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Electrochemistry forges C–C bonds in 2 new cross-electrophile couplings

Reactions show off electrochemistry’s scope

by Bethany Halford
March 6, 2022 | A version of this story appeared in Volume 100, Issue 9

Chemical structure of a terpene.

Chemists are amped up about two new reactions that use electricity to form different types of carbon-carbon bonds. One transformation builds sp3-sp3 C–C bonds, and the other creates sp2-sp3 C–C bonds. Adding these transformations to the synthetic chemist’s toolbox should spark interest in electrochemistry, an increasingly popular molecule-building tool, experts say.

Electrochemical transformations use electricity rather than chemical reagents to perform reactions. Both of the new reactions are cross-electrophile couplings, which wed two different electrophiles. Although there are ways to do cross-electrophile couplings using chemical reagents, these alternatives are often plagued by homocouplings, in which one electrophile forms a bond with another electrophile of the same kind instead of with a different type of electrophile.

Shannon Stahl, an expert in organic synthesis at the University of Wisconsin–Madison who was not involved in the research, says in an email that “both of these studies show that organic electrochemistry is evolving to a point that it’s positioned to challenge conventional catalytic methods for bond construction.”

In one reaction, chemists led by Cornell University’s Song Lin and the California Institute of Technology’s Kimberly A. See discovered that they could use electrochemistry to form bonds between alkyl halides in an electrochemical version of the classic SN2 reaction (Nature 2022, DOI: 10.1038/s41586-022-04540-4).

“Our idea was really to think about how electrochemistry can provide new reactivities,” Lin says. Chemists can dial in electrochemical potentials that allow them to differentiate between two different alkyl halide electrophiles, he explains. Injecting electrons turns the more substituted electrophile into a nucleophile, which attacks the less substituted electrophile to make a new bond. The team used this reaction to combine myriad electrophiles to create compounds, including an analog of the nonsteroidal anti-inflammatory drug zaltoprofen (shown, new bond in red).

The other cross-electrophile coupling reaction, from a team led by Phil S. Baran of Scripps Research in California, Héctor D. Abruña of Cornell University, and Scott L. Anderson of the University of Utah, builds terpenes and polyenes (example shown, new bonds in red) in a modular manner by coupling vinyl halides with redox-active esters (Science 2022, DOI: 10.1126/science.abn1395).

The key to getting this nickel-catalyzed reaction to work, Baran says, was to add silver nitrate. It’s not an intuitive addition: the reaction is a reduction, and silver nitrate is an oxidant. But ultimately the silver nitrate deposits silver nanoparticles onto the electrodes. The deposited matetial fine-tunes the electrodes’ reactivity. “The silver nanoparticle effect is a general one,” Baran says, “and one that I would bet will find extensive use in modern pharmaceutical chemistry.”

Daniel J. Weix, an expert on cross-couplings at the University of Wisconsin–Madison, says in an email that “these two breakthroughs show how combining electrochemistry with cross-electrophile coupling can enable synthetic disconnections and allow for a degree of control not possible with simple chemical reductants.” He says the work builds on other examples to make “a convincing case that electrochemistry tools should be standard equipment in any synthetic laboratory.”


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