Ruthenium complexes with triazenide ligands bearing an N-heterocyclic moiety, and their catalytic properties in the reduction of nitroarenes.

A series of ruthenium complexes of formulae [RuCl(triazenide)(p-cymene)] have been synthesized using as ligand a triazenide monofunctionalized with an N-heterocyclic moiety. Nuclear magnetic resonance, high resolution mass spectrometry and X-ray diffraction were used to characterize the triazenide ligands and their complexes. In addition, these ruthenium complexes catalyzed the reduction of nitrobenzene to aniline in the presence of sodium borohydride and ethanol as solvent at room temperature. Notably, complex 5 was especially active in the reduction of nitroarenes substituted at the aromatic ring with electron-withdrawing or electron-donating fuctional groups affording the desired arylamines in good to excellent yields (80-100%). The role of the N-heterocyclic moiety on catalysis was explored.

(CAAC)Copper Catalysis Enables Regioselective Three-Component Carboboration of Terminal Alkynes.

Cyclic(alkyl)(amino)carbene (CAAC) ligands are found to perturb regioselectivity of the copper-catalyzed carboboration of terminal alkynes, favoring the less commonly observed internal alkenylboron regiosomer through an α-selective borylcupration step. A variety of carbon electrophiles participate in the reaction, including allyl alcohols derivatives and alkyl halides. The method provides a straightforward and selective route to versatile tri-substituted alkenylboron compounds that are otherwise challenging to access.

Stable Singlet Carbenes as Organic Superbases.

A simple experimental procedure for scaling carbene Brønsted basicity is described. The results highlight the strong basicity of pyrazol-4-ylidenes, a type of mesoionic carbene, also named cyclic-bentallenes (CBA). They are more basic (pKaH >42.7 in acetonitrile) than the popular proazaphosphatrane Verkade bases, and even the Schwesinger phosphazene superbase P4 (t Bu). The basicity of these compounds can readily be tuned, and they are accessible in multigram quantities. These results open new avenues for carbon centered superbases.

Cyclic (Alkyl)(amino)carbene Ligands Enable Cu-Catalyzed Markovnikov Protoboration and Protosilylation of Terminal Alkynes: A Versatile Portal to Functionalized Alkenes*.

Regioselective hydrofunctionalization of alkynes represents a straightforward route to access alkenyl boronate and silane building blocks. In previously reported catalytic systems, high selectivity is achieved with a limited scope of substrates and/or reagents, with general solutions lacking. Herein, we describe a selective copper-catalyzed Markovnikov hydrofunctionalization of terminal alkynes that is facilitated by strongly donating cyclic (alkyl)(amino)carbene (CAAC) ligands. Using this method, both alkyl- and aryl-substituted alkynes are coupled with a variety of boryl and silyl reagents with high α-selectivity. The reaction is scalable, and the products are versatile intermediates that can participate in various downstream transformations. Preliminary mechanistic experiments shed light on the role of CAAC ligands in this process.

An Active-Site Sulfonate Group Creates a Fast Water Oxidation Electrocatalyst That Exhibits High Activity in Acid.

The storage of solar energy in chemical bonds will depend on pH-universal catalysts that are not only impervious to acid, but actually thrive in it. Whereas other homogeneous water oxidation catalysts are less active in acid, we report a catalyst that maintained high electrocatalytic turnover frequency at pH values as low as 1.1 and 0.43 (kcat =1501±608 s-1 and 831±254 s-1 , respectively). Moreover, current densities, related to catalytic reaction rates, ranged from 15 to 50 mA cm-2 mM-1 comparable to those reported for state-of-the-art heterogeneous catalysts and 30 to 100 times greater than those measured for two prominent literature homogeneous catalysts at pH 1.1 and 0.43. The catalyst also exhibited excellent durability when a chemical oxidant was used (CeIV , 7400 turnovers, TOF 0.88 s-1 ). Preliminary computational studies suggest that the unusual active-site sulfonate group acts a proton relay even in strong acid, as intended.

Understanding the performance of a bisphosphonate Ru water oxidation catalyst.

