How have recent experiments disproven Bredt’s rule? Photo credit: Terry Vlisidis via Unsplash
In November 2024, Neil Garg and his team have synthesised a new class of molecules previously thought too unstable to exist, lighting up a new path to synthesising challenging drugs. For 100 years, it was believed to be impossible, yet chemists have now succeeded.
Organic compounds typically adopt specific conformations because of their bonding properties. Unsaturated compounds such as alkenes contain double bonds between two carbon atoms. These double bonds consist of a sigma (σ) bond and a pi () bond, formed by the overlap of s and p orbitals (Figure 1). The atoms arrange themselves in the same plane to maximise the interaction between p orbitals in a pi bond. However, the orientation of such double bonds in a bicyclic system, where two rings share atoms, raises an interesting question: can double bonds exist at the shared carbons (bridgeheads)? This is the basis of Bredt’s rule.
Figure 1: Orbital representation of carbon-carbon double bond. A sigma bond is formed by the end on overlap of s or p orbitals. A pi bond is formed by sideways overlap of p orbitals.
In 1924, organic chemist Julius Bredt proposed that small molecules with overlapping rings cannot have a carbon double bond at the bridgehead positions. For this to occur, the double bond must be trans (in the correct orientation) in at least one ring. However, this cannot be achieved for small rings of fewer than seven carbons due to improper alignment of p orbitals (Figure 2). This forms a strained 3D shape that makes it highly reactive and unstable. Despite Bredt’s rule, many challenges have been made to generate and study alkenes with a bridgehead double bond, known as anti-Bredt olefins (ABOs). Several exceptions to the rule have been known since. However, only recently, chemists from the University of California, Los Angeles, demonstrated a general method to access ABOs with small bicyclic rings.
Figure 2: Norbornene on the left, forbidden norbornene isomers on the right. Isomers contain strained bridgehead double bond at the red carbons, geometrically twisting the double bond.
In 2024, Neil Garg and his colleagues synthesised several different ABOs using silyl precursors, which have a bulky silicone-containing group attached to a carbon in a bicyclic system. After treatment with a fluoride source, the silyl group can be easily removed by an elimination reaction. This allows the strained ABO intermediate to be made under mild conditions. However, ABOs are too unstable to isolate, so various trapping agents are incorporated to capture highly unstable molecules as they react. These produce complex 3D structures that can be isolated and analysed. ‘Now, we’ve made ABOs synthetically useful chemists can not only use them practically, but can more generally consider them in synthetic design plans,’ adds Garg.
ABOs are too unstable to isolate, so various trapping agents are incorporated to capture highly unstable molecules as they react.
Another key experiment focussed on the chirality of anti-Bredt olefins. For a molecule to be chiral, it must be asymmetric so the mirror images will not be identical. Unlike typical alkenes, anti-Bredt olefins are chiral compounds as they do not perfectly align with their mirror images. Stereochemistry solely depends on the orientation of groups surrounding the double bond. Considering this property, Garg and his team synthesised and trapped a chiral ABO using anthracene and formed a single-enantiomer product. This confirmed that chiral properties are effectively transferred from the precursor to the product, proving that the reaction went through an anti-Bredt intermediate to maintain its stereochemistry. Therefore, ABOs can be used as building blocks to produce enantioenriched compounds, which are widely seen in pharmaceutical drugs.
After several reactions, the ring undergoing expansion becomes too large and strained, makeing it harder to insert carbons.
Craig Williams’ team at the University of Queensland, Australia, explored the synthesis of hyperstable alkenes, a class of alkenes with minimal double-bond strain. They developed a one-pot synthesis of four bicyclic hyperstable alkenes through a series of ring-expansion reactions involving boron intermediates. However, this approach has a limit. After several reactions, the ring undergoing expansion becomes too large and strained, makeing it harder to insert carbons. Initially, hyperstable alkenes were thought to be entirely inert, but they showed slight reactivity, including oxidation. ‘What is cool and complementary is that, in our study, the bridgehead alkenes are highly reactive, but in the Williams’ study, their bridgehead alkenes are stabilised. So, bridgehead alkenes in small (anti-Bredt) versus large rings lead to very different reactivity,’ stated Garg.
This provided a new strategy for producing reactive molecules and those with seemingly impossible structures…
The synthesis of anti-Bredt olefins marks a groundbreaking achievement in organic chemistry, overcoming long-standing limitations by Bredt’s rule. This provided a new strategy for producing reactive molecules and those with seemingly impossible structures, inspiring researchers to challenge other long-standing rules. Complementary work on hyperstable alkenes highlights the diverse reactivity of bridgehead alkenes, offering valuable insight into their potential for synthetic and pharmaceutical innovation.
