Chemists at UCLA have shaken the foundation of organic chemistry with a groundbreaking discovery that overturns a principle that has guided scientists for nearly a century. The research team, led by Professor Neil Garg, has disproven Bredt’s rule—a key concept in organic chemistry—by successfully creating molecules that were previously thought to be impossible to form. The findings, published in the journal Science, suggest that this rule, which has stood unchallenged since 1924, may require a revision in the field’s foundational textbooks. This breakthrough could have significant implications for drug discovery, where new three-dimensional molecular structures are highly sought after.

Organic chemistry focuses on the study of carbon-based molecules and the ways in which atoms are organized and bonded to form various structures. Some of these molecules, known as olefins (or alkenes), are characterized by a double bond between two carbon atoms, giving them a flat or two-dimensional structure. For decades, scientists have adhered to Bredt’s rule, which states that a carbon-carbon double bond cannot exist at the bridgehead position of a bicyclic molecule. This rule emerged from the belief that placing a double bond in such a location would result in an unstable, twisted structure. Consequently, chemists have avoided exploring such structures, limiting potential discoveries in molecular chemistry and pharmaceuticals.

The UCLA team’s work not only questions the validity of Bredt’s rule but also demonstrates that creating these so-called “anti-Bredt olefins” (ABOs) is indeed possible. By pioneering new chemical techniques, Garg and his colleagues were able to synthesize these once-unthinkable molecules. Their success has sparked excitement within the scientific community, as it suggests that other “impossible” structures might also be achievable with the right approach. In particular, the pharmaceutical industry stands to benefit from these findings, as the new molecular shapes unlocked by this research could lead to innovative drug development pathways.

To create these ABOs, the UCLA researchers used a specific chemical process involving a molecule called a silyl halide. This substance was combined with another reactant to initiate a reaction that produced the desired ABO molecules. Given the inherent instability of these structures, an additional chemical was added to “trap” or stabilize them, making it feasible to examine and apply these molecules in further research.

The importance of Garg’s research lies not only in the creation of new molecular structures but also in the mindset it promotes. Garg pointed out that rules like Bredt’s should not be treated as absolute laws but as guidelines that can be explored and, in some cases, broken. He emphasized that viewing scientific principles as unbreakable can restrict creativity and limit the scope of scientific inquiry. In this case, Bredt’s rule was perceived as an immutable barrier, halting research into a specific class of molecules for decades. However, Garg’s work shows that pushing the boundaries of established knowledge can reveal new avenues for discovery.

Garg highlighted a current push in the pharmaceutical field to develop reactions that yield complex three-dimensional molecular structures, which have considerable potential in drug discovery. By demonstrating that anti-Bredt olefins can indeed be created, Garg and his team have opened new possibilities for pharmaceutical chemists seeking novel molecules for medical applications. These findings underscore the importance of questioning and re-evaluating scientific “rules” that have long been assumed to be incontrovertible. Now, with a precedent for their synthesis, anti-Bredt olefins might play a role in the development of next-generation medicines and other valuable chemical products.

This UCLA discovery signifies a shift in the perception of molecular stability and reactivity. The researchers’ success in breaking Bredt’s rule not only expands the boundaries of organic chemistry but also encourages a more flexible, creative approach to scientific inquiry. It serves as a reminder that rules in science, while valuable, should sometimes be viewed as challenges rather than constraints. By daring to question and ultimately redefine what is possible, the UCLA team has made a lasting impact on the field of organic chemistry and potentially on the future of drug development.

Reference:

1. McDermott, Luca, Zach G. Walters, Sarah A. French, Allison M. Clark, Jiaming Ding, Andrew V. Kelleghan, K. N. Houk, and Neil K. Garg. “A Solution to the Anti-Bredt Olefin Synthesis Problem.” Science 386, no. 6721 (November 2024). https://doi.org/10.1126/science.adq3519.

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