Issue Date: October 29, 2012
Chemists Approach Elusive Breslow Intermediate
A 54-year quest for carbene chemists just took a big step toward resolution: German researchers say they’ve generated and characterized elusive Breslow intermediates, which are crucial players in biochemistry and catalysis (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201205878).
“The Breslow intermediate is the Higgs boson of the N-heterocyclic carbene catalysis field,” says Jeffrey W. Bode of ETH Zurich, who was not involved in the work. Columbia University’s Ronald Breslow first proposed the intermediates that bear his name in 1958, when he suggested that thiamine-mediated reactions in biochemistry hinge on carbene reactivity. Everyone who works with these types of carbenes believes they exist, Bode says. The field’s foundations rely on the existence of these intermediates, he adds, but they have never been isolated.
Albrecht Berkessel of the University of Cologne and colleagues made their intermediates by combining aromatic aldehydes with a saturated carbene. They surmised that their carbene catalysts were sufficiently slow to make intermediates detectable. “We were lucky enough to hit the sweet spot,” Berkessel says. Their intermediates are stable enough to be characterized but reactive enough to behave as expected by NMR.
“We’ve seen hints of the Breslow intermediate before,” Bode says, but this report “is the first to conclusively capture it.”
As with the Higgs boson, chemists will disagree whether the intermediates have now really been cornered, warns Karl A. Scheidt of Northwestern University. Most of the new intermediates lack a sulfur atom and are not fully aromatic as Breslow proposed, he says. However, this work “is an important step forward” and should be taken together with reports of deoxy, methylated, and nitrogen Breslow analogs detected earlier this year by groups at Colorado State University and the University of Munich. Together, Scheidt says, the studies are “an excellent foundation” for understanding carbenes’ versatility.
“This nice piece of work shows you can get a species that’s very closely related to what I proposed and look at its properties,” Breslow says. Berkessel is a former postdoc, he says, “and I’m proud of the guy.”
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