Org Prep Daily

November 10, 2009

8-bromoquinoline – a painless Skraup synthesis

Filed under: Chris Douglas, procedures — milkshake @ 2:44 pm

Skraup

A 1-L 3-neck round bottom flask was equipped with an overhead mechanical stirrer, an internal temperature thermometer, and a dropping funnel. The flask was charged with methanesulfonic acid (250 mL) and warmed with stirring to an internal temperature of 125 °C. 2-Bromoaniline (80.55 g, 0.468 mol) was added portion-wise, followed by meta-nitrobenzenesulfonic acid sodium salt (66.30 g, 0.293 mol) and FeSO4.7H2O (3.90 g, 14 mmol). The addition funnel was charged with glycerol (28.3 mL, 0.39 mol) and the glycerol was added dropwise over 15 min. Two additional portions of glycerol (2 x 28.3 mL, 0.78 mol) were added at three-hour intervals. After the last portion of glycerol was added the brown solution was maintained at 125 °C for 12 hours. The reaction mixture was allowed to cool to RT and water (250 mL) was added. The resulting brown-black solution was transferred to a 4-L beaker with the aid of 100 mL water. The beaker was placed in an ice bath and an aqueous NaOH solution (50% m/v) was added with stirring until the solution was basified to ~ pH 14. The heterogeneous mixture was extracted with Et2O (3 x 500 mL), allowing the emulsion to settle for ~10 min each time. The combined organic extracts were washed with brine (1 x 400 mL), dried over Na2SO4 and filtered through Celite. Concentration of the resulting solution to a viscous brown oil provided the title compound (86.55 g, 0.426 mol, 89%) in ~95% purity as judged by 1H NMR. The crude product was then purified by kugelrohr distillation (0.14 mm Hg; pot temp, 180–205 °C) to give a yellow oil that solidified on standing (83.69 g, 0.402 mol, 86%)

1H NMR (300 MHz, CDCl3): 8.98 (dd, J = 4.2, 1.8, 1H), 8.08 (dd, J = 8.3, 1.7, 1H), 7.98 (dd, J = 7.4, 1.4, 1H), 7.72 (dd, J = 8.1, 1.2, 1H), 7.39 (dd, J = 8.1, 4.2, 1H), 7.32 (t, J = 8.0, 1H); 13C NMR (75 MHz, CDCl3): 151.1, 145.0, 136.5, 133.0, 129.4, 127.7, 126.8, 124.5, 121.8.
This material identical to 8-bromoquinoline prepared by other methods.

15 Comments »

  1. Sorry if this is an ignorant question – what’s the role of the nitrobenznensulfonate salt in this reaction?

    Comment by Russ — November 11, 2009 @ 9:13 am

  2. …Nevermind. I was just pushing some arrows and realized we also need an oxidizing agent, and then it occurs to me that this might be the role of the nitro compound. Sure enough, that’s what it does. Now I look like a dummy – serves me right for asking questions first and looking things up later…

    Comment by Russ — November 11, 2009 @ 9:21 am

  3. The original Skraup was done in concentrated sulfuric acid with nitrobenene – the work-up was always horrible. Replacing nitrobenzene with nitrobenzenesulfonic acid and replacing sulfuric acid (which can cause aniline sulfonation) is a great improvement

    Comment by milkshake — November 11, 2009 @ 10:10 am

  4. How do you draw the arrows for the final step: the oxidation of the dihydroquinoline by the nitroarene?

    Comment by Base Man — November 11, 2009 @ 11:44 pm

  5. I think Fe oxidation catalyst is in there for this purpose – it is probably some sorta stepwise single electron oxidation

    Comment by milkshake — November 12, 2009 @ 7:39 am

  6. One other minor comment on the procedure. The listed order of addition isn’t critical to the success of the rxn (aside from the glycerol), but it makes your life a lot easier. make sure the MeSO3H is hot and stirring when you add the bromoaniline. otherwise the nice bromoaniline crystals from Acros form a big solid mass at the bottom of your 3-neck, caked around your stir-rod, taking forever to dissolve. Even the big Arrow overhead stirrer wouldn’t budge.

    Other than that little speed-bump, this was the nicest Skraup I’d ever seen.

    Comment by Chris Douglas — November 12, 2009 @ 7:18 pm

  7. i have a serious interest in chemistry please contact

    Comment by eddie — December 22, 2009 @ 11:39 pm

  8. Very nice version of Scraup indeed!

    Comment by horks — December 27, 2009 @ 9:34 am

  9. It was a nic improvement as i hav done without using any nitro compound.

    Comment by raja shekar — March 11, 2010 @ 1:00 am

  10. I have an interesting situation where I am required to perform a skraup synthesis. The issue is that I have two substituents off my aromatic system, which depending on what reaction routes I take, are an aldoxime, primary amide, or primary amine (an aniline, via hoffman degredation). I am wondering if anyone has had experience with performing skraup synthesis with an amine-y species already present on the ring. I am not sure if an N-BOC or CBZ group will withstand the extreme conditions of the skraup reaction. Currently the ‘amine’ i want to perform skraup synthesis on is in the form of a nitro group, so there’s a problem with possibly ambiguous reduction/oxidation to/from nitro/amine, as well (as reduction could lead to a di-amine system or oxidation could lead to a dinitro system…

    Any ideas would be appreciated!

    Comment by Sebastian — December 6, 2010 @ 2:40 am

    • this is tough situation – in my opinion Skraup is notoriously dirty, harsh and nasty hence it is suitable only for simplest molecules/building blocks but not for anything fancy. Maybe can you find a way to introduce quinoline early on, and elaborate it by functional group transformations instead? Or use some other method for making quinolines.

      Comment by milkshake — December 6, 2010 @ 12:44 pm

  11. i still cant draw the arrows where nitrobenzene is used

    Comment by saira — January 22, 2011 @ 1:03 pm

  12. Can anybody educate me whether the Skraup synthesis described above can be used for the synthesis of 8-Hydroxy quinoline and if so what are the advantages over the conventional synthesis from the sulfonic acid derivative

    Comment by Dr. Iyer V. Sankar — February 15, 2011 @ 5:31 am

    • I think the answer is yes but the reaction conditions for 8-hydroxyquinoline need to be somewhat milder because the substrate is more electron rich. The problem with sulfuric acid as a reaction media is that can cause unwanted ring sulfonation of the starting aniline. By the way, 8-hydroxyquinoline is cheap and commercially available

      Comment by milkshake — February 15, 2011 @ 9:38 am


RSS feed for comments on this post. TrackBack URI

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

The Shocking Blue Green Theme. Blog at WordPress.com.

Follow

Get every new post delivered to your Inbox.

Join 138 other followers

%d bloggers like this: