Three years later. I'm surprised that I still manage to keep Curly Arrow alive. The reason that things are still happening is you guys that read my stuff and send me some very positive and enthusiastic emails. I'm getting a lot of hits from Google and the blog appears to have a tremendous impact. For example if you do a Google search on Click Chemistry you'll see the Wikipedia entry as the top hit followed by Curly Arrow. Curly Arrow has a higher rating than the original literature on Click Chemistry! So I guess I'll just keep at it and see what happens. I have listed the stats for the past year below. Numbers are up but the top 10 visitors (that I can identify) haven't changed much. The major difference is that the only company (GSK) is out and that Japan has made an entry. I can see a whole bunch of european networks that I get a ton of hits from and I suspect that certain German Universities should be on the list. As a consequence this year I have also included top 10 contries that visit the blog. D!
gs generally go according to plan. However, what if you are stuck with an amine and want to substitute it with a nucleophile. There are a number of ways to do this but it's not just a walk in the park. Until recently I had never had to do this but then one fine morning I wanted to do the reaction above. How does one go about doing t
his? Is there a simple method by which I could activate the amine and displace it with the anion of 2-nitropropane, followed by a simple reduction to get the amine I wanted? Well, as it turns out Katritzky and co-workers published a paper in 1979 introducing triphenylpyrylium salts that can convert amines to leaving groups. Granted, the atom economy in this process is (to say th
e least) poor. However, the required pyrylium salt is commertcially available at a resonable price. All you do is stir it up with the amine. Prior to adding the amine the suspension is pale yellow and then when you toss the amine in it becomes a deep red slurry. In the photo the amine has just been added. It's always exciting with a bit of colour if your an organic chemist. The product is isolated by filtration. In this case the pyridinium salt was isolated as a light brown solid in 63% yield, perfectly clean by NMR. Next the pyridinium salt was treated with deprotonated 2-nitropropane in hot DMSO to give the nitro compound that was reduced using old school conditions. Interestingly, we could not get any reduction AT ALL of the nitro compound by catalytic hydrogentaion (at atmospheric pressure). Very odd! I would have ex
pected to see at least a few percent of the reduced stuff. Any ideas out there? Anyway, the amine was isolated in good yield over two steps after a short (2 cm tall) DCVC column. Yes a wastefull method but it is simple and fast. D!
I have previosuly been moaning about the fear of stereogenic centers that industry seems to suffer from here. So it was with great pleasure that I read Derek Lowe's latest contribution to Chemistry World were he appears to share some of my views.
I keep thinking that I'm all done paper pushing and then somehow magically I'm back at it full force. So recently I've submitted four grant proposals, written a chapter for a book, started teaching again and in parallel I'm doing a half hearted attempt at some lab work. So the last thing I needed to see was this paper Don't read that paper if you are a suicidal post doc.
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!
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.
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