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Author: Subject: Methyl ester formation by methylation
aonomus
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[*] posted on 19-2-2011 at 22:47
Methyl ester formation by methylation


So this problem has been nagging me since yesterday when I set up a reaction late in the day before heading home from work.

I'm methylating a carboxylic acid to form the methyl ester, the starting material is somewhat sensitive to nucleophillic aromatic substitution but only under forcing conditions (6N HCl, 80-85degC or higher).

The carboxylic acid was dissolved in THF, 1eq of DBU was charged with slight exotherm, then 8 eq of MeI was charged slowly (yes, a tad overkill). Temperature was adjusted to 30-35degC. After approximately 10-15 minutes white solid began to form (most likely the DBUH+ I- salt) (at this point by HPLC, purity was estimated 60%), with the suspension becoming thicker and more opaque over time. After about an hour the reaction was perhaps 80% complete and I left for the long weekend.

So the problem racking my brain is that this *should* have been a fairly fast reaction, the proton transfer is fast, and the methylation of the carboxylate should be relatively fast as well. At this point I'm suspecting that perhaps my THF wasn't absolutely anhydrous and perhaps I should have charged in a bit more than 1eq of base. Thoughts from the audience?
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DJF90
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[*] posted on 20-2-2011 at 02:50


I'm not entirely sure what your question/problem is? Are you saying that you'd expect the reaction to be complete in a shorter time than observed? Carboxylates aren't such great nucleopiles, but there are a couple of tricks you could have taken advantage of; the use of the silver carboxylate, which works because the silver cation is halophilic, or, given that this is "at work", perhaps it would be possible for you to use diazomethane to form the methyl ester? It would save any worries about SnAr, and should be quick and high yielding.
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aonomus
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[*] posted on 20-2-2011 at 05:20


There is a policy against using diazomethane at my workplace. We do scale up and process chemistry.... you could imagine what happens when diazomethane gets used at scale!

My question is a bit open ended, I was expecting it to proceed a bit quicker, and perhaps I'm just being overly worried (long weekend, task still on the table and in my mind).

With the silver carboxylate, could I charge in a small amount of aqueous AgNO3 after the reaction has been started to try to abstract any iodide and force the reaction forward? By Tuesday all the MeI will probably be gone considering its vapor pressure...
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Ozone
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[*] posted on 20-2-2011 at 06:04


Methanolic HCl works pretty well. If you can't saturate your methanol with dry HCl gas, you can mix excess acetyl chloride into it. The result is dry methanolic HCl with an equivalent amount of methyl acetate (which does not appear to interfere with the methylation).

I use the latter method for identification/quantification of FAME's isolated from various plants/algae via GC.

Cheers,

O3




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DJF90
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[*] posted on 20-2-2011 at 08:02


Yes I understand, but for making a small amount of product for characterisation it would be ideal. A quick question - is your acid aliphatic (despite the aromatic ring in your substrate)?
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smuv
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[*] posted on 20-2-2011 at 09:42


If you are after the quickest reaction rates, THF is good but not the best solvent to choose, look towards DMF, DMSO or acetonitrile. Given the fact that you have not given what your substrate is, it is hard to say more, but 80% after an hour is pretty damn good IMO especially considering the (aforementioned) low nucleophilicity of carboxylates.
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aonomus
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[*] posted on 20-2-2011 at 14:52


@DJF90: Without getting into the proprietary specifics, the acid is sticking off of a heterocycle next to the aromatic.

@smurv: Good thought on the reaction solvent, though the particular starting material is particularly insoluble in DMF and ACN. I would need about 300 parts ACN wrt. starting material to get it all into solution, and with that dilution the kinetics might be even slower. I thought that THF would be the best solvent due to solubility of both starting material and product with insolubility of the DBU salt. This is on the gram scale too, so 3 litres of ACN is a bit infeasible when something like 250-300mL of THF can do the job.

My hope is that by Tuesday morning the reaction is done and I can work it up, otherwise I'm making more starting material. I had run this on the 100mg scale previously and it worked fine, though I did have it at a higher temperature (40-45degC) with a lower concern for exotherm on base addition. Perhaps it needs to be warmer to go that fast.

Anyway, the point of this thread was just to sanity check my stuff, I still have 1 more day off so I should relax! Thanks for all the input guys.
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[*] posted on 21-2-2011 at 07:16


If tomorrow you find the HPLC conversion is still the same you can try adding some more DBU. Contrary to popular believe, DBU is somewhat nucleophilic and can be alkylated. Though in this case it is quite protected having been protonated by the acid, so I do not fully believe methylation of DBU is to blame, but it might be worth trying. If the reaction is only slow and is not really stalled, then just heat it, after all you said it worked on a smaller scale.
If you are doing this for a process development, then I suggest you to try dimethyl sulfate with K2CO3 in acetone. Esterifications with ortoformates are also performed in not very acidic conditions (1 mol% TsOH is usually enough), but require heating.




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aonomus
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[*] posted on 21-2-2011 at 09:10


@Nicodem Most of what I do is for process development, but this is just sample prep for a QC standard for purity and assay (lord forbid I try and use lots and lots of THF on scale and work in a distillation-solvent exchange!). I didn't know that DBU could be alkylated, that is a bit surprising and hopefully it doesn't result in an impurity (or at least one that can't be removed by workup).
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aonomus
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[*] posted on 22-2-2011 at 14:48


I'd edit my previous post but the forum won't let me.

The reaction was stalled at about 85%, I suspect either the DBU was quenched by residual water, or that it was getting old and expired. Charged in 0.1eq DBU and 0.5eq MeI, went to completion, worked it up. 95% purity without really trying too hard.
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