UCLA Chemists Challenge a Century-Old Rule in Organic Chemistry

UCLA chemists have identified a significant flaw in a fundamental rule of organic chemistry that has persisted for 100 years, prompting calls to rewrite textbooks. This rule, known as Bredt's rule, asserts that molecules cannot have a carbon-carbon double bond at the ring junction of a bridged bicyclic molecule, also referred to as the "bridgehead" position. Traditionally, olefins, which are characterized by double bonds between carbon atoms, are expected to maintain a specific geometry, with atoms lying in the same 3D plane. Bredt's rule, introduced in 1924, suggests that double bonds at these junctions would lead to distorted shapes inconsistent with the rigid geometry of alkenes.

This long-held belief has limited the types of synthetic molecules chemists could conceive and, consequently, hindered potential applications in pharmaceutical research. However, a new study published in the journal *Science* by UCLA scientists has overturned this notion, demonstrating the feasibility of synthesizing molecules known as anti-Bredt olefins (ABOs). Corresponding author Neil Garg, the Kenneth N. Trueblood Distinguished Professor of Chemistry and Biochemistry at UCLA, emphasizes that the perception of ABOs as unattainable has stifled innovation. "We shouldn't have rules like this -- or if we have them, they should only exist with the constant reminder that they're guidelines, not rules. It destroys creativity when we have rules that supposedly can't be overcome," Garg stated.

In their research, Garg's lab employed a technique involving the treatment of silyl (pseudo)halides with a fluoride source to initiate an elimination reaction that produces ABOs. Given the high instability of ABOs, they incorporated a trapping agent to stabilize these molecules, allowing for the isolation of products with practical value. Garg noted, "There's a big push in the pharmaceutical industry to develop chemical reactions that yield three-dimensional structures like ours because they can be used to discover new medicines. This study shows that, contrary to one hundred years of conventional wisdom, chemists can make and use anti-Bredt olefins to create valuable products." The research involved contributions from UCLA graduate students and postdoctoral scholars, alongside collaboration with computational chemistry expert Ken Houk. Funding for the study was provided by the National Institutes of Health.