Researchers led by Neil Garg have extended a recent challenge to Bredt’s rule by synthesizing three-dimensional, hyperpyramidalized alkenes — cubene and quadricyclene — from silyl-substituted precursors using fluoride-triggered leaving groups. The severe geometric distortion reduces the effective C=C bond order toward ~1.5, producing highly strained, reactive, and short-lived species. Despite stability challenges, their unique 3D frameworks offer promising new scaffolds for medicinal chemistry and inspire novel synthetic strategies.
Chemists Break a 100-Year-Old Bonding Rule — Twice — And Push Alkenes Into 3D
Scientists Just Broke a 100-Year-Old Rule—TwiceKinoMasterskaya - Getty Images
Researchers led by UCLA chemist Neil Garg have not only challenged a century-old restriction in organic chemistry known as Bredt’s rule, they’ve pushed alkene geometry into three dimensions to create extremely strained, short-lived molecules with intriguing potential for drug design.
What Was Bredt’s Rule?
Bredt’s rule, formulated in 1924, held that double bonds (alkenes) cannot be placed at certain bridgehead positions in bicyclic systems because the required planar geometry is sterically impossible. That long-standing constraint was questioned recently by Garg and colleagues, and the team has now extended that work to produce unusually distorted, three-dimensional alkenes.
How the Team Made These Strange Alkenes
Garg’s group accessed two highly unusual hydrocarbons — cubene and quadricyclene — from silyl-substituted precursors. Those precursors contained leaving groups that, when treated with fluoride salts, fragmented to afford the target strained systems. Silyl groups (silicon-centered substituents) and carefully chosen departing groups were essential to this strategy.
What Makes These Molecules Unusual?
Most simple alkenes (for example, ethylene) have carbon atoms in a trigonal-planar arrangement. In cubene and quadricyclene, the double-bond carbons deviate from this planar geometry — they are pyramidalized. Garg describes the distortion as hyperpyramidalization, because one or both alkene carbons are forced far out of the plane formed by their three attachments.
“It is well understood that the geometry at each alkene carbon is typically trigonal planar. However, it is also possible to deviate from this conventional trigonal planar geometry when an alkene is generated in a confined ring system.” — Neil Garg
This extreme pyramidalization lowers the effective bond order of the C=C bond toward roughly 1.5 rather than the classical value of two, producing a non-integer sharing of electron density and unusual bonding properties.
Strain, Reactivity, and Practical Challenges
Hyperpyramidalized compounds are highly strained: many bonds are weakened, internal energy is elevated, and the species are highly reactive and often short-lived. These characteristics make isolation and direct observation difficult. Historically, cubene and quadricyclene were first synthesized decades ago (quadricyclene in 1961 and cubene in 1964), but Garg’s work accesses similarly contorted alkene geometries via a new synthetic route and highlights the extreme distortion of their double bonds.
Why It Matters
Despite their fleeting nature, these three-dimensional frameworks are attractive to medicinal chemists because they offer complex, non-planar scaffolds that differ from the mostly flat structures common in many drugs. The new methods give chemists access to intricate shapes and bonding patterns that could inspire novel scaffolds and synthetic tactics exploiting hyperpyramidalization or non-integer bond orders.
Garg and his team published the work in Nature and plan to continue exploring these strained systems and their potential applications, particularly in pharmaceutical discovery. Their discoveries suggest that other long-accepted constraints in organic chemistry may be revisited with creative synthetic approaches.
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