If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



Iron Spurs C–H Bond Reactivity

Organometallics: Catalyst creates drug scaffolds quickly

by Bethany Halford
May 6, 2013 | A version of this story appeared in Volume 91, Issue 18

Iron catalyst transforms linear alkyl azides into cyclic amines via C–H functionalization.
A reaction scheme of an iron catalyst transforming a linear alkyl azide into a cyclic amine through C–H bond activation.
Iron catalyst transforms linear alkyl azides into cyclic amines via C–H functionalization.

Finding inspiration in the iron-based enzymes that metabolize drugs and other chemicals, chemists have come up with a catalyst that turns unreactive C–H bonds into useful C–N bonds (Science, DOI: 10.1126/science.1233701). The transformation gives chemists rapid access to saturated heterocycles, which are common structural motifs in drugs and other biologically relevant molecules.

“One of the grand challenges in organic synthesis and organometallic research is to be able to render every portion of a molecule into a reactive entity,” says Theodore A. Betley, the Harvard University chemistry professor who developed the catalyst with colleague Elisabeth T. Hennessy. To that end, Betley and Hennessey created a catalyst that can transform linear alkyl azides into cyclic amines. “What we were able to do is render very unreactive C–H bonds into a reactive component by making a catalyst that has the ability to pull apart the C–H bond and then also catalyze the follow-up reaction, which makes a new carbon-heteroatom bond,” Betley explains.

The key to getting the catalyst to work, he says, was to ensure the electrons in the catalyst’s iron atom were in the same configuration as they are in natural metabolic iron enzymes. “All we did was look at the design principle that makes the natural system so effective and try to mimic it,” Betley tells C&EN. “In doing so, I think we made something that might be even more reactive than what you find in nature.”

“Betley and Hennessy’s method provides a solution for a long-standing, unsolved problem,” comments Tom G. Driver, a chemistry professor at the University of Illinois, Chicago, who studies how to transform C–H bonds into amines. “The method provides access to a wide range of N-heterocycles that were not accessible with other methods. I suspect the work will resonate in the synthetic community by enabling construction of these important scaffolds through manipulation of C–H bonds.”


This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.