Tuesday, January 13, 2009

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!

14 comments:

Ψ*Ψ said...

Any reaction done in sulfuric acid is exciting by definition! Gotta love old-school aromatic chemistry. :)

Anonymous said...

That might sound silly. May I learn the use of the first step?

Daniel Sejer said...

It's a one step reaction. I split it up in two to show the order of events a bit clearer. D!

milkshake said...

You forgot to mention the addition of nitrobenzene co-oxidant. I have seen a procedure in Org Process R&D journal (always a good source of reliable procedures) last year and they used meta-nitrobenzesulfonic acid as a co-oxidant, because the produced side-products are water-soluble. I remember their isolated yields were fine, somewhere in 70s

The fact that such an medieval torture reaction is done in industry on ton scale is not a convincing argument for saying "see, its not so bad, mate". Lots of horrid reactions are used in industry, beginning with pyrrolytic distillation of coal and hydrocarbon cracking.

Daniel Sejer said...

Milkshake, no nitrobenzene required. NaI seems to do just fine, so all that's required is there. True about industry processes being unpleasant but that wasn't really what I meant. What I was trying to say is that if it's such a terribly poor reaction surely industry wouldn't be doing it on mega scale if there was a better alternative. D!

Edvinas said...

This is one of the reactions that makes us chemists look like magicians.I remember my girlfriend visiting me in the lab i was doing the Scraup. She was wondering why I'm so stupid to expect to get something valuable from the sh** looking dark tar. To her surprise, it eventually resulted in colorless mixture of 7 an 5-methyl quinoline.

David said...

Oh my late father would have loved this. And I remembered the aq meant aqueous. Bring us more of this stuff!

Anonymous said...

Milkshake - Don't be so down on industrial chemistry! Just because a reaction involves harsh conditions which are difficult and unpleasant to realize on a laboratory scale doesn't mean that it's bad chemistry. Just as a counterpoint example, ruthenium metathesis is a totally elegant and low-hassle method of making macrocycles on a small scale with high dilution, and I've yet to hear of anyone successfully solving the throughput problem on an industrial scale. P.S. you should update org prep daily sometime soon!

Daniel Sejer said...

I agree that Milkshake should post something at Org Prep Daily. It's one of my favourite blogs but it's awfully quite these days. Pretty soon I'll have to move it from the blog list to Chemistry Resources. D!

milkshake said...

"Werewolf cannot speak, therefore must be silent."

freezedream said...

Sounds like a fun reaction to do!

dtb said...

Re: anonymous' comment on the use of RCM for macrocycle synthesis in process chemistry - you should take a look at the work done by Boehringer-Ingelheim's process group on BILN 2061 - they make a 15-membered macrocycle using RCM on scales >400 kg; they've optimised the reaction to the point that it can be run at 0.2 M concentration (!):

http://pubs.acs.org/doi/pdf/10.1021/op0580015

http://pubs.acs.org/doi/pdf/10.1021/op800225f

Pretty cool/impressive stuff, IMO.

Anonymous said...

Milkshake, hah! what is it w/ Czechs and wolfs?

Anonymous said...

You need to use 80% sulphuric is better and also add a Dean Stark trap to collect water, avoid tar by using very slow (hours) glycerol addition. For workup steam distillation is great if you eliminate any starting material or volatile, thf often dissolves very weel tars generated