accomplished under open‐vessel conditions resulting in a net dehydrogenative coupling reaction. This protocol has been used to transform benzene‐1,2‐diamines to benzimidazoles with high productivity (12000 turnovers). DFT studies indicate that while β‐hydride elimination is rate‐determining (RDTS: 24.31 kcal/mol) for the alcohol dehydrogenation segment which is endothermic, insertion of the imine is rate‐determining (RDTS: 11.26 kcal/mol) for its hydrogenation that is exothermic.