UCLA researchers have developed new cage-shaped molecules that challenge established rules in organic chemistry, with potential implications for drug discovery. The study, published in Nature Chemistry, was led by Neil Garg, the Kenneth N. Trueblood professor of Chemistry and Biochemistry at UCLA, and involved collaboration with computational chemist Ken Houk.
Traditionally, chemical bonds and molecular shapes are thought to follow strict guidelines. For example, alkenes—molecules containing double-bonded carbon atoms—are typically flat according to conventional organic chemistry. However, the UCLA team created unusual molecules called cubene and quadricyclene that defy these expectations.
In 2024, Garg’s laboratory previously violated Bredt’s rule, a century-old principle stating that carbon-carbon double bonds cannot exist at the “bridgehead” position of a bridged bicyclic molecule. Building on this work, the team has now developed methods to synthesize cubene and quadricyclene. These molecules have double bonds but feature three-dimensional structures instead of the usual planar arrangement.
“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 Garg. “But it turns out almost all of these rules should be treated more like guidelines.”
The process began by making stable precursors with silyl groups and adjacent leaving groups. Treating these precursors with fluoride salts generated either cubene or quadricyclene within the reaction vessel. These unstable molecules were then immediately reacted with other chemicals to form complex products not easily accessible through traditional methods.
According to Houk, “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.”
Garg explained that their findings introduce a new term: “hyperpyramidalized,” referring to the highly distorted geometries around the alkene carbons in cubene and quadricyclene. Computational studies indicated that the bond order in these molecules is closer to 1.5 rather than two—the typical value for double bonds—due to their unique shapes.
“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. If we don’t push the limits of our knowledge or imaginations, we can’t develop new things.”
The researchers believe this breakthrough could help pharmaceutical companies develop drugs using more complex three-dimensional structures rather than relying on simpler flat molecules.
“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.”
Garg emphasized three priorities for his lab: advancing fundamental knowledge; pursuing chemistry useful for society; and training students who go on to careers in academia or industry.
“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 said. “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 included postdoctoral scholars Jiaming Ding and Sarah French; graduate students Christina Rivera, Arismel Tena Meza, Dominick Witkowski; as well as longtime collaborator Ken Houk.
This work highlights UCLA’s commitment as a public research institution dedicated to advancing knowledge across disciplines while supporting diversity and excellence among its global network of students and scholars (https://www.ucla.edu/).
Funding for this research came from the National Institutes of Health.
