Curly Arrow - Established 18th October 2006

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)

Pageviews: 84,446

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

(3) Germany

(4) India

(5) Canada

(6) Australia

(7) Denmark

(8) Japan

(9) France

(10) South Korea

----

D!

Diazomethane and the Arndt-Eistert Homologation

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.

There is a number of ways to make beta-3 amino acids but from personal experience one method stands out as the best route to these molecules: the Arndt-Eistert homologation. In this classic approach an alpha amino acid is converted to a diazoketone followed by the Wolff rearrangement to provide beta-3 amino acids. The Arndt-Eistert homologation basically homologates a carboxylic acid with one methylene group as shown in the scheme below.

The last step, the Wolff rearrangement, is carried out by sonicating the diazoketone in the presence of a silver catalyst (in the dark). Because nitrogen is evolved during the course of the reaction we normally have an empty balloon fitted on the flask to avoid pressure build up. I rather like the feature that the balloon slowly gets inflated during the course of the reaction as shown in the picture below.

Silver catalysed Wolff rearragement in a sonicator. Left t = 0 hr; Right t = 2 hr.

However, as you may have noticed there is a down side to the Arndt-Eistert homologation: diazomethane! The reagent has a fearsome reputation and I have heard of a couple of guys who have managed to blow themselves up and gone deaf in the process. Allegedly, one chemist at our department even managed to set fire to himself! This was a long time a go when less attention was being paid to laboratory safety and the accidents were due to sloppiness and improper handling of diazomethane. If you are careful and use the correct glassware (with clear seal joints) there is (almost) nothing to worry about. We have purchased the setup shown on the picture below. This is a very nice diazomethane still consisting of only three pieces that will produce up to 40 mmol of diazomethane in approximately one hour. We only use hot water as the heating source and keep everything behind a blast shield just in case. Diazomethan is generated from Diazald  as shown in the scheme below and used immediately. The procedure it quite simple. In the separatory funnel you place a solution of Diazald in ether this is added dropwise to a heated mixture of aqueous potassium hydroxide, ether and a high boiling alcohol [commonly 2-(2-ethoxy-ethoxy)ethanol]. Diazald reacts with the base to produce diazomethane that is distilled with ether to the receiving flask.

Notice that diazomethane is always handled in solution. The neat stuff is known to explode unpredictably so don't even think about doing that. Because of the way that diazomethane is produced it is hard to add an exact number of equivalents to a reaction. For the synthesis of diazoketones we simply go for an excess of diazomethane (approximately 2-3 equivalents based on a 70% yield of diazomethane). We commonly distill the diazomethan directly into the reaction flask to minimise handling. For the synthesis of beta-3 amino acids the alpha amino acid is first transformed into a mixed anhydride which is exposed directly to an excess of diazomethane.

Diazoinsane clear seal distillation kit purchased from Sigma-Aldrich.

Unlike diazomethane, Diazald is reasonably stable and easy to handle yellow solid. Unfortunately, Diazald has obtained a rather bad reputation despite being relatively safe to deal with as long as you don't eat it, set fire to it, beat it with a hammer or something similarly stupid. Consequently, it can be rather hard to get hold of. When I worked in Australia it was particularly problematic as it can only be shipped by road and isn't produced in the country! Here in Denmark we get it from Germany but it does take a while because they don't send it with the regular shipments so you have to plan a bit ahead.

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!