In a groundbreaking development, UCLA organic chemists have defied century-old principles of organic chemistry to create unprecedented cage-shaped molecules with double bonds. This achievement, led by Neil Garg’s lab, was recently published in Nature Chemistry and challenges the long-standing Bredt’s rule, which has dictated molecular structure for over 100 years.
Bredt’s rule traditionally prohibits the presence of a carbon-carbon double bond at the “bridgehead” position of a bridged bicyclic molecule. However, Garg’s team has successfully developed the chemistry of cubene and quadricyclene, unusual molecules that defy this rule. These molecules, which contain double bonds, are not constrained to the planar structures typically associated with alkenes.
Redefining Molecular Boundaries
The discovery marks a significant shift in the field of organic chemistry, where the established rules of structure and reactivity have long been considered absolute. “Decades ago, chemists found strong support that we should be able to make alkene molecules like these,” said Garg, the distinguished Kenneth N. Trueblood professor of Chemistry and Biochemistry at UCLA. “But it turns out almost all of these rules should be treated more like guidelines.”
In organic molecules, single, double, and triple bonds are common, with double bonds between carbon atoms known as alkenes. These typically have a flat, planar structure. However, the molecules studied by Garg’s team exhibit a bond order closer to 1.5 due to their exotic three-dimensional shapes, a discovery that could pave the way for future drug discovery.
Implications for Drug Discovery
The implications of this discovery are vast, particularly in the realm of pharmaceuticals. As researchers strive to develop new medicines, the need for molecules with complex 3D structures has grown. “Making cubene and quadricyclene was likely considered pretty niche in the 20th century,” Garg noted. “But nowadays we are beginning to exhaust the possibilities of the regular, more flat structures.”
To synthesize these rule-breaking molecules, the researchers first created stable precursors with silyl groups and adjacent leaving groups. These were then treated with fluoride salts to produce cubene or quadricyclene, which were intercepted directly with another reactant to yield complex products. The rapid reactions occur due to the severely pyramidalized geometries of these molecules, a stark contrast to the typical flat geometries of alkenes.
Challenging the Status Quo
The term “hyperpyramidalized” was introduced by the researchers to describe the distorted structures of cubene and quadricyclene. Although these molecules are highly strained and unstable, experimental and computational studies confirm their short-lived existence. “Having bond orders that are not one, two, or three is pretty different from how we think and teach right now,” Garg stated. “Time will tell how important this is, but it’s essential for scientists to question the rules.”
Garg’s team anticipates that their discovery will assist pharmaceutical companies in developing future medicines with intricate structures. The study exemplifies the innovative thinking that has made Garg’s courses at UCLA highly popular and has propelled his students into successful careers.
Looking Ahead
Garg emphasizes the importance of pushing the boundaries of scientific knowledge. “In my lab, three things are most important. One is pushing the fundamentals of what we know. Second is doing chemistry that may be useful to others and have practical value for society,” he explained. “And third is training all the really bright people who come to UCLA for a world-class education and then go into academia, where they continue to discover new things and teach others, or into industry, where they’re making medicines or doing other cool things to benefit our world.”
The research team, which includes UCLA postdoctoral scholars and graduate students from Garg’s lab, as well as computational chemistry expert Ken Houk, received funding from the National Institutes of Health. As the scientific community continues to explore the potential of these novel molecules, the study stands as a testament to the power of questioning established norms and the endless possibilities of scientific innovation.
