Bringing Selectivity in H/D Exchange Reactions Catalyzed by Metal Nanoparticles through Modulation of the Metal and the Ligand Shell.

Ru and Rh nanoparticles catalyze the selective H/D exchange in phosphines using D2 as the deuterium source. The position of the deuterium incorporation is determined by the structure of the P-based substrates, while activity depends on the nature of the metal, the properties of the stabilizing agents, and the type of the substituent on phosphorus. The appropriate catalyst can thus be selected either for the exclusive H/D exchange in aromatic rings or also for alkyl substituents. The selectivity observed in each case provides relevant information on the coordination mode of the ligand. Density functional theory calculations provide insights into the H/D exchange mechanism and reveal a strong influence of the phosphine structure on the selectivity. The isotope exchange proceeds via C-H bond activation at nanoparticle edges. Phosphines with strong coordination through the phosphorus atom such as PPh3 or PPh2Me show preferred deuteration at ortho positions of aromatic rings and at the methyl substituents. This selectivity is observed because the corresponding C-H moieties can interact with the nanoparticle surface while the phosphine is P-coordinated, and the C-H activation results in stable metallacyclic intermediates. For weakly coordinating phosphines such as P(o-tolyl)3, the interaction with the nanoparticle can occur directly through phosphine substituents, and then, other deuteration patterns are observed.

In situ Generated Iridium Nanoparticles as Hydride Donors in Photoredox-Catalyzed Hydrogen Isotope Exchange Reactions with Deuterium and Tritium Gas.

We have studied the photoredox-catalyzed hydrogen isotope exchange (HIE) reaction with deuterium or tritium gas as isotope sources and in situ formed transition metal nanoparticles as hydrogen atom transfer pre-catalysts. By this means we have found synergistic reactivities applying two different HIE mechanisms, namely photoredox-catalyzed and CH-functionalization HIE leading to the synthesis of highly deuterated complex molecules. Finally, we adopted these findings successfully to tritium chemistry.

Nanocatalyzed Hydrogen Isotope Exchange.

Recently, hydrogen isotope exchange (HIE) reactions have experienced impressive development due to the growing importance of isotope containing compounds in various fields including materials and life sciences, in addition to their classical use for mechanistic studies in chemistry and biology. Tritium-labeled compounds are also of crucial interest to study the in vivo fate of a bioactive substance or in radioligand binding assays. Over the past few years, deuterium-labeled drugs have been extensively studied for the improvement of ADME (absorption, distribution, metabolism, excretion) properties of existing bioactive molecules as a consequence of the primary kinetic isotope effect. Furthermore, in the emergent "omic" fields, the need for new stable isotopically labeled internal standards (SILS) for quantitative GC- or LC-MS analyses is increasing. Because of their numerous applications, the development of powerful synthetic methods to access deuterated and tritiated molecules with either high isotope incorporation and/or selectivities is of paramount importance.HIE reactions allow a late-stage incorporation of hydrogen isotopes in a single synthetic step, thus representing an advantageous alternative to conventional multistep synthesis approaches which are time- and resource-consuming. Moreover, HIE reactions can be considered as the most fundamental C-H functionalization processes and are therefore of great interest for the chemists' community. Depending on the purpose, HIE reactions must either be highly regioselective or allow a maximal incorporation of hydrogen isotopes, sometimes both. In this context, metal-catalyzed HIE reactions are generally performed using either homogeneous or heterogeneous catalysis which may have considerable drawbacks including an insufficient isotope incorporation and a lack of chemo- and/or regioselectivity, respectively.Over the past 6 years, we have shown that nanocatalysis can be considered as a powerful tool to access complex labeled molecules (e.g., pharmaceuticals, peptides and oligonucleotides) via regio- and chemoselective or even enantiospecific labeling processes occurring at the surface of metallic nanoclusters (Ru or Ir). Numerous heterocyclic (both saturated and unsaturated) and acyclic scaffolds have been labeled with an impressive functional group tolerance, and highly deuterated compounds or high molar activity tritiated drugs have been obtained. An insight into mechanisms has also been provided by theoretical calculations to explain the regioselectivities of the isotope incorporation. Our studies have suggested that undisclosed key intermediates, including 4- and 5-membered dimetallacycles, account for the particular regioselectivities observed during the process, in contrast to the 5- or 6-membered metallacycle key intermediates usually encountered in homogeneous catalysis. These findings together with the important number of available coordination sites explain the compelling reactivity of metal nanoparticles, in between homogeneous and heterogeneous catalysis. They represent innovative tools combining the advantages of both methods for the isotopic labeling and activation of C-H bonds of complex molecules.

