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Photoredox catalysis unleashes elusive carbynes for synthesis

New method installs versatile diazo carbyne equivalents on arenes

by Tien Nguyen
February 1, 2018 | A version of this story appeared in Volume 96, Issue 6

Orbital depictions of radical carbenes and carbynes.
These carbon species all have nonbonded electrons.

Methylidyne, a carbon-based gas believed to have helped form the first molecules of life and one of the earliest molecules ever discovered among the stars, belongs to an unusual class of compounds called carbynes. These highly reactive compounds are not to be confused with the contentiously categorized, one-dimensional string of carbons of the same name or with the more familiar carbenes.

Carbynes, according to organic chemistry’s definition, are monovalent carbon species with three nonbonded electrons. These species have tantalized researchers with the prospect of forming three new bonds from a single atom, but synthetic chemists have been unable to tame these unruly molecules.

Reaction scheme of carbyne equivalent functionalization.
Example of a diazoacetate carbyne equivalent installed onto an arene using photoredox chemistry.

A team led by Marcos G. Suero at the Institute of Chemical Research of Catalonia has developed a new method that sidesteps carbyne’s unstable nature by generating its molecular equivalent, a diazomethyl radical species, using photoredox catalysis (Nature 2018, DOI: 10.1038/nature25185). The researchers can install these radical species directly onto arene rings to give diazo products that can be readily transformed into more complex, chiral molecules.

The team demonstrated their reaction on more than three dozen substrates, including 12 medicinally relevant compounds via a late-stage functionalization of an arene C–H bond, a feat that Huw M. L. Davies of Emory University describes as “most impressive.” He adds that “this approach complements the traditional methods to access these types of compounds—the diazo transfer and palladium-catalyzed cross-coupling reactions.”

Select examples of "assembly-point" functionalization of arene substrates (shown in blue).
Structures of 4 different products of the photocatalytic reaction including those that have undergone a single step functionalization to form chiral compound.
Select examples of "assembly-point" functionalization of arene substrates (shown in blue).

The work also fulfills the promise of forming more than one new bond at a single carbon atom by exploiting the sensitive nature of the diazo products. By using blue light, which more readily decomposes the diazo group than white light, and adding simple reagents to the reaction, such as water, amides, halogen salts, and styrenes, they can obtain further functionalized products. Notably, this strategy, termed “assembly-point functionalization” by the authors, enabled the double C–H functionalization of an isobutylbenzene compound to produce an indane ring.

“I think this concept of assembly-point functionalization, shown here as carbynes that can undergo two C–H functionalization events, is going to change the way people think about retrosynthesis,” says Tim Cernak of Merck Research Labs in Boston. “It just stitches molecules together.”

In a perspective accompanying the research article, Rohan E. J. Beckwith of Novartis Institutes for BioMedical Research notes some limitations of the reaction, such as its incompatibility with substrates containing basic amines and low to moderate yields in some cases. However, “these are minor issues compared with the benefits of this approach for drug discovery and development,” he writes, adding that this work is “the first evidence that carbynes can be harnessed effectively for practical organic synthesis.”

This article has been translated into Spanish by and can be found here.



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