I am trying to do a small scale (approximately 20 micromol of azide and 50 micromol of alkyne) click reaction using CuSO4.5H2O (5-10 mole%) and (+) sodium -L-ascorbate (20 mole%). My alkyne and the diazide are only soluble in organic solvents. I have to do the "click" on two azide groups. I tried this reaction in different solvent combinations like DMF:water, THF:water, MeOH:water, t-butanol:water in 2:1 ratios. Overnight stirring give no new spots on tlc. I tried lot's of ways but after adding CuSO4 and ascorbate my reaction mixture getting turbid or getting precipitation. Now what could I do ?
Use CuBr, or eventually CuI and ultrasound (lab cleaner is OK) in DMF for a couple of hours (or more). CuBr has a little higher solubility.
1) Do you do degas and argon (or nitrogen) atmosphere? Oxygen in solvent or reaction vessel kills Cu(I) catalyst.
2) Use Cu(I) substrate, possibly with a ligand for solubility, like L-histidine
https://www.tcichemicals.com/assets/brochure-pdfs/Brochure_RR117_E.pdf
3) Try DMSO as solvent, it keeps many things afloat.
4) Up your copper concentration. Reaction speed is squarely proportional to it, so increase might help, especially if you're not instantly killing your catalyst.
Hello Puneet,
thank you for sharing this very interesting chemical problem with the RG community. My first question would be: Did you follow a literature procedure? Click reactions between azides and alkynes are normally catalyzed by copper(I) compounds. This is why in your case you added (+)-sodium-L-ascorbate as a reducing agent to reduce the copper(II) sulfate to copper(I) species. Copper(I) compounds are all insoluble in water and mixtures with water. When you ask "I tried lot's of ways but after adding CuSO4 and ascorbate my reaction mixture getting turbid or getting precipitation" I would answer that this is not surprising at all. Why did you expect to get a clear solution when copper(I) compounds are foemed which are all insoluble in water? Even if you have turbidity or formation of a precipitate you can normally extract your product with e.g. diethyl ether. I suggest that you search the "Publications" section of RG for the term "click reactions with azides". Then click on "Publications". This will provide you with numerous helpful literature references about this topic which have been posted by RG members, many of them even as public full texts:
https://www.researchgate.net/search.Search.html?type=publication&query=click%20reaction%20with%20azides
Good luck with your experiments and best wishes, Frank Edelmann
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