Friday, April 20, 2007

Tempo Oxidations Part II

I've previously mentioned the TEMPO/BAIB combo for oxidising alcohols to carboxylic acid. A very smooth and mild oxidation. Back when we discussed this particular reaction we had a brief discussion about stopping this reaction at the aldehyde stage. This is indeed what this particular reaction type was developed for originally and so when I recently had to oxidise a primary alcohol to an aldehyde I thought I'd give it a go. By chance Delfourne et al. (DOI: 10.1021/jm0308702) had previously made the same compound using a TEMPO oxidation. Too easy! According to the procedure the product was obtained in quantitative yield and purification wasn't required! This particular procedure involves a crazy cocktail of reagents. This is what I did:Fortunately, all the ingredients are reasonably affordable. Mixing it all up and adding the alcohol gives a biphasic reaction mixture that looks a bit like Schweppes Orange:
However, unlike Delfourne et al. my final product wasn't clean after a simple work up. Succinimide was simply precipitating everywhere and hence some silica was required. In the end a filtration through a silica plug proved sufficient to give clean product on a reasonably large scale (18 grams) in excellent yield (97%). So despite the fact that a simple work up wasn't sufficient to clean the product up this is an easy to do reaction that I would recommend to anyone who's tired of stinky old Swern. D!

9 comments:

Jordan said...

Looks good, but it would be great if the chloroform co-solvent could be replaced with something more environmentally benign, or eliminated altogether.

philip said...

I've done these with Clorox and methylene chloride (instead of chloroform and NCS) and, if you stir them very well, they work fine. If you run the reaction under more basic conditions (i.e. no bicarb) with XS bleach, you get the acid. I don't know why anyone would run a Swern oxidation without trying TEMPO first.

Anelli, P. L. et al; J. Org. Chem., Vol. 52, No. 12, 1987

Leanna, M.R. et al, Tet. Lett Vol. 33, No. 35, 1992, 5029.

Bunsen Honeydew said...

I agree with Philip. I use pH 8.6 buffer, 0.1 equiv. of KBr, 0.02 equiv. of TEMPO, and the alcohol in methylene chloride. Then I cool it to 0 degrees, add 1.05 equiv. of NaOCl and stir the heck out of it. It usually takes about 10 minutes. The trick I found, especially on large scale is that you have to keep it cold and titrate your bleach. Aqueous bleach solutions above 5% w/w lose about one fifth of their bleach a month until they reach about 5% and then it stabilizes. The titration takes about 20 minutes and the result is good for at least 2 weeks if you keep your bleach in the fridge (i.e. cold and dark).

Come now, Beaker. Hold this...

silverback said...

Any oxidation that doesn't use heavy metals is for pansies. I add stoichiometric lead and tin to my reactions as a matter of practice.

Steve Ley said...

Did you try TPAP ?

Daniel Sejer said...

Thanks for the info Philip and Bunsen. Especially the references from Philip were very useful - the Tet. Lett, was particularly interesting with respect to avoiding epimerisation during oxidation of sensitive compounds. Hey Bunsen how do you go about titrating bleach? D!

Daniel Sejer said...

Steve Ley indeed...I've actually heard Steve ask that question on several occasions. I have in fact been using a bit of TPAP lately to great effect so maybe I'll do a little post on this soon. D!

Bunsen Honeydew said...

Beaker found this procedure online. You make a standard solution of Na2S2O3 and put that into your buret. Take a diluted sample of your bleach, add excess KI and H2SO4 and you get I2. Use the Na2S2O3 to titrate the I2. Apparently Teva Pharmaceuticals in Israel favours the TEMPO/bleach approach. Bleach is certainly cheaper than DIAB. Here is Beaker's procedure:

http://www.cofc.edu/~kinard/153L_HONS_HonorsChemistryLaboratory/Exp4_ChlorineBleachTitration.pdf

Daniel Sejer said...

Excellent! Thanks for that Bunsen. I'll give the bleach method a go next time. D!