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The advancement of metal-catalyzed carbon-carbon bond forming reactions represents one of the most significant contributions to contemporary organic synthesis. Innovations in the area of palladium catalyzed homogeneous cross-coupling catalysis have dominated this area of chem. and are playing an increasingly important role in the area of pharmaceutical drug discovery and development. However, the use of these catalysts under homogeneous conditions has limited their com. viability due to product contamination as a direct result of inability to effectively sep. the catalyst from the reaction product. Ligand-free heterogeneous catalysis presents a promising option to address this problem as evidenced by the significant increase in research activity in this area. We have recently developed a simple, one-step method for the preparation of bimetallic nickel-palladium nanoparticles supported on multi-walled carbon nanotubes (Ni-Pd/MWCNTs) under mech. shaking in a ball- mill. The preparation method is very fast and straightforward which does not require any chems., solvents, or addnl. ligands. Notably, the concentration of palladium can be lowered to a min. amount of 1% and replaced by more abundant and less expensive nickel nanoparticles while effectively catalyzing the reaction. The as-prepared nanoparticles demonstrated remarkable catalytic activities in cross-coupling catalysis such as Suzuki and Sonoga shira reactions with functionalized substrates in batch with high turnover number in a single catalytic reaction. Batch operations have several inherent limitations that include reproducibility, scalability, and reactor productivity. Continuous flow chem. has been considered as an alternative approach in academic and industrial processes due to its efficient and innovative synthetic design. The low palladium loading and excellent recyclability of the catalyst make this an affordable and clean option for cross-coupling catalysis under continuous flow conditions, a feature that enables the large-scale industrial and pharmaceutical applications of this method in the future. 

Metal catalyzed carbon-carbon bond forming reactions have rapidly become one of the most effective tools in organic synthesis for the assembly of highly functionalized molecules. These reactions have typically been carried out under homogeneous reaction conditions, which require the use of ligands to solubilize the catalyst and broaden its window of reactivity. However, the use of these catalysts under homogeneous conditions has limited their commercial viability due to product contamination as a direct result of inability to effectively separate the catalyst from the reaction product. Ligand-free heterogeneous catalysis presents a promising option to address this problem as evidenced by the significant increase in research activity in this area. We have recently developed a simple, one-step method for the preparation nickel nanoparticles supported on multi-walled carbon nanotubes (Ni/MWCNTs) under mechanical shaking in a ball-mill. The preparation method is very fast and straightforward which does not require any chemicals, solvents, or additional ligands. The as-prepared nanoparticles demonstrated remarkable catalytic activities in Suzuki cross-coupling reactions of the functionalized aryl halides and phenylboronic acids in batch with high turnover number in a single catalytic reaction. Batch operations have several inherent limitations that include reproducibility, scalability, and reactor productivity. Continuous flow chemistry has been considered as an alternative approach in academic and industrial processes due to its efficient and innovative synthetic design. Due to the low level of leaching observed in batch reactions as well as remarkable recyclability, the Ni/MWCNTs nanoparticles demonstrated remarkable catalytic activity in Suzuki coupling reactions with a diverse range of functionalized aryl halides and phenyl boronic acids under continuous flow conditions. Further optimization of the method including the reaction time, temperature, required solvents, flow rate, and minimum residence time will be discussed in this presentation. 

