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LOS ANGELES — In a discovery that’s sending ripples through the chemistry world, UCLA scientists have proven that a fundamental rule of organic chemistry – one that has held back researchers for 100 years – isn’t as unbreakable as everyone thought. The breakthrough could open new paths for drug development and pharmaceutical research.
The rule in question, known as Bredt’s rule, has been chemistry gospel since 1924. It’s like telling architects they can never build a certain type of bridge because the laws of physics won’t allow it. But now, UCLA researchers have not only built that “impossible” bridge – they’ve shown others how to do it too.
“People aren’t exploring anti-Bredt olefins because they think they can’t,” says Neil Garg, UCLA’s Kenneth N. Trueblood Distinguished Professor of Chemistry and Biochemistry, who led the research, in a media release. “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.”
To understand why this matters, imagine organic molecules as tiny 3D structures, like molecular Lego builds. These structures often contain what chemists call “double bonds” between carbon atoms. According to the traditional rules, these double bonds must lie flat – like a tabletop – and can’t exist in certain twisted positions within the molecule. Bredt’s rule specifically said you couldn’t put these double bonds at certain junction points in more complex molecular structures.
However, Garg’s team found a way around this limitation. Using a clever chemical strategy, they created these supposedly impossible structures by treating specific molecules (called silyl pseudohalides) with fluoride. Because these “forbidden” structures are highly unstable – think of a house of cards in a windstorm – the team also developed a way to “trap” them, making them useful for further chemical reactions. The implications could be significant for drug development.
“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 explains.
The research, published in the prestigious journal Science, was a team effort involving UCLA graduate students and postdoctoral scholars Luca McDermott, Zachary Walters, Sarah French, Allison Clark, Jiaming Ding, and Andrew Kelleghan, along with computational chemistry expert Ken Houk.
This discovery serves as a powerful reminder that in science, even our most trusted rules sometimes need revisiting. After all, as the UCLA team has shown, sometimes breaking the rules can lead to breakthrough discoveries.
Paper Summary
Methodology
In this study, the researchers aimed to synthesize and trap anti-Bredt olefins (ABOs), a highly reactive and traditionally unstable type of molecule. They used a novel approach involving specially designed precursors treated with fluoride sources, which enabled the in-situ formation of ABOs.
They conducted these reactions in the presence of various trapping agents to stabilize and capture the ABOs for analysis. Additionally, they applied computational models to predict and confirm the structures and reactivities of ABOs, using density functional theory (DFT) to understand the unique geometric distortions these molecules undergo.
Key Results
The study successfully generated ABOs and showed they could be trapped and stabilized using specific chemicals. The results indicated that ABOs are more reactive due to the unusual shapes of their bonds. The team created several different ABOs, each with unique structures, and was able to confirm that these molecules could lead to the creation of complex new compounds. This achievement challenges the long-standing belief that ABOs could not be easily made or used in chemical reactions.
Study Limitations
First, the synthesis of ABOs requires precise conditions, including specific temperature and chemical combinations, which might limit its practical applications. Additionally, the computational models, while robust, may still have limitations in predicting all possible behaviors of ABOs. Lastly, the stability of ABOs remains a challenge, as they are still prone to decomposition outside of controlled environments.
Discussion & Takeaways
This research provides new insights into how ABOs, previously considered inaccessible, can be created and used in chemical synthesis. The success of this approach not only challenges Bredt’s rule — a long-held guideline in organic chemistry — but also opens doors for creating complex compounds that may have applications in pharmaceuticals and materials science. This study highlights the potential of leveraging distorted geometries in organic compounds to unlock new reactivity and applications.
Funding & Disclosures
The study was funded by the National Institutes of Health. The authors declare that they have no competing interests.
