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Offline leander

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HPLC monitoring of acid to anhydride conversion
« on: September 05, 2018, 04:35:04 PM »
Hello everyone,

I'm new here and this is my first post, also english is not my main language so sorry in advance if I make any mistakes.

So, the problem that I have is that I need to prepare a mixed anhydride from a carboxylic acid and methanesulfonyl chloride and triethylamine, as an activation method for the preparation of a certain amide. I've found in the available literature that, when carrying out this reaction, two other subproducts may be obtained: the symmetric anhydride and the acyl chloride.

Neither the starting carboxylic acid, nor the products can be analysed by gas chromatography since they rather decompose or are not volatile enough. So, we are trying to monitor the reaction by HPLC analysis, using a reverse phase column and a water:solvent mixture as the eluent.

The problem is that the mixed anhydride, the symmetric anhydride and the acyl chloride are readily hydrolyzed by the aqueous mobile phase, so some derivatization method must be found in order to differentiate the aforementioned compounds. The thing is that, for the symmetric anhydride, if you use a nucleophile as a derivatizing agent, such as an amine or alcohol, for each derivatized molecule you also get a caboxylic acid molecule as a subproduct. As a result, you never know if the acid that you are seeing comes from the derivatization or from an incomplete reaction, thus making this monitoring method useless for the needed purpose. The other obvious problem with nucleophilic derivitizing agents is that the mixed anhydride, the symmetric anhydride and the acyl chloride give all the same product.

Any ideas about how to differentiate this compounds in an HPLC analysis?

Thanks in advance!

Offline wildfyr

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Re: HPLC monitoring of acid to anhydride conversion
« Reply #1 on: September 05, 2018, 04:57:21 PM »
I'm going to chew on this for a few hours but wow, you've presented a tough problem!

NMR is not an option?

Also, might a fluoride source trap the acid fluoride (much more hydrolytically stable than acid chloride), while leaving the other two untouched, or at least separating one item of the three. Acid fluorides also have some unique further reactivity to take advantage of as compared to the anhydrides.

Offline TheUnassuming

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Re: HPLC monitoring of acid to anhydride conversion
« Reply #2 on: September 05, 2018, 08:42:09 PM »
The simplest solution is to watch the reaction using the nucleophile quench method you describe (I usually use methylamine).  Eventually, you should hit a plateau where you see X% amide and X% carboxylic acid, then add more reagent, see if that ratio changes, and assuming it doesn't change you can extrapolate amounts based on that.  This won't give you ratio of acid chloride to mixed anhydride, but if you are just using this to make amides than it shouldn't matter since they will both give you desired product.  As long as you are minimizing your symmetrical anhydride formation which effectively halves your yield, you should be good to go.

I would second the NMR suggestion if you really need to know ratios. 

You also might be able to use IR (if you can get separation of the bands and no cross-interference) to at least tell you qualitatively if one of the forms is present or not.
When in doubt, avoid the Stille coupling.

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