Streamlining the synthesis of amides using Nickel-based nanocatalysts

Amide synthesis is a cornerstone technology in the production of fine and bulk chemicals, as well as countless everyday products. Its central role in organic synthesis and the creation of numerous biomolecules underscores its significance. Traditional amide bond formation often involves the condensation of a carboxylic acid (or derivative) and an amine, releasing water. To enhance this reaction, activated carboxylic acid derivatives (acyl chlorides, anhydrides) are frequently employed, reacting with amines or utilizing stoichiometric coupling reagents. However, these classic methods suffer from several drawbacks: they generate substantial waste from stoichiometric activating agents (e.g., carbodiimides, ammonium or phosphonium salts, thionyl chloride), and product purification is often challenging and expensive. The inherent limitations of these traditional approaches, coupled with the ubiquitous nature of amide bonds in pharmaceuticals (73 of the top 200 selling drugs in 2020 contained amide derivatives), necessitate the development of more sustainable and efficient methods. Carboxylic esters offer a promising alternative to carboxylic acids for amide bond formation. Furthermore, the direct use of nitroarenes, which are readily reduced to anilines, presents a step-economic advantage for amide synthesis. While some homogeneous catalytic systems have been reported, they often require stoichiometric additives or expensive reducing agents. The use of a heterogeneous catalyst would offer advantages in terms of ease of separation, cost-effectiveness, and practical applicability. This study addresses the need for a more sustainable and efficient method by exploring a heterogeneous nickel-based catalyst for the direct reductive amidation of nitro compounds and esters using molecular hydrogen.

The existing literature extensively documents various methods for amide synthesis, ranging from the use of activated carboxylic acid derivatives and coupling reagents to more recent approaches employing transition metal catalysis. However, many established methods struggle with atom economy, generate significant waste, or require harsh reaction conditions. The use of carboxylic esters as starting materials for amide synthesis offers a potential improvement in atom economy and reduced waste, but existing methods using this approach are often limited in scope or require specific reaction conditions. The direct use of nitroarenes as precursors to anilines in amide synthesis has been sparsely explored. While homogeneous nickel catalysts have been employed, they often rely on stoichiometric amounts of reducing agents. Ir-Fe homogeneous photocatalyst systems have also been reported, but these involve the use of expensive reducing agents like PhSiH3. The development of a heterogeneous catalyst for this transformation is highly desirable, offering benefits in terms of catalyst recyclability and ease of product separation. The existing literature highlights the importance of this endeavor due to the prevalence of amides in pharmaceuticals and other important molecules, and the limitations of current methodologies in terms of efficiency, waste generation, and cost.

The researchers synthesized various nanostructured 3d metal catalysts supported on different materials (TiO2, γ-Al2O3, SiO2, Vulcan carbon) using a facile approach. The catalysts were prepared by in situ mixing of metal nitrates (Fe, Co, Ni) with aniline ligands (o-phenylenediamine, p-phenylenediamine, aniline) in methanol, followed by immobilization on the support and pyrolysis under an argon atmosphere. The resulting materials, denoted as M-L@Support-T (M=metal, L=ligand, T=pyrolysis temperature), were characterized using various techniques such as TEM, XRD, XPS, TPD, and BET. The catalytic activity was evaluated using the reductive amidation of 4-nitrophenol with ethyl acetate to produce 4-acetaminophen (paracetamol) as a model reaction under industrially relevant conditions (20 bar H2, 130 °C). The effects of different metals, ligands, supports, and pyrolysis temperatures were investigated to optimize the catalyst performance. Catalyst stability and recyclability were assessed through multiple reaction cycles, followed by characterization of the recycled catalyst to understand any changes in morphology or composition. In situ XPS experiments were conducted to monitor changes in the catalyst's surface oxidation state under different reaction conditions. DFT computations were performed to gain insights into the adsorption and activation of reactants on the catalyst surface. The general applicability of the optimized catalyst was demonstrated by conducting amidation reactions with a wide range of nitro compounds and esters, including those bearing various functional groups. Late-stage modifications of bioactive compounds and the synthesis of several drug molecules were also performed to illustrate the practicality of this methodology. Scale-up reactions were carried out to demonstrate the scalability of the process.

