UCLA researchers, led by chemist Neil Garg, are challenging long-established rules in organic chemistry, demonstrating greater flexibility in molecular structure and bonding than previously understood.
In 2024, Garg's research group overturned Bredt's rule, a century-old principle that stated molecules could not form a carbon-carbon double bond at a bridgehead position. Building on this, the team has now developed methods to create cage-shaped molecules, known as cubene and quadricyclene, which feature highly unusual distorted double bonds.
Distorted Double Bonds
Unlike most molecules where atoms connected by a double bond are arranged in a flat plane, cubene and quadricyclene force double bonds into distorted three-dimensional shapes. These findings, published in Nature Chemistry, expand the range of molecular structures that chemists can consider.
Professor Garg noted that while chemists previously found support for the possibility of such alkene molecules, traditional textbook rules led to them being avoided. He stated that many chemical rules should be considered more as guidelines.
Rethinking Chemical Bonds
Organic molecules commonly contain single, double, or triple bonds. Carbon-carbon double bonds (alkenes) typically have a bond order of 2, with carbons adopting a trigonal planar geometry. However, the molecules studied by Garg's team, in collaboration with computational chemist Ken Houk, behave differently.
Due to their compact and strained shapes, the double bonds in cubene and quadricyclene exhibit a bond order closer to 1.5 than 2. This unusual bonding results directly from their three-dimensional geometry.
Implications for Medicine
This discovery is relevant to the ongoing search for new types of three-dimensional molecules to improve drug design. Modern medicines increasingly rely on complex shapes for more precise interactions with biological targets. The development of cubene and quadricyclene provides new molecular building blocks that could support advanced drug discovery efforts.
Molecular Synthesis and Properties
To generate cubene and quadricyclene, researchers synthesized stable precursor compounds containing silyl groups and nearby leaving groups. When these precursors were treated with fluoride salts, cubene or quadricyclene formed within the reaction vessel. Due to their extreme reactivity, these molecules were immediately captured by other reactants, yielding complex chemical products difficult to produce through traditional methods.
The alkene carbons in cubene and quadricyclene are described as "hyperpyramidalized," indicating severe distortion from the typical flat geometry. Computational studies revealed that the bonds in these molecules are unusually weak. Cubene and quadricyclene are highly strained and unstable, meaning they cannot currently be isolated or directly observed. Their transient existence during reactions is supported by a combination of experimental evidence and computational modeling.
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. Ken Houk, a distinguished research professor at UCLA, also contributed. The research received funding from the National Institutes of Health.