Research Revisited: Rice University’s Light-Driven Chemistry

In this inaugural edition of “Research Revisited,” a Rice University researcher provides an update on the anti-Markovnikov hydrochlorination project aimed at developing more eco-friendly ways to integrate chlorine into chemical building blocks. 

As Chemical Processing reported in January 2025, the research team developed a photocatalytic process that uses iron and sulfur catalysts activated by mild visible light to add chlorine atoms to organic molecules. This innovation eliminates the need for harsh chemicals or high temperatures typically required in chlorination, which can generate difficult-to-purify byproducts.

After publishing the initial findings in Nature Synthesis Jan. 2, 2025, the team advanced on the research to add an azide group (N₃) to simple hydrocarbon molecules, or alkenes. The work on alkyl azides is important because it’s a versatile building block for introducing amines and other nitrogen-containing functionalities, which are important in pharmaceutical production, said

Kangjie “Harry” Bian, a graduate student at Rice University’s West Research Lab. 

The Rice team’s latest findings were published Aug. 25 in Nature Communications. 

Markovnikov vs. Anti-Markovnikov

Prior methods for anti-Markovnikov hydrochlorination exist but require multistep synthesis and more costly reagents, Bian said. 

The Markovnikov rule was named after Vladimir Markovnikov, a Russian organic chemist who stated in 1869 that when adding hydrogen halides to an alkene, the hydrogen attaches to the carbon that already has more hydrogens. Anti-Markovnikov states the opposite, where hydrogen atoms attach to the carbon with fewer hydrogen atoms in the alkene. 

For hydroazidation reactions, anti-Markovnikov selectivity enables access to linear alkyl azides, which are important pharmaceutical intermediates but difficult to produce through conventional methods that favor more stable branched products.

The Nature Communications article noted that previous hydroazidation reactions used hydrazoic acid (HN₃), which is both explosive and gaseous, making it extremely dangerous to handle in laboratory settings. This created significant safety concerns that limited practical application.

Later research resulted in safer alternatives using metal-hydride atom transfer (MHAT) catalysis, which avoided the HN₃ reagent, but it required multistep synthesis, inefficient step or atom economy. 

To address these limitations, the Rice team created a blue-light-driven process that uses inexpensive iron and a small amount of sulfur-based catalyst to safely generate the reactive species needed for anti-Markovnikov hydroazidation. This approach avoids explosive reagents and complex multistep methods, allowing the reaction to work under gentle conditions with a much wider range of alkene starting materials than before.

What’s Next: Shifting to Visible Light and Scaling Up

The process, which the Rice team calls cooperative photocatalytic hydro- and haloazidation of alkenes, shows promise for other applications, Bian said. 

“The next step, more broadly speaking, is to use this cooperative catalysis process to do many other cool chemistries that conventional methods cannot do or require multistep synthesis where in many cases a stoichiometric, strong oxidant or reductant need to be applied to overcome other challenges.”

The method still faces hurdles for commercial scale-up, said Bian. 

“One common challenge in photochemical transformation to be applied to industrial settings that we are also facing is finding the right photochemistry setup,” he said. “Owing to photon transport limitations, such as attenuation effect, the typical scale-up strategy of dimension enlargement of the reactor vessel is not effective for photochemistry. The use of larger-diameter reactors would result in low penetration of crucial irradiation, thus leading to longer reaction times and possible byproduct formation.”

If they can develop a more general light source and vessel for larger-scale reaction, Bian said he thinks the process has scale-up potential. Meanwhile, adoption of continuous-flow chemistry and similar technologies could provide an alternative solution as these processes have better surface-area-to-volume ratios that can provide uniform irradiation of an entire reaction mixture compared with batch photochemical processes. This enables shorter reaction time and improved mass balance, according to Bian. 

“Meanwhile, our team and researchers in our community have been studying the effect of ligand to enable not only the use of more cost-effective visible light versus near-UV activation but also enhanced reactivity in photochemical transformations,” Bian explained. “You need an additive like ligand to coordinate with iron, so you can absorb some of that visible light.”