Chemists at UCLA, led by distinguished professor Neil Garg, have successfully created previously considered “impossible” cage-shaped molecules, directly challenging a century-old rule of chemistry. This groundbreaking work, detailed recently in Nature Chemistry and reported by ScienceDaily.com, redefines our understanding of molecular structure and bonding, offering a new toolkit for chemical innovation.
The discovery builds on Garg’s earlier work in 2024, which overturned Bredt’s rule, a fundamental principle stating that molecules cannot form a carbon-carbon double bond at a “bridgehead” position. This latest advancement pushes the boundaries even further, demonstrating that even more unusual structures, like cubene and quadricyclene, can exist despite their highly strained double bonds.
For decades, organic chemistry has relied on established rules governing how atoms connect and how chemical bonds form, guiding scientists in predicting molecular behavior. This new research suggests that many of these long-held principles should be viewed more as flexible guidelines than unbreakable laws, potentially reshaping how future medicines are made.
Rethinking fundamental chemical bonds
In most molecules, atoms connected by a carbon-carbon double bond, known as alkenes, typically adopt a flat, trigonal planar geometry. However, Garg’s team discovered that this familiar arrangement does not hold true for cubene and quadricyclene. These unique, compact molecules force their double bonds into dramatically distorted three-dimensional shapes, a phenomenon long considered chemically unstable.
Working closely with UCLA computational chemist Ken Houk, the researchers found that the double bonds in these molecules exhibit a bond order closer to 1.5 than the usual 2. This unusual bonding characteristic is a direct consequence of their highly strained and compact geometry. According to Professor Garg, “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.” He adds, “But it turns out almost all of these rules should be treated more like guidelines.”
The implications for 3D drug design
This breakthrough in creating impossible chemistry molecules arrives at a critical juncture for drug development. Modern medicine increasingly seeks new types of three-dimensional molecules because their complex shapes allow for more precise interactions with biological targets, leading to more effective and targeted therapies. Traditional, flatter molecular structures are beginning to reach their limits in terms of novelty and functionality.
The synthesis of cubene and quadricyclene involves a clever method where researchers first create stable precursor compounds containing silyl groups and nearby leaving groups. When these precursors are treated with fluoride salts, the highly reactive cubene or quadricyclene forms transiently within the reaction vessel. These fleeting molecules are then immediately captured by other reactants, yielding complex and novel chemical products that would be exceedingly difficult to produce using conventional methods, as described by the UCLA Chemistry Department.
The ability to engineer these hyperpyramidalized and highly unstable structures expands the chemical toolkit available to scientists. This shift from rigid rules to flexible guidelines opens up an exciting frontier, allowing chemists to imagine and construct entirely new classes of molecules. The long-term implications for developing new pharmaceuticals, advanced materials, and even novel chemical reactions are profound, promising a future where molecular design is limited only by imagination, not by century-old dogma.
