The Skraup Reaction - How to Make a Quinoline

Recently, Derek Lowe was discussing reactions he hadn't done at his blog In the Pipeline. Among these were, in his own words "the widely disliked Skraup cyclization for quinolines". This was somewhat surprising to me. I have very limited experience with the Skraup reaction but it has worked for me and one of my former colleagues said it had always been a great reaction in his hands. Personally I was surprised how well it worked considering the reaction conditions. This is what I did: 

Easily the most extreme reaction conditions I have employed. Hardly surprising this is a lively reaction. Adding acrolein (boiling point of 53 oC) to a 70% sulfuric acid cocktail at 110 oC is rather exciting. Things are vaporising, spraying, hissing and instantly turns into jet black tarry goo. After 45 minutes the reaction is allowed to cool and then you attempt to work the black polymeric goo up with 25% aq. NaOH, brine and ethyl acetate. I suspect that the modest yield is due to loss of material during this annoying work-up. Scaling the reaction up is likely to improve the yield. The Skarup reaction is indeed performed on ridiculous industrial scale so it can't be all that bad. My system was rather elaborate containing two phenolic ethers and still I managed to pull out 47% and it was reproducible. Unfortunately, I cannot give full structural details as this was done in industry and I seem to recall some papers I signed explaining my life would end if I ever mentioned any of that stuff.

I should mention that it is rather important that you don't use too much acrolein as this will turn the whole thing into a rubbery solid (as I discovered) that is impossible to work with.

Anyway, the conditions I employed here a slightly different from the standard method so it may be worth giving a go if you are into quinolines. The full experimental details can be found here: C. O'Murcho, Synthesis, 1989, 880-882. By the way that's Zdenko Hans Skraup himself on the photo above. D!

Whatman Phase Separators

I hope everyone had a merry Christmas and I wish you all a happy and prosperous New Year. Time for the first post of 2009.
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A former colleague of mine introduced me to the ingenious invention: Phase Separators. This is a big help in the lab and really saves me a lot of time, particularly with qualitative work. A Phase Separator is essentially a piece of filter paper that has been treated with silicone. If you fold it up and stick it in a funnel and pour a mix of organic solvent and water on it it will only let the organic solvent pour through. It only works well with solvents more dense than water, typically dichloromethane or chloroform. They are best employed for qualitative work where all that's required is a quick NMR to determine a ratio between isomers, whether a reaction is finished etc. For this type of work I basically transfer my reaction to a separation funnel with dichloromethane and wash it with appropriate aqueous phases. After the final wash the whole thing is poured directly into a Phase Separator, the organic phase is collected in a round bottom flask and concentrated in vacuo. I never observe any residual water in my NMR spectra so drying the organic solvent is unnecessary. D!