In a groundbreaking development, scientists at UCLA have successfully synthesized cage-shaped molecules featuring double bonds, challenging long-standing principles in organic chemistry. This achievement, led by Professor Neil Garg, has significant implications for drug discovery and the future of molecular design.
The research, published in Nature Chemistry, focuses on molecules known as cubene and quadricyclene. These structures defy Bredt’s rule, a century-old guideline that prohibits carbon-carbon double bonds at the “bridgehead” position of bridged bicyclic molecules. The breakthrough marks a significant departure from traditional textbook rules regarding molecular structure and reactivity.
Breaking the Rules of Organic Chemistry
Organic chemistry has long adhered to specific rules governing the formation and shape of chemical bonds. Typically, atoms around double bonds lie in the same plane, forming flat structures. However, the UCLA team discovered that these rules do not apply to the cage-like molecules they synthesized. The implications of this discovery extend to the development of new, complex molecular structures.
“Decades ago, chemists found strong support that we should be able to make alkene molecules like these, but because we’re still very used to thinking about textbook rules of structure, bonding and reactivity in organic chemistry, molecules like cubene and quadricyclene have been avoided,” said Neil Garg, the distinguished Kenneth N. Trueblood Professor of Chemistry and Biochemistry at UCLA.
Garg’s research, in collaboration with UCLA colleague Ken Houk, reveals that the bond order in these molecules is closer to 1.5 rather than the typical 2 found in alkenes. This is due to their exotic three-dimensional shape, which deviates from the standard planar geometry.
Implications for Drug Discovery
The discovery comes at a time when the pharmaceutical industry is increasingly interested in three-dimensional molecular structures for drug development. Traditional flat molecules are reaching their limits, prompting a shift towards more complex, rigid 3D structures.
“Making cubene and quadricyclene was likely considered pretty niche in the 20th century,” said Garg. “But nowadays we are beginning to exhaust the possibilities of the regular, more flat structures, and there’s more of a need to make unusual, rigid 3D molecules.”
To synthesize these rule-breaking molecules, the researchers first created stable precursors with silyl groups and adjacent leaving groups. Treating these precursors with fluoride salts in the reaction vessel resulted in the formation of cubene or quadricyclene, which were then intercepted with another reactant to produce complex products.
Scientific and Educational Impact
The rapid reactions that produce cubene and quadricyclene are attributed to their “hyperpyramidalized” geometries, a term introduced by the researchers to describe the distorted structures. Although these molecules are highly strained and unstable, computational studies support their transient existence.
“Having bond orders that are not one, two or three is pretty different from how we think and teach right now,” said Garg. “Time will tell how important this is, but it’s essential for scientists to question the rules.”
Garg’s team hopes that their discovery will inspire pharmaceutical companies to explore new molecular designs for future medicines. The study highlights the creative thinking that has made Garg’s courses at UCLA among the most popular and has helped his students pursue successful careers in academia and industry.
The Path Forward
Looking ahead, Garg emphasizes the importance of pushing the boundaries of scientific knowledge and training the next generation of chemists. The study’s authors include UCLA postdoctoral scholars and graduate students from Garg’s lab, as well as Ken Houk, a distinguished research professor at UCLA.
The research was funded by the National Institutes of Health, underscoring the significance of this work in advancing the field of organic chemistry.
As the scientific community continues to explore the potential of these novel molecular structures, the implications for drug discovery and other applications remain vast and promising.