σ-H-H, σ-C-H, and σ-Si-H Bond Activation Catalyzed by Metal Nanoparticles.

Activation of H-H, Si-H, and C-H bonds through σ-bond coordination has grown in the past 30 years from a scientific curiosity to an important tool in the functionalization of hydrocarbons. Several mechanisms were discovered via which the initially σ-bonded substrate could be converted: oxidative addition, heterolytic cleavage, σ-bond metathesis, electrophilic attack, etc. The use of metal nanoparticles (NPs) in this area is a more recent development, but obviously nanoparticles offer a much richer basis than classical homogeneous and heterogeneous catalysts for tuning reactivity for such a demanding process as C-H functionalization. Here, we will review the surface chemistry of nanoparticles and catalytic reactions occurring in the liquid phase, catalyzed by either colloidal or supported metal NPs. We consider nanoparticles prepared in solution, which are stabilized and tuned by polymers, ligands, and supports. The question we have addressed concerns the differences and similarities between molecular complexes and metal NPs in their reactivity toward σ-bond activation and functionalization.

Single-Crystalline Body Centered FeCo Nano-Octopods: From One-Pot Chemical Growth to a Complex 3D Magnetic Configuration.

Single crystalline magnetic FeCo nanostars were prepared using an organometallic approach under mild conditions. The fine-tuning of the experimental conditions allowed the direct synthesis of these nano-octopods with body-centered cubic (bcc) structure through a one-pot reaction, contrarily to the seed-mediated growth classically used. The FeCo nanostars consist of 8 tetrahedrons exposing {311} facets, as revealed by high resolution transmission electron microscopy (HRTEM) imaging and electron tomography (ET), and exhibit a high magnetization comparable with the bulk one (Ms = 235 A·m2·kg-1). Complex 3D spin configurations resulting from the competition between dipolar and exchange interactions are revealed by electron holography. This spin structures are stabilized by the high aspect ratio tetrahedral branches of the nanostars, as confirmed by micromagnetic simulations. This illustrates how magnetic properties can be significantly tuned by nanoscale shape control.

Organometallic Synthesis of Magnetic Metal Nanoparticles.

Magnetic nanoparticles (NPs) are attractive both for their fundamental properties and for their potential in a variety of applications ranging from nanomedicine and biology to micro/nanoelectronics and catalysis. While these fields are dominated by the use of iron oxides, reduced metal NPs are of interest since they display high magnetization and adjustable anisotropy according to their size, shape and composition. The use of organometallic precursors makes it possible to adjust the size, shape (sphere, cube, rod, wire, urchin, …) and composition (alloys, core-shell, composition gradient, dumbbell, …) of the resulting NPs and hence their magnetic properties. We discuss here the synthesis of magnetic metal NPs from organometallic precursors carried out in Toulouse, as well as their associated properties and their potential in applications.

Organometallic Synthesis of Bimetallic Cobalt-Rhodium Nanoparticles in Supported Ionic Liquid Phases (Cox Rh100- x @SILP) as Catalysts for the Selective Hydrogenation of Multifunctional Aromatic Substrates.

