There’s a reagent used in chemical biology and protein labeling that should be getting a bit more attention than it does. Not because it’s useful – that’s already known – but because it can explode.
Here’s the paper (from UC-Irvine and Amgen), and the compound is the 4-azido derivative of phenylalanine. Interestingly, the authors were not trying to investigate its hazards, but were after an easier, safer, and cheaper synthetic route. They succeeded, by the way, along with providing some valuable reference work about how to determine its chiral purity and also (re)establishing a poorly characterized coupling reagent (Boc-Oxyma) as a useful species. Now, some people will look at this target compound and say “Well, yeah, sure, azide”, but organoazides are not all explosive. The lower the molecular weight, the more likely you are to run into trouble, but there are smaller azides than this one that still aren’t a problem to handle. I’ll say right off that I don’t know of any incidents with azido-Phe, which is a good thing, but the data in this paper suggest that such an incident is certainly possible. More on that in a moment.
One of the concerns about the synthetic routes to this compound, I should note, is the presence of an azide ion / copper combination. It is a very solid general rule to avoid the formation of any transition-metal or heavy-metal azide species; they should all be considered explosion hazards (“Things I Won’t Work With” reference, for emphasis). Want some more backing for that statement?
. . .The sensitivity of dry cupric azide to friction is so great that it is prone to explosion during its removal from filter paper. Copper(I) azide (cuprous azide) is similarly perilous, and explosions have been reported for this complex while completely submerged in water and after being lightly touched with a feather in open air. An intelligence bulletin from The National Institute for Occupational Safety and Health warned in 1976 that several explosions had occurred in the United States and Canada, apparently resulting from the accumulation of heavy-metal azides in hospital plumbing. These events were likely due to the routine disposal of NaN3-laced waste from automatic blood cell counting machines directly into hospital drains. Since many of these incidents occurred while attempting to clear a blocked pipe, it seems unlikely that any metal azides present were dry.
Said the manuscript, dryly. So no, I don’t think we’ll be wanting any copper azide species if that can be helped (the covalent azides used in the copper-catalyzed “click” reaction are a different thing altogether). Since this new synthesis does still involve a copper-catalyzed azide formation, the authors carefully investigated the material in each step for explosion hazards. The good news is that none of the intermediates (nor the precipitates formed) seem to be hazardous. The bad news is that the final product is.
This was determined through differential scanning calorimetry (DSC), a technique where a (small!) sample is heated to increasing temperatures and monitored for excess heat being given off (exothermic decomposition), and its partner technique, accelerating-rate calorimetry (ARC). What these show is that the N-Boc derivative of azido-Phe is possibly a cause for concern, but the unprotected species is absolutely a problem. Its calorimetric behavior is similar to that of a high explosive, and it appears as if it could be shock-sensitive as well. I would say that this problem is unappreciated in the chemical literature, and it’s a good thing that no one discovered this the hard way. Perhaps a salt of the compound has better behavior and would be a safer reagent and article of commerce?