Water oxidation catalysts (WOCs) create electrons that allow generating H2 from water and sunlight, a promising process for the production of clean energy. The mechanism of water oxidation mediated by Ru(2,2'-bipyridine-6,6'-diphosphonato)(4-picoline)2 has been studied computationally to comprehend the results obtained in the experiments performed by the Concepcion and Grotjahn groups. Our study was performed at pH = 8 and 1. At pH = 8, the phosphonates are fully deprotonated and the catalysis, which is shown to be more energetically costly than that of the dicarboxylato Ru catalyst counterpart, takes place through a mechanism that involves a bimolecular interaction between two metal-oxo units (I2M). At pH = 1, only one of the phosphonates of the catalyst can deprotonate. After testing all possible pathways and comparing with experimental data, we conclude that the catalysis proceeds neither through a water nucleophilic attack nor via I2M, but rather we hypothesize that the rate-determining step involves both the catalyst and the ceric ammonium nitrate.

An Overview of Significant Achievements in Ruthenium-Based Molecular Water Oxidation Catalysis.

Fossil fuels (coal, oil, natural gas) are becoming increasingly disfavored as long-term energy options due to concerns of scarcity and environmental consequences (e.g., release of anthropogenic CO2). Hydrogen gas, on the other hand, has gained popularity as a clean-burning fuel because the only byproduct from its reaction with O2 is H2O. In recent decades, hydrogen derived from water splitting has been a topic of extensive research. The bottleneck of the water splitting reaction is the difficult water oxidation step (2H2O → O2 + 4H⁺ + 4e-), which requires an effective and robust catalyst to overcome its high kinetic barrier. Research in water oxidation by molecular ruthenium catalysts enjoys a rich history spanning nearly 40 years. As the diversity of novel ligands continues to widen, the relationship between ligand geometry or electronics, and catalyst activity is undoubtedly becoming clearer. The present review highlights, in the authors' opinion, some of the most impactful discoveries in the field and explores the evolution of ligand design that has led to the current state of the art.

Sequential Alkene Isomerization and Ring-Closing Metathesis in Production of Macrocyclic Musks from Biomass.

We report successful utilization of sequential alkene isomerization and ring-closing metathesis of dec-9-enoic acid based dienes in synthesis of macrocyclic lactones that possess a strong scent of musk. This catalytic sequence was essential to trim the chain length of starting dienes to yield macrocycles of the right size. Dec-9-enoic acid is conveniently obtainable from oleic esters by Ru-catalysed ethenolysis.

Ruthenium (II) and Iridium (III) Complexes of N-Heterocyclic Carbene and Pyridinol Derived Bidentate Chelates: Synthesis, Characterization, and Reactivity.

We report the synthesis and characterization of new ruthenium(II) and iridium(III) complexes of a new bidentate chelate, NHCR'-pyOR (OR = OMe, OtBu, OH and R' = Me, Et). Synthesis and characterization studies were done on the following compounds: four ligand precursors (1-4); two silver complexes of these NHCR'-pyOR ligands (5-7); six ruthenium complexes of the type [η6-(p-cymene)Ru(NHCR'-pyOR)Cl]X with R' = Me, Et and R = Me, tBu, H and X = OTf-, PF6- and PO2F2- (8-13); and two iridium complexes, [Cp*Ir(NHCMe-pyOtBu)Cl]PF6 (14) and [Cp*Ir(NHCMe-pyOH)Cl]PO2F2 (15). The complexes are air stable and were isolated in moderate yield. However, for the PF6- salts, hydrolysis of the PF6- counter anion to PO2F2- during t-butyl ether deprotection was observed. Most of the complexes were characterized by 1H and 13C-NMR, MS, IR, and X-ray diffraction. The ruthenium complexes [η6-(p-cymene)Ru(NHCMe-pyOR)Cl]OTf (R = Me (8) and tBu (9)) were tested for their ability to accelerate CO2 hydrogenation and formic acid dehydrogenation. However, our studies show that the complexes transform during the reaction and these complexes are best thought of as pre-catalysts.

Iridium and Ruthenium Complexes of N-Heterocyclic Carbene- and Pyridinol-Derived Chelates as Catalysts for Aqueous Carbon Dioxide Hydrogenation and Formic Acid Dehydrogenation: The Role of the Alkali Metal.