The synthesis, characterization, and catalytic properties of bimetallic cobalt-rhodium nanoparticles of defined Co:Rh ratios immobilized in an imidazolium-based supported ionic liquid phase (Cox Rh100- x @SILP) are described. Following an organometallic approach, precise control of the Co:Rh ratios is accomplished. Electron microscopy and X-ray absorption spectroscopy confirm the formation of small, well-dispersed, and homogeneously alloyed zero-valent bimetallic nanoparticles in all investigated materials. Benzylideneacetone and various bicyclic heteroaromatics are used as chemical probes to investigate the hydrogenation performances of the Cox Rh100- x @SILP materials. The Co:Rh ratio of the nanoparticles is found to have a critical influence on observed activity and selectivity, with clear synergistic effects arising from the combination of the noble metal and its 3d congener. In particular, the ability of Cox Rh100- x @SILP catalysts to hydrogenate 6-membered aromatic rings is found to experience a remarkable sharp switch in a narrow composition range between Co25 Rh75 (full ring hydrogenation) and Co30 Rh70 (no ring hydrogenation).

Commercial Cu2 Cr2 O5 Decorated with Iron Carbide Nanoparticles as a Multifunctional Catalyst for Magnetically Induced Continuous-Flow Hydrogenation of Aromatic Ketones.

Copper chromite is decorated with iron carbide nanoparticles, producing a magnetically activatable multifunctional catalytic system. This system (ICNPs@Cu2 Cr2 O5 ) can reduce aromatic ketones to aromatic alcohols when exposed to magnetic induction. Under magnetic excitation, the ICNPs generate locally confined hot spots, selectively activating the Cu2 Cr2 O5 surface while the global temperature remains low (≈80 °C). The catalyst selectively hydrogenates a scope of benzylic and non-benzylic ketones under mild conditions (3 bar H2 , heptane), while ICNPs@Cu2 Cr2 O5 or Cu2 Cr2 O5 are inactive when the same global temperature is adjusted by conventional heating. A flow reactor is presented that allows the use of magnetic induction for continuous-flow hydrogenation at elevated pressure. The excellent catalytic properties of ICNPs@Cu2 Cr2 O5 for the hydrogenation of biomass-derived furfuralacetone are conserved for at least 17 h on stream, demonstrating for the first time the application of a magnetically heated catalyst to a continuously operated hydrogenation reaction in the liquid phase.

Hydrogen Isotope Exchange Catalyzed by Ru Nanocatalysts: Labelling of Complex Molecules Containing N-Heterocycles and Reaction Mechanism Insights.

Ruthenium nanocatalysis can provide effective deuteration and tritiation of oxazole, imidazole, triazole and carbazole substructures in complex molecules using D2 or T2 gas as isotopic sources. Depending on the substructure considered, this approach does not only represent a significant step forward in practice, with notably higher isotope uptakes, a broader substrate scope and a higher solvent applicability compared to existing procedures, but also the unique way to label important heterocycles using hydrogen isotope exchange. In terms of applications, the high incorporation of deuterium atoms, allows the synthesis of internal standards for LC-MS quantification. Moreover, the efficacy of the catalyst permits, even under subatmospheric pressure of T2 gas, the preparation of complex radiolabeled drugs owning high molar activities. From a fundamental point of view, a detailed DFT-based mechanistic study identifying undisclosed key intermediates, allowed a deeper understanding of C-H (and N-H) activation processes occurring at the surface of metallic nanoclusters.

Chemical Ordering in Bimetallic FeCo Nanoparticles: From a Direct Chemical Synthesis to Application As Efficient High-Frequency Magnetic Material.

Single-crystalline FeCo nanoparticles with tunable size and shape were prepared by co-decomposing two metal-amide precursors under mild conditions. The nature of the ligands introduced in this organometallic synthesis drastically affects the reactivity of the precursors and, thus, the chemical distribution within the nanoparticles. The presence of the B2 short-range order was evidenced in FeCo nanoparticles prepared in the presence of HDAHCl ligands, combining 57Fe Mössbauer, zero-field 59Co ferromagnetic nuclear resonance (FNR), and X-ray diffraction studies. This is the first time that the B2 structure is directly formed during synthesis without the need of any annealing step. The as-prepared nanoparticles exhibit magnetic properties comparable with the ones for the bulk ( Ms = 226 Am2·kg-1). Composite magnetic materials prepared from these FeCo nanoparticles led to a successful proof-of-concept of the integration on inductor-based filters (27% enhancement of the inductance value at 100 MHz).

