michalJenco
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Synthesis of diethyl diethylmalonate
Hi fellow chemists.
I am currently running a synthesis of diethyl diethylmalonate according to this procedure on a 1/4 scale.
However, after I added diethyl malonate to the ethanol solution of sodium ethoxide a huge amount of white precipitate formed in a few seconds. I
presume this is the sodium salt of diethyl malonate. After adding in the half of ethyl halide (I am using bromide instead of iodide) I started reflux,
but even after an hour the reflux temperature is still low (68 °C), which indicates to me that the bromoethane still hasn't reacted. I had to add a
lot more ethanol and break up the sodium salt to even enable stirring. Also the procedure specifies wayy too little ethanol to even react with sodium
and dissolve the resulting ethoxide, I had to use at least twice their amount.
Am I doing something wrong or is the procedure bogus? It doesn't even mention the white precipitate. It also doesn't say anything about the reaction
mixture temperatures at points of additions of reagents .. I added diethyl malonate to the reaction while it was around 70 °C, could that be an
issue?
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michalJenco
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After reading further I found a synthesis of diethyl butylmalonate where they specify to add the diethyl malonate to sodium ethoxide solution slowly
at 50 °C which should make a colorless solution. I added at once at 70, so I guess I blundered on that step :/.
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michalJenco
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Ok I repeated the experiment and added diethyl malonate to sodium ethoxide slowly at under 50°C and it still formed the white precipitate, albeit it
happened slower this time. The temperature, however, rose to 60 after 1/3 was added. What is happening here? This procedure talks about a colorless solution.
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Pumukli
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Water in the malonate?
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michalJenco
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I bought it just a few weeks ago and the label says >99%. But I guess I'll throw in some sieves and try again.
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michalJenco
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This synthesis is absolute nonsense, even after adding a few milliliters of dried ester to ethoxide at 37°C I get the white precipitate after a few
seconds. I know my ethanol is good enough for this because I've done a few Williamson ether syntheses with the same batch and I got up to 70% yield. I
am at a loss here.
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Pumukli
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Has bromoethane the required reactivity for this reaction? What if you added some dry KI as a catalyst? Have you checked the malonic ester synthesis
in general for clues?
If the precipitate is the expected sodium salt of the ester, (most probable), then the alkylating step is not going well.
[Edited on 6-6-2020 by Pumukli]
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michalJenco
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From what I've seen alkyl bromides are used. But even if not, I haven't even got to that step because of the precipitate forming immediately after
start of addition of diethyl malonate to NaOET in EtOH.
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Pumukli
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I may overlooked something, but have not seen written that there won't be any precipitate! The sodium salt is just that: a salt! Its solubility in
anhydrous ethanol is probably not too high. According to the recipe the final concentration of the salt should be around 20%, roughly, and I doubt it
won't precipitate...
This is exactly why I questioned whether you checked other, analogous synthesis descriptions, one may give you a hint or two.
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michalJenco
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I linked this procedure in a previous post where they talk about a colorless solution, that was my "proof" something is wrong with my synthesis. Usually
when reactants make insoluble salts that prevent stirring completely the procedure mentions that fact.
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michalJenco
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Btw your advice to add KI as a "catalyst" is exactly what I've been thinking about myself but couldn't find any mention of that procedure, so thanks
for confirming that thought!
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Pumukli
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I found an old article by Perkin, who prepared methyl-isopropyl-diethylmalonate by the reaction of isopropyl-bromide on Na-methyl-diethylmalonate. So
the bromides (at least the isopropyl) seems to be working.
The above reaction is reportedly very exothermic and requires only gentle warming otherwise a fountain through the reflux condenser results.
Here's the article:
XCV.—Some derivatives of propionic acid, of acrylic acid, and of glutaric acid
William Henry Perkin
J. Chem. Soc., Trans., 1896,69, 1457-1506
https://pubs.rsc.org/en/journals/journalissues/ct#!issueid=c...
sci-hub helps
This is another interesting article, it says something about the separation of a white, gelatinous mass (sodium salt of diethyl-malonate):
I.—The synthetical formation of closed carbon-chains. Part II. On some derivatives of tetramethylene
W. H. Perkin
J. Chem. Soc., Trans., 1887,51, 1-28
https://doi.org/10.1039/CT8875100001
[Edited on 6-6-2020 by Pumukli]
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Methyl.Magic
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Hi, this is completely normal. When you added the base it will form the Na-salt and this latter is not soluble in ethanol until it react with
bromoethane.