The study identified Ni-L1@TiO2-800 (Ni nanoparticles supported on TiO2 with o-phenylenediamine ligand, pyrolyzed at 800 °C) as the optimal catalyst for the reductive amidation reaction. This catalyst demonstrated high activity and selectivity, achieving >99% conversion and 85% yield of paracetamol in the model reaction. The other supports (carbon, SiO2, γ-Al2O3) proved less selective, yielding mixtures of products. The ligand was crucial for catalytic activity; catalysts prepared without the ligand showed negligible activity. The pyrolysis temperature significantly affected the catalyst's performance, with 800 °C yielding the best results. The catalyst could also be employed under transfer hydrogenation conditions (using formic acid) and with CO as a reductant, showcasing its robustness. The catalyst exhibited good stability and could be recycled for at least 7 cycles with a gradual loss in activity attributed to the aggregation of Ni nanoparticles (increase in average particle size from 11.7 nm to 24.2 nm after 8 cycles), not Ni leaching. Characterization revealed the presence of metallic Ni⁰ and Ni3S2 species, along with anatase TiO2. XPS analysis showed that the proportion of Ni⁰ at the surface was maximized (around 43%) at 800 °C. In situ XPS studies under hydrogen revealed the reduction of Ni²⁺ to Ni⁰ and the formation of low-valent Ti species (Ti³⁺ and Ti²⁺) at the surface of the catalyst, but not under nitrogen. DFT calculations indicated that aniline preferentially interacts with Ti³⁺, suggesting a role of low-valent Ti species in activating the aniline. The optimized catalyst showed excellent substrate scope, enabling the synthesis of a wide array of amides from various nitro compounds (both aromatic and aliphatic) and esters, with functional groups such as halogens, ketones, carboxylic acids, esters, nitriles, and vinyl groups being well tolerated. The synthesis of several drug molecules and the late-stage functionalization of bioactive compounds were successfully demonstrated on both small and large scales (gram-scale).

The findings demonstrate a highly efficient and sustainable approach to amide synthesis, addressing the limitations of traditional methods. The use of a heterogeneous nickel-based catalyst, molecular hydrogen as a reductant, and additive-free conditions significantly enhance the sustainability and atom economy of the process. The excellent substrate scope and functional group tolerance broaden the applicability of this methodology beyond simple model reactions. The ability to synthesize various drug molecules and modify bioactive compounds showcases its practical value in pharmaceutical and medicinal chemistry. The mechanistic studies provide important insights into the synergistic roles of metallic nickel and low-valent Ti species in this tandem catalytic process, suggesting a mechanism involving nitro reduction by metallic nickel followed by amidation facilitated by the TiO2 support and low-valent titanium. The success of the gram-scale reactions emphasizes the scalability of this approach for industrial applications. This work contributes significantly to the field by providing a novel, highly efficient, and sustainable method for amide synthesis, opening new avenues for the preparation of valuable fine chemicals and pharmaceuticals.

This research successfully developed a practical and efficient reductive amidation methodology for the direct synthesis of amides from nitro compounds and esters using a nickel-based nanocatalyst. The method offers significant advantages over traditional approaches in terms of sustainability, step economy, and functional group tolerance. The successful synthesis of various drug molecules and the modification of bioactive compounds highlight its practical value. Further research could explore other metal catalysts, ligands, and support materials to further optimize the catalyst performance and expand the scope of this methodology. Investigating the application of this approach to other important chemical transformations would also be a valuable future direction.

While the catalyst showed good recyclability for several cycles, gradual deactivation due to nanoparticle aggregation was observed. The scope of esters used in this methodology could be further expanded. While a wide variety of functional groups were tolerated, some substrates might exhibit limitations in reactivity or selectivity. The detailed mechanism needs further investigation, particularly clarifying the exact role of the low-valent Ti species in the amidation step.