Engineering Iron-Nickel Nanoparticles for Magnetically Induced CO2 Methanation in Continuous Flow.

Induction heating of magnetic nanoparticles (NPs) is a method to activate heterogeneous catalytic reactions. It requires nano-objects displaying high heating power and excellent catalytic activity. Here, using a surface engineering approach, bimetallic NPs are used for magnetically induced CO2 methanation, acting both as heating agent and catalyst. The organometallic synthesis of Fe30 Ni70 NPs displaying high heating powers at low magnetic field amplitudes is described. The NPs are active but only slightly selective for CH4 after deposition on SiRAlOx owing to an iron-rich shell (25 mL min-1 , 25 mT, 300 kHz, conversion 71 %, methane selectivity 65 %). Proper surface engineering consisting of depositing a thin Ni layer leads to Fe30 Ni70 @Ni NPs displaying a very high activity for CO2 hydrogenation and a full selectivity. A quantitative yield in methane is obtained at low magnetic field and mild conditions (25 mL min-1 , 19 mT, 300 kHz, conversion 100 %, methane selectivity 100 %).

Magnetically Induced CO2 Methanation Using Exchange-Coupled Spinel Ferrites in Cuboctahedron-Shaped Nanocrystals.

Magnetically induced catalysis can be promoted taking advantage of optimal heating properties from the magnetic nanoparticles to be employed. However, when unprotected, these heating agents that are usually air-sensitive, get sintered under the harsh catalytic conditions. In this context, we present, to the best of our knowledge, the first example of air-stable magnetic nanoparticles that: 1) show excellent performance as heating agents in the CO2 methanation catalyzed by Ni/SiRAlOx, with CH4 yields above 95 %, and 2) do not sinter under reaction conditions. To attain both characteristics we demonstrate, first the exchange-coupled magnetic approach as an alternative and effective way to tune the magnetic response and heating efficiency, and second, the chemical stability of cuboctahedron-shaped core-shell hard CoFe2 O4 -soft Fe3 O4 nanoparticles.

NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines.

The preparation of N-heterocyclic carbene-stabilized iridium nanoparticles and their application in hydrogen isotope exchange reactions is reported. These air-stable and easy-to-handle iridium nanoparticles showed a unique catalytic activity, allowing selective and efficient hydrogen isotope incorporation on anilines using D2 or T2 as isotopic source. The usefulness of this transformation has been demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.

Tuning the Reactivity of a Heterogeneous Catalyst using N-Heterocyclic Carbene Ligands for C-H Activation Reactions.

We report the dramatic impact of the addition of N-heterocyclic carbenes (NHCs) on the reactivity and selectivity of heterogeneous Ru catalysts in the context of C-H activation reactions. Using a simple and robust method, we prepared a series of new air-stable catalysts starting from commercially available Ru on carbon (Ru/C) and differently substituted NHCs. Associated with C-H deuteration processes, depending on Ru/C-NHC ratios, the chemical outcome can be controlled to a large extent. Indeed, tuning the reactivity of the Ru catalyst with NHC enabled: 1) increased chemoselectivity and the regioselectivity for the deuteration of alcohols in organic media; 2) the synthesis of fragile pharmaceutically relevant deuterated heterocycles (azine, purine) that are otherwise completely reduced using unmodified commercial catalysts; 3) the discovery of a novel reactivity for such heterogeneous Ru catalysts, namely the selective C-1 deuteration of aldehydes.

Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals.

