For over a century, one of chemistry’s most important reactions has kept a secret.
The Ullmann reaction, first discovered in the early 1900s, is widely used to link together molecules, helping chemists build medicines, advanced materials, and electronic components.
The reaction relies on copper as a catalyst, but exactly how copper drives the reaction has long been a subject of debate.
Now, chemists from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, working with colleagues at UCLA, have finally uncovered the detailed mechanism.
Their findings, published in Nature on September 22, reveal that the process is more complex than previously believed, involving a multi-step cycle of copper shifting between three oxidation states.
The traditional view of the Ullmann reaction was that copper switched back and forth between two states, Cu(I) and Cu(III), in what is called a redox cycle.
But there was a problem: copper(III) is notoriously unstable and difficult to detect under real reaction conditions, leaving many chemists unconvinced that this was the full story.
To get answers, Shen Qilong’s lab carefully controlled the reaction between copper(I) trifluoromethyl complexes and aryl iodides—key ingredients in Ullmann-type reactions—while adjusting the temperature.
At very cold temperatures, around -20°C, the team observed the rapid formation of copper(II) species through a process called comproportionation.
As the temperature was raised slightly to -10°C, the copper(II) intermediates transformed again, splitting into both copper(I) and copper(III) species. Near room temperature, the copper(III) intermediates carried out the crucial step of reductive elimination, releasing the desired product and regenerating copper(I) to restart the cycle.
The researchers confirmed each stage of this process using a suite of advanced techniques, including nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and ultraviolet-visible spectroscopy.
This gave them solid, real-time evidence of the copper species at work.
What they discovered was that the Ullmann reaction doesn’t simply rely on a Cu(I)/Cu(III) loop, as many had assumed. Instead, it follows a more intricate Cu(I)/Cu(III)/Cu(II)/Cu(III)/Cu(I) cycle, with copper moving through three distinct states in a carefully choreographed sequence.
Importantly, the team found similar behavior in other Ullmann-type reactions, such as trifluoromethylation and biphenyl synthesis. This suggests that the newly uncovered mechanism may apply broadly across a wide range of copper-catalyzed cross-coupling reactions.
By solving this long-standing puzzle, the researchers have not only clarified how one of chemistry’s most fundamental reactions works, but also opened the door to designing new and improved copper-catalyzed reactions.
Their findings may influence the development of more efficient methods for producing pharmaceuticals, agrochemicals, and advanced materials.
As Professor Shen’s team and their collaborators point out, this discovery reshapes our understanding of copper chemistry and highlights how even reactions known for more than a hundred years can still surprise us.
