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Copper Catalysis That Clicks

Reaction Mechanism: Research reveals details of a workhorse chemical transformation

by Bethany Halford
April 8, 2013 | A version of this story appeared in Volume 91, Issue 14

This catalytic cycle shows how two copper atoms play roles in the CuAAC reaction. The team was able to determine via isotopic labeling that both copper atoms bind equivalently in a reaction intermediate.
This scheme shows how two copper atoms take part in this click chemistry reaction.
This catalytic cycle shows how two copper atoms play roles in the CuAAC reaction. The team was able to determine via isotopic labeling that both copper atoms bind equivalently in a reaction intermediate.

The copper-catalyzed addition of azides and alkynes to form triazoles has been hailed as the crème de la crème of click chemistry—a way to assemble molecules via rapid, irreversible reactions. It is an efficient way to make biological probes, novel polymers, drug candidates, and smart materials.

Now, researchers looking under the hood of this chemical transformation have found a few surprises in its mechanism (Science, DOI: 10.1126/science.1229506). They hope their new knowledge will lead to further improvements in the design of reactions for synthetic chemistry and perhaps to new uses for copper isotope analysis.

Most notably in the recent work, chemists have been able to prove that two copper atoms are involved in the Cu(I)-catalyzed azide-alkyne cycloaddition, also known as the CuAAC reaction. “Copper is one of those elements that’s very slippery. It’s very difficult to catch it in action,” says Valery V. Fokin, an organic chemist at Scripps Research Institute in California, who nailed down the mechanistic details along with graduate students Brady T. Worrell and Jamal A. Malik. “This is the first time someone was able to show there is a two-copper intermediate that is very short-lived. We cannot isolate it. We cannot see it. But we can implicate its existence unambiguously,” Fokin adds.

Earlier work by Fokin with colleague M. G. Finn, now at Georgia Tech, had suggested that two copper atoms were involved in the CuAAC reaction, but they couldn’t establish this definitively. Fokin and his students followed up with heat-flow calorimetry experiments that showed a second copper atom was necessary. They thought they understood the role of the first copper atom but weren’t certain of the role of the second. They speculated that the second copper atom was interacting with the alkyne solely through π interactions.

Then Fokin struck upon the idea of using copper isotopes and mass spectrometric analysis to track the reaction. Copper naturally occurs in a 7:3 ratio as Cu-63:Cu-65. Fokin and coworkers introduced pure Cu-63 instead of mixed-isotope copper into the reaction. If their hypothesis that the second copper was simply interacting via π-bonding with the alkyne was correct, the pure isotope wouldn’t be incorporated in the copper-triazolide product.

But surprisingly, the pure copper isotope was incorporated into the triazolide 50% of the time. The result indicates that the two metal atoms become equivalent in an intermediate that is converted directly into the final cycloaddition product.

“We have all been looking for a plausible mechanism for the CuAAC reaction, since this will allow us to rational­ize results and design novel and improved systems,” comments Morten P. Meldal, a chemistry professor at the University of Copenhagen. “Now we are finally getting some solid evidence, so thumbs up to Fokin and his coworkers for that, particularly for the enrichment experiments.” Meldal led one of two teams—the other was spearheaded by Fokin and Scripps chemist K. Barry Sharpless—that introduced the CuAAC reaction around the same time in 2002.

Fokin notes that the implications of the mechanistic discovery will go beyond the CuAAC reaction. “It’s really telling us how metals interact with carbon-carbon multiple bonds,” he says. Furthermore, he notes that the report shows how copper isotope analysis might be used to track the metal in biological systems where its function is important but often not well understood.


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