Radiolabelling is fundamental in drug discovery and development as it is mandatory for preclinical ADME studies and late-stage human clinical trials. Herein, a general, effective, and easy to implement method for the multiple site incorporation of deuterium and tritium atoms using the commercially available and air-stable iridium precatalyst [Ir(COD)(OMe)]2 is described. A large scope of pharmaceutically relevant substructures can be labelled using this method including pyridine, pyrazine, indole, carbazole, aniline, oxa-/thia-zoles, thiophene, but also electron-rich phenyl groups. The high functional group tolerance of the reaction is highlighted by the labelling of a wide range of complex pharmaceuticals, containing notably halogen or sulfur atoms and nitrile groups. The multiple site hydrogen isotope incorporation has been explained by the in situ formation of complementary catalytically active species: monometallic iridium complexes and iridium nanoparticles.

Organometallic Ruthenium Nanoparticles: Synthesis, Surface Chemistry, and Insights into Ligand Coordination.

Although there has been for the past 20 years great interest in the synthesis and use of metal nanoparticles, little attention has been paid to the complexity of the surface of these species. In particular, the different aspects concerning the ligands present, their location, their mode of binding, and their dynamics have been little studied. Our group has started in the early 1990s an investigation of the surface coordination chemistry of ruthenium and platinum nanoparticles but at that time with a lack of adequate techniques to fulfill our ambition. Over 10 years later, we went back to this problem and could obtain a more precise vision of the surface species. This Account is centered on ruthenium chemistry. This metal has been the most studied in our group, first thanks to the availability of a precursor, Ru(cyclooctadiene)(cyclooctatriene) (Ru(COD)(COT)), which possesses the ability to decompose in very mild conditions without leaving residues on the resulting nanoparticles and second because of the absence of magnetic perturbations (Knight shift, paramagnetism, ferromagnetism, etc.), which has allowed the use of solution and solid state NMR. In this respect, it has been possible to evidence the presence of a high concentration of hydrides on the surface of these particles, to study their dynamics, and to show that since the polarity of the Ru-H bond is similar to that of the C-H bond, a Ru/H NP would behave as a big lipophilic entity. The second point was to characterize the coordination of ancillary ligands. This has been achieved for different ligands, in particular phosphines and carbenes, which made possible the study of the modification of NP reactivity induced by surface ligands. This led to the conclusion that the presence of surface ligands can benefit both the activity of NP catalysts and their selectivity. If it was expected that the selectivity could be modulated, the promoting effect from the presence of ligands on, for example, arene or CO hydrogenation was totally unexpected. Playing with poison atoms (Sn, Fe, etc.) or ligands (CO) may allow us to play with the reactivity of the NPs to make them more selective for selected reactions. Finally, the search for specific ligands for nanoparticles is still in its infancy, but some examples have been found as have specific reactions of nanoparticles. Obviously arene hydrogenation and CO hydrogenation were well-known in heterogeneous catalysis, but we could demonstrate that they can be carried out in very mild conditions on ligand stabilized RuNPs. On the other hand, the enantiospecific C-H activation leading to enantioselective labeling of large organic or biomolecules or the C-C bond cleavage in mild conditions were both unexpected. There is still much work to perform for reaching the degree of control on nanoparticles that is presently achieved in organometallic molecular chemistry, but this work shows that it is possible.

Hydrodeoxygenation Using Magnetic Induction: High-Temperature Heterogeneous Catalysis in Solution.

Magnetic heating has recently been demonstrated as an efficient way to perform catalytic reactions after deposition of the heating agent and the catalyst on a support. Here we show that in solution, and under mild conditions of mean temperature and pressure, it is possible to use magnetic heating to carry out transformations that are otherwise performed heterogeneously at high pressure and/or high temperature. As a proof of concept, we chose the hydrodeoxygenation of acetophenone derivatives and of biomass-derived molecules, namely furfural and hydroxymethylfurfural. These reactions are difficult, require heterogeneous catalysts and high pressures, and, to the best of our knowledge, have no precedent in standard solution. Here, hydrodeoxygenations are fully selective under mild conditions (3 bar H2 , moderate mean temperature of the solvent). The reason for this reactivity is the fast heating of the particles well above the boiling temperature of the solvent and the local creation of hot spots surrounded by a vapor layer, in which high temperature and pressure may be present. This technology may be practicable for many organic transformations.

