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!

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!

TEMPO - BAIB oxidation

Have you ever had to oxidise a primary alcohol to a carboxylic acid? Well as you know there is a ridiculous number of methods available. However, a common problem with many of the more traditional methods is that they are very harsh and could potentially rip your molecule apart. Just what you want after a 21-step linear synthesis innit? Moreover, many of the traditional metal-based oxidations can be a serious pain to work up so a mild and simple method would be kinda nice. Well one method that fulfills these criteria has been around for a while. I stumbled across it back in 1999 when I had to do one of these oxidations myself. A very nice piece of work on the oxidation of nucleosides: Now you have to admit that this oxidation uses the coolest reagents ever just judged by their abbreviations. BAIB should obviously be pronounced BABE. Anyway, at first I had no idea what TEMPO and BAIB were:Both TEMPO and BAIB are commercially available. Don't you just love stuff like TEMPO. A radical you just scoop out of the flask and throw into your RBF! So how does the reaction work? We'll TEMPO does the hard work of oxidising the alcohol. However, as it is only used in a catalytic amount a stoichiometric amount of BAIB is required to regenerate TEMPO. As far as I know no one has yet figured the exact mechanism out. However, for those interested there is a good review in Synthesis that takes a close look at the mechanism and shows the most plausible pathways: Nooy et al., Synthesis, 1996, pp. 1153 - 1174. The paper is worth looking up just to check out the photos of the guys who wrote it - absolutely priceless! Anyway, to get to the point the method is very user-friendly you basically just mix a big pile of BAIB with a small quantity of TEMPO add your alcohol and some acetonitrile and water and stir it for a couple of hours. The method is compatible with a whole range of functional groups (double and triple bonds, esters, ethers, acetals, epoxides, amides, halides, and azides) as well as protection groups (TBDMS, THP, MOM, Boc, Cbz, Benzyl and acetyl etc.). I have recommended the method to a number of people and they have all used it with great success even with very sensitive compounds so I suggest you give it a go if you are in an oxidising mood.

And finally a practical note. If you like me have managed to get stuck in the middle of nowhere and hence has to wait for 9-12 months to receive your BAIB by ship from the US you may consider just making it yourself. I haven't tried this myself but the guys in the lab do it frequently using a simple prep from Synthesis: Kazmierczak et al., Synthesis, 1998, pp. 1721 - 1723. The final stuff is supposed to be bright yellow but the guys assure me that the pseudo-yellowish stuff you for unknown reasons obtain sometimes works just as well. Here's a picture of the pseudo-yellowish BAIB one of the guys made a couple of weeks ago:

If you plan to hold on to it for a while it has to go in the freezer otherwise it goes off fast. Have fun, D!