From left: UChicago scientists and study co-authors Alexander Fanourakis, Abby Bracken, Liao Chen, and Yahia Ali, in the Levin lab.
Photo by Jean Lachat
‘The shape is everything’
When you’re making a molecule, you have to make sure every atom in the molecule is in the proper place. “The shape is everything. For example, if you’re making drugs, molecules that are connected properly are medicine. A molecule that is not connected properly is no longer a medicine, and may even be harmful,” said Mark Levin, associate professor of chemistry at UChicago and senior author on the paper.
To build this molecule correctly, you need a very good recipe. If you combine the ingredients for a cake in the wrong order, the recipe won’t work. Likewise, molecules need to be crafted in a very precise series of steps.
One such commonly used class of molecules is known as pyrazoles. They are used in many drugs and also to make agricultural chemicals, such as fungicides. Though useful, these molecules had a persistent issue.
“The reaction to make them is simple, but it almost always gives a mixture of two end products, so you then have to spend time and effort to purify it to get only the one you want,” explained Fanourakis. “To make matters worse, sometimes you’re only interested in the minor end product, meaning that you have to throw the majority of your yield away, which is very wasteful.”
The biggest problem lies in a step that requires two different kinds of atoms to latch onto different landing sites on the molecule. But to an atom, these two landing sites look basically the same. Usually, chemists just have to sigh and accept that some of each atom will wind up on both sites, and the batch will yield at least some of the incorrect one.
“We took a step back and said, what if we turn this into a different problem entirely?” said Yahia Ali, graduate student and second author of the paper.
Instead, the team engineered a new process in which they build the molecule through a different route—tapping a class of previously underexplored reactions—so that one of the tricky landing sites is occupied by an atomic “placeholder” while its compatriot is filled. Then, further reactions directly swap the placeholder for the desired set of atoms.
The team tested the method with different types of molecules, some of which are normally extremely difficult to make without creating byproducts. “These sites are incredibly subtly differentiated, and we can get perfect selectivity,” said Levin.
“We’re excited because it’s a new way to address a very fundamental problem,” said Ali.