My tip # 1 ) Dissolve malonate and bromoethane in ethanol. Add the ethylate solution dropwise. Check whether the salt is NaBr.
My tip #2 ) It sounds shitty reaction. DO IT IN DMSO !!! Or any other polar aprotic solvent. DMF or acetonitrile should be better. But DMSO is non
toxic and fairly cheap
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Newton2.0
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So did anyone have success with the method given by Methyl Magic?
It would be interesting to what ended up becoming of this!
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Dr.Bob
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I have actually alkylated diethylmalonate before (with a complex alkylating agent, not ethyl bromide), you need to use good sodium ethoxide, and the
deprotonated diethylmalonate will precipitate (I got a pinkish thick slurry), but if you then add the alkylating agent, and then stir a few hours and
then start heating it, it will eventually react, although an excess of the alkylating agent is needed. Sometimes, you might then need to add even
more base while cooled and then add more alkylating agent. My yield was not great, but it worked.
If you get some monoethyl material and some diethyl, you can then react the monoethyl or the mixture with sodium hydride in THF and then add the
second alkylating agent. I was making a complex diacid ester, and while I got some, it took several tries to get the yield up. You might be able
to separate them all apart with a high vacuum distillation and fractionating the distillates.
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Newton2.0
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Excellent, thanks for the reply! I destroyed my first attempt due to inattentiveness.
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S.C. Wack
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BTW Professor Buzz also gives a recipe for this in Recreational Drugs, right above barbital.
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theAngryLittleBunny
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I did this reaction several times a while ago and I also always got a white precipitate when adding the diethyl malonate to the sodium butoxide (I
always used n-butanol as solvent). And alkyl bromides including ethyl bromide work well and it should be fully reacted after 2 to 3 hours of boiling
if I remember correctly.
I used n-butanol specifically because it has a higher boiling point, so maybe that's why it worked. In the synthesis procedure they used ethanol and
heated it in a metal container to I think 120°C.
[Edited on 5-11-2021 by theAngryLittleBunny]
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S.C. Wack
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Wouldn't butanol give some butyl ester by transesterification? Probably no big deal for diethylbarbituric acid, unless one wants ester purified by
distillation.
BTW the OP offsite link is not a quote from the book...apparently whoever is behind this is putting it in their own words now. The author states in
the foreward that not everything there is his, and specifically says this one is not, so it's no surprise he doesn't mention precipitate. Had the OP
quoted instead of leaving a link which no one read, it would have been obvious that the reaction was not performed correctly.
I'd think that directions for the monoethyl diester would also work for the diethyl if repeated (after removing solvent), keeping in mind that some
adjustment should be made, since it would have been optimized for producing as little diethyl diester as possible.
The reason why I brought up the original text is because of how it begins (not in the link): "The essential requirement in the preparation of
diethylmalonic ester and "veronal" is that all reagents must be absolutely anhydrous, otherwise the yields will be vanishingly small. All reagents and
solutions must therefore be protected from the moisture of the air after drying."
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theAngryLittleBunny
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Quote: Originally posted by S.C. Wack  | Wouldn't butanol give some butyl ester by transesterification? Probably no big deal for diethylbarbituric acid, unless one wants ester purified by
distillation.
BTW the OP offsite link is not a quote from the book...apparently whoever is behind this is putting it in their own words now. The author states in
the foreward that not everything there is his, and specifically says this one is not, so it's no surprise he doesn't mention precipitate. Had the OP
quoted instead of leaving a link which no one read, it would have been obvious that the reaction was not performed correctly.
I'd think that directions for the monoethyl diester would also work for the diethyl if repeated (after removing solvent), keeping in mind that some
adjustment should be made, since it would have been optimized for producing as little diethyl diester as possible.
The reason why I brought up the original text is because of how it begins (not in the link): "The essential requirement in the preparation of
diethylmalonic ester and "veronal" is that all reagents must be absolutely anhydrous, otherwise the yields will be vanishingly small. All reagents and
solutions must therefore be protected from the moisture of the air after drying." |
No, there is no transesterification, the alcohol you use doesn't matter, because the alkoxide immediately deprotonates the diethyl malonate and turns
back to the alcohol. Afterwards the deprotonated diethyl malonate salt reacts with the alkyl halide. I'm pretty sure the white precipitate you see
when adding the diethyl malonate is the sodium salt of the deprotonated diethyl malonate, the reaction mix also heats up quite a bit when adding the
diethyl malonate.
