Organic chemistry relies on long established rules that describe how atoms connect, how chemical bonds form, and how molecules take shape. These principles guide how scientists understand reactions and predict molecular behavior. While many of these rules are treated as fixed truths, researchers at UCLA are showing that chemistry has more flexibility than once believed.
In 2024, a research group led by UCLA chemist Neil Garg overturned Bredt’s rule, a principle that had stood for more than a century. The rule states that molecules cannot form a carbon-carbon double bond at the “bridgehead” position (the ring junction of a bridged bicyclic molecule). Building on that breakthrough, Garg’s team has now developed methods to create even stranger structures: cage-shaped molecules known as cubene and quadricyclene that contain highly unusual double bonds.
When Double Bonds Refuse to Stay Flat
In most molecules, atoms connected by a double bond sit in a flat arrangement. Garg’s team discovered that this familiar geometry does not apply to cubene and quadricyclene. Their findings, published in Nature Chemistry, show that these molecules force double bonds into distorted three-dimensional shapes. This expands the range of molecular structures chemists can imagine and could play an important role in future drug development.
“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 corresponding author Garg, 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.”
Rethinking Chemical Bonds
Organic molecules commonly contain three types of bonds: single, double, and triple. Carbon-carbon double bonds are called alkenes and have a bond order of 2, which reflects how many electron pairs are shared between the bonded atoms. In typical alkenes, the carbons adopt a trigonal planar geometry, creating a flat structure around the double bond.
The molecules studied by Garg’s team, working closely with UCLA computational chemist Ken Houk, behave differently. Because of their compact and strained shapes, the double bonds in cubene and quadricyclene have a bond order closer to 1.5 than to 2. This unusual bonding arises directly from their three-dimensional geometry.
“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,” says Houk.
Why 3D Molecules Matter for Medicine
The discovery arrives at a moment when scientists are actively searching for new types of three-dimensional molecules to improve drug design. Many modern medicines rely on complex shapes that interact more precisely with biological targets.
“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.”
How the Molecules Are Made
To generate cubene and quadricyclene, the researchers first synthesized stable precursor compounds. These precursors contained silyl groups, which are groups of atoms with a silicon atom at the center, along with nearby leaving groups. When the precursors were treated with fluoride salts, cubene or quadricyclene formed inside the reaction vessel.
Because these molecules are extremely reactive, they were immediately captured by other reactants. This process produced complex and unusual chemical products that are otherwise very difficult to make using traditional methods.
Hyperpyramidalized and Highly Unstable
According to the researchers, the reactions proceed rapidly because the alkene carbons in cubene and quadricyclene are severely pyramidalized instead of flat. To describe this extreme distortion, the team introduced the term “hyperpyramidalized.” Computational studies revealed that the bonds in these molecules are unusually weak.
Cubene and quadricyclene are highly strained and unstable, which means they cannot yet be isolated or directly observed. However, a combination of experimental evidence and computational modeling supports their brief existence during the reactions.
“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.”
Implications for Future Drug Discovery
Garg’s team believes these findings could help pharmaceutical researchers design the next generation of medicines. Compared with drugs developed decades ago, many new candidates feature more complex three-dimensional shapes. This shift reflects a broader change in how scientists think about what effective medicines can look like.
The researchers see a growing practical need to develop new molecular building blocks that can support increasingly sophisticated drug discovery efforts.
Training the Next Generation of Chemists
The study also highlights the creative approach that has made Garg’s organic chemistry courses among the most popular at UCLA. Many of the students trained in his lab have gone on to successful careers in both academia and 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.”
Study Authors and Funding
The authors of the study include UCLA postdoctoral scholars and graduate students from Garg’s lab: Jiaming Ding, Sarah French, Christina Rivera, Arismel Tena Meza, and Dominick Witkowski, along with Garg’s longtime collaborator and computational chemistry expert Ken Houk, a distinguished research professor at UCLA.
The research was funded by the National Institutes of Health.