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Process Chemistry

Safe and scalable electroreduction

Lithium-ion battery technology inspires strategy for electrochemical reaction

by Bethany Halford
February 21, 2019 | APPEARED IN VOLUME 97, ISSUE 8

 

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When chemists at Pfizer examined routes to make anti-Parkinson’s drug candidate sumanirole at the kilogram scale, they saw only one option for the final step. They would need to do a Birch reduction—a reaction that involves using sodium or lithium metal in liquid ammonia. This was a reaction of last resort: It required cryogenic temperatures, custom equipment to deliver the lithium metal, and enough gaseous ammonia to fill three Boeing 747 airliners. When the leftover lithium was quenched, it generated 2,300 L of hydrogen gas.

“They vowed never to do that again,” says Phil S. Baran, an organic chemist at Scripps Research. Having learned of Pfizer’s difficulty, Baran joined forces with University of Utah electrochemist Shelley D. Minteer and University of Minnesota computational chemist Matthew Neurock to lead a group that explored the possibility of doing the reduction electrochemically.

Although there are many examples of electrochemical oxidations, reductions are rare. The problem, explains Minteer, is that the extreme electrical potentials required destabilize the electrodes. The researchers realized they could borrow a coating strategy used to protect lithium-ion batteries so they don’t burn up after a single charge. The team added a chemical, tris(pyrrolidino)phosphoramide (TPPA), that would form a protective layer over the cathode during the reaction (Science 2019, DOI: 10.1126/science.aav5606).

The strategy works not only in the synthesis of sumanirole (shown) but also for several other dissolving metal–type reductions, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings. The reduction takes place at room temperature in ambient air.

Jie An, an electrochemist at China Agricultural University, calls the process a “useful tool for synthetic chemists.” But he notes that it will be more accessible if TPPA, which costs $133 for 5 mL from MilliporeSigma, can be replaced by a cheaper and more environmentally friendly alternative. Baran says a TPPA-free protocol works for certain substrates in a large-scale flow system.

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