Scientists just broke a 100-year-old rule in chemistry – it’s time to rewrite textbooks

Chemists at UCLA have discovered a flaw in one of organic chemistry’s longstanding principles, challenging a rule that's guided synthetic chemistry for a century. Known as Bredt’s rule, the principle suggests that certain structures—particularly those involving carbon-carbon double bonds at specific positions in ring systems—are inherently impossible.

This breakthrough, published in the journal Science, proposes a fresh approach to synthetic chemistry and could unlock new possibilities for drug discovery.

Organic molecules, primarily composed of carbon atoms, are often described by their specific three-dimensional shapes. A key class of these molecules, known as olefins or alkenes, features carbon-carbon double bonds that traditionally lay flat in a plane.

When olefins are part of more complex ringed structures, certain positions, like the "bridgehead" junction, are believed to be incompatible with double bonds due to the distorted shapes they’d take on. Bredt’s rule, established in 1924, claimed that double bonds couldn’t form in these bridgehead positions. This assumption has limited the types of molecules scientists attempted to synthesize for decades.

Led by Neil Garg, a distinguished chemistry professor at UCLA, the research team set out to challenge this restrictive rule. Garg explained, “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. It destroys creativity when we have rules that supposedly can’t be overcome.”

The research focused on creating anti-Bredt olefins (ABOs)—molecules that directly contradict Bredt’s rule. These ABOs exhibit twisted or bent structures that, according to traditional organic chemistry, shouldn’t exist in a stable form.

Garg’s team devised a method to synthesize these unique molecules by treating silyl (pseudo)halides with a fluoride source, which triggers a reaction leading to ABO formation. Recognizing the instability of ABOs, the chemists added a “trapping” chemical to capture the newly formed molecules, enabling their isolation and further study.

This advancement offers more than just a theoretical breakthrough. By demonstrating a practical way to produce and stabilize ABOs, UCLA’s research opens up potential applications for these molecules in drug discovery. Garg highlighted the pharmaceutical industry’s ongoing push to develop three-dimensional chemical structures, as these configurations often enhance the effectiveness of new medications.

“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,” Garg noted.

The research team, comprising graduate students and postdoctoral scholars Luca McDermott, Zachary Walters, Sarah French, Allison Clark, Jiaming Ding, and Andrew Kelleghan, collaborated with computational chemist Ken Houk, a respected research professor at UCLA. Their combined expertise in synthetic and computational chemistry played a crucial role in exploring and verifying the properties of these challenging molecules.

Olefinic compounds, or those containing π-bonds, usually adhere to well-defined geometries that hold across various structures. However, these geometries can be altered under certain conditions, leading to higher reactivity.

Synthetic chemistry has made strides in leveraging π-bonded compounds with bent geometries, but the realm of twisted or pyramidal configurations has remained largely unexplored, partly due to the strictures of Bredt’s rule. ABOs represent a significant leap in this field, as they embody the twisted or pyramidalized geometries once considered too unstable for practical use.

ABOs’ potential has intrigued chemists since the early 1900s, when German chemist Julius Bredt investigated ringed molecules like camphane and pinane. From his work emerged the concept that certain molecular structures couldn’t support double bonds, particularly at the bridgehead of strained systems. Despite isolated attempts to synthesize ABOs in the past, they were either fleeting or prone to rapid breakdown, reinforcing the belief that these configurations were inaccessible.

Garg’s study demonstrates a reliable method to create and stabilize these molecules, allowing chemists to explore their reactivity and applications further. This breakthrough suggests that ABOs could become a valuable tool for synthesizing complex, three-dimensional structures, potentially leading to new therapeutic molecules with unique functionalities.

This research not only challenges a century-old notion but also paves the way for new chemical syntheses. As modern pharmaceutical research increasingly values three-dimensional molecular architectures, the potential applications of ABOs appear promising.

With these findings, Bredt’s rule, once regarded as an immutable law, now serves as a reminder that scientific principles must remain flexible to adapt to new discoveries.

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