by Chemistry is littered with rules that, on closer inspection, are alarmingly fragile.
Researchers are calling for a century-old rule to be abolished, after creating molecules that defy it.
They have published their findings in Science.
“We shouldn’t have these kinds of rules – or if we do have them, they should only exist with the constant reminder that they are guidelines and not rules,” says corresponding author Professor Neil Garg, a chemist at the University of California, Los Angeles. Angeles.
“It destroys creativity when we have rules that supposedly can’t be overcome.”
The rule, called the Bredt rule, concerns a class of molecules called olefins. These are carbon-based (organic) molecules, which contain a double bond where 2 carbon atoms share 2 electron pairs.
Carbon-carbon double bonds are common in nature, but are especially coveted by the pharmaceutical industry and other areas of synthetic chemistry.
This is because they are valuable building blocks: the double bond can be manipulated much more easily in chemical reactions than singly bonded carbon atoms, allowing a wider range of products to be formed.
In 1924, the German chemist Julius Bredt published a rule on certain types of olefins, called ‘bridged bicyclic’ molecules.
These molecules are shaped like rings, with a ‘bridge’ branching across the top. Bredt postulated that a double bond could not form at a specific location in the molecule, the so-called “bridgehead position”.
Such a bond, Bredt judged, would be too tense to exist – atoms tend to sit in certain, neat geometries determined by physics. Although these shapes can be bent, they can only bend so far before the molecule will fail to form.
Bredt’s Rule has since become a staple of organic chemistry textbooks and is recognized by the global authority on chemists: the International Union of Pure and Applied Chemistry.
Researchers have previously been able to create ‘anti-Bredt olefins’. But these were usually very unstable and did not last long. Research on it has been scarce over the past century.
“People don’t investigate anti-Bredt olefins because they don’t think they can,” says Garg.
But his team made several, with double bonds that sat – well, not comfortably, but at least stable – in the beachhead position.
They made their molecules from compounds called silyl(pseudo)halides. These materials contain silicon atoms, as well as atoms from the halogen class of elements, including fluorine and chlorine.
When treated with fluoride-based compounds, the molecules formed into anti-Bredt olefins. The team used a ‘capture agent’ to stabilize the molecules as they formed, allowing them to be isolated and analyzed.
“There is a big push in the pharmaceutical industry to develop chemical reactions that produce three-dimensional structures like ours because they can be used to discover new drugs,” says Garg.
“What this study shows is that, contrary to a hundred years of conventional wisdom, chemists can create and use anti-Bredt olefins to create value-added products.”
