Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

I don’t think that anyone really likes diazomethane. Organic chemists like what it can do (cyclopropane formation, cycloadditions, fast, clean methyl ester formation, etc.), but the compound itself is very hard to have warm feelings for. It’s unstable on storage, and thus has to be prepared fresh. That preparation is fairly tedious, and you have to pay close attention to what you’re doing (unlike this guy), because the diazomethane product can and will decompose violently (and even explode) if you mishandle it. “Mishandle” includes, but is not limited to, making it too concentrated, exposing it to friction or rough surfaces, the presence of metals, etc. It’s also quite volatile and very toxic, explosions aside. That goes even for the less explosive form, trimethylsilyldiazomethane, which is stable enough to be an article of commerce but which is sadly just as deadly as the original item.

This would explain why you don’t see an awful lot of plain diazo compounds in the literature. The stabilized ones like ethyl diazoacetate are pretty common, but when’s the last time you heard about diazopropane? Or cyclopropyldiazomethane? Right, probably never, and that’s largely because the higher diazos, being less volatile, are no fun to prepare because you can’t distill them over in ether like you can the parent compound. By the time you’ve purified them, there’s not much left.

This new paper, though, could change that. A group at Montréal has adapted a solution-phase prep (silver oxide and potassium carbonate) to flow chemistry, which is the natural home for these kinds of compounds. (Update: see also this recent paper from the Ley group – another flow approach). Running hydrazones in dichloromethane through a column of these reagents (mixed with Celite) gives you diazo compounds out the other end. But you can tell that these are lively compounds – when they tried this on acetone hydrazone at room temperature, they got a colorless stream and plenty of gas bubbles, because the 2-diazopropane had already decomposed. Lowering the temperature to -20C and cranking up the flow rate, though, gave a red solution which is the real thing, ready to use.

They used this setup to produce a whole range of basically unknown diazo compounds (they’re yellow, orange, red, and purple in solution), and took them directly into esterification, cycloaddition, and cyclopropanation reactions. You’re not going to let these things sit around; unstabilized diazo formation is going to be an on-demand process no matter how it’s done. But it looks like these compounds are now open to experimentation in a way that they’ve never been before.