October 17, 2021, 10:33:32 PM
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Topic: copper sulfate washes, lutidine, and DCM  (Read 308 times)

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Offline Babcock_Hall

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copper sulfate washes, lutidine, and DCM
« on: September 30, 2021, 05:04:16 PM »
We are adding tert-butyldimethylsilyl groups to an aromatic glycoside, following a publshed procedure.  We used 4% (w/v of solution) copper sulfate to try to remove excess lutidine from our synthesis (which also involved an excess of TBDMSOTf and the solvent, which was DCM).  We obtained an emulsion, which broke over a long time as we filtered through Whatman #1.  A milk chocolate colored solid remained on the paper.  On the one hand, I am tempted to increase the copper sulfate concentration to about 25% or so in the future (which we also did in our second wash), in the belief that higher ionic strength disfavors emulsions.  On the other hand after our second copper sulfate wash, we tried a brine wash, and some of the extraction became an emulsion also, which we also broke by filtration.  The procedure did not specify two copper sulfate washes, only one, and it did not suggest a brine step.

We attempted a similar reaction a few months ago, which used an HCl wash, not a copper sulfate wash.  Based on crude mass, I don't believe that we removed all of the by-products.  That is one reason we tried a different literature protocol for this reaction.

Does anyone have any suggestions for ways to avoid the emulsions or any other things we should change?

Offline Babcock_Hall

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Re: copper sulfate washes, lutidine, and DCM
« Reply #1 on: October 01, 2021, 01:15:44 PM »
The paper that we followed with the copper sulfate washes was Barrett Anthony, J Organic Chemistry 2000 65(20) 6508-6514.  10.1021/jo000690p.

We patterned an earlier synthesis, the one with a 1 M HCl wash, after the supporting information in Lindner J-P 2011 Chemistry a European Journal 17(15):4090-95. DOI: 10.1002/chem.201003163.

Both papers produced tetra-TBDMS ethers of glycosides from TBDMSOTf and lutidine.  Lindner's paper had more washes, including a brine wash.  Barrett used DCM as the solvent whereas Lindner used diethyl ether.
« Last Edit: October 01, 2021, 01:46:02 PM by Babcock_Hall »

Offline rolnor

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Re: copper sulfate washes, lutidine, and DCM
« Reply #2 on: October 02, 2021, 05:30:13 AM »
I think 1M HCl is a bit acidic for TBDMS-ethers. You can shake with copper sulfate then add Celite and filter through a pad of Celite, then separate. Also if you use chromatography lutidine will be removed I think.

Offline Babcock_Hall

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Re: copper sulfate washes, lutidine, and DCM
« Reply #3 on: October 02, 2021, 11:37:49 AM »
Thank you; your replies are always helpful.  Chromatography is the next step, but I was trying to get ride of as much stuff as I could before then.  We will try celite next time, but I think that some DCM will evaporate if we do it under vacuum.

Offline rolnor

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Re: copper sulfate washes, lutidine, and DCM
« Reply #4 on: October 04, 2021, 10:53:25 AM »
You will probably wash the Celite so there will be plenty DCM? Dont use full-vacuum when you filter, it just cloggs the filter.

Offline Babcock_Hall

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Re: copper sulfate washes, lutidine, and DCM
« Reply #5 on: October 12, 2021, 11:35:05 AM »
We attempted to purify by means of a silica column but did not observe the desired product in any fractions.  My tentative conclusion is that we broke the glycosidic bond somehow.  We are very puzzled. Could prolonged exposure to the copper sulfate solution have this effect?
EDT
We rechecked the calculations for the synthesis, and there was more TBDMSOTf than we intended to add.  This might or might not have been the problem.
« Last Edit: October 12, 2021, 01:29:13 PM by Babcock_Hall »

Offline rolnor

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Re: copper sulfate washes, lutidine, and DCM
« Reply #6 on: October 12, 2021, 02:40:37 PM »
You could have hydrolysis of excess tbdmsotf on the column or in the workup, this make triflic acid so hydrolysis can be quick. You can add a little MeOH+TEA before workup, this will quench the reagent and keep pH high.
Edit: It is actually possible to break/activate glycosidic bonds with tbdsotf so this can be a concern. This is used in nucleoside synthesis, I have made that myself several times. So excess tbdsotf is no good and it could be a problem even if no excess is used.
« Last Edit: October 12, 2021, 05:02:20 PM by rolnor »

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