Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on March 25, 2017, 04:27:30 PM
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We are trying to make a diester of dibromosuccinic acid from the free acid. We would prefer to make something that will deprotect easily in the presence of a vinyl sulfone, but at this point I would settle for just about any ester. The two problems we envision are low solubility in some common organic solvents and the possible replacement of bromine by a nucleophile. When we tried DCC/catalytic DMAP coupling in acetonitrile, the crude yield was very low, possibly because the acid did not want to go into solution. When we tried DCC/catalytic DMAP in DMF, I was unable to interpret the NMR. So far our literature searching has not been very successful, but we did turn up a protocol of an acid-catalyzed esterification of a di-acid that used cation-exchange resin as the catalyst, which I thought was promising.
If we try acid-catalyzed esterification, the only way that I can think to avoid a substitution entirely is to use HBr (not HCl) as the catalyst. However, cation-exchange resin and para-toluenesulfonic acid are not very nucleophilic to the best of my knowledge. If we try DCC-promoted coupling again, it occurred to me that we could try dissolving the acid in an excess of the alcohol that we wish to use, then add DCC and catalytic DMAP. Once the reaction is done, we could add ether or DCM to precipitate out the dicyclohexylurea. Does anyone have any advice for us?
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Have you tried the standard way to dissolve the acid in large eccess alcohol an add some sulphuric acid?
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You should also try DMSO for DDC/DMAP too. And have you heated up any of these reactions? You can easily push DMF/DMSO all the way up to 120C. Refluxing AcCN is worth trying too. You might have to try with more exotic solvents like diphenyl ether, anisole, or HMPA(heaven forbid). Getting DCU out of a reaction is a total pain though, so may I suggest trying the acid catalyzed route?
You can run acid catalyzed esterification best with catalytic sulfuric acid, not HBr. Sulfate is a terrible nucleophile and won't attack. This reaction might even work heterogenously in pure methanol/ethanol/t-butanol whatever you want. You will need to drive water out of the reaction. The simplest way to do this I've seen is to reflux the reaction and put an addition funnel with molecular sieves above it, and a condenser above that.
Make sure your solvents and reagents are rigorously dry. I once again bring up sieves and their efficacy at drying virtually all solvents (including alcohols!) by citing this great paper https://pdfs.semanticscholar.org/ec7d/d3c01b54535f93d48187980c11e0f789f47f.pdf
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great minds think alike Rolnor, you posted while I was typing :)
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Thank you; those all sound like reasonable suggestions. We have not tried acid-catalyzed reactions yet. Do you see any advantage in Dowex 50 as the acid catalyst over sulfuric? The only potential one I see is that Dowex resin is easy to remove. My only reservation about molecular sieves concerns how to activate them. I am not sure that I have an oven that goes to 300 °C, but I will look into it.
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I have often had perfectly good success using sieves baked in our normal glassware oven at 80°C for a week or so. I just put a bunch in at a time and use as needed. Get as hot as you reasonably can for a few days, they don't need to be 100% activated. You could even put some in a rbf in an oil bath at 100°C+ with a good vacuum pump on overnight and that would likely work fine.
Well the advantage of sulfuric over Dowex is your solubility problem. If dibromosuccinic acid isnt soluble in the alcohol, then this is a heterogenous reaction, and you aren't gonna get your suspended powder to interact much with the Dowex. I personally consider the drop or so of sulfuric acid you use to catalyze the reaction pretty easy to remove (bicarb wash).
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Also, did you check scifinder? someone else must have esterified this thing before
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I am also thinking maby you can make the acid bromide with oxalylbromide?
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PBr3 will work in that pathway if you dont have oxalyl bromide. Either way just quench the reaction with the alcohol of the desired ester
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Also, did you check scifinder? someone else must have esterified this thing before
IIRC we found one procedure in a patent that suggested that the esterification could proceed at room temperature. I will double-check on this, but I am somewhat skeptical.
I had forgotten the oil-bath idea for activating sieves...
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We rechecked SciFinger and found a reference from the patent literature. It describes what appears to be the formation of the dimethylester of dibromosuccinicate with catalytic sulfuric acid in water as the solvent. The conditions are room temperature and two hours. This does not sound reasonable to me. Given these conditions, I have to wonder whether or not this was meant as a hydrolysis step of the diester to the free acid, although why one would want to do that is open to question.
Reference
Process for the preparation of dimethyl acetylenedicarboxylate, By Chen, Xueping, From Faming Zhuanli Shenqing, 103664600, 26 Mar 2014
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Do you need to start with the dibromo compound? Could you instead form the diester of fumaric acid then brominate it? I'm sure you could hit it pretty hard then, using Fischer esterification conditions without worrying about any possible elimination reactions etc.
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We had the dibromo free acid on hand already, and I was trying to cut down on the number of steps (this is an undergraduate independent study project). However, we had thought a little about esters derived from fumaric and maleic acids. These esters could be dibrominated, or there are other routes to the vinyl sulfone (though less attractive ones at first glance) that do not proceed via dibromosuccinate esters. Di-tert-butylfumarate is beyond our price point, but diethylfumarate is not.