Buchwald-Hartwig amination is a cross-coupling reaction between aryl halides or pseudohalides and primary or secondary amines to produce aryl amines. The reaction has become a fundamental tool in organic synthesis for the formation of carbon-nitrogen bonds in a variety of biologically active molecules, natural products, pharmaceuticals, and material science. These reactions usually employ a palladium complex in homogeneous form along with a ligand to stabilize the metal center. In this regard, there are many disadvantages for using homogeneous catalysis including the potential contamination of the metal in the final product and lack of recyclability of the catalyst. Heterogeneous catalysis is an alternative attractive approach to construct carbon-nitrogen bonds in which the metal is fixed on variety of solid supports such as zeolites, polymers, mesoporous silica, and carbon materials. This would allow for ease of separation of the catalyst from the reaction and reusability for the subsequent runs. In this presentation, we will introduce the synthesis of amine-functionalized carbon nanotubes (CNTs) supported Pd nanoparticles (Pd/MWCNTs-NH2) via simple dry mixing of the corresponding palladium salts and amine-functionalized CNTs using the mechanical energy of a ball-mill mixer. The method is very straightforward and rapid and does not require any solvent or reducing agents, a feature that allows for large-scale preparation of these materials. The as-prepared catalyst demonstrated excellent catalytic activity for the Buchwald-Hartwig carbon–nitrogen cross-coupling reactions of variety of aryl halides and functionalized amines under microwave irradiation conditions and short reaction time. The Pd/MWCNTs-NH2 nanoparticles prepared by this simple, solventless, and inexpensive preparation provide a more direct, cost-efficient, and streamlined means to accomplish often-challenging Buchwald-Hartwig amination reactions. 

Cross-coupling reactions are typically carried out under batch reaction conditions in which the reactants and catalyst are charged to a vessel that is then heated for a specified period of time followed by removal of the reaction product mixture However, it would be difficult to effectively take advantage of the elevated catalytic activity exhibited by the catalyst under batch reaction conditions given the short reaction times required to affect conversion to product. We have recently prepared nickel nanoparticles supported on multi-walled carbon nanotubes (Ni/MWCNTs) by dry mixing of the corresponding nickel salts and multi-walled carbon nanotubes using a mechanical shaking of the ball-mill. The method allows for bulk production of Ni/M WCNTs nanoparticles with small particle size of 5- 10 nm ideal for application in batch and continuous flow cross-coupling catalysis. As an alternative approach to batch reactions, we successfully evaluated the Ni/MWCNTs system for Suzuki cross-coupling reactions under continuous flow reaction conditions by which the reactants can be fed onto a catalyst bed at a specified feed rate and reaction temperature while the Suzuki product is continuously recovered. This approach has the additional advantage of a significantly greater surface-to-volume ratio which significantly reduces the catalyst contact time. Furthermore, various functionalized aryl halides and phenylboronic acids can be prepared under continuous flow conditions in high conversion %, a feature which allows for industrial and pharmaceutical applications of this method in future. 

Nickel-palladium bimetallic nanoparticles supported on multi-walled carbon nanotubes (Ni-Pd/MWCNTs) were prepared by dry mixing of the nickel and palladium salts using the mechanical energy of a ball-mill. These nanoparticles demonstrated remarkable catalytic activity in Sonogashira cross-coupling reactions with a wide range of functionalized aryl halides and terminal alkynes under ligand and copper free conditions using Monowave 50 heating reactor. The catalyst is air-stable and can be easily removed from the reaction mixture by centrifugation and reused several times with minimal loss of catalytic activity. Furthermore, the concentration of catalyst in Sonogashira reactions can be lowered to a minimum amount of 0.01 mol%while still providing a high conversion of the Sonogashira product with an excellent turnover number (TON) of 7200 and turnover frequency (TOF) of 21600 h. The Ni-Pd/MWCNTs nanoparticles were fully characterized by a variety of spectroscopic techniques including X-ray diffraction (XRD), transmission electron microscopy(TEM) and X-ray photoelectron spectroscopy (XPS). The remarkable reactivity of the Ni-Pd/MWCNTs catalyst toward Sonogashira cross-coupling reactions is attributed to the high degree of the dispersion of Ni-Pdnanoparticles with small particle size of 5-10 nm due to an efficient grinding method. This work provides a facile, solventless and inexpensive method for large-scale preparation of Ni-Pd/MWCNTs to accomplish often-challenging Sonogashira cross coupling reactions. 

