UCLA Chemists Shatter 100-Year-Old Chemistry Rule – Textbooks Need a Rewrite

UCLA chemists have overturned a century-old rule in organic chemistry that limited molecular design by proving that anti-Bredt olefins can be synthesized and stabilized. This finding opens new paths in drug discovery and innovation.

• According to Bredt’s rule, double bonds cannot exist at certain positions on organic molecules if the molecule’s geometry deviates too far from what we learn in textbooks.
• This rule has constrained chemists for a century.
• A new paper in Science shows how to make molecules that violate Bredt’s rule, allowing chemists to find practical ways to make and use them in reactions.

UCLA Chemists Challenge Century-Old Rule

UCLA chemists have discovered a major flaw in a fundamental rule of organic chemistry that has held for 100 years. They say it’s time to rewrite the textbooks.

Organic molecules, which are primarily made of carbon, have specific shapes and arrangements of atoms. Molecules called olefins contain double bonds, or alkenes, between two carbon atoms. Typically, these atoms and their attached groups lie in the same 3D plane, and deviations from this structure are rare.

The rule being questioned, known as Bredt’s rule, was established in 1924. It asserts that molecules cannot have a double bond at the “bridgehead” position—the junction of a bridged bicyclic molecule—because this position would distort the geometry of the double bond. Bredt’s rule has constrained the design of synthetic molecules by preventing chemists from creating certain structures. Since olefins play a critical role in pharmaceutical research, Bredt’s rule has limited the types of molecules that scientists could envision, potentially holding back innovations in drug discovery.

Researchers Break the Mold With Anti-Bredt Olefins

A new paper published on November 1 by UCLA scientists in the journal Science has invalidated that idea. They show how to make several kinds of molecules that violate Bredt’s rule, called anti-Bredt olefins, or ABOs, allowing chemists to find practical ways to make and use them in reactions.

“People aren’t exploring anti-Bredt olefins because they think they can’t,” said corresponding author Neil Garg, the Kenneth N. Trueblood Distinguished Professor of Chemistry and Biochemistry at UCLA. “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. It destroys creativity when we have rules that supposedly can’t be overcome.”

Practical Applications: Developing Useful Chemical Reactions

Garg’s lab treated molecules called silyl (pseudo)halides with a fluoride source to induce an elimination reaction that forms ABOs. Because ABOs are highly unstable, they included another chemical that can “trap” the unstable ABO molecules and yield products that can be isolated. The resulting reaction indicated that ABOs can be generated and trapped to give structures of practical value.

“There’s a big push in the pharmaceutical industry to develop chemical reactions that give three-dimensional structures like ours because they can be used to discover new medicines,” Garg said. “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.”

Reference: “A solution to the anti-Bredt olefin synthesis problem” by Luca McDermott, Zach G. Walters, Sarah A. French, Allison M. Clark, Jiaming Ding, Andrew V. Kelleghan, K. N. Houk and Neil K. Garg, 1 November 2024, Science.
DOI: 10.1126/science.adq3519

The authors on the study include UCLA graduate students and postdoctoral scholars, Luca McDermott, Zachary Walters, Sarah French, Allison Clark, Jiaming Ding and Andrew Kelleghan, as well as Garg’s longstanding collaborator and computational chemistry expert Ken Houk, a distinguished research professor at UCLA.

The research was funded by the National Institutes of Health.

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