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Unlikely radical reaction coerces stubborn carbons to bond

Photochemical reaction makes clean and selective quaternary carbon bonds

by Leigh Krietsch Boerner
November 22, 2021


The structure of a two-radical reaction that results in a quaternary carbon bond.

Making molecules with quaternary carbon bonds—four carbons attached to a central C—is tricky but necessary for medicinal chemists. Quaternary C bonds have a discrete shape, Princeton University chemist David MacMillan says, so they can fit very specifically into binding sites in a lock-and-key type interaction. However, quaternary Cs are hard to synthesize because they’re so bulky. MacMillan and coworkers at Princeton University and Janssen-Cilag have figured out a fix for this troublesome problem, by using a radical reaction scientists in the past speculated wasn’t possible. In what’s called an SH2 mechanism, the group used blue light and two catalysts to trigger the addition of a three-carbon radical to the end of a linear hydrocarbon (Science 2021, DOI: 10.1126/science.abl4322). The reaction is highly selective, and results in a new quaternary C bond.

An SN2 reaction, common in organic chemistry, is when one reactant attacks another, resulting in a new double bond. An SH2 reaction is essentially the same, MacMillan says, except the reactants are radicals. Here, the team used an iridium photocatalyst and an iron porphyrin catalyst to simultaneously create one radical from the end of an alkyl bromide molecule and another radical from a carboxylic ester. The two radicals combine via the SH2 reaction to make the new, quaternary group at the end of the alkyl chain.

How neatly the reaction worked surprised the team, MacMillan says. “You can actually create two different radicals at the same time. And basically, when we do that normally, it’s just an uncontrollable holy mess,” he says. The key was how the two radicals interact with the Fe porphyrin. The alkyl radical binds tightly to the iron. “It doesn’t really come off,” MacMillan says. But the other radical “immediately pops right back off again. It’s a really weak bond.” The Fe porphyrin effectively holds one radical in place, leaving the other free to attack the end of the bound complex, forming the new quaternary carbon bond (shown). The team made over 50 compounds from a variety of starting materials.

The reaction “was actually much better than we were hoping for,” MacMillan says.

Radical chemistry has huge potential as a synthetic tool, but it’s difficult to control the reactivity and selectivity, says X. Peter Zhang, an organic chemist at Boston College. “This beautiful work should stimulate further exploration of radical substitution, among other fundamental radical reactions, for molecular construction,” he says.



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