Charging up hydrogen as a greener reductant

Chemists and chemical engineers from the University of Wisconsin–Madison and Merck & Co. have devised an effective and scalable way to use hydrogen’s electrons in an electrochemical reduction reaction under water-free conditions (Nature 2023, DOI: 10.1038/s41586-023-06534-2).

Conventional reductions use metals such as zinc, manganese, and magnesium as sacrificial electron sources. Merck and other companies are interested in finding ways to drive organic reactions with electrochemistry, but “they weren’t excited about making equimolar amounts of zinc salts,” says Daniel Weix, a UW chemistry professor who lent his expertise in cross-electrophile couplings to the project.

Enter hydrogen. H₂ is increasingly made using renewable energy, and taking its two electrons leaves two protons, which like to join up with oxygen atoms to make water.

“It’s tough to find a reductant that’s greener than hydrogen,” says UW’s Shannon Stahl, who led the collaboration.

He and his colleagues took inspiration from hydrogen fuel cells, which split H₂ to make electricity and water. Unlike those fuel cells, however, the researchers channel the electrons into an organic cross-​electrophile coupling reaction. And all of the power generated—plus a little extra to overcome hydrogen’s relatively weak reducing ability­—is used to drive the reaction forward.

The reactor the team used has two chambers, separated by a membrane. On the anode side, H₂ is used to reduce anthraquinone-2-​ sulfonate (AQS), a well-known organic redox shuttle, in a traditional palladium-​catalyzed hydrogenation. Each reduced AQS molecule passes two electrons into the cell’s wiring, where their energy is boosted so that a nickel catalyst can use them in a coupling reaction in the cathode chamber.

To ensure that there are no loose protons around, which would wreak havoc on the reaction they wanted to do, the researchers added lithium carbonate to the anode chamber to act as a base. They used a lithium salt as the electrolyte so that Li⁺ ions and not H⁺ would be responsible for balancing the charges.

The researchers proved the concept by performing a variety of 1 gram-scale couplings, including a key step in synthesizing the antidepressant rolipram. They also scaled up the reactor to make a precursor to cenerimod, a lupus drug candidate, on a 100 g scale. Stahl says he expects that this hydrogen-based reactor concept could work for many other types of reductions that need to be water-free. He and his collaborators are also working on strategies to make the process faster and more efficient.

Morris Bullock, who directs the Center for Molecular Electrocatalysis at Pacific Northwest National Lab, calls the work a “landmark advance” for using H₂ in a practical, scalable electrochemical synthesis. Karthish Manthiram, who researches renewable electrosynthesis methods at California Institute of Technology, says he expects that it will help accelerate hydrogen anodes’ adoption in industry.

Stahl and Weix both say the project owes its success to the way scientists from multiple specialties collaborated to design and develop a new way to use hydrogen. “It was a dream you could doodle down, but realizing it took a multidisciplinary team,” Weix says.