Hydrogenation reactions can be used to store energy in chemical bonds, and if these reactions are reversible, that energy can be released on demand. Some of the most effective transition metal catalysts for CO2 hydrogenation have featured pyridin-2-ol-based ligands (e.g., 6,6'-dihydroxybipyridine (6,6'-dhbp)) for both their proton-responsive features and for metal-ligand bifunctional catalysis. We aimed to compare bidentate pyridin-2-ol based ligands with a new scaffold featuring an N-heterocyclic carbene (NHC) bound to pyridin-2-ol. Toward this aim, we have synthesized a series of [Cp*Ir(NHC-pyOR)Cl]OTf complexes where R = t Bu (1), H (2), or Me (3). For comparison, we tested analogous bipy-derived iridium complexes as catalysts, specifically [Cp*Ir(6,6'-dxbp)Cl]OTf, where x = hydroxy (4Ir ) or methoxy (5Ir ); 4Ir was reported previously, but 5Ir is new. The analogous ruthenium complexes were also tested using [(η6-cymene)Ru(6,6'-dxbp)Cl]OTf, where x = hydroxy (4Ru ) or methoxy (5Ru ); 4Ru and 5Ru were both reported previously. All new complexes were fully characterized by spectroscopic and analytical methods and by single-crystal X-ray diffraction for 1, 2, 3, 5Ir , and for two [Ag(NHC-pyOR)2]OTf complexes 6 (R = t Bu) and 7 (R = Me). The aqueous catalytic studies of both CO2 hydrogenation and formic acid dehydrogenation were performed with catalysts 1-5. In general, NHC-pyOR complexes 1-3 were modest precatalysts for both reactions. NHC complexes 1-3 all underwent transformations under basic CO2 hydrogenation conditions, and for 3, we trapped a product of its transformation, 3SP , which we characterized crystallographically. For CO2 hydrogenation with base and dxbp-based catalysts, we observed that x = hydroxy (4Ir ) is 5-8 times more active than x = methoxy (5Ir ). Notably, ruthenium complex 4Ru showed 95% of the activity of 4Ir . For formic acid dehydrogenation, the trends were quite different with catalytic activity showing 4Ir ≫ 4Ru and 4Ir ≈ 5Ir . Secondary coordination sphere effects are important under basic hydrogenation conditions where the OH groups of 6,6'-dhbp are deprotonated and alkali metals can bind and help to activate CO2. Computational DFT studies have confirmed these trends and have been used to study the mechanisms of both CO2 hydrogenation and formic acid dehydrogenation.

Reactivity studies of pincer bis-protic N-heterocyclic carbene complexes of platinum and palladium under basic conditions.

Bis-protic N-heterocyclic carbene complexes of platinum and palladium (4) yield dimeric structures 6 when treated with sodium tert-butoxide in CH2Cl2. The use of a more polar solvent (THF) and a strong base (LiN(iPr)2) gave the lithium chloride adducts monobasic complex 7 or analogous dibasic complex 8.

Azide Tripodal Dendrons from Behera's Amine and Their Clicked Dendrimers.

Diazo transfer reactions on Behera's amine and its next-generation analogue formed G0 and G1 azide dendrons bearing three and nine tert-butyl-protected esters, respectively. The utility of the new dendrons was demonstrated by copper-catalyzed azide-alkyne cycloaddition, with 1,3,5-triethynylbenzene, forming two novel dendrimers in a convergent manner. Acid-mediated dendrimer deprotection was successful, and the resulting carboxy-terminated dendrimers were analyzed by NMR and DOSY experiments.

Hydrogen-bonding pincer complexes with two protic N-heterocyclic carbenes from direct metalation of a 1,8-bis(imidazol-1-yl)carbazole by platinum, palladium, and nickel.

Pincer protic N-heterocyclic carbene (PNHC) complexes were synthesized by direct metalation, the formation of a metal carbon bond from an unfunctionalized CH bond in a single synthetic step. Significantly, direct metalation succeeded even for a first-row metal, nickel. The chloride complexes were isolated and then converted to the acetate, triflate, or in the platinum case, a hydride analogue. Crystal structures and (1) H, (13) C, and (15) N NMR data, as well as IR spectra, document the effects of intramolecular hydrogen bonding and the planar but flexible pincer framework. Anti-Markovnikov addition of OH bonds to alkynes, including catalyzed alkyne hydration, were demonstrated on the Pt triflate analog.

Bifunctional chelates optimized for molecular MRI.

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α(1)R,α(4)R,α(7)R,α(10)R)-α(1),α(4),α(7),α(10)-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, (17)O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin-avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent.

Supported imidazolylphosphine catalysts for highly (E)-selective alkene isomerization.

