Organic chemist Neil A. Garg and his team at the University of California, Los Angeles, have pushed the boundaries of what molecules can do, challenging a long-standing principle in the field. Their latest research upends Bredt's rule, a 100-year-old guideline that was thought to be an immutable law of chemistry.

Unlocking the Potential of Twisted Molecules

Defying Bredt's Rule

Bredt's rule has long held that certain types of bridged compounds, with their unique peaked shapes, were incapable of forming a double bond at the junction between the rings. The reasoning was that such a bond would require an extreme twist and bend, leading to an unacceptable amount of strain. However, Garg and his team have shown that these so-called "anti-Bredt olefins" are not only possible to create, but they can also serve as valuable intermediates in the construction of complex three-dimensional molecules.

A Breakthrough in Molecular Geometry

Chemists have steadily improved their ability to work with unusual molecular geometries over the past century. "We know a lot about how to make strained intermediates and trap them," Garg explains. This newfound expertise has enabled the researchers to successfully synthesize a variety of anti-Bredt olefins, using silyl precursors and elimination reactions to generate the elusive double bonds. While these molecules are too unstable to isolate, the team has leveraged them as key intermediates in a range of cycloaddition reactions, leading to the construction of complex three-dimensional structures.

Transferring Stereochemistry

In a particularly noteworthy experiment, the researchers created a chiral anti-Bredt olefin whose stereochemistry was solely derived from the twistedness of the molecule. By trapping this intermediate with anthracene, they were able to produce a single-enantiomer product, providing strong evidence that the reaction had indeed proceeded through an anti-Bredt intermediate. This achievement, witnessed by co-lead author Luca McDermott while attending the American Chemical Society Spring 2024 meeting, solidified the team's conviction that they were successfully synthesizing these elusive compounds.

Practical Implications and Future Directions

The significance of Garg and his team's work extends beyond the academic realm. Organic chemist Paul Wender of Stanford University, who was not involved in the research, praised it as a "thorough, fundamental organic study with potentially huge practical value." While others had previously challenged Bredt's rule, Garg and his colleagues have made important strides in making these unusual molecules more accessible and useful for the broader chemistry community.Carolyn Bertozzi, also of Stanford and a Nobel Prize–winning researcher in chemical biology, lauded the paper for building on "curiosity-driven basic research on twisted olefins" to transform these molecular curiosities into powerful synthetic intermediates. "I love when an old, forgotten functionality is reborn for modern use," she remarked.Garg and his group are continuing to explore the world of alkenes with "messed-up geometries," and they hope that their work will inspire more chemists to join them in seeking opportunities to bend the rules and unlock the potential of these unconventional molecules.