Tuesday, July 28, 2009

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!

13 comments:

andreew said...

Never used PDC before. Any chance of doing an aqueous extraction with EDTA or something to remove chromium first?

Stefanie said...

Hi don't wanna be a pedantic idiot, but there is actually a method to use Chromiumreagents catalytically by Mo Hunsen, but apparently no one is really willing to use those (although it is one of the top downloaded THL papers). I have tried it and it is a fantastic reaction: so if you have the time, check it out:

Hunsen, Mo. “Pyridinium chlorochromate catalyzed oxidation of alcohols to aldehydes and ketones,” Tetrahedron Letters, 2005, 46, 1651-1653.

Daniel Sejer said...

Stefanie, there is absolutely nothimg pedantic about your comment. The whole point of the blog is to exchange knowledge and make everyone smarter. Thanks for the refrence. I don't know this stuff but will check it out at work tomorrow. D!

Kai said...

I looked at that THL paper... Mostly shows benzylic alcohols, and ALL reported alcohol to aldehyde oxidations are benzylic. Doesn't look like it'll work for others. Maybe that's why it's much downloaded but not much used...

milkshake said...

there is also Meck process group paper about "Jones-like" reagent catalytic in Cr, it is basically periodic acid solution in wet MeCN with a catalytic (like 0.5 mol%) CrO3. It worked for me well for a benzhydrol-kind of substrate but sucked and more sensitive material.

Btw., I worked for old carbohydrate dude in Prague, and he would allways use PDC on his cyclic-acetal-partially protected sugars. He insisted that one must add an excess of 4A powdered sieves to PDC also, to make the reaction reasonably fast. The sieves also make the workup by silica filtration easier.

TPAP is lovely but not very gentle, with sensitive substrates for small-scale experments I would rather use Dess-Martin periodnane with few drops of pyridine.

Anonymous said...

In my experience TPAP/NMO system is also prone to epoxidizing styrenes - although this is probably all to do with the NMO.

freezedream said...

PDC is terrible. I have previously used it for oxidation of simple cycloalkanemethanols, but this often resulted in some over-oxidation and one particular reaction even somehow produced what seemed to be an ester!

Then there's the clean up afterwards. The amount of chromium residues that you get from doing a moderate scale reaction is incredible.

Anonymous said...

Both PCC and PDC has worked excellently for me so far - just use Celite in the reaction on a gram for gram basis, It'll absorb the black shit and in my case case didn't co-elute.

Anonymous said...

the celite thing also worked well for me.

Jimbo said...

Nice article.

In my experience with PDC, reaction can be enhanced via the inclusion of 3A molecular sieves (JCS, 1980, 561). Further to this, PDC can be used catalytically (10mol%) with bis(trimethylsilyl)peroxide (Tet lett., 1983, 24, 2185).

Jimbo said...

If you have divergent pathways emerging as a consequence of using NMO, oxygen can be used instead and there are several papers out there from Ley and others.

In another interesting paper by Ley, polymer supported TPAP is used catalytically (10ml%) and purification naturally becomes very simple. The oxidant in this case oxygen (Synthesis 1998, 977). Unfortunately, the material is not commercially available.

OrganicOverdose said...

Thanks for the post D and the comments everyone. I am going to use PDC today after several weeks of putting it off due to damn Erin Brockovich. I have read a lot of information on PDC/PCC regarding using sieves and Celite. A nice book by Gabriel Tojo called Oxidation of alcohols to aldehydes & ketones has everything you might need in these cases. Google books lets you read it for free for a little while.

mohan said...

In addition to all this I would like to bring SO3.Py complex in combination with DIPEA works really well for oxidation. I had terrible time doing oxidation for one of the dithiane conatining alcohol. I used Swern protocol, IBX, Dess-Martin periodinane and even TPAP. I always used to get bad yield and sometimes product used to decompose during work-up.