Organic chemistry is built on established rules about how atoms bond and how molecules are structured. Recently, a team at UCLA, led by chemist Neil Garg, has shown that these rules can be more flexible than previously thought.
In 2024, Garg’s group challenged Bredt’s rule, a guideline that has been accepted for over a century. This rule says that carbon-carbon double bonds can’t form in certain positions within bridged bicyclic molecules. With their innovative methods, Garg’s team went a step further, creating unusual shapes called cubene and quadricyclene, which include surprising double bonds.
Typically, double-bonded atoms are flat. However, cubene and quadricyclene force these bonds into unique three-dimensional shapes. Their findings, published in Nature Chemistry, expand the range of molecular designs that can be explored, potentially leading to breakthroughs in drug development.
Garg explains, “Chemists have long believed we could create such molecules, but the rigid rules we were taught held many back. Now, we see that most of these rules are more like guidelines.”
In standard organic molecules, three types of bonds exist: single, double, and triple. Double bonds, known as alkenes, usually lie flat in a trigonal planar arrangement. In contrast, cubene and quadricyclene have a bond order of about 1.5, not the expected 2. This deviation stems from their compact, strained shapes.
Ken Houk, a computational chemist working with Garg, notes, “Neil’s lab has successfully crafted these distorted molecules, and there’s excitement about their potential applications.”
Why are these three-dimensional molecules so important? Today, scientists are eager to explore new types of molecular shapes that could enhance drug design. Complex structures can interact with biological targets more accurately, which is crucial for developing effective treatments. Garg highlights the shift in focus: “While creating cubene and quadricyclene might have felt niche in the past, current medicine demands innovative, rigid 3D molecules.”
To synthesize these unique shapes, the team created precursor compounds with specific atomic groups. When they treated these with fluoride salts, cubene or quadricyclene emerged. Because these molecules are highly reactive, they quickly interacted with other reagents, resulting in complex chemical compounds that are challenging to create with traditional techniques.
Interestingly, cubene and quadricyclene exhibit what researchers have termed “hyperpyramidalized” structures, meaning their carbon atoms are significantly distorted instead of being flat. This distortion weakens the bonds within these molecules, making them highly strained and unstable. Although they can’t be isolated for direct observation, computational models and experimental evidence suggest they exist momentarily during reactions.
Garg emphasizes the significance of questioning established norms: “Having non-standard bond orders prompts us to rethink how we approach chemistry. This questioning is essential for developing new insights.”
These discoveries could revolutionize drug discovery. Today’s pharmaceutical candidates often feature intricate 3D shapes, revealing a major shift in how researchers envision drug design. Increased complexity in molecular structures is now critical for developing effective drugs.
Also noteworthy is the educational impact of Garg’s research. His approach to teaching organic chemistry at UCLA has made his classes immensely popular. His students frequently advance to promising careers, whether in academia or in the pharmaceutical industry, where they continue contributing to innovative discoveries.
The study involved contributions from multiple postdoctoral researchers and graduate students from Garg’s lab, alongside Houk. Funding came from the National Institutes of Health, emphasizing the importance of collaborative research in advancing the field.
In summary, Garg’s team’s work reshapes our understanding of molecular structures, opening new avenues for drug discovery and highlighting the need for creativity in scientific education.
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Chemistry; Inorganic Chemistry; Physics; Organic Chemistry; Graphene; Engineering and Construction; Nanotechnology; Quantum Physics
