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Chemists tame the vinyl carbocation

Confined in a catalyst, this reactive intermediate can enantioselectively insert into a C–H bond

by Bethany Halford
December 8, 2022


In the realm of reactivity, the vinyl carbocation is a beast so fleeting, so keen to combine or rearrange, that many have doubted that it can be tamed to create molecules in a stereoselective way. But by confining a vinyl carbocation within a bulky catalyst, chemists have now shown they can coax this wildly reactive intermediate to insert itself into a carbon-hydrogen bond in an enantioselective manner.

A space-filling catalyst wraps around a small molecule.
Credit: Science
Confined to an organic catalyst (space-filling model), this vinyl carbocation substrate (stick model) is poised to react stereoselectively.

The work comes from the collaboration of researchers in Hosea M. Nelson’s group at the California Institute of Technology, Matthew S. Sigman’s group at the University of Utah, and K. N. Houk’s group at the University of California, Los Angeles.

“Historically, we’ve really struggled to make these cations catalytically and use them in synthesis,” says Sepand K. Nistanaki, a graduate student in Nelson’s lab who is the paper’s first author. “The fact that these types of carbocations can do this C–H insertion chemistry is fundamentally unique and interesting and, we think, synthetically is going to be very powerful for chemists.”

When the researchers in Nelson’s group started this project, they didn’t know if they would be able to harness the vinyl carbocation intermediates because of their extreme reactivity. After screening dozens of catalysts, the chemists found that a family of imidodiphosphorimidate organocatalysts developed by Ben List’s lab at the Max Planck Institute for Kohlenforschung were able to create and confine the vinyl cation in such a way that it would only react to form one of two possible enantiomers in a C–H insertion reaction. The chemists liken the catalyst to an enzyme in that it is able to exert stereocontrol over a highly reactive intermediate (Science 2022, DOI: 10.1126/science.ade5320).

Once his lab had observed enantioselectivity in the reaction, Nelson turned to Houk and Sigman to model the behavior computationally and verify that the reaction is indeed going through the vinyl carbocation. Now that chemists know these intermediates can be harnessed, Sigman says, they can be creative about what kind of molecules they make with this type of reaction.

“The C–H insertion of vinyl cations can be nearly barrierless,” says Matthias Brewer, a chemist at the University of Vermont who develops new reactions. “Imparting stereocontrol to this process with List’s chiral imidodiphosphorimidate catalyst is a significant achievement,” he says in an email.

“The idea that carbocations as reactive as unstabilized vinyl cations could be engaged in highly enantioselective reactions would have seemed quite unlikely until recently,” says Harvard University’s Eric N. Jacobsen, who also develops new reactions. He says in an email that the work represents “a significant advance in asymmetric catalysis with highly reactive intermediates.”

The chemists think the area is still rich for exploration. Sigman says the information they’ve gleaned could help their team redesign the catalysts to be more practical. The chemists would also like to expand their substrates. In this work, the C–H insertion was an intramolecular transformation, in which the vinyl cation and the C–H bond were in the same molecule. Chloe G. Williams, another graduate student in Nelson’s lab, says she’d like to see the work extended to intermolecular reactions—in which the vinyl cation and the C–H bond it inserts into are on different molecules. She says the chemists would like to “understand how we can potentially use what we have learned throughout this project and apply that to other types of C–H insertion reactions to make more complex products stereoselectively.”


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