UCLA Chemists Lead the Way in Revising Organic Chemistry Textbooks
How does questioning well-established scientific principles such as Bredt’s rule lead to creativity and innovation in contexts like drug discovery and molecular engineering?
What are the potential benefits and harms of pursuing the synthesis of unstable or traditionally “forbidden” molecules like anti-Bredt olefins in real-world chemical contexts?
How can flexible educational models like AIU facilitate the kind of innovative thinking necessary to question and redefine principles of science?
With the recent breakthrough announced by chemists at UCLA who evaluated Bredt’s rule, I am asking students to compose an analytical essay that examines the broader consequences of this announcement. In your essay, consider the three open-ended questions you have been provided with, and think about how doing away with long-held laws of science can spur products and innovation, what anti-Bredt olefins could offer practical chemistry, and how can flexible educational frameworks such as at AIU support those who think differently. Use appropriate examples, scientific reasoning, and your own rationale when writing a cohesive essay that shows creativity of different forms, critical thinking and a deeper understanding of the relationship between science, creativity, and education.(Login to your student section to access the AIU Additional Resources Library.)
Challenging Tradition: UCLA Chemists Lead the Way in Revising Organic Chemistry Textbooks
In a potentially ground-breaking find that could change fundamental parts of chemistry, a team of researchers from the University of California, Los Angeles (UCLA) overturned a long-held practice in organic chemistry that is 100 years old. Bredt’s rule is an age-old orthodoxy that restricts where double bonds (in particular, olefin double bonds) can be located in a complex organic molecule. The UCLA chemists, lead by Professor Neil Garg, published in Science a paper in which they illustrated the synthesis and stabilization of anti-Bredt olefins (ABOs)—the corresponding molecular structures that are prohibited per Bredt’s rule. The demonstration of ABOs is an excellent theoretical advancement, whether in terms of transformations, cycloadditions, ionic intermediates, or Catalytic cycles.
The successful realization of an ABO will hence not only redefine one of the tenets of chemical theory, but it will be a key step toward realizing molecular designs with complex structural constructs—a definite boon to the rapidly evolving landscape of drug discovery. For the scientific community, and particularly organic and pharmaceutical chemists, the successful synthesis of ABOs marks a turning point of creative molecular design where colorful ‘prohibited’ structures will now likely move to market as new entities with a benefit.
Introducing... Bredt's Rule: An Academic "Rule" Nearly 100 Years Old
Bredt’s rule was first put to print in 1924 by the German chemist Julius Bredt as a structural constraint that prohibited double bonds from being at the bridgehead of a bridged bicyclic molecule. A bridgehead is defined as the connection point of two or more rings within bridged bicyclic systems. In other words, what Bredt said was that at the bridgehead, if a double bond were at the bridgehead, the carbons involved in the double bond would cause an unacceptable physical strain on the molecule because the involved carbon atoms cannot adopt the ideal planar configurational arrangement of a stable double bond.
Bredt’s rule, first and foremost, is firmly rooted in an understanding of the concepts of orbital hybridization and molecular strain. In olefins (olefins are also known as alkenes), the involved carbon atoms in a double bond are typically sp² hybridized and prefer to lie in a planar configuration. However, through a bridgehead location (in a constrained bicyclic system), it is simply geometrically impossible to achieve planarity. Ultimately the result is instability and decomposition at the bridgehead site. For many generations, chemists avoided trying to make these types of configurations, assuming Bredt’s rule was an inviolable building block of molecular architecture.
Eventually, Bredt’s rule secured its place in academic training and research as a practical fixture in the chemical literature. Inorganic and organic chemistry textbooks added Bredt’s rule to their structures and it was taught within the context of a hard-no constraint and established a structural “no go zone” for generations of researchers. By taking this structural no-go zone for granted, chemists literally constrained and limited their thinking about what kinds of molecules might even be possible or conceivable to think about, especially with respect to drug design where structure-function relationships are core.
UCLA’s Paradigm-Shifting Discovery: Making the Impossible Possible
In an unprecedented scientific challenge, the chemistry department at UCLA has demonstrated, in clarity, given the empirical foundation needed, that anti-Bredit olefins, once presumed intrinsically unstable or impossible to synthesize, can, in fact, be synthesized and utilized in actual chemical transformations. The work, published on November 1st in Science, provides not only a theoretical scenario against Bredt’s rule, but also provides a way to synthesize these anti-Bredt olefins.