Also n-Butanol is super easy to dry, I just added anhydrous sodium sulfate and this seemed to dry it enough for the reaction to work. Another
advantage of n-Butanol is that it phase seperates from water. So after you reacted the dialkylmalonic ester with sodium butoxide and urea in n-butanol
you can just add water to extract to sodium salt of the barbiturate. You will have two clean layers, the upper one being n-butanol and the lower one
being the water layer with the barbiturate salt, sodium hydroxide and excess urea.
I usually extracted the water layer once with hexanes before acidifying it with HCl to get out any dissolved n-Butanol, because it might hinder the
barbiturate from solidifying. The weird thing is that when acidifying it the barbiturate would separate as an oil that floats on top. But that's no
reason to panic, it would usually solidify into a crystalline solid after putting it in the freezer for an hour, and after that the melting point
would be about right (it can easily be recrystallized from water), pretty weird. But maybe that's just because I was a bit sloppy in the synthesis. My
yields were usually around 50% with that methode for dipropyl-/ ethylpropyl-/ and ethylbutylbarbituric acid. I'm sure it could be increased with
better drying and protection from moisture, I just did it in a 1L beaker with some plastic foil and a flask with water on top of it.
After alkylating the diethyl malonate I would just continue with the crude ester since I didn't have a vacuum pump. Sometimes I didn't even isolate it
and just added more sodium butoxide plus urea after the alkylation which turned it into a one pot reaction. The sodium bromide/ iodide side product
from the alkylation doesn't interfere with anything at all. I hope that helps, and please be careful with barbiturates, they are no joke.
[Edited on 6-12-2021 by theAngryLittleBunny]
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S.C. Wack
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The alkoxide in this case being butoxide...you're seriously going to argue that alkoxides don't transesterify esters...
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theAngryLittleBunny
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| Quote: Originally posted by S.C. Wack |
The alkoxide in this case being butoxide...you're seriously going to argue that alkoxides don't transesterify esters... |
Oh you mean turning the diethyl malonate into ethyl butyl/ dibutylmalonate, right sure that could happen, and I actually never thought about this. But
it shouldn't be a problem since it doesn't matter when malonic ester you use, I think sometimes dimethyl malonate is used too.
Also it might not happen since the alkoxide immediately deprotonates the ester and therefore doesn't stay in the reaction mix, but any excess alkoxide
would do that. The deprotonated malonic ester might catalyze the reaction too.
[Edited on 7-12-2021 by theAngryLittleBunny]
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S.C. Wack
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BTW if anyone cares, the Organikum's non-specific directions give 85% yield they say of ethyl ethylmalonate (bp10 95C) or 75% yield of ethyl
diethylmalonate (bp12 100C, i.e. they are not particularly separable), from ethyl malonate and ethyl bromide.
General experimental details for the alkylation of ß-dicarbonyl compounds
Warning. Take care in working with sodium (see Reagent Appendix).
A solution of sodium alkoxide is prepared (cf. Reagent Appendix) in a 1-litre three-necked flask with stirrer, dropping funnel, reflux condenser, and
calcium chloride tube from 1 gram-atom of sodium and 500 ml of an absolute alcohol (which, in the case of an ester, unless transesterification
is required, should be identical with the alcohol of the ester). The stirred, hot alkoxide is treated dropwise first with 1 mole of the
ß-dicarbonyl compound and subsequently with 1.05 mole of the alkylating agent in such a way that the solution boils gently. Then it is heated with
stirring until there is a practically neutral reaction (2-16 hr). The bulk of the alcohol is distilled off in a low vacuum with stirring (the mixture
bumps violently because of the salt that has separated out). Since this alcohol is absolute, it can be re-used very satisfactorily for the same
preparation. After cooling just sufficient ice-water is added to dissolve the salt that has separated out, the organic phase is separated off in a
separating funnel, and the aqueous phase is extracted twice more with ether. The combined organic phases are dried over sodium sulphate, the solvent
is evaporated off, and the residue is fractionated through a 30-cm Vigreux column.
For dialkylation, the unsubstituted ß-dicarbonyl compound is placed in the flask with a good 2 moles of alkylating agent, and the sodium
alkoxide prepared separately (two molar proportions) is added with stirring and the exclusion of moisture. It is also possible to place an
already monoalkylated product in the flask together with a slight excess of alkylating agent and add 1 mole of sodium alkoxide (this method enables
unsymmetrically dialkylated ß-dicarbonyl compounds to be prepared).
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