Scientific textbooks are going to need a rewrite after U.S. researchers broke a fundamental rule of chemistry, tearing up “one hundred years of conventional wisdom.”
The team from the University of California, Los Angeles, showed how it is actually possible to create compounds with a special structure and pattern of molecular bonds that was long deemed impossible.
“There’s a big push in the pharmaceutical industry to develop chemical reactions that give three-dimensional structures like ours,” said paper author and chemist professor Neil Garg in a statement.
“They can be used to discover new medicines,” he added.
An example of an anti-Bredt olefin. Such molecules were thought for 100 years to be impossible to synthesize.
Neil Garg
The victim of the groundbreaking discovery is “Bredt’s rule,” which was first proposed in 1902 by the German chemist Julius Bredt, and then codified in 1924.
It concerns small organic (that is, carbon-based) molecules made up atoms structured into a pair of joined, or “bicylcic” rings—with each ring sharing three atoms.
According to Bredt, it is impossible for these molecules to have a carbon–carbon double bond on either of the “bridgehead” atoms where the two ring structures meet.
Molecules with carbon–carbon double bonds are known as “olefins.” Typically, the carbon atoms in these bonds, and the atoms attached to them, lie in the same geometric plane.
This is because the bonds require the carbon atoms to share electrons. In small bicyclic rings, the “orbitals” of the bridgehead atoms—the space around them in which electrons are likely to be found—don’t easily overlap.
German organic chemist Julies Bredt argued in 1924 that a carbon double bond (the double line in the left image) could not occur as the branching positions of a small bicyclic molecule—one with a structure like two joined rings. (Note: “Gibt Nicht” translates from German as “does not exist”)
McDermott et al. / Science
Only when the rings are large enough (eight atoms or more) can double bonds form off the bridgehead atoms without significant geometric strain, supposedly making them too unstable to prepare.
In their study, however, the researchers show that it is possible to create several kinds of molecules dubbed “anti-Bredt olefins” that deviate from the conventional geometry of olefins taught in textbooks.
Their process involved taking molecules called silyl (pseudo) halides and treating them with a source of fluoride, removing elements from the former leave an anti-Bredt olefin behind.
To overcome the inherent instability of the anti-Bredt olefins, they added a third chemical to trap them, allowing them to be used in other reactions—such as, for example, those involved in drug-making research.
“What this study shows is that, contrary to one hundred years of conventional wisdom, chemists can make and use anti-Bredt olefins to make value-added products,” said Garg.
He added: “People aren’t exploring anti-Bredt olefins because they think they can’t.”
“We shouldn’t have rules like this—or if we have them, they should only exist with the constant reminder that they’re guidelines, not rules.”
He added: “It destroys creativity when we have rules that supposedly can’t be overcome.”
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Reference
McDermott, L., Walters, Z. G., French, S. A., Clark, A. M., Ding, J. Kelleghan, A. V., Houk, K. N., & Garg, N. K. (2024.) A solution to the anti-Bredt olefin synthesis problem. Science, 386(6721). https://doi.org/10.1126/science.adq3519
