Researchers at the Chinese Academy of Sciences’ Hangzhou Institute for Advanced Study have come up with a new strategy to help chemists get more figurative bang from aromatic amine building blocks with less chance of literal explosions.
Since 1884, the copper-mediated Sandmeyer reaction has been the status quo for turning amines into bromides or chlorides. But the Sandmeyer method has a notorious downside: the diazonium intermediates can be explosive. The reaction also uses large amounts of copper salts as halide sources, thus leading to substantial waste when the process is used on an industrial scale.
Xiaheng Zhang and his team have figured out an alternative to the Sandmeyer reaction that uses nitro groups instead of diazoniums (Nature 2025, DOI: 10.1038/s41586-025-09791-5). Because their method doesn’t use any metal, the products can be funneled directly into metal-catalyzed cross-couplings without the need to run purification steps—saving chemists time and money.
“I think industrial people will really, really benefit with this chemistry,” Zhang says.
A reaction scheme showing the an aminopyridine molecule being converted to a chlorinated version.
Xiaheng Zhang and his team collaborated with Heilongjiang Record New Materials to run this new deamination reaction on a kilogram scale.
Zhang has been working on deamination chemistry since he started his independent career in 2021. The nitro approach is based on something his team stumbled on while trying to attach electron-withdrawing groups to an aminopyridine derivative in the hopes of weakening its C–N bond. Instead of attaching to a carbon atom in the ring, the researchers found that the nitro group ended up on the amine nitrogen.
Treating that N-nitroamine species with a chlorine source gave the researchers the chlorinated product they had been seeking. They found that the reaction works on many types of aromatic amines—even ones attached to rings with multiple heteroatoms, which typically don’t play well with Sandmeyer chemistry. And they were able to install a variety of halides and other groups in place of the nitrogen, as long as they could find a good nucleophile to react with the nitro intermediate.
The aspect Zhang was most excited about was being able to carry out deamination followed by cross-coupling in the same reaction vessel without worrying about residual metal, which can interfere with the reaction. He says that pretty much all the classic coupling reactions are compatible: Suzuki, Heck, Sonogashira—you name it. “Any reaction you can imagine, [it] can tolerate.”
This is one of those rare papers that “you know the second it’s published, people can and will use it,” says the Max Planck Institute for Kohlenforschung’s Tobias Ritter, who published his own safer take on the Sandmeyer reaction in 2024. The starting materials in Zhang’s method are widely available, the procedure is straightforward, and the products are the types of molecules that agrochemical and pharmaceutical companies are interested in manipulating. It remains to be seen if this method will actually unseat Sandmeyer chemistry as the go-to deamination technique, but “it just looks robust and very practical,” Ritter says.
Patrick Fier, a process chemist at Merck & Co., who was not involved in the work, says in an email that a more rigorous safety evaluation is necessary to figure out if this reaction would truly be a good alternative on the process scale.
Zhang and his group are continuing to work with local pharmaceutical and chemical companies to develop this reaction. They’ve already demonstrated one example that works at a kilogram scale and are planning to scale it up further.
Brianna Barbu Brianna Barbu is a physical sciences reporter at C&EN. Bri is a DC-based science reporter covering organic chemistry and related topics. She also makes up 1/3 of C&EN’s structures team and is a regular contributor to the Chemistry in Pictures blog and Newscripts. Bri studied chemistry and creative writing at Hope College and earned a master’s degree in organic materials chemistry from the University of Michigan in 2019 before escaping the lab to pursue a career in journalism. Prior to joining C&EN, she was a 2021 AAAS Mass Media fellow at Discover magazine. When she’s not contemplating the weird world of carbon-based molecules, Bri enjoys swimming, crocheting, reading novels with her cat, and playing D&D.
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