UCLA chemists break 100-year-old rule, creating unstable organic molecules with distorted geometries
A new paper published on November 1, 2024, by UCLA scientists in the journal Science details a groundbreaking discovery that challenges a century-old principle in organic chemistry known as Bredt's rule. Led by Professor Neil Garg, a distinguished professor of chemistry and biochemistry at UCLA, the research team has successfully created molecules that violate Bredt's rule, opening up new possibilities in molecular design and pharmaceutical research.
Bredt's rule, established in 1924 by German chemist Julius Bredt, has been a guiding principle in organic chemistry for a hundred years. The rule states that a double bond cannot exist at the "bridgehead" position of a bridged bicyclic molecule because placing a double bond there would twist the molecule in unstable ways. This principle has been widely disseminated in academic texts and is recognized by the International Union of Pure and Applied Chemistry.
For decades, Bredt's rule has constrained chemists by preventing the placement of double bonds between carbon atoms in certain positions within complex molecular structures, particularly at the bridgehead position of bicyclic molecules. This limitation has restricted the types of synthetic molecules that scientists could imagine and create, notably impacting the exploration of olefins—hydrocarbons characterized by having one or more double bonds between two carbon atoms.
Professor Neil Garg's team set out to challenge this long-held assumption. "People aren't exploring anti-Bredt olefins because they think they can't," Garg noted. Deciding to question the rule's absolute nature, the team focused on creating anti-Bredt olefins (ABOs), the molecules that violate Bredt's rule.
The UCLA scientists developed a method to synthesize and stabilize these anti-Bredt olefins. They began with a type of molecule known as silyl (pseudo)halides and treated them with a fluoride source to produce the ABOs. Recognizing that anti-Bredt olefins are highly unstable, Garg’s lab included another chemical that can "trap" the unstable molecules. This approach allowed them to generate stable olefins that can be used in other chemical reactions, resulting in the production of several complex compounds that could be isolated and studied.
"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 explained. By trapping the anti-Bredt olefins, the team could capture them long enough to study them and use them to make new, valuable compounds. This breakthrough indicates that ABOs can be generated and utilized effectively, challenging the notion that they were inaccessible due to their instability.
The implications of this discovery are significant for drug development and pharmaceutical research. Since reactions using anti-Bredt olefins could lead to new types of medicines, the ability to create these previously "impossible" molecules opens up a new realm of compounds for scientists to explore. "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 emphasized.
By demonstrating that Bredt's rule is not as absolute as previously thought, the UCLA chemists suggest that their findings call for a textbook update. "It's time to rewrite the textbooks," Garg stated, raising questions about how often textbooks might be wrong in other ways. He further highlighted the importance of flexibility in scientific rules: "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."
This sentiment reflects a broader call to action within the scientific community to rethink long-held beliefs that may hinder innovation. By challenging Bredt's rule, Garg's team is advocating for a more flexible and innovative approach to chemistry, encouraging chemists to explore molecules that were previously considered impossible. "Breaking the rules can lead to groundbreaking discoveries," he noted, emphasizing that questioning established norms can lead to significant advancements in the field.
The study was authored by UCLA graduate students and postdoctoral scholars Luca McDermott, Zachary Walters, Sarah French, Allison Clark, Jiaming Ding, and Andrew Kelleghan. Distinguished research professor Ken Houk contributed to the study as a computational chemistry expert. The research was funded by the National Institutes of Health, providing new insights into how to create and use Bredt's rule-breaking olefins.
By opening the door to many new types of molecules that can be constructed and potentially prove useful, particularly in pharmaceuticals and materials science, Garg's team's discovery serves as a stepping stone to numerous possibilities in organic chemistry. It reminds us that science is always evolving, and sometimes, all it takes is a fresh perspective and a willingness to challenge the status quo to achieve breakthroughs. As Garg's work illustrates, questioning assumptions and pushing boundaries can lead to significant advancements that benefit a wide range of fields.
Breaking 100-year Chemistry Rule: Scientific Breakthrough in Chemistry, Time to rewrite textbooks
