Who I'm Reading Today

https://www.science.org/content/blog-post/sandmeyer-replacement

I enjoyed reading this new synthetic paper, because I can still remember when I learned about the good ol’ Sandmeyer reaction in sophomore organic chemistry class and these authors are among the many people trying to replace it.

There’s a reason for that, because while the Sandmeyer is definitely old, it ain’t always good. It’s a reaction that lets you take an aromatic amine (of which there are a great many) and convert that amino group into a wide variety of others, which is in theory extremely useful. It goes back to 1884 (!), and a lot of people don’t realize that its discovery was more or less accidental. Traugott Sandmeyer (you don’t run into many Traugotts these days) was trying to do an arylamine coupling, for sure, by first converting the amine into a reactive benzenediazonium chloride salt. But when he brought in his coupling partner (copper acetylide) he didn’t get a new bond between the aryl ring and the acetylene - instead, he got chlorobenzene, because the chloride counterion hopped in there instead. 

That’s because those aryldiazoniums are pretty lively creatures. A constant theme of the “Things I Won’t Work With” posts here is the yearning that polynitrogen compounds have to turn into nitrogen gas, and that’s just what happens here. A diazonium salt just needs the lightest push to have its two nitrogen atoms bubble away as N2 gas, leaving an extremely reactive aryl radical behind. In practice, copper salts are the classic way to run the reaction, because the copper decomposes the diazonium readily (and forms a reactive arylcopper species as an intermediate). I was taken with the reaction because of the way it was drawn in our textbook - an arylamine at the center of the diagram, with arrows radiating out from it as it transformed into an aryl chloride, aryl bromide, a phenol, an aryl nitrile, etc. It looked kind of magical, because up until then I had thought of these things are sort of separate orders of things - it was like watching some sort of amazing farm animal that could give birth to fish, frogs, or birds depending on what you fed it. I wanted to go run one right then!

Variations of the reaction will bring in a fluorine or a trifluoromethyl group and allow for some other types of coupling reactions as well. So you might imagine that Sandmeyers just get used all the time, but ’tis not the case. Those aryldiazonium salts are just too touchy and hazardous, especially on scale, and especially if you have fantasies about making a big batch and storing it in a flask to turn it into whatever you want to later on. Don’t try that! The reaction can be run industrially, but only with extremely careful attention to detail, and there have been many injuries (and even fatalities) over the years, some of which are detailed here. In general, the less you handle or concentrate the diazonium salt the better off you'll be, but there are no guarantees. 

There have naturally been many attempts to improve on this situation, and the new paper linked above summarizes several of them. But their new method seems like it might be more general than most, assuming that your starting material can tolerate nitration conditions. That’s because you take the arylamine and make an N-nitro derivative of it, and this can be made to kick out an OH after tautomerization and make a very labile NNO derivative that leaves as gaseous nitrous oxide in a pretty direct analogy to the Sandmeyer being driven by loss of nitrogen. A big difference, though, is that all of this happens in the same pot in situ - you start with the arylamine and isolate the coupling product, with no isolation or handling of any of the intermediates. Mechanistically, this one also looks much more like an aryl cation intermediate than an aryl radical.

The authors demonstrate this across a very wide range of substrates, including a lot of heterocyclic amines where the classic Sandmeyer doesn’t perform well, and they bring in halides, thiocyanates, OH, O-tosyl, O-triflate and a number of other coupling partners, including some intramolecular C-C bond forming reactions. They also demonstrate one-pot procedures to take some of these on to now-traditional metal-catalyzed couplings of many types, which gives you a lot of versatility in a synthetic sequence.

If the calorimetric profiles look good, this reaction could be quite useful on a larger scale - I’m sure that there will be some process chemists taking a look at that to make sure that the nitration step and the subsequent loss of nitrous oxide don’t present possible thermodynamic hazards. On the bench scale, though, this looks a lot more doable than the Sandmeyer, which as a reaction may be headed into the History of Organic Chemistry department and leaving the Useful Laboratory Transformations one. And to be honest, it was always an uneasy member of that second group anyway!

https://www.science.org/content/blog-post/sandmeyer-replacement