By Adding Single Carbon Atom to a Molecule, Researchers Spark New Horizons in Drug Design

The study introduces a new, simpler way to modify carboxylic acids, which are widely available and incredibly versatile building blocks in chemistry. They appear in everything from natural products to pharmaceutical drugs.

January 21, 2025 I By Dave DeFusco
Imagine being able to add a single carbon atom to a molecule quickly and efficiently, potentially creating new drugs with better properties. That’s exactly what a team of researchers, including Dr. Erik Alexanian, a professor in the Department of Chemistry at UNC-Chapel Hill, has achieved. Their study, “Homologation of Carboxylic Acids Using a Radical-Polar Conjunctive Reagent,” published in the Journal of the American Chemical Society, introduces a new, simpler way to modify carboxylic acids—a common feature in many bioactive compounds and drugs.
Carboxylic acids are widely available and incredibly versatile building blocks in chemistry. They appear in everything from natural products to pharmaceutical drugs. A valuable, yet challenging, transformation is to “homologate” these acids, which means adding a single carbon atom to their structure. This process can provide direct access to new carboxylic acids, expanding the number of building blocks available for chemical synthesis. In drug development, it can enhance a drug’s properties, such as making it more effective or easier for the body to absorb.
“Until now this simple yet challenging transformation has been a complicated and time-consuming process,” said Dr. Alexanian. “Existing methods required multiple steps and hazardous chemicals, and were often unsuitable for complex molecules. Our new method offers a one-step solution that’s safer, faster and much more practical.”
The key to the homologation was the development of a new (1-phosphoryl)vinyl sulfonate) reagent, allowing for homologation in a single step. It’s stable, easy to handle and works under mild conditions—qualities that make it a game-changer for chemists. Here’s how it works:
- Radical Chain Reaction: The process starts with the activation of the carboxylic acid which, following decarboxylation, generates a carbon-centered radical.
- Addition of the Reagent: The new reagent adds the desired carbon atoms to the molecule.
- Final Touch: The intermediate product is then easily transformed to the desired homologated molecule, such as an ester, amide or another carboxylic acid.
This streamlined approach eliminates the need for dangerous chemicals and multistep processes, making it safer and more efficient. The potential of this method in drug discovery is immense. By making it easier to create molecular homologues, researchers can quickly test new variations of drug molecules. For example:
- Enhanced Properties: Adding a single carbon atom can improve a drug’s solubility, stability or ability to bind to its target.
- Late-Stage Modifications: The method works well with complex molecules, allowing chemists to modify drugs or natural products without damaging other parts of the molecule.
The study demonstrated this versatility by successfully applying the method to a wide range of molecules, including those used in medicines and natural products. In addition to the radical chain reaction, the team also developed a complementary method using photoredox catalysis, which uses light to drive chemical reactions through the activation of a photocatalyst.
“This alternative approach complements the radical-chain process by requiring less reagent overall,” said Dr. Alexanian. “The homologation simplifies a long-standing challenge in organic chemistry. It has the potential to accelerate the development of new drugs by making it easier to create and test variations of molecules, opening up new possibilities for designing molecules that were previously too difficult or expensive to make.”