[darkdevil]

Hi, this is the problem I am facing now. Suppose I can do a 100% conversion with 4-hydroxybenzaldehyde as starting material under this Williamson type reaction. But with R = two bromines, the conversion dropped to 24%.  I am trying to change the solvent to DMSO and the base to NaOH and add a little PTC to see if it works.. I just wonder if there are any other ways to increase the yield? or this is dead-end ? Thank you so much!!

[Babcock_Hall]

I don't have specific experience with the Williamson ether synthesis.  But what if you did a Finkelstein reaction to change bromide into iodide, so that you have a better leaving group?

[orgopete]

Just looking at the conditions, I'd wonder if you are getting elimination because the reaction is heated. Besides adding iodide ion as a catalyst, I'd run the reaction at room temperature. I agree with changing from potassium carbonate, which I presume is not too soluble.

[kriggy]

What about doing ether synthesis 1st and then brominate?

[zsinger]

100% conversion.....NOT LIKELY!!!!!
      -Zack

[discodermolide]

Try potassium carbonate in acetone at reflux.

[darkdevil]

What about doing ether synthesis 1st and then brominate?

I tried, the reaction did not proceed well and it is hard to separate and purify

[darkdevil]

Try potassium carbonate in acetone at reflux.

I am trying this now.
And the DMSO/NaOH method I tried yesterday did not give me any product as monitored from TLC after 18 hours of heating and even with PTC added.

[clarkstill]

Try silver carbonate? It should activate the alkyl bromide towards attack...

[darkdevil]

Try potassium carbonate in acetone at reflux.

I am trying this now.
And the DMSO/NaOH method I tried yesterday did not give me any product as monitored from TLC after 18 hours of heating and even with PTC added.

Hi, I tried refluxing with potassium carbonate in acetone. There were no product given
I am wondering if using potassium carbonate in DMF and add a little potassium iodide would help?

[Babcock_Hall]

Orgopete suggested iodide as a catalyst, and I had previously suggested doing a halogen-exchange.

[orgopete]

Iodide would help, but so would knowing what is happening. Is the reaction going slowly which is what 24% yield might indicate, or are side products increasing? It would not be surprising to find elimination competing with the more hindered phenol. Elimination also increases with heating. How do you know when to stop the reaction? Did  the 24% yield correspond with a 70% recovery of starting material? Is the challenge to suppress side reactions?

[darkdevil]

Iodide would help, but so would knowing what is happening. Is the reaction going slowly which is what 24% yield might indicate, or are side products increasing? It would not be surprising to find elimination competing with the more hindered phenol. Elimination also increases with heating. How do you know when to stop the reaction? Did  the 24% yield correspond with a 70% recovery of starting material? Is the challenge to suppress side reactions?

I think side product is increasing through time.
I tried DMF, K2CO3 at 168 degrees celsius. In the first 38 minutes, I saw my product coming out in TLC. And after 1 day the product spot in TLC dropped.

[orgopete]

I'm guessing the aldehyde cannot withstand the beating. This is what I would try. I'd use KOtBu as base with KI catalyst in DMF under an inert atmosphere. Everything should be soluble so I'd start the reaction at room temp. I'd monitor the disappearance of the bromide by GC. You should see how fast it is converted to iodide and if elimination or other reactions are occurring. You might want to use an internal standard for this.

I'd watch to see what was happening. Then I'd slowly heat the reaction to 50-60C. Repeat, heat higher, etc. you may find that heating results in a second set of side reactions that you didn't see before heating. If the reaction is proceeding, you can judge how much heat you can tolerate to get your product and not have it disappear.

I don't know whether economics is an issue here or not, but the kinetics are concentration dependent. I'd try to increase the concentrations and I'd use as large of an excess of the bromide as I could. Hypothetically, it can be recycled.

On the practical side, you could set up the reaction and then split it into aliquots that you heat at different temperatures. If you wanted to get really careful, I'd distill my solvents and keep them under an inert atmosphere to keep oxidation of the aldehyde to a minimum.

You could try DMSO, but I don't know if it would oxidize the bromide.

[orgopete]

Try potassium carbonate in acetone at reflux.

Can anyone tell me if this works? It seems like a way to make mesityl oxide. Does that not happen?