For fine chemical synthesis, immobilized catalysts offer little advantage if they produce a product mixture that must be separated. Selective isomerization of terminal olefins is achieved by heterogenized bifunctional catalysts. Outstanding and consistent (E)-selectivity (>99%) even in cases where (E) and (Z) isomers are of comparable stability, combined with modest catalyst loadings (1 to 2 mol %), set these catalysts apart from previously reported systems. Ease of catalyst removal and high geometric selectivity avoid tedious purifications.

General catalyst control of the monoisomerization of 1-alkenes to trans-2-alkenes.

After searching for the proper catalyst, the dual challenges of controlling the position of the double bond, and cis/trans-selectivity in isomerization of terminal alkenes to their 2-isomers are finally met in a general sense by mixtures of (C5Me5)Ru complexes 1 and 3 featuring a bifunctional phosphine. Typically, catalyst loadings of 1 mol % of 1 and 3 can be employed for the production of (E)-2-alkenes at 40-70 °C. Catalyst comprising 1 and 3 avoids more than any other known example the thermodynamic equilibration of alkene isomers, as the trans-2-alkenes of both nonfunctionalized and functionalized alkenes are generated.

Stereoselective alkene isomerization over one position.

Although controlling both the position of the double bond and E:Z selectivity in alkene isomerization is difficult, 1 is a very efficient catalyst for selective mono-isomerization of a variety of multifunctional alkenes to afford >99.5% E-products. Many reactions are complete within 10 min at room temperature. Even sensitive enols and enamides susceptible to further reaction can be generated. Catalyst loadings in the 0.01-0.1 mol% range can be employed. E-to-Z isomerization of the product from diallyl ether was only <10(-6) times as fast as its formation, showing the extremely high kinetic selectivity of 1.

PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses.

The peptide vaccine clinical trials encountered limited success because of difficulties associated with stability and delivery, resulting in inefficient antigen presentation and low response rates in patients with cancer. The purpose of this study was to develop a novel delivery approach for tumor antigenic peptides in order to elicit enhanced immune responses using poly(DL-lactide-co-glycolide) nanoparticles (PLGA-NPs) encapsulating tumor antigenic peptides. PLGA-NPs were made using the double emulsion-solvent evaporation method. Artificial antigen-presenting cells were generated by human dendritic cells (DCs) loaded with PLGA-NPs encapsulating tumor antigenic peptide(s). The efficiency of the antigen presentation was measured by interferon-γ ELISpot assay (Vector Laboratories, Burlingame, CA). Antigen-specific cytotoxic T lymphocytes (CTLs) were generated and evaluated by CytoTox 96(®) Non-Radioactive Cytotoxicity Assay (Promega, Fitchburg, WI). The efficiency of the peptide delivery was compared between the methods of emulsification in incomplete Freund's adjuvant and encapsulation in PLGA-NPs. Our results showed that most of the PLGA-NPs were from 150 nm to 500 nm in diameter, and were negatively charged at pH 7.4 with a mean zeta potential of -15.53 ± 0.71 mV; the PLGA-NPs could be colocalized in human DCs in 30 minutes of incubation. Human DCs loaded with PLGA-NPs encapsulating peptide induced significantly stronger CTL cytotoxicity than those pulsed with free peptide, while human DCs loaded with PLGA-NPs encapsulating a three-peptide cocktail induced a significantly greater CTL response than those encapsulating a two-peptide cocktail. Most importantly, the peptide dose encapsulated in PLGA-NPs was 63 times less than that emulsified in incomplete Freund's adjuvant, but it induced a more powerful CTL response in vivo. These results demonstrate that the delivery of peptides encapsulated in PLGA-NPs is a promising approach to induce effective antitumor CTL responses in vivo.

Evolution of iridium-based molecular catalysts during water oxidation with ceric ammonium nitrate.

Organometallic iridium complexes have been reported as water oxidation catalysts (WOCs) in the presence of ceric ammonium nitrate (CAN). One challenge for all WOCs regardless of the metal used is stability. Here we provide evidence for extensive modification of many Ir-based WOCs even after exposure to only 5 or 15 equiv of Ce(IV) (whereas typically 100-10000 equiv are employed during WOC testing). We also show formation of Ir-rich nanoparticles (likely IrO(x)) even in the first 20 min of reaction, associated with a Ce matrix. A combination of UV-vis and NMR spectroscopy, scanning transmission electron microscopy, and powder X-ray diffraction is used. Even simple IrCl(3) is an excellent catalyst. Our results point to the pitfalls of studying Ir WOCs using CAN.