Efficient Access to Deuterated and Tritiated Nucleobase Pharmaceuticals and Oligonucleotides using Hydrogen-Isotope Exchange.

A general approach for the efficient hydrogen-isotope exchange of nucleobase derivatives is described. Catalyzed by ruthenium nanoparticles, using mild reaction conditions, and involving either D2 or T2 as isotopic sources, this reaction possesses a wide substrate scope and a high solvent tolerability. This novel method facilitates the access to essential diagnostic tools in drug discovery and development: tritiated pharmaceuticals with high specific activities and deuterated oligonucleotides suitable for use as internal standards during LC-MS quantification.

Synergism of Au and Ru Nanoparticles in Low-Temperature Photoassisted CO2 Methanation.

Au and Ru nanoparticles (NPs) have been deposited on Siralox® substrate by impregnation and chemical reduction, respectively (Au-Ru-S). The as-prepared material is very active in the selective CO2 methanation to CH4 at temperatures below 250 °C. In addition, Au-Ru-S shows enhanced CH4 production upon irradiation with UV/Vis light starting at temperatures higher than 200 °C, although the contribution of the photoassisted pathway of CH4 production decreases as the temperature increases. Thus, a maximum CH4 production of 204 mmol gRu -1 at 250 °C upon 100 mW cm-2 irradiation was achieved. Control experiments, in which Ru-S and Au-S materials were used, revealed that Ru NPs are the CO2 methanation active sites, while Au NPs contribute by harvesting light, mainly visible as a consequence of the strong Au plasmon band centered at 529 nm. The visible light absorbed by the plasmonic band of Au NPs could make them act ass local heaters of the neighboring Ru NPs, increasing their temperature and enhancing CH4 production.

Gas phase 1H NMR studies and kinetic modeling of dihydrogen isotope equilibration catalyzed by Ru-nanoparticles under normal conditions: dissociative vs. associative exchange.

The equilibration of H2, HD and D2 between the gas phase and surface hydrides of solid organic-ligand-stabilized Ru metal nanoparticles has been studied by gas phase 1H NMR spectroscopy using closed NMR tubes as batch reactors at room temperature and 800 mbar. When two different nanoparticle systems, Ru/PVP (PVP ≡ polyvinylpyrrolidone) and Ru/HDA (HDA ≡ hexadecylamine) were exposed to D2 gas, only the release of HD from the hydride containing surface could be detected in the initial stages of the reaction, but no H2. In the case of Ru/HDA also the reverse experiment was performed where surface deuterated nanoparticles were exposed to H2. In that case, the conversion of H2 into gaseous HD was detected. In order to analyze the experimental kinetic and spectroscopic data, we explored two different mechanisms taking into account potential kinetic and equilibrium H/D isotope effects. Firstly, we explored the dissociative exchange mechanism consisting of dissociative adsorption of dihydrogen, fast hydride surface diffusion and associative desorption of dihydrogen. It is shown that if D2 is the reaction partner, only H2 will be released in the beginning of the reaction, and HD only in later reaction stages. The second mechanism, dubbed here associative exchange consists of the binding of dihydrogen to Ru surface atoms, followed by a H-transfer to or by H-exchange with an adjacent hydride site, and finally of the associative desorption of dihydrogen. In that case, in the exchange with D2, only HD will be released in the beginning of the reaction. Our experimental results are not compatible with the dissociative exchange but can be explained in terms of the associative exchange. Whereas the former will dominate at low temperatures and pressures, the latter will prevail around room temperature and normal pressures where transition metal nanoparticles are generally used as reaction catalysts.