UCLA chemists redefine a 100-year-old rule of chemistry: Here’s everything you need to know

A recent discovery by UCLA scientists has challenged a century-old principle in organic chemistry, reshaping fundamental knowledge and expanding the possibilities of pharmaceutical research. Researchers led by Professor Neil Garg have found a way to synthesize and stabilize the molecular structures of anti-Bredt olefins (ABOs). These structures have long been considered too unstable to exist. This achievement dismantles Bredt’s rule, a 1924 restriction that has influenced molecular design for decades, allowing chemists to explore new chemical reactions in drug development.

Bredt’s rule and its historical significance

Established by chemist Julius Bredt almost a hundred years ago, Bredt’s rule states that double bonds cannot exist at the bridgehead in certain molecules because this structure would disrupt molecular stability. Bredt’s rule remained strong for decades, prohibiting chemists from designing certain types of synthetic compounds. Since double bonds, or olefins, are widely used in pharmaceuticals, this limitation has affected the drug design landscape by limiting the diversity of possible molecular structures.

How UCLA Researchers Did the Impossible

In a paper published In Science, Garg and his team reveal a method for creating ABOs by treating molecules known as silyl (pseudo)halides with a fluoride source, which triggers an elimination reaction leading to the formation of ABOs . To manage ABO instability, the team introduced a trapping agent to stabilize the molecules, allowing them to isolate practical reaction products. This approach provides chemists with a controlled way of working with ABOs, paving the way for designing unique compounds with real-world applications.

Implications for the future of drug discovery

According to Garg, the pharmaceutical industry has every interest in generating 3D structures like those that are now achievable with ABOs. This could be essential for discovering new drugs. “For more than a century, chemists have avoided anti-Bredt olefins, believing that it was impossible to work with them,” Garg said, highlighting the potential of these newly accessible compounds for pharmaceutical innovation. The collaboration of Professor Ken Houk, co-author and expert in computational chemistry, also helped elucidate the potential of these compounds in practical applications.

This discovery challenges chemists to rethink molecular rules as flexible guidelines rather than fixed laws, which could catalyze a wave of innovation in synthetic chemistry and pharmaceutical development.