Chemists can easily convert diazo compounds to carbenes or metal carbenes, which can then go on to participate in a wide range of powerful insertion chemistry. But diazo compounds can also explode when they rapidly decompose, giving off heat and nitrogen gas, making them potentially dangerous to work with. Exactly how dangerous has been hearsay for a long time, since there haven’t been any systematic studies on the hazards of these dinitrogen compounds. Now, along with scientists at GlaxoSmithKline, James Bull and coworkers from Imperial College London have assessed the stability of a number of diazo compounds (Org. Process Res. Dev. 2019, DOI: 10.1021/acs.oprd.9b00422). They found that not all diazo compounds are explosion hazards, and their stability depends on the nature of their substituents.
Bull’s group has worked with diazo compounds for many years and lamented the lack of published data on their stability. “These compounds are often a no-no for large-scale chemistries due to safety concerns with their perceived instability and explosivity,” he says. “The reality is that the stability of a diazo compound is highly substituent dependent, and we were interested in quantifying how structure affects thermal stability.”
To carry out that analysis, the researchers first synthesized 44 diazo compounds with a range of substituents. They then performed differential scanning calorimetry (DSC) on the compounds to find the temperature at which they decomposed. That value provides an estimate of the temperature a molecule reacts, with low temperatures indicating low stability and high ones indicating high stability. But DSC doesn’t capture the whole thermal picture, says Sebastian Green, a PhD student in Bull’s group. The decomposition reaction of the diazo compound could happen at a lower temperature than DSC can detect, he says. So the group got further thermal data on three model compounds (shown) using accelerating rate calorimetry, which is a more precise technique. The group then used the thermal data to estimate the compounds’ impact sensitivity, which is another indication of a material’s explosive potential.
What the researchers found was similar to what they were expecting in terms of the effect of substituents on stability, Green says. Diazo compounds react to form N2 gas and a highly reactive carbene. Anything that can increase reactivity of the resulting carbene can in turn stabilize the diazo compound. For example, electron-withdrawing substituents tend to lead to greater stability, Green says.
Anita Maguire, an organic chemist at University College Cork who often works with the pharmaceutical industry, called the study welcome, useful, and timely. “While diazo compounds are versatile synthetic reagents, their use at large scale is avoided due to safety concerns,” she says. She thinks the data could open up opportunities for industry to consider the use of the reagents at large scale.
For Green, the lesson of the study is that diazo compounds are “just another important tool in the tool kit that shouldn’t be disregarded out of hand.”