A simple solution to a chlorination challenge

One of the first reactions that students learn in college-level organic chemistry is hydrochlorination—adding hydrogen chloride to a carbon-carbon double or triple bond. The classic textbook version preferentially installs the chlorine atom on the more substituted carbon in the bond, according to a selectivity principle known as the Markovnikov rule. Sticking the chlorine to the less substituted carbon is a much trickier proposition.

Traditionally, chemists have had to resort to harsh conditions, pricey reagents, or multiple synthetic steps to manage anti-Markovnikov hydrochlorination. But Julian West and his team at Rice University have devised a new way to do it with inexpensive catalysts and mild conditions (Nat. Synth. 2025, DOI: 10.1038/s44160-024-00698-z).

West says he and his group had been looking for ways to extend the iron-based radical photocatalyst system they had developed for attaching fluorinated groups to double bonds. They realized that if they used their system to generate chlorine radicals, they could do hydrochlorination chemistry with flipped selectivity.

“It’s really selective for a wide range of alkenes and alkynes, but it’s also really easy to set up,” says West.

Because the new approach uses inner-sphere electron transfer to generate the radicals and a thiophenol cocatalyst to shuttle hydrogen atoms, it is compatible with molecules that are easily oxidized or sensitive to acid—which other methods often are not.

The researchers also found that doubly hydrochlorinating a triple bond with this reaction gives a product with each chlorine bound to a different carbon atom, whereas the classic method would stick them both on the same carbon.

Using heavy water, the researchers could also selectively introduce deuterium atoms along with chlorine. The weightier hydrogen isotope is useful for probing reaction mechanisms, as well as studying and tuning drugs’ metabolic stability.

To showcase the reaction’s versatility and selectivity for installing chlorine, hydrogen, and deuterium atoms in previously hard-to-access positions on molecules, the researchers reported 125 molecules made with the new chemistry, including derivatives of drugs and natural products.

Elias Picazo, an organic chemist at the University of Southern California who was not involved in the work, says it’s “definitely a synthetic advance” in terms of its scope and selectivity. He thinks that the commercially available iron catalyst will be appealing to chemists in both academia and industry.

West says he and his group aim to develop chemistry that people will find useful and approachable. The goal, he says, is to make reactions where “If somebody likes them, they could try [them] the same day.”