B. Frank Gupton

Palladium nanoparticles supported on carbon nanotubes from solventless preparations: versatile catalysts for ligand-free Suzuki cross coupling reactions

Palladium nanoparticles supported on single- or multi-walled carbon nanotubes (Pd/SWCNT and Pd/MWCNT) were prepared by a rapid, solventless method that does not require reducing agents or electric current. The method involves a straightforward process using dry mixing of a precursor Pd salt (e.g., palladium acetate) with carbon nanotubes at ambient temperature by ball-milling (mechanochemical route) or with subsequent annealing at 300 °C (thermal route) in an inert atmosphere. The Pd/MWCNT sample with Pd nanoparticle size of 1–3 nm and uniform dispersion prepared by mechanochemical ball-milling at room temperature [designated as (Pd/MWCNT)M] displayed remarkable catalytic activity towards Suzuki cross coupling reactions with a high turn over number (TON) of 7250 and turn over frequency (TOF) of 217500 h−1. These nanoparticles were characterized by a variety of techniques including transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Additionally, the (Pd/MWCNT)M sample was successfully employed in Suzuki cross coupling reactions with a wide variety of functionalized substrates.

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

Summary 2-Chloro-3-amino-4-picoline (CAPIC) is a strategic building block for the preparation of nevirapine, a widely-prescribed non-nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.

Selective N-Chelation-Directed C–H Activation Reactions Catalyzed by Pd(II) Nanoparticles Supported on Multiwalled Carbon Nanotubes

N-Chelation-directed C-H activation reactions that utilize the Pd(II)/Pd(IV) catalytic cycle have been previously reported. To date, these reactions employ only homogeneous palladium catalysts. The first use of a solid-supported Pd(II) catalyst [Pd(II) nanoparticles on multiwalled carbon nanotubes, Pd(II)/MWCNT] to carry out N-chelation-directed C-H to C-O, C-Cl, and C-Br transformations is reported. The results presented demonstrate that the solid-supported Pd(II)/MWCNT catalyst can effectively catalyze C-H activation reactions using the Pd(II)/Pd(IV) catalytic cycle.

Microwave-assisted synthesis of Pd nanoparticles supported on Fe3O4, Co3O4, and Ni(OH)2 nanoplates and catalysis application for CO oxidation

AbstractIn this paper, we report a simple, versatile, and rapid method for the synthesis of Pd nanoparticle catalysts supported on Fe3O4, Co3O4, and Ni(OH)2 nanoplates via microwave irradiation. The important advantage of microwave dielectric heating over convective heating is that the reactants can be added at room temperature (or slightly higher temperatures) without the need for high-temperature injection. Furthermore, the method can be used to synthesize metal nanoparticle catalysts supported on metal oxide nanoparticles in one step. We also demonstrate that the catalyst-support interaction plays an important role in the low temperature oxidation of CO. The current results reveal that the Pd/Co3O4 catalyst has particularly high activity for CO oxidation as a result of the strong interaction between the Pd nanoparticles and the Co3O4 nanoplates. Optimizations of the size, composition, and shape of these catalysts could provide a new family of efficient nanocatalysts for the low temperature oxidation of CO.

Improved Synthesis of Mono- and Disubstituted 2-Halonicotinonitriles from Alkylidene Malononitriles

Pyridines with 2,3,4 and/or 5 substitution remain challenging to prepare. Existing strategies to form multisubstituted 2-halonicotinonitriles via enamines suffer from dimerization of the starting alkylidene malononitriles resulting in low yields. Through alteration of reaction conditions, a new high yielding method into enamines was realized by condensing DMF-DMA and alkylidene malononitriles in the presence of substoichiometric acetic anhydride. Cyclization of the resulting enamines under Pinner conditions provided 2-halonicotinonitriles in high overall yields.

A convergent approach to the total synthesis of telmisartan via a Suzuki cross-coupling reaction between two functionalized benzimidazoles.

A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.

A flow-based synthesis of telmisartan

A highly efficient continuous synthesis has been developed for telmisartan, the active ingredient in the antihypertensive drug, Micardis. This synthetic route employs a convergent strategy that requires no intermediate purifications or solvent exchanges. The key step in the reaction scheme is a Suzuki cross-coupling reaction between two functionalized benzimi-dazoles that is catalyzed by a solid-supported Pd catalyst. This flow-based approach utilizes a tubular reactor system coupled with a plug flow packed bed cartridge unit that produces telmisartan in an 81% isolated yield.

A fundamental analysis of enhanced cross-coupling catalytic activity for palladium clusters on graphene supports

Combining the recyclability of heterogeneous catalysts with the high activity of ligated homogeneous catalysts for the production of complex organic molecules is a cardinal goal of catalyst development. We have investigated the activity of ultra-fine Pd clusters bound to vacancy defective sites in graphene and found that the defective graphene both serves as a support to stabilize the recyclable catalyst, and also functions as a ligand enhancing the catalytic activity. In this paper, we report computational and experimental results that provide insights into the nature of the interfacial interactions between metal nanoparticles and defect sites on the graphene surface. Theoretical investigations reveal that while the vacancy/void sites on the graphene surface strongly bind to the metal clusters providing enhanced stability against leaching, graphene also serves as a reservoir of electron density that effectively reduces the activation energy of specific steps within the catalytic cycle. Furthermore, multiple experimental methods were used to unambiguously demonstrate that these cross-coupling reactions are occurring at the Pd/G catalyst surface.

Increasing global access to the high-volume HIV drug nevirapine through process intensification

Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.

CuPd nanoparticles as a catalyst in carbon–carbon cross-coupling reactions by a facile oleylamine synthesis

CuPd bi-metallic nanoparticles were synthesized in oleylamine without the use of additional surfactants, ligands, or reducing agents. The alloyed nanoparticles showed high catalytic activity in Suzuki cross-coupling reactions with excellent turnover number (6000) and turnover frequency of 72 000 h−1 under microwave irradiation. These nanoparticles were successfully utilized in a Suzuki coupling reaction with a diverse range of functionalized substrates. The catalyst also demonstrated multiple recyclability for Suzuki coupling reactions. The CuPd nanoparticles have also probed the utility in other cross-coupling reactions such as Heck and Sonogashira coupling reactions. According to the XPS data, two oxidation states of each metal exist on the surface of the nanoparticle. This is advantageous especially for Sonogashira cross-coupling reactions because having Cu+ present on the surface of the catalyst eliminates the need for a copper salt to stabilize the alkyne during the reaction.