I can’t say that I’ve ever done any flash vacuum pyrolysis, and I’ll bet that most chemists reading this haven’t, either. I’ve seen papers on it for many years, including some pretty unusual reactions, but it’s never been a tool that I’ve reached for. Here’s a new paper in the Journal of Organic Chemistry on the technique, a Perspective by Lawrence Scott (now retired from Boston College), and it’s almost enough to make me want to run some of the reactions.
The idea is pretty simple. You take your starting material, in the vapor phase, through a short very-high-temperature zone (up to, say, 1000 degrees C). At those temperatures, an awful lot of reactions become possible (that T-delta-S term in the thermodynamics!), which is one reason why you need to keep things rather dilute, even in the vapor phase. (Needless the say, at 1000C, the vapor phase part is pretty much mandatory – that’s well above the boiling point of, say, liquid sodium metal). As Scott’s synthesis of C60 fullerenes under these conditions shows, you really have to think about conformational energies and strain differently at these temperatures, because the molecules themselves are going to be populating a lot of conformations that you’d otherwise never think about. If there are energetically feasible reactions within reach of these conformers, you’ll get some pretty unusual products.
The Perspective is mostly about the preparation of numerous bowl-shaped hydrocarbons, and (eventually) C60 itself, but you can imagine a lot of other things happening as well. Scott mentions that they did try to make a di-aza compound in one series, but with no success whatsoever. Later calculations showed that the nitriles in the starting material were much less likely to participate in the necessary cyclization reactions than the plain acetylenes that they’d been using, and the reduced aromaticity of the pyridine products helped make the whole process thermodynamically unfavorable.
But it’s not like heterocycles in general can’t be prepared by FVP techniques, of course – here’s a recent review. And here are some nice slides from one of Phil Baran’s group meetings a few years ago, with a good collection of FVP transformations (both heterocyclic and carbocyclic). Just looking over the literature on this sort of thing briefly in this way, you can see that there’s a lot of chemical diversity that’s relatively unexplored. The upswing of interest in flow chemistry over the last few years makes me wonder if this isn’t another possible market for the flow equipment makers – after all, the FVP folks have been doing their work under flow conditions from the very beginning, just from a slightly different (and slightly warmer) perspective.
With such equipment, the whole area looks like a good place for the “Reaction Discovery” techniques that people have been using to find new catalytic reactions. You could imagine taking a plate of model systems through some FVP conditions and just analyzing the products by LC/MS to see what happened to them, looking for new ring-forming reactions, rearrangements, and so on. The only thing I would have to fear, working in the pharma labs, is the wrath of the scale-up chemists if we used one of these scaffolds in a drug candidate. But that could turn into a problem worth solving, under the right conditions. . .