TPAP vs. PDC

After this rather interesting paper on the oxidation powers of sodium hydride (That has been slapped around by the blogging community in a big way) it seems appropriate with a post on reagents that actually are capable of performing oxidations.

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We all know pydridinium dichromate (PDC). It's one of these hopeless reagents that still gets taught on undergraduate chemistry courses despite the fact that A LOT has happened since 1979. I guess students should be aware of the existence of these reagents and maybe their use can be justified sometimes (Please let us know if you believe this to be the case). The "marvellous" thing about PDC is that it oxidises primary alcohols to aldehydes. And to be fair, when this was first discovered and described by Corey and Schmidt in 1979 it was probably an important contribution to synthetic organic chemistry (Click on image for enlargement).
The fun part with PDC is making it which is very simple and produces a beautiful bright orange/metallic crystalline substance (See picture).

However, this is where the fun stops. To oxidise a primary alcohol to an aldehyde we must expose it to stoichiometric (!!!) PDC. The reaction mixture is nasty (See picture of black suspension from hell).
Finally when the reaction is finished you have to get rid of a lot of chromium stuff. Filtration through a tightly packed silica plug is the way forward. However, due to the presence of pyridine the chromium junk will start moving and co-eluting even in straight hexane (See picture of horrible filtration).
There is a long, long list of old school reagents (e.g. Swern oxidation) and more modern ones (e.g. TPAP) that will carry this transformation out under much nicer conditions. TPAP (Tetra Propyl Ammonium Perruthanate) is a personal favourite that has worked wonders for me. TPAP is great for a number of reasons. Firstly, it is used in low catalyst loadings with the co-oxidant NMO (N-methylmorpholine N-oxide).

Secondly, the work-up is very simple normally just involving filtration through a plug of Celite followed by column chromatography. Some readers may have noticed that I on several occasions have mentioned some of Steven Ley's wonderful contributions to synthetic organic chemistry. Well TPAP is yet another of his little wonder reagents. The Ley group published a review on TPAP back in 1994 that illustrates its versatility. However, allow me to use one of my own examples where we compared PDC to TPAP. The oxidation of lactols to lactones can be tricky because of the equilibrium between open chain aldehyde and lactone, as illustrated.
However, both PDC and TPAP selectively oxidise to give the desired lactone. In this case PDC even when the rate enhancing additive pyridinium trifluoroacetate was added took 4 to 11 days to go to completion with 2 equivalents of oxidant. In the end high yields of clean material was obtained but as described above the work-up procedure is tedious. TPAP on the other hand provided the desired material overnight (In reality the reaction was probably done within an hour but I was at the pub at this point in time) followed by filtration and chromatography to give excellent yields of lactone. I should mention the major down side to TPAP. It is very expensive! However, due to low catalyst loadings, high yields, fast and simple purification I believe that the expense is easily justified for valuable starting materials. D!

Coffee Break

I'm having coffee and missed having some some Curly Arrow links to fun stuff. So a list of links has been added (bottom right on the front page). Chemical Stick Figures and xkcd are personal favourites. Also Org Prep Daily has started posting again and so has been upgraded from a chemistry resource to a blog.
Have a nice weekend, D!

Lithium Aluminium Hydride Reductions - Rochelle's Salt

Haha I'm still (barely) alive. Thanks for sticking around. Been busier than usual sorting my private and professional life out. Wrote a ton of grant proposals, published some papers (here, here, here and here), writing a book chapter, trying to be productive in the lab (fat chance) as well as having a life after work and some time off. So Curly Arrow got down prioritised for a while. Hopefully that is changing now.

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Last week I did a lithium aluminium hydride reduction on large scale (see picture). This reminded me of the first time I had to work a reaction of this type up. My first experience (sometime last century) was a DIBAL reduction and if you haven't tried this stuff yet I can tell you that all these aluminium hydride reagents end up forming massive aluminium emulsions that are impossible to work with. The first time round I ended up making an utter mess and getting a very low yield. Realising that I couldn't possibly be the first chemist to encounter this problem I looked into things. The trick is obviously to break the emulsion up. There is a number of ways to do this. My favourite method is to use a saturated aqueous solution of Rochelle's salt (sodium potassium tartrate). Rochelle's salt is an excellent ligand for aluminium and breaks the aluminium emulsion. The procedure is simple. Cool your finished reduction down to 0 degrees C, or lower depending on the situation (For my large scale reduction I cooled it with acetone/dry ice) and quench excess reducing agent with something non-protic. For example ethyl acetate or acetone works well. Just remember to use something you can easily evaporate off when things are done. Don't be impatient and add it dropwise with vigorous stirring. Use a addition funnel for larger scale reactions. When the quench is complete remove the cooling bath.

I find it convenient to have a saturated aqueous solution of Rochelle's salt standing around. Please note that Rochelle's salt has a ridiculously high solubility in water so when preparing the aqueous solution go easy on the water and pick a small flask. When my reaction is quenched and everything looks like jelly I add some Rochelle's salt solution. Often I'll add it as a half saturated (or even more dilute) solution (a larger aqueous layer sometimes makes separation of the phases at the end easier). After pouring Rochelle's into your flask get the mixture stirring vigorously, have a cup of coffee and check your email. The better stirring and the more Rochelle's you use the faster it'll break up the emulsion. Ultimately you end up with two nice and clear phases that are simple to separate in a separatory funnel. D!