Neil Garg and his group of researchers showed that a class of silyl (pseudo)halides reacts with a fluoride source, which then promotes an elimination reaction which gives anti-Bredt olefins. The critical advances in their approach were to use a reagent that traps the unstable anti-Bredt olefins–basically, a compound that will capture the unstable anti-Bredt olefins, before they decompose, and mediocrely stable, isolable products. This not only shows that anti-Bredt olefins exist, but they can be formed, and they can be controlled and used for chemical transformations.
The implementation of this work transcends theoretical chemistry–it is a road map of how creativity, experimentations, and hard thinking can all come together well beyond the single “type” of molecule–this reshapes how chemists might think when it comes to constraints and possibilities!
Practical Applications: Exciting New Possibilities for Drug Discovery
Perhaps the most exciting option of this discovery is the practical ramifications in the real world, particularly for the pharmaceutical industry. The synthesis of anti-Bredt olefins opens up the possibility for researchers to build three-dimensional molecular architectures previously thought unattainable. These structures may afford binding affinities that are superior, selectivity that is enhanced, and pharmacological properties that are unique when used as drug candidates.
Modern drug discovery has relied on structural diversity and molecular complexity to create subtleties in the interactions between the drug and the biological target. In some instances, flat or planar molecules cannot provide sufficient biological effectiveness or activity. Three-dimensional molecules, such as those with bridgehead double bonds, can access a greater portion of the spatial landscape of biological receptors or enzymes and therefore provide greater therapeutic efficacy than planar or flat analogues.
Pharmaceuticals have currently been focusing on increasing the sp³ character of the molecules—the indicator of 3D complexity—in drug candidates to allow for improved solubility, specificity, and increased drug-like properties. Anti-Bredt olefins allow chemists yet another class of molecules to achieve this end, allowing drug discoverers to break into an inaccessible structural motif to help synthesize next generation therapeutics with innovative mechanisms of action.
Breaking Barriers: A Call for Creativity in Science
Neil Garg’s commentary on the research reveals an important philosophical point concerning the nature of science itself. “People aren’t thinking about looking into anti-Brexit olefins because they think they can’t,” Garg said. “We shouldn’t have rules like this—or if we do, they should always have the reminder that they are such and general, not rules.”
This mindset prompts the scientific community to rethink how we present “rules” and how they become accepted by the community. While there can be value in principles like Bredt’s rule as heuristics, they need not be fences. When scientists start using this or any type of rule without realizing that it is questionable, it inhibits curiosity, exploration, and innovation, which are the cornerstones of the scientific endeavor.
This research advance is proof of the power of open-minded experimentation and questioning of established tenets. Garg’s team not only illustrated that anti-Bredt olefins are achievable—they also restored a sense of daring hypothesis-driven science; reminding, both researchers and students, that chemistry and science are not static entities, but rather a dynamic entity filled with opportunities for discovery.
Summary: An Exciting New Era for Organic Chemistry
UCLA chemists showed that the technical breakthrough they accomplished was more than that: they achieved a paradigm shift. By demonstrating that anti-Bredt olefins can be prepared and stabilized, they transformed the perspective of organic chemists about molecular design. The implications of this present a prospective challenge to over a century of chemical orthodoxy, providing chemists a new opportunity to revise textbooks and provincial perspectives and challenge barriers in molecular construction.
Their ability to design and effectively work with molecules that contravene Bredt’s rule has profound repercussions for the extent of possibilities in synthetic chemistry, material sciences and pharmaceutical design-movements we have already begun and are increasing in intensity. As scientists open up their exploratory minds to a new structural frontier in drugs, they will now have an expanded capacity to experiment in diverse areas from which they are able to conceive molecules that were previously relegated to fiction.
Ultimately, this work serves as a reminder of the power of skeptical scientific thinking, creative experimentation and the willingness to challenge community tenets. As Professor Garg discussed, rules in science should never be construed as boundless absolutes – they are the start of the conversation not the end. And thus, organic chemistry is ready to move into the next chapter.
Think Beyond Discovery – Join AIU
At Atlantic International University (AIU), we believe that education should remove barriers rather than create them. Much like UCLA’s researchers disregarded a century-old hypothesis to advance science, AIU encourages our students to question, innovate and to shape futures through personalized, purpose driven learning.
No matter what you love learning about— chemistry, pharmacy, engineering, or science, AIU offers a flexible and transformative education that encourages curiosity and rewards creativity with self-paced course materials, exploratory opportunities and program flexibility, letting you learn on your own terms, like the “rule breakers” who change the world.
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References
- UCLA Chemists Shatters 100-Years Old Chemistry Rule
- UCLA Chemists Discard Bredt’s Rule
- How organic chemistry became one of UCLA’s most popular classes ASBMB AWARD ARTICLE: Organic chemistry: One of UCLA’s most popular classes
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