Binghamton University chemists have discovered a new mechanism that could potentially lead to quicker outcomes in pharmaceutical research.
Carbon-halogen bonds are among the most common "handles" in organic chemistry, meaning that they're added to molecules to enable or control a chemical reaction.
"They follow a simple rule: one handle, one substitution," explained Binghamton University Associate Professor of Chemistry Jennifer Hirschi.
The halogen atom is removed and replaced with a new molecule, known as a functionality - a reaction taught in undergraduate courses. But in a recent study published in the journal Science, chemists outline a method that breaks this rule, using a single handle to add different groups to two neighboring carbon atoms.
The work was co-led by Hirschi and Patricia Musacchio, assistant professor of chemistry at the University at Buffalo, with the mechanistic studies carried out by Tamal Das, a postdoctoral researcher in the Hirschi lab. The research was funded by the National Institutes of Health.
Carbon atoms are integral to the molecules that make up many pharmaceuticals. In drug discovery research, these molecules are typically built one reaction at a time. Creating two chemical changes in a single step may shorten the route to a target, Hirschi explained.
Musacchio's lab at Buffalo synthesized the new molecules, using off-the-shelf blue LED lights and a commercially available alcohol solvent familiar to undergraduate chemistry students. Meanwhile, Binghamton researchers used computational modeling to determine how the reaction happens, relying on density functional theory and ab initio molecular dynamics.
The blue light triggers a transfer of a hydrogen atom; this, along with an internal electronic rearrangement, converts a single carbon-halogen bond directly into a reactive intermediate known as an alkene radical cation. Typically, alkene radical cations only occur with strongly oxidizing catalysts, Hirschi explained.
The modeling revealed the driving force. The reaction occurs in a fluorinated alcohol solvent whose molecules form a network of hydrogen bonds around the departing halogen atom. That network stabilizes the halogen so effectively that the energy gained outweighs the energy required to break the carbon-halogen bond, allowing the intermediate to form under milder conditions.
Understanding this pathway served as a guide for the chemistry itself. Because the reactive intermediate presents two reactive sites side by side, a single handle can install two different groups on adjacent carbons in one operation. Guided by the mechanism, the researchers applied the approach to a range of everyday starting materials, including bromides, chlorides, fluorides, and even unprotected alcohols, forming new bonds to nitrogen, oxygen, and sulfur, and assembling small ring structures.
In a related variation, the halogen is shuttled to the neighboring carbon, where it becomes a fresh handle for further reactions. The mechanism now provides a framework for both the current method and future work, giving chemists a way to turn ordinary building blocks into more complex, drug-relevant structures in fewer steps, Hirschi said.
"The hope is to not only make drugs faster, but also make more complex drugs that can target more challenging medicinal goals," Musacchio said.
