Tuesday, December 11, 2012
So I missed my blog birthday again this year! As usual the stats for the past year at Curly Arrow follows below. Thanks to all the blog followers and everyone else who is using the blog. I wish I had more time to post stuff here but running my university research is very time consuming. When I finally get home I really need to do something that isn't chemistry to avoid going insane.
However, the many posts from over the years and the many very valuable comments by the visitors makes this a great resource and forum for exchange of knowledge for students and more experienced chemists. It really is amazing how may people make it here every day in the search for tips and tricks. Merry Christmas and Happy New Year to those of you that are into that stuff, D!
From 18th October 2011 to 18th October 2012:
Absolute unique visitors: 40,669
Total visits: 57,222 (157 visits/day)
Average time on site: 2:27 min
The 10 most frequent visitors identifiable:
(1) Oxford University
(2) Princeton University
(3) Universite de Liege
(4) University of California San Diego
(5) University of Cambridge
(6) Imperial College London
(7) Universidade de Sao Paulo
(8) University of Wisconsin Madison
(9) Stanford University
(10) University of Hull
Top 10 countries that visit the blog:(1) United States
(2) United Kingdom
(10) South Korea
For the past year we have been starting peptidomimetic chemistry up as a new research area in our group. Many chemists believe that peptide chemistry is easy and that peptide chemists aren't "real chemists". However, let me tell you from personal experience that there is absolutely nothing trivial about peptide chemistry. Even short sequences with normal alpha amino acids can be a nightmare to make, troubleshooting is complicated, purification can be a major pain and yields that a small molecule chemist would consider a total fail is generally acceptable in this area of research. Some years ago I was working with a Post Doc that came from Dieter Seebach's lab at ETH. He introduced me to beta amino acids and ever since I have been fascinated by the use of these building blocks in peptidomimetic research. Inspired by the work of Samuel Gellman we are focusing on the use of beta-3 amino acids in combination with alpha amino acids. Consequently, we synthesise beta-3 amino acids to incorporate these in our peptides.
|Silver catalysed Wolff rearragement in a sonicator. Left t = 0 hr; Right t = 2 hr.|
|Diazoinsane clear seal distillation kit purchased from Sigma-Aldrich.|
If you think that playing around with beta-3 amino acids could be fun I can recommend the company Anand Chem based in Slovakia. They produce almost all beta-3 amino acids with the proteinogenic side chains of excellent quality at a highly competitive price. Depending on what they have in stock you may have to wait a couple of weeks for the stuff but it is worth the wait considering the quality and the price. D!
Sunday, November 18, 2012
In our group we work a lot with diazotransfer reagents and diazomethane so I thought it might be a good idea to share some of our knowledge. These reaction involve reagents that are very dangerous and azide products can also be explosive so you shouldn't do any of this chemistry without being 100% sure you know what you are doing. However, if experiments are performed thoughtfully and with care the chemistry is predictable and well behaved. We are doing diazotransfer all the time these days to convert amino acids into azide derivatives. There are many reagents available for the diazotransfer reaction with the most common depicted in the figure below.
We recently, published a review that gives a detailed description of the various diazotransfer reagents when used on amino acids but I believe it would be of interest to anyone attempting the conversion of an amine to an azide. Check it out here for the full story. The conclusion is that we favour reagents 4 that was developed by Goddard-Borger and Stick and first reported here. Later a safety update was published here followed by a comprehensive stability study that was published here. The problem is that the HCl salt of 4 is hygroscopic and when it becomes wet is starts to decompose forming hydrazoic acid (HN3) which is very nasty and totally unpredictable. Fortunately, it is easy to see when the decomposition has kicked in because the product turns into a black tar. The tetrafluoroborate and hydrogensulfate salts of 4 were found to be much better with respect to shelf life. In the future we will use the hydrogensulfate salt of 4, however, we have a big pile of the HCl salt we have to get through first. Fortunately, we discovered that rigorous drying of the HCl salt of 4 followed by storage at -20 oC makes it stable for >1 year. Anyway, if you are new to this stuff you should definitely go for the hydrogensulfate salt. Using the HCl salt of 4 we regularly synthesise amino acids with terminal azides in the side chain (see below).
This is easily achieved from the corresponding amine (in this example lysine). The pH of the reaction has to be adjusted to approx. 8 to get it going. We normally insert a pH meter to keep an eye on things and simply adjust pH by adding sat. aq. NaHCO3 when required. The fantastic thing about this reaction is that the crude product is of such high purity that we never perform any chromatography but simply dry it and use it as it is. The synthesis of this particular azide has been reported many times in the literature. For a recent detailed procedure check out our SYNLETT paper on the synthesis of Fmoc-L-Lys(N3)-OH and a number of other azide and alkyne derivatised amino acids.
Note that we are synthesising high molecular weight azides so these guys are not explosive. However, if you consider synthesising smaller azides please be aware that it isn't considered safe to handle azides with less than 6 heavy atoms per azido group (see our recent review for details).
Some of you are probably thinking what is the mechanism for this reaction? Well I'll leave that to someone else to have a go at. I don't think the actual mechanism has been conclusively established and the suggested arrow pushing is rather exotic. Suffice to say that it works and that nitrogen gets transferred from reagent to product without too much fuss. Have fun diazotransferring. D!
If you don't have access to our papers reprints can be requested from firstname.lastname@example.org
On a non-chemistry note I have started the blog Molt Bé, No? about Barcelona (and Catalonia). I spend a lot of time in Barcelona since my better half lives there and now I have started writing about our favourite spots. I find that guide books, news papers etc. are a disaster regarding their recommended restaurants, bars etc. so I thought I would do my bit to help visitors to Barcelona have a nice and authentic experience when visiting the Catalan capital (and the surrounding area). Check it out here if you are heading in that direction. D!