[MAHDEMA]

Hi,
I was making a click reaction, but I forgot to add Cu catalyst at the begining and I left it stirring for a while. I made TLC which showed no reaction occured (of course) and I rememeberd I didn't add it. But now I have added it and left it stirr for about 24 hrs and TLC shows also no reaction.
It seems that adding the Cu catalyst at the beginning is important, which I don't find logical since it is a catalyst, it activates the reaction when it is added (wherever timing it is). Here comes my question: Is it really important to add it at the beginning or my reaction isn't working?! Should I repeat it?!

[rolnor]

What reaction are you performing?

[MAHDEMA]

I am reacting an R-alkyl with R-azide to form a triazole ring (R-triazole-R). I am using DMF as a solvent and Cu/Naascorbate as the catalyst. I leave it to stirr on cold.

[clarkstill]

Maybe the ascorbate was oxidized by air, so there was none left to reduce your Cu(II) to the active Cu(I) species?

[wildfyr]

Hey, I'm a click chemist! Did you start with Cu(I) or (Cu(II)? And what counter ion? Was the DMF degassed prior to use?

Also, copper click performs best in water/alcohol. It is exothermic in aqueous solutions, but in pure organics it can be a little endothermic, and is often heated to 60-80°C. I'm a little confused why you cooled it, this is not typically done for CuAAC.

I would suggest you do the reaction in water/propanol at room temp. Thats what the sodium ascorbate system was designed for. If you don't degas the solvents, then you should add a large excess of ascorbate. Also, water/propanol is easier to workup than DMF.

And yes, you should add all the compounds at the beginning of the reaction. It will turn blue/green as the copper salt dissolves. You are right though the reaction is inert until the catalyst is added, so if it sat stirring for a while as long as you weren't shoving oxygen through it, it was probably fine, and the late catalyst addition was not the problem.

[MAHDEMA]

In case my ascorbate was oxidized, the solution is to add another unoxidized Cu/Asc...or shall I repeat all Reaction from the beginning ?!?

I use CuSO4 and DMF analytical grade. By stirring on cold I mean I don't heat it, sorry for such confusion.
I work in DMF, because I prepare the azide in DMF and I can't get a good yield of it, so I work in the same pot (in sito), I just add the alkyl part. Then I dissolve CuSO4 in the least amount of water in a test tube until it turns blue then I add ascorbate and shake till it turns yellow/orange and I add this to the flask containing alkyl and azide. Can I use a better solvent for the azide reaction ?!?
Cu : Asc ratio is 1:4

[wildfyr]

DMF/water should be OK. I think you should shoot for something like 50:50 ratio of them as long as everything stays soluble. More water=faster reaction. However if you prepare the azide in DMF, you will have leftover NaN3 floating around (I assume). You'll also have leftover starting material from the pre-azide (alkyl halide? tosylate?). Its sloppy chemistry which will make the final workup that much harder. You don't typically do that one pot stuff until you nail down each step and feel confident to start combining them.

I guess it wont hurt to degas the solution then add more CuSO₄/Asc as solids. I dont like this preparing of it in water outside the reaction, because I'm sure that step introduces a bunch of oxygen. Worst thing that happens is that its a mess and you have to start over. If it still has no conversion try heating it up (slowly and carefully! Organic azides are dangerous).

[wildfyr]

PS, by R-alkyl, you me R-alkyne right?

[MAHDEMA]

First of all thanks a lot for your help
Secondly yes I mean alkyne and I use alkyl halide. According to TLC I don't have leftovers from pre azides reaction (every step was done separately except when reacting the alkyne with azide since I don't get a good yield). I guess I have NaN3 floating around as you have said, but I don't think it is a prob.
I will just do as you said (add CuSO4/ASc as solids to this reaction and I will heat a bit). If it doesn't work, I will repeat it.
thank youuuuuuuu