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The Ullmann reaction is one of the oldest reactions in organometallic chemistry. It is one of the most widely used copper-mediated coupling reactions, widely applied in the construction of carbon-carbon and carbon-heteroatom bonds due to its excellent substrate generality.

There has been considerable controversy regarding the redox mechanism of copper in this reaction for a long time. The widely accepted mechanistic hypothesis involves a Cu(I/III) cycle. However, copper(III) species are extremely difficult to observe in real reaction systems, and whether other interactions exist between copper species remains unknown.

In a study in Nature on September 22, Shen Qilong's lab from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences, along with Professor K. N. Houk from the University of California, Los Angeles, provided solid evidence that the Ullmann-type reaction might proceed via a Cu(I)/Cu(III)/Cu(II)/Cu(III)/Cu(I) catalytic cycle.

By controlling the reaction progress between copper(I) trifluoromethyl complexes and electron-deficient aryl iodides through temperature regulation, the researchers revealed the complex redox behavior of copper species in the Ullmann-type reaction.

At -20°C, oxidative addition and comproportionation occurred fast, generating copper(II) species. Further increasing the reaction temperature to -10°C, the Cu(II) species underwent disproportionation to form copper(III) and copper(I) species. The copper(III) species underwent reductive elimination near room temperature, regenerating copper(I) species and completing the entire redox cycle.

These processes were cross-validated by multiple spectroscopic techniques including nuclear magnetic resonance, electron paramagnetic resonance, and ultraviolet-visible spectroscopy.

Moreover, the researchers observed similar reaction behaviors in the trifluoromethylation of various electron-deficient aryl iodides and in Ullmann biphenyl synthesis, suggesting that this mechanism might be a common pathway in Ullmann-type cross-coupling reactions.

This study reveals a multi-step cycle involving Cu(I)/Cu(III)/Cu(II)/Cu(III)/Cu(I), which indicates that the mechanism of the Ullmann reaction is far more complex than any previously proposed hypothesis. It also provides new insights into other copper-catalyzed reactions.