[Guitarmaniac86]

I have a suzuki reaction where I am coupling a benzothiophene derivative to a substituted phenylboronic acid.


The conditions are thus:


1 equiv benzothiophene
1.1 equiv boronic acid
Potassium carbonate
2.5% Pd(dba)₂
5% SPhos
Toluene at 120 degrees
2 hours


I put my benzothiophene derivative, boronic acid and potassium carbonate in toluene and sparge with nitrogen for 1 hour whilst stirring. I then add the catalyst and ligand, and heat the reaction.

On a 500 mg scale I got 100% conversion and an 80% yield.
On a 5 g scale I got 100% conversion and a 91% yield.


In both instances there was no homocoupling of the boronic acid observed nor was there any proto-dehalogenation observed.

I have since repeated the reaction in two more 5 g batches and I am getting only 50% conversion and my yield has dropped in half. All batches of the chemicals are the same, the conditions are the same, the order of addition is the same, the solvent volume has not changed. The only difference is the colour of the reaction has changed.


In the 500 mg batch and the first 5 g batch the colour of the solution was a deep purple/black colour. In the last two batches the catalyst goes from the deep purple colour to a yellow/green colour.


I have checked or done the following:

-Made sure there was no oxygen in the solvent by sparging for longer. No change in reaction profile.
-Repeated the reaction in darkness. No change in reaction profile.
-Checked quality of all reagents. Fine by LC and NMR.
-Checked the solvent purity. Solvent is pure.
-I added more catalyst and ligand but the reaction did not proceed further.
-I cooled the reaction down, resparged it and added more catalyst and ligand. No change in reaction profile.

I feel like I am missing something here. Due to time constraints, I don't have time to do anymore trials on this reaction. This Suzuki reaction did not work with Pd(PPh₃)₄ in dioxane:water but there was some conversion with other catalysts and ligands (50 - 60% conversion by LC but these conditions had significant homocoupling product). The conditions discussed are the best of those trials... Until the last two batches.


If there is something glaringly obvious, let me know please! I am at my wits end!

[rolnor]

If this is Suzuki you have bromobenzothiophene or similar halide?
Nice yield in the 5g run.
I guess the carbonate does not dissolve, could this be a problem, that you need better stirring or ground carbonate?
Its good that you exclude oxygen, this would be a first to check.

[phth]

If your technique is the exact same (very easy for a trained chemist), then it must be the reagent purity. Maybe something is catalyzing nanoparticle formation over time, precipitation.... It sounds like you did exactly what you should have, so just report that the yield became irrepreducible. There is nothing wrong with that, and it's a great observation.  Happens all the time.

Check your Schlenk line. Are the tubes new? Is the drying tube good? Are the joints recently greased?

[Guitarmaniac86]

If this is Suzuki you have bromobenzothiophene or similar halide?
Nice yield in the 5g run.
I guess the carbonate does not dissolve, could this be a problem, that you need better stirring or ground carbonate?
Its good that you exclude oxygen, this would be a first to check.

I am using 2-bromobenzothiophene. I am waiting for more boronic acid to come in before I grind the carbonate or use caesium carbonate instead as in the lab this is a powder vs large granules for the pot carb.

If your technique is the exact same (very easy for a trained chemist), then it must be the reagent purity. Maybe something is catalyzing nanoparticle formation over time, precipitation.... It sounds like you did exactly what you should have, so just report that the yield became irrepreducible. There is nothing wrong with that, and it's a great observation.  Happens all the time.

Check your Schlenk line. Are the tubes new? Is the drying tube good? Are the joints recently greased?

Schlenk line is clean and everything is greased and the drying tube is fine... For now!

[Guitarmaniac86]

Not sure if it is worth posting an update, but it could be useful if others are having the same issue.

Traced the problem back to the base. Granules are terrible for this reaction, whereas the powdered form was superior and yields were restored when using powdered pot carb and not the granules. So lesson learned. The form in which the material comes in is very important.

[wildfyr]

I guess the carbonate does not dissolve, could this be a problem, that you need better stirring or ground carbonate?

Rolnor called it!

Thanks for the update, we really appreciate when people do that.

[rolnor]

Glad to be of service!