A year after undermining Bredt’s rule, UCLA scientists have made cage-shaped, double-bonded molecules that defy expectations

Organic chemistry is packed with rules about structure and reactivity, especially when it comes to making and breaking chemical bonds. The rules governing how these bonds, which hold atoms together in molecules, form and the shapes they give molecules are often thought to be absolute, but UCLA organic chemists are pushing the boundaries of the possible.

In 2024, Neil Garg's labviolated Bredt's rule, a 100-year-old rule stating that molecules cannot have a carbon-carbon double bond at the "bridgehead" position (the ring junction of a bridged bicyclic molecule). Now, they've developed the chemistry of more unusual, cage-shaped molecules that contain double-bonds called cubene and quadricyclene.

Usually, the atoms around double bonds lie in the same plane, but the rules break down for cubene and quadricyclene, the team discovered. The achievement, published in Nature Chemistry, stretches the imagination for the types of molecules chemists can make and, in doing so, enables future drug discovery.

"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."

Three types of bonds are common in organic molecules: single, double and triple. Double bonds between carbon atoms are known as alkenes, which have a bond order of 2, defined by the number of electron pairs shared between the bonding carbons and correlating to the "double" bond. In a typical alkene molecule, the carbon atoms have trigonal planar geometries, which means the atoms of the double bond have a flat or planar structure. The molecules studied by Garg's team and his close collaborator, UCLA colleague Ken Houk, have a bond order closer to 1.5 than to 2 due to their exotic three-dimensional shape.

"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.

The discovery comes at a time when researchers are striving to make new types of molecules with 3-dimensional shapes for the development of new medicines.

"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 get at the two rule-breaking molecules, the researchers first made stable precursors with silyl groups, or a group of atoms containing a silicon atom at the center, and adjacent group known as leaving groups. Then they treated either precursor with fluoride salts to create cubene or quadricyclene in the reaction vessel. Those molecules are intercepted directly with another reactant, giving unusual and complex products that are otherwise difficult for chemists to make.

The researchers say that the reactions occur rapidly because cubene and quadricyclene have severely pyramidalized geometries at the alkene carbons, rather than typical flat geometries that alkene carbons are well known for. The researchers introduced the term "hyperpyramidalized" to describe the distorted structures and then computationally studied the unusually weak bonding. Although cubene and quadricyclene are highly strained and unstable molecules that cannot be isolated or observed yet, experimental and computational studies support the short-lived existence of the molecules.

"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."

Garg's team hopes that their new discovery will help pharmaceutical companies make medicines of the future. Many new drugs don't have the simple and flat structures that they had in past decades. Instead, increasingly complicated 3D structures are investigated, which indicates a big shift in what a medicine can look like.

Garg's team sees a practical need to develop new molecules that can be used to discover increasingly sophisticated drugs.

The study shows the creative, outside-the-box thinking that has made Garg's organic chemistry courses among the most popular at UCLA and has propelled the students he mentors into successful careers.

"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 authors of the new study include UCLA postdoctoral scholars and graduate students from Garg's lab: Jiaming Ding, Sarah French, Christina Rivera, Arismel Tena Meza, Dominick Witkowski, as well as Garg's longstanding collaborator and computational chemistry expert Ken Houk, a distinguished research professor at UCLA.

The research was funded by the National Institutes of Health.