I have reacted my alkyne and azide in a solvent mixture of t-BuOH:H2O (1:2), CuSO4.5H2O and Na-Ascorbate. However, I usually obtain a yellow solid after my workup, and when I run an H-NMR analysis for this yellow solid, I get a spectrum with almost no unique peaks apart from the solvent peaks. I suspect this could be the Cu-acetylide intermediate. Is it possible for a CLICK reaction to never work on certain compounds, or is the mistake from my side?
I do not think hindrance is an issue in my reaction. Could it be that the solvent volume is quite high? I have repeated the reaction several times and I always obtain that yellow solid in the end that does not show any peaks in H-NMR. Really wondering what the issue is.
The azide-alkyne click is definitely not as straightforward as you would expect a "click" reaction to be. Cu (I), which is being formed in situ after reduction of CuSO4 by sodium ascorbate, is a sensitive catalyst. Considering the way you have described your experiment, I would suggest 3 things-
1. Using a large excess of sodium ascorbate: the reduced Cu (I) has a tendency to disproportionate into Cu (II) and Cu (0). A large excess of sodium ascorbate will help keep it in Cu (I) state, also compensating for atmospheric oxidation.
2. Using a ligand to stabilize the Cu (I): I have used BTTAA for click reaction on proteins. It might help your organic reaction too. You can also look up other Cu (I) stabilizing ligands, or ways to synthesize them yourself. Here is where I bought the BTTAA:
https://www.jenabioscience.com/click-chemistry/click-reagents-by-chemistry/auxiliary-cu-i-click-reagents/clk-067-bttaa
3. Order of adding reagents: Start with the alkyne in solvent, add the azide, then add the catalyst (if you are using a ligand for Cu (I), pre-incubate the ligand and Cu (I) before adding to reaction), and finally add the sodium ascorbate.
I am not sure why such a delicate ordered addition is needed, but I saw this order suggested in a recent paper and it worked for me.
Thanks Ashima for your detailed answer. I will-God willing-consider the tips that you have provided and see what happens. But do you have any idea what could that yellow solid be?
Not sure what that might be.
Also, try heating it a bit. 37-40 degrees works better than room temp.
Good luck!
- Badges
- Science topic