Researchers at the University of California, Los Angeles, have synthesized cage-shaped molecules featuring unusually warped double bonds, defying long-held principles of organic chemistry. This breakthrough builds on their 2024 overturning of Bredt's rule and could influence future drug design. The findings appear in Nature Chemistry.
Organic chemistry has long been guided by rules dictating how atoms bond and molecules form. In 2024, a team led by UCLA chemist Neil Garg challenged Bredt's rule, which prohibits carbon-carbon double bonds at the bridgehead of bridged bicyclic molecules. Now, Garg's group has pushed further by creating cubene and quadricyclene, compact structures with double bonds forced into three-dimensional distortions rather than the typical flat arrangement.
These molecules exhibit bond orders around 1.5, between single and double, due to their strained geometry. The researchers, including computational chemist Ken Houk, used precursors with silyl groups treated by fluoride salts to generate the reactive compounds, which were quickly captured to form complex products. Though too unstable for isolation, evidence from experiments and modeling confirms their fleeting existence, marked by severe pyramidalization termed "hyperpyramidalized."
"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," Garg said. "But it turns out almost all of these rules should be treated more like guidelines."
Houk noted, "Neil's lab has figured out how to make these incredibly distorted molecules, and organic chemists are excited by what might be done with these unique structures."
The work addresses a need in pharmaceuticals for rigid, three-dimensional scaffolds beyond flat structures. "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," Garg explained. Funded by the National Institutes of Health, the study involved postdocs and graduate students from Garg's lab.