Am I correct to say that you do NOT see any reaction, at all? Yrur reaction conditions look standard, should work... on paper anyway! N2 is not going to change anything.

I would retry with heat, 40-50+ degrees to start and take it from there... good luck

After there is many options, but I would try the basic, heat.

I would propose CuI as catalyst and DIPEA as a base in acetonitrile or methanol (degased with N2). It worked for almost any compound, including higly polar ones and zwitterions, without any troubles. Better results were usually obtained in MeOH with 20 mol% CuI then in ACN. The amount of DIPEA is sometimes compound dependent, in case you have acidic substance 2 equiv. of the base should provide better results. You may also check the link below.

http://onlinelibrary.wiley.com/doi/10.1002/jssc.201300559/abstract

In my experience O2 is not a problem for click chemsitry on Cu2+/Ascorbate system. I agree with Michal Kohout if the solubility of your azide and alkyne is a problem you should go for CuI in organic solvent-s. . . Some time for slow reacttion we use to add after 18h, fresh CuSO4 and ascorbate and after that we get reaction completion, we did not need to increase temp.

I would agree with the idea of using an organic solvent/solvent system and a source of Cu+ that is soluble in that solvent. Heat should help - I have commonly found that click reactions heated up to 50 degrees work quite nicely. Shouldn't take all that long, either, with an overnight reaction being the worst case scenario I encountered. The big question is why you don't see any reaction at all under your conditions. Make sure your azide and alkyne are sterically available for reaction. This can require a surprising amount of space!

Thank you guys. I will try under organic conditions with CuI.

Oxygen is for sure a problem for click chemistry, so degass your solvent by Freeeze-Pump-Thaw-technique when you use just 20mol% of Na-Ascorbate or use equimolar amount of sodium ascorbate. I always use 2-5 mol% of CuSO4 5H2O as catalyst and never got problems. It would be unusual but try to heat up the reaction as well, but normally a catalyzed alkyne-azide-click works at room temperature. We were also able to react geminal di- and triazides.

I've established very good reactions conditions for molecules with a multiple azide/alkyne bonds.

M. Wyszogrodzka, R. Haag, A Convergent Approach To Biocompatible Polyglycerol “Click” Dendrons and Synthesis of Modular Core-Shell Architectures. Chem. Eur. J., 2008, 14, 9202-9214.

Thank you Philipp and Monika

We have a reliable methodology using in situ generated Cu nano particles. We have reduced Cu 2+ using hydrazine hydrate. Also you can do the reaction in both organic and aqueous medium. good Luck!

Appl. Catal. A: General 2013, 453, 151-158.

Cool, thanks suresh

First thing to check is in which solvent both of your compounds (azide/ alkyne) are soluble. Try to estimate in which compound the final triazolyl- product should be soluble (triazole makes the final products more polar). So choose THF/ water or acetonitrile/ water or even DCM/water can work! Solubilise your precursors in the let's say distilled THF and then add water distilled little-by little and u should stop the addition before it gets turbid the solution and of'course no precipitation!!Then u add the Cu( II) (u can put a more than 5%) solubilised in water drop by drop and directly after u add the ascorbate( 2 equiv compared to copper)! U should see a change in colour (which indicates that the reduction from Cu (II) to Cu (I) works) and all the mixture together should be clear and soluble (no turbid mixture)! So the last thing u could do is to heat at 40- 60° max! U leave ur reaction one night for instance! To check if ur reaction is finished u could try the more reliable method to follow it by IR! If u have no signal at about 2085-2097 cm-1 (v-N3) it means there is no free azide in ur solution and that ur reaction is finished! I hope I helped! Good luck :)

Thanks for the detailed procedure Amalia.

We worked on a somewhat similar but opposite problem. Reaction of a dialkyne with two azide containing molecules. You can check the paper: Bioorg Med Chem. 2013, 21:4225-32. Synthesis and preliminary biological evaluation of a compound library of triazolylcyclitols.

I would try use a mixture of three solvents, such as methanol, DCM and water.

Thanks guys

Use an accelerating ligand if you haven't already. TBTA works well in most cases with high substrate concentrations (i.e. mM range)

Have you though in using microwave enhancement?

Try using Cu(O) with CuSO4 or Cu(II) with TBTA and reducing agent like sodium ascorbate. i.e copper wire washed with 50% HNO3 in water and then with water to remove traces of acid) sometimes helps to keep Cu(I) stable in reaction mixture.

I would like to suggest use of CuSO4.5H2O and ascorbic acid in t-butanol:water solvent mixture. Initialy stir the reaction mixture at RT and then maintain it at 75-80°C. Hope you will get desired product.

did you considered the possibility to use micelles as a reactor like system?

just conduct your reaction in water and use a proper surfactant.

Let me know

Thank you all

Have you tried PEG-water? condition reported by Parang et al.; see

Journal of Colloid and Interface Science, Volume 358, Issue 1, 1 June 2011, Pages 116-122, Xiang Liu, Hong-Ning Zheng, Yin-Zhou Ma, Qing Yan, Shou-Jun Xiao

Also

Recently, Xiao et al. reported on microwave irradiated Click reaction on silicon surface, this condition might help, see

Journal of Colloid and Interface Science, Volume 358, Issue 1, 1 June 2011, Pages 116-122; Xiang Liu, Hong-Ning Zheng, Yin-Zhou Ma, Qing Yan, Shou-Jun Xiao

Good luck

I obtained good results with click reactions in this scale by using an excess of CuSO4 and sodium ascorbate. I assume you are working also with very small amounts of solvent to keep the concentration high.

Try do dissolve your organic compounds in THF of Dichloromethane add the same amount of water followed by CuSO4 and sodium ascorbate (a few crystals should be enough). I used vials for the GC auto sampler with a volume of 500 micro L to carry out the reactions.

Success!

We do multiple click (up to 14-fold) with poly-alkyne scaffolds and azide ligands with CuSO4.5H2O and sodium ascorbate under microwave irradiation in DMF/H2O 4:1 (v/v). Yields are excellent (up to 99%).

Use tBuOH- H2O(1:1) under microwave 70-80 C..

Use CuI and lutidine (excess).

The Clic reaction can be conduced even in water, so it may be that you have an other problem such as handrences or hydrogen interactions which can decrease the reaction rate.

You can use CuCl in 5% in toluen under heat or the microwave method

Sorry, but without structure or at least one idea of it and about electron density around alkyne and azide functionalities suggestions may be erroneous. Do you really need Cu catalysis? Using Cu, as you know you are dealing with other reaction but not cycloaddiiton… In all cycloadditions a proper balance between stability/reactivity shoud or must be attained…Your alkyne may not require activation if is already very electrophilic and a more “traditional” approach (alkyne, azide and heat – sealed tube?) may give you better results.

Good luck and good work

In CuSO4.5H2O and sodium ascorbate  DMF system, how you dissolve  sodium ascorbate in DMF?

Just you go for heating up to 65 degree in t-butanol:water in 3:1 ratios

Did you try the reaction in acetonitrile with CuI as catalyst?