New Wittig pathway proves old dogs can learn new tricks | Research

What began as an attempt to improve an established reaction has led to the discovery of an entirely new path in chemistry.

Christian Hering-Junghans and Torsten Beweries, leaders of a team at the Leibniz Institute for Catalysis, have debunked long-held assumptions about the Wittig reaction – a process that has been fundamental to chemistry for almost a century. This breakthrough also opens a new route to the production of triazabutadienes, a class of molecules with applications in synthesis, biochemistry and polymer chemistry.

“Triazabutadienes are currently produced by combining organic azides N-heterocyclic carbenes. However, this always results in the carbonyl carbon atom being incorporated into a N-Heterocycle,” says Hering-Junghans. This limits the types of triazabutadienes that can be synthesized. “Our methodology fundamentally allows us to explore new substitution patterns,” he adds.

This new approach has attracted attention because of its potential. Michael Cowley from the University of Edinburgh, who was not involved in the study, sees this as a “fairly simple way to make different triazabutadienes” that could be used to label or functionalize proteins.

The Wittig reaction is one of the proven methods for forming carbon-carbon double bonds with precise control of the reaction outcome. However, when the team first tried to develop new phosphorus ligands using the phospha-Wittig reaction, something unexpected happened: only one aldehyde group in a dialdehyde was converted into the “phosphaalkene” moiety (Mes*P=C(H)R).

This surprised the team and led them down a completely new path. Hering-Junghans says he saw the free aldehyde group as an opportunity to introduce a nitrogen-carbon double bond in addition to the phosphorus-carbon double bond.

“This was the first time that we had a precursor in which both a phosphaalkene and an aldehyde moiety were present at the same time,” says Hering-Junghans. “Since conversion to a second phosphaalkene unit could not be achieved, the aza-Wittig reaction seemed to be the obvious choice to install an imine unit alongside.”

Beweries explains: “These types of ligands are well established for various types of transformations in organometallic chemistry and homogeneous catalysis.” However, this reaction failed (as expected).’

NMR spectroscopy showed that the nitrogen-carbon double bond was incorporated, but the data was inconclusive. “X-ray crystallography was the key to understanding what was happening,” says Beweries.

Instead of incorporating just one nitrogen atom into the ligand, the entire azide moiety was transferred into the product, creating a triazabutadiene rather than the expected imine. Normally, the formation of an imine would release nitrogen, as this is typically the energetically most favorable route. However, the bulky groups already present in the ligand prevented this by stabilizing the nitrogen and keeping it bound to the molecule. This led to a new reaction pathway that they called the azide-Wittig reaction.

“It’s always exciting to see an old dog perform new tricks,” comments Laura Cunningham from the University of Galway, who was not involved in the study. “The Aza-Wittig reaction has been around for decades, so this discovery serves as a reminder that something new can be happening right under our noses.”

Cunningham also points out that the ability to convert aldehydes into triazabutadienes in one step significantly increases their synthetic versatility. “Forming triazabutadienes from something as ubiquitous and diverse as aldehydes could lead to far greater interest and new applications.”

While there may still be limitations in methodology that need to be overcome, Cowley emphasizes the importance of flexibility and accepting unexpected results. “This result did not arise from an attempt to solve a specific problem, but it nevertheless uncovered useful new pathways and possibilities,” he notes. “The most important takeaway from the paper is: “This transformation is possible.” From my perspective, I am someone who approaches chemistry with a focus on “What can we make?” Instead of asking, “How do we do this?”, potential limitations to transformation do not diminish the value of knowing that it is even possible.”