Radical reactions for reversible click chemistry

Click reactions—the subject of the 2022 Nobel Prize in Chemistry—come in many forms, but they all share a few key features. Namely, click chemistry forges new chemical bonds quickly, selectively, and irreversibly.

That last feature has now become a bit more optional.

A team at Tsinghua University led by Jiang-Fei Xu and Xi Zhang have published a paper detailing their radical new approach to click chemistry: a bond formation between phenothiazine dyes and amines that can be undone using ultraviolet light (Science 2024, DOI: 10.1126/science.adn2259).

“The more I read this paper, the more I liked it,” says Craig Hawker, a chemist at the University of California, Santa Barbara, who was not involved in the work. He says it’s interesting, useful chemistry with a lot of potential for researchers to continue building upon.

In an email, Xu says the paper started with a serendipitous discovery made while he and his teammates were investigating supramolecular host-guest chemistry using phenothiazine radical cations. They found that if they oxidized the nitrogen- and sulfur-containing heterocycles with a chemical oxidant such as N-bromosuccinimide, the resulting cationic radicals reacted with amines to form positively charged sulfilimine products.

This reaction isn’t new. Henry J. Shine and coworkers first reported it nearly 50 years ago, (J. Org. Chem. 1975, DOI: 10.1021/jo00906a004). But it hadn’t garnered much attention back then, and Xu and his colleagues thought it merited a closer look. They found that the bond-forming reaction is fast and high yielding, works at room temperature in open air with water as the solvent, and is compatible with a variety of functional groups on the amine—all qualities associated with click reactions.

Xu and coworkers also found that exposing the sulfilimine products to ultraviolet light breaks the sulfur-nitrogen bond and regenerates the phenothiazine and amine starting products. This photochemical reaction also happens in water, though it doesn’t work if there is oxygen present. The bond clipping uses a different radical mechanism from the bond clicking and can be controlled independently. The researchers demonstrated the capabilities of their click-clip strategy by reversibly modifying a cyclodextrin and creating a polymer that breaks down when triggered by light.

Hawker says that sulfilimines are an underexplored class of molecules, and coupling versatile bond forming with light-responsive bond breaking “opens up really significant opportunities” for follow-up work. Figuring out how to do the bond breaking with visible light would be particularly powerful, as would other tweaks to make the chemistry more compatible with biological systems. And there’s a deep well of chemists with expertise in organic radicals and photochemistry that would be poised to build on this preliminary work.

“There’s a reason why we love radical reactions,” Hawker says.