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

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 ways to do cross-electrophile couplings using chemical reagents, these alternatives are often plagued by homocouplings, where one electrophile forms a bond with another electrophile of the same kind instead of with the second 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 California Institute of Technology’s Kimberly A. See discovered they could use electrochemistry to form bonds between alkyl halides in an electrochemical version of the classic S_N2 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, 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 the silver nitrate deposits silver nanoparticles onto the electrodes, which fine-tunes their 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.” This work, he says, builds on other examples to make “a convincing case that electrochemistry tools should be standard equipment in any synthetic laboratory.”