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Dissolving fumaric acid in dry tert-butanol with sulfuric acid catalyst doesn't seem like such a bad step. Probably just cook it overnight, bicarb wash, then a dead easy distillation (tert-butanol BP=82°C). I can't believe Oakwood is selling it for $1800/5gram! If it doesn't want to esterify easily then you could use the acid chloride pathway of fumaric acid+SOCl2 then quench that with tert-butanol. Distill off tert-butyl chloride and tertbutanol and wash with water.
After that its just stirring with bromine and voila your final product! This really might be easier than fighting the solubility battle of that other compound.
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Just a quick and incomplete update. One attempt to make di-tert-butyl-dibromosuccinic acid seems to have failed. We tried 1.6 moles of DMAP per mole of di-acid (having seen a couple of protocols which suggested near stoichiometric amounts). It is unclear what happened to the starting acid. It might have eliminated in some way (when attempting to make a vinylsulfone from this compound, we saw evidence of a decarboxylation).
We tried to prepare the dimethylester of fumaric acid using acid-catalyzed conditions. This reaction went with low yield, but I will take what I can get. My student found an old thesis in which there are conditions for adding bromine to the ester, which is what Clark suggested IIUC.
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Thanks for the update. Not to be a hater, but I'll be a shiny nickel that your student had something a little wet in there or the evolved water wasn't being removed well, but the materials are cheap so if you need a bunch the scale up is no sweat even at low yield. Don't forget to do the bromination workup cold or the whole reaction with NBS, or that hard earned ester will hydrolyze from the HBr.
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We found a paper by Neises and Steglich that converted 0.20 moles of monoethyl fumarate into the corresponding tert-butylester. The reference is Organic Synthesis 1985 63, p. 183 DOI:10.15227/orgsyn.063.0183. The question I have concerns the amount and mass of DMAP (MW 122.17), which is given as 2.00 grams, 0.16 moles. There is a tenfold discrepancy: either it should be 20 grams or it should be 0.016 moles. It occurs to me that a tert-butylester might require a high mole ratio of DMAP to monoethyl fumarate because of an undesirable side reaction (the isomerization of the acylurea). If the value of 0.16 moles is correct, then the ratio of DMAP to acid is 0.80. I have seen one protocol for the production of tert-butyl aminoacid esters that used 0.50 equivalents of DMAP. Does anyone have an opinion as to what the authors intended?
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I think the grams is correct. DMAP is typically catalytic in this reaction and it called for 0.22 mols of DCC. On the other hand, I have trouble thinking of a way in which excess DMAP will screw things up. Perhaps this reaction could be run both ways in an NMR tube to get an idea? No aqueous workup needed. The conversion should be trackable by loss of the C=C-H next to the carboxylic acid and conversion to ester by 1H.
I looked at OrgSyns site a bit and they are extremely fastidious about this sort of thing, perhaps an email to them might help clear this up if they have some other documentation associated with the reaction. The way Orgsyn works is that a reaction is submitted to them, then repeated in an editor's lab, so there might be some extra stuff they can refer to.
No luck on improving the Fischer esterification route? I've just always had such terrible luck with Steglich, and getting DCU out of this kind of moderately polar molecule one of my personal nightmares. Even the excellent suggestion of recrystallization in MeCN doesn't always work.
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Madhup K. Dhaon, Richard K. Olsen,* and K. Ramasamy J. Org. Chem. 1982, 47, 1962-1965 report using 0.5 equivalents of DMAP in making the tert-buytesters of amino acids. BTW they discuss the issue of racemization, but that is not presently an issue for us.
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Dimethylfumarate is comersially available?
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Yes, it is, thank you. I had seen diethyl fumarate, but I missed dimethyl fumarate.
My student found the Ph.D. thesis of Victor Francis Hoffman from the University of Iowa in 1981 that gives information on the addition of bromine to fumaric esters, acid, and salts. He provides stereochemical information for a variety of reaction conditions. We are just starting to look this over for useful information.
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My student determined that a solid that was thought to be waste produced in one reaction was actually the dimethylester of dibromosuccinic acid. We plan to add sodium phenulsulfinate to this to make the sulfone. That just leaves deprotection. I found one procedure in which TMSBr was used to deprotect a methyl ester. We will explore other ideas as we go forward.
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Oy. Which version of the reaction was producing good product that was being thrown away?
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It was a Fischer-type esterification with sulfuric acid as the catalyst. Nothing had been thrown away, to the best of my knowledge. However, the solid was not initially analyzed, and the supposition was that it was solid sodium sulfate generated in the workup of the reaction. IIRC the procedure calls for the addition of a solution of sodium carbonate.
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haha yeah, always analyze everything I guess (learned the hard way).
I wonder though, how much of H2SO4 did you use and what was the scale ? Seems odd to confuse sodium sulfate and product. Just the amount of solid should say something aboout it (how much of H2SO4 would you need to get reasonable amounts of sulfate?
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There were 0.22 mL sulfuric acid and 3 grams of starting material, which was the di-acid. Undergraduate students need a certain number of experience in a lab before they get to the point of realizing when an explanation is untenable IMO.
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Babcock, you must have the patience of a saint. It was hard enough for me to teach 1st year grad students who had a lot more time and skin in the game. So many little points of technique to correct, let alone the analysis side which becomes second nature after a few years.