Bredt’s rule was first reported in textbooks in 1924: double bonds cannot exist at certain positions on organic molecules if the molecule’s geometry deviates too far from what we learn in textbooks. UCLA chemists say it’s not true. Their rebuttal, published in Science, shows how to make molecules that violate Bredt’s rule, enabling chemists to find practical ways to make and use them in reactions.
Organic molecules have specific shapes and arrangements of atoms. Molecules called olefins have double bonds, or alkenes, between two carbon atoms that ordinarily lie in the same 3D plane. Few molecules deviate from this geometry.
Bredt’s rule states that molecules cannot have a carbon-carbon double bond at the ring junction of a bridged bicyclic molecule, the “bridgehead” position. The double bond on these structures would have distorted, twisted geometrical shapes that deviate from the rigid geometry of alkenes taught in textbooks. Olefins are useful in pharmaceutical research; however, Bredt’s rule has constrained the kind of synthetic molecules scientists can imagine making with them and prevented possible applications of their use in drug discovery.
Now, UCLA scientists invalidated that idea, showing how to make several kinds of molecules that violate Bredt’s rule, called anti-Bredt olefins, or ABOs.
“People aren’t exploring anti-Bredt olefins because they think they can’t,” said corresponding author Neil Garg, the Kenneth N. Trueblood Distinguished Professor of Chemistry and Biochemistry at UCLA. “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’s lab molecules are called silyl (pseudo) halides with a fluoride source to induce an elimination reaction that forms ABOs. ABOs are unstable and include another chemical that can “trap” the unstable ABO molecules and yield products that can be isolated. ABOs can be generated and trapped to give structures of practical value.
“There’s a big push in the pharmaceutical industry to develop chemical reactions that give three-dimensional structures like ours because they can be used to discover new medicines,” Garg said. “What this study shows is that contrary to one hundred years of conventional wisdom, chemists can make and use anti-Bredt olefins to make value-added products.”
