Bending the rules for twisted double bonds

Organic chemist Neil A. Garg and his team at the University of California, Los Angeles, love testing the limits of what molecules can do.

Their latest paper upends Bredt’s rule, a 100-year-old guideline that applies to molecules called bridged compounds. These molecules contain two rings that have more than one side in common, giving them a peaked shape. The rule says it is impossible for these compounds to have a double bond connected to the carbon at the junction between the rings because the bond would have to be twisted and bent far outside its usual planar arrangement, a configuration that would lead to a huge amount of strain.

Garg and his team showed that these molecules, called anti-Bredt olefins, are not only possible to make but potentially useful for chemists interested in constructing complex 3D molecules (Science 2024, DOI: 10.1126/science.adq3519).

“I think maybe impossible will go away now with this paper,” says Luca McDermott, a PhD student in Garg’s lab who co-led the project.

Challenges to Bredt’s rule in the literature go back as far as 1967. But these past attempts were a mixed bag of harsh conditions, low yields, and unwanted rearrangement products—“so scattered and so unuseful that people still go by Bredt’s rule,” Garg says. “We wanted to flip the script on how the rule is viewed.”

Chemists have gotten better at working with unusual molecular geometries over the past century. “We know a lot about how to make strained intermediates and trap them,” Garg says. That’s why he thinks it’s high time people stopped thinking they have to play by Bredt’s rule.

The researchers created several different anti-Bredt olefins by making silyl precursors and then carrying out an elimination reaction to create the elusive double bond. The molecules are too strained and unstable to isolate, but the researchers used them as intermediates in a variety of cycloaddition reactions to construct complex 3D structures.

In a key experiment, the researchers created a chiral anti-Bredt olefin whose stereochemistry derives solely from the twistedness of the molecule, and trapped it with anthracene to create a single-enantiomer product. Transferring the stereochemistry was strong proof that the reaction went through an anti-Bredt intermediate, Garg says. McDermott recalls excitedly watching his lab mates analyze the experimental results over Zoom while he was in New Orleans for the American Chemical Society Spring 2024 meeting in March. “It really solidifed for me that we were actually making these compounds,” he says.

Paul Wender, an organic chemist at Stanford University who was not involved in the work, praised it as a thorough, fundamental organic study with “potentially huge” practical value. He says that although Garg and coworkers weren’t the first to make anti-Bredt olefins, they are “bridge builders,” advancing the future of chemistry by making it easier for more people to study and use these unusual molecules.

Carolyn Bertozzi, also of Stanford and also not involved with the work, whose Nobel Prize–winning research in chemical biology used strained triple bonds to do reactions in live cells, praised the paper for building on “curiosity-driven basic research on twisted olefins” to transform obscure molecular curiosities into powerful synthetic intermediates. “I love when an old, forgotten functionality is reborn for modern use.”

Garg says he and his group are continuing to explore the world of alkenes that have “messed-up geometries,” and he hopes more people will join them in seeking opportunities to bend the rules.