Wednesday, November 05, 2008

What is Click Chemistry?

2001 was a big year for K.B. Sharpless. He received the coveted Nobel Prize in Chemistry and introduced the concept Click Chemistry. I had the great pleasure of meeting him in 2001 and his lecture on Click Chemistry completely changed the way I think about chemistry.
I do not do Click Chemistry or even Click Reactions but I like the overall concept and I fulfil about half of the Click Chemistry commandments in my daily research.
Most chemists have no idea what Click Chemistry really is and think making a triazole makes you a Click Chemist. This is incorrect and many papers are published with Click Chemistry in the title even though it isn't Click Chemistry! Click Chemistry is not a specific reaction it is a concept. Here's a condensed version of rules you have to fulfil to become a Click Chemist.:
The reaction must be:
(1) modular
(2) wide in scope
(3) give very high yields
(4) generate only inoffensive byproducts
(5) stereopecific
The process must be:
(6) simple reaction conditions
(7) readily available starting materials and reagents
(8) use no solvent or a solvent that is benign or easily removed
(9) simple product isolation by non-chromatographic methods
Sharpless published an excellent paper introducing the concept
Click Chemistry: Diverse Chemical Function from a Few Good Reactions, H.C. Kolb, M.G. Finn and K.B. Sharpless, Angew. Chem. Int. Ed., 2001, 40, pp. 2004-2021.


Anonymous said...

This is an absolutely excellent paper to read. I read it when I first started my graduate studies and now that I am actullay doing some Cu catalysed Huisgen cycloadditions (I guess we can call them Click, though purists might argue with my protocols) I cna recognise the excellence of this concept. Simply put, using a Click Chem reaction as opposed to a traditional technique for ligation can drastically reduce purification times and increase final purified yields especially if you are carrying out multiple reactions on the same molecule in one step, and if you are working with complicated molecules like peptides. It really is a lifesaver.

alessandro said...

Purists will argue that CuAAC is only one of the many reactions that satisfy the 'click' definition. A recent and very smart example is the thiol-ene reaction:

(as a former student of Dondoni, I might be accused of being in a conflict of interest here ;))

Anonymous said...

Dear Daniel,
I really like you blog and read it quite often.
I would like to add a comment about click chemistry. I think that nowadays there is an abuse of the click reaction (especially the CuAAC reaction). I mean that you can see very nice works where the CuAAC reaction is smartly used for solving a chemical problem (e.g. the introduction of stoppers in rotaxanes) but it's also true that nowadays one can find papers where the reaction is used even when it's not necessary (i.e. when other "classical" reactions work very well). The "click chemistry" concept became very popular and I think sometimes that this led to miss one of the requirements of the synthetic art: the elegance of a synthetic pathway. IMHO, of course!

anitesh said...

I am a 3rd year undergraduate student from INDIAN INSTITUTE OF TECHNOLOGY KHARAGPUR ,INDIA. I want to work in this field during my summer vacation (around 10-12 weeks) .Can anyone plz tell me which will be the best place for this.
Anitesh Dharam
e mail-

Aizuddin said...

Hi Daniel,
enjoy reading your blog, I'm currently trying to click a really hydrophobic azidopyrene to a simple peptide. It works beautifully in solution phase but it's a sad story when it comes to the solid phase. Any advice? I use DMF for solvent since need to have the azidopyrene in solution, CuSO4 reduced to Cu(I) with addition of NaAsc and TBTA to stabilize the Cu(I). I even try microwave reaction but it comes to no avail. Thanks in advance

Daniel Sejer said...

@Aizuddin, Things can be complicated on solid phase. There are many things to consider. My best advice would be read up on things in the review by Meldal and Tornø:
Chem. Rev. 2008, 108 (8), 2952-3015
or their recent book chapter:
Tornøe, C.W. and Meldal, M., Dipolar Cycloadditions in Peptide Chemistry, in Organic Azides: Syntheses and Applications, Bräse, S. and Banert, K. (Eds.), Wiley, 2009.
Also a recent paper by Finn and co-workers may be useful to you:
J. Org. Chem. 2009, 74 (8), 2964-2974.

Daniel Sejer said...

@Aizuddin, Believe it or not but I just had an email from the God of Click Chemistry, recommending that you have a look at the following paper from 2009:
Hong et al., Angew. Chem. Int. Ed., 2009, 48, pp. 1-7.
The paper only describes chemistry in solution, however, I may still be worthwhile to have a look at this excellent publication that solves many of the problems that the Huisgen cycloaddition is facing within bio-conjugation. D!