PFI-RP: Electrochemical Technologies for Pharmaceutical Synthesis via Nickel-Catalyzed Aryl-Alkyl Cross-Coupling

The broader impact/commercial potential of this Partnerships for Innovation – Research Partnerships (PFI-RP) project led by the University of Wisconsin-Madison and Merck & Co. Inc. lies in the development of a new environmentally benign electrochemical strategy for the synthesis of active pharmaceutical ingredients and their precursors. Electrochemical methods often bypass the requirement for costly, unsafe, toxic, and/or environmentally hazardous chemicals used in conventional thermal processes.

The electrification of organic synthesis has potential to revolutionize pharmaceutical manufacturing. Reduction reactions involve the net transfer to electrons to a target molecule and they are commonly encountered in chemical manufacturing. Hydrogen gas, which may be produced from water using renewable energy, represents an ideal source of electrons for these reactions; However, hydrogen gas lacks the driving force needed to accomplish many important reduction reactions.

Consequently, alternative reductants, such zinc, magnesium, and other metals are often used as a source of electrons. This project will develop electrochemical reactor technologies capable of using hydrogen as a source of electrons to accomplish reductive cross-coupling reactions that form carbon-carbon bonds commonly encountered in pharmaceuticals and other industrial chemicals.

The proposed project targets the development of electrochemical technologies that will enable nickel-catalyzed, cross-electrophile coupling reactions to be performed with hydrogen (H2) as the source of electrons. Several different H2-anode technologies will be evaluated and optimized for integration with cathodes that drive the nickel-catalyzed reductive coupling methods.

This project will leverage established membrane-electrode assemblies and gas-diffusion hydrogen anode technologies used in commercial fuel cells. Technical challenges that must be addressed include the management of protons and water that migrate across the membrane of the electrochemical cell, both of which could interfere with the catalytic coupling reactions.

These challenges will be overcome through the design and testing of various reactor configurations that offer different strategies to address these issues. By combining the expertise of synthetic chemists, engineers and leading practitioners from the pharmaceutical industry, this project will elevate the technology-readiness level of electrochemical carbon-carbon bond forming reactions using H2 as an electron source.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.