Novel photocatalytic process enables precise chlorination for drug development
A breakthrough in chemical synthesis methodology offers pharmaceutical manufacturers a more environmentally sustainable approach to incorporating chlorine into drug compounds, with implications for both process efficiency and molecular modification.
Rice University chemists have developed an innovative photocatalytic process that could transform how pharmaceutical companies incorporate chlorine atoms into drug molecules. The new method, published in Nature Synthesis on 2 January 2025, utilises iron and sulfur catalysts activated by blue light to achieve precise chlorination of organic molecules at room temperature, which may help streamline drug manufacturing processes.
Anti-Markovnikov hydrochlorination
The technique, known as anti-Markovnikov hydrochlorination, allows chemists to attach chlorine atoms to specific locations on molecular structures with high precision, addressing a longstanding challenge in pharmaceutical synthesis. This selective approach could significantly reduce the purification steps required in drug manufacturing, leading to more cost-effective production methods.
Traditional chlorination methods typically require harsh chemical conditions or elevated temperatures, often generating unwanted byproducts that necessitate extensive purification procedures. The new approach operates under considerably milder conditions, reducing the environmental impact of pharmaceutical manufacturing processes.
“Our method uses sustainable, low-cost catalysts and operates at room temperature with gentle blue light,” explains Julian West, assistant professor of chemistry at Rice University and CPRIT Scholar. “It provides a targeted, efficient way to chlorinate molecules without conventional approaches’ environmental and purification challenges.”
Implications for drug development
One of the most significant aspects of the research is the team’s demonstration that their method can incorporate deuterium – a stable hydrogen isotope – through the use of heavy water. This capability could have important implications for drug development, as deuterated compounds often exhibit enhanced metabolic stability, potentially leading to improved drug half-lives and therapeutic efficacy.
The research team, led by West, demonstrated the method’s versatility across 125 different examples, suggesting broad applicability in pharmaceutical synthesis. The process shows high selectivity in terms of both regioselectivity (position specificity) and stereoselectivity (spatial arrangement), crucial factors in pharmaceutical manufacturing where molecular precision is paramount.
Technical innovation
The breakthrough relies on two key chemical processes working in concert: the ligand-to-metal charge transfer photoreactivity of iron, an earth-abundant element, and the hydrogen atom transfer reactivity of redox-active thiol. This dual mechanism enables the selective addition of chlorine atoms to unsaturated hydrocarbons – a fundamental reaction in organic synthesis – while maintaining precise control over the final product structure.
The development represents a significant step forward in sustainable chemical synthesis methodology, particularly for pharmaceutical applications. The method’s ability to work with both alkenes and alkynes under mild conditions, combined with its high selectivity and broad substrate scope, suggests potential applications beyond pharmaceutical synthesis, including in the production of speciality chemicals and materials.
Reference:
Bian, K. J., Nemoto, D., Chen, Y., et. al. (2025). Anti-Markovnikov hydro- and deuterochlorination of unsaturated hydrocarbons using iron photocatalysis. Nature Synthesis.
https://doi.org/10.1038/s44160-024-00698-z