We have developed an efficient method to generate highly active nickel–palladium bimetallic nanoparticles supported on multi-walled carbon nanotubes (Ni–Pd/MWCNTs) by dry mixing of the nickel and palladium salts utilizing the mechanical energy of a ball-mill. These nanoparticles were successfully employed in Sonogashira cross-coupling reactions with a wide array of functionalized aryl halides and terminal alkynes under ligand and copper free conditions using a Monowave 50 heating reactor. Notably, the concentration of palladium can be lowered to a minimum amount of 0.81% and replaced by more abundant and less expensive nickel nanoparticles while effectively catalyzing the reaction. The remarkable reactivity of the Ni–Pd/MWCNTs catalyst toward Sonogashira cross-coupling reactions is attributed to the high degree of the dispersion of Ni–Pd nanoparticles with small particle size of 5–10 nm due to an efficient grinding method. The catalyst was easily removed from the reaction mixture by centrifugation and reused several times with minimal loss of catalytic activity. Furthermore, the concentration of catalyst in Sonogashira reactions can be reduced to a minimum amount of 0.01 mol% while still providing a high conversion of the Sonogashira product with a remarkable turnover number (TON) of 7200 and turnover frequency (TOF) of 21 600 h −1 . The catalyst was fully characterized by a variety of spectroscopic techniques including X-ray diffraction (XRD), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). 

Nickel-palladium bimetallic nanoparticles supported on multi-walled carbon nanotubes (Ni-Pd/MWCNTs) were prepared by dry mixing of the nickel and palladium salts using the mechanical energy of a ball-mill. These nanoparticles demonstrated remarkable catalytic activity in Sonogashira cross-coupling reactions with a wide range of functionalized aryl halides and terminal alkynes under ligand and copper free conditions using Monowave 50 heating reactor. The catalyst is air-stable and can be easily removed from the reaction mixture by centrifugation and reused several times with minimal loss of catalytic activity. Furthermore, the concentration of catalyst in Sonogashira reactions can be lowered to a minimum amount of 0.01 mol%while still providing a high conversion of the Sonogashira product with an excellent turnover number (TON) of 7200 and turnover frequency (TOF) of 21600 h. The Ni-Pd/MWCNTs nanoparticles were fully characterized by a variety of spectroscopic techniques including X-ray diffraction (XRD), transmission electron microscopy(TEM) and X-ray photoelectron spectroscopy (XPS). The remarkable reactivity of the Ni-Pd/MWCNTs catalyst toward Sonogashira cross-coupling reactions is attributed to the high degree of the dispersion of Ni-Pdnanoparticles with small particle size of 5-10 nm due to an efficient grinding method. This work provides a facile, solventless and inexpensive method for large-scale preparation of Ni-Pd/MWCNTs to accomplish often-challenging Sonogashira cross-coupling reactions. 

Sonogashira cross coupling reactions have a wide range of applications in pharmaceutical industry for drug discovery and organic synthesis of natural products and pharmaceutical compounds. These reactions typically involve the coupling of aryl halides with terminal alkynes in the presence of palladium catalyst under appropriate reaction conditions. Most Sonogashira reactions have been carried out with homogeneous Pd catalysis, in which the catalyst is soluble in the reaction mixture. There are many disadvantages to this method including the difficulty to remove the catalyst from the sample and recyclability. Heterogeneous catalysis is an alternative approach to address the issues associated with homogeneous system mainly due to facile and clean removal of the catalyst and minimum metal residual contamination. Herein, we report the preparation of nickel-palladium nanoparticles supported on multi-walled carbon nanotubes (Ni-Pd/MWCNTs) as an effective heterogeneous catalyst for Sonogashira coupling reactions. The catalyst was prepared by mixing the appropriate ratio of nickel-palladium salts with multi-walled carbon nanotubes using a mechanical power of a ball mill. The nanoparticles prepared by this method were successfully used to catalyze Sonogashira coupling reactions of various substituted aryl halides and terminal alkynes using an equal amount of water and ethanol as an environmentally benign solvent system. This project provides a facile and effective method for largescale preparation of Ni-Pd/MWCNTs to catalyze Sonogashira cross-coupling reactions. The recyclability of the catalyst makes this an affordable and clean option for pharmaceutical and industrial applications.