Sauron
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Malonyl Chloride and Other Oddball Derivatives of Malonic Acid
In another thread I remarked in passing about this compound, which is the acyl dichloride of malonic acid and the one C homolog of oxalyl chloride.
Information about it is scarce. I was not sure it even existed. Well, it does.
My uncertainty was because I remembered that TCT fails to react with malonic acid, even though oxalic acid and succinic acid both gives good to
excellent yields of their acid chlorides with that reagent. I ventured the guess, quite mistakenly as it turns out, that SOCl2 would also fail (since
TCT usually works better) and that PCl5 would be required.
Both statements are flase.
SOCl2 seems to be the only reagent that chlorinates malonic acid to malonyl chloride.
PCl5 and malonic acid produce carbon suboxide and no malonyl chloride.
Aldrich sells malonyl chloride (largest packing 100 ml sealed ampule). Acros does not list it.
I found and obtained an old JACS paper on effects of thionyl chloride on carboxylic acids. This will finish off the raging controversy (in another
thread) about whether or not SOCl2 will produce oxalyl chloride from anhydrous oxalic acid. The answer is NO.
See attached.
Malonyl chloride per the JACS article bp 55 C/15 mm and 60% yield. It is said to turn dark red on standing. Perhaps this is why Aldrich packs it in
ampules. 100 g = c.67 ml.
From Aldrich:
Packaging 5, 25, 100 g in ampule
Properties
assay 97%
refractive index n20/D 1.465(lit.)
bp 53-55 °C/19 mmHg(lit.)
density 1.449 g/mL at 25 °C(lit.)
References
Beilstein Beil. 2,IV,1887
Fieser Fieser 12,291
reference Aldrich MSDS 1, 1156:A / Corp MSDS 1 (2), 2191 / FT-IR 2 (1), 1245:C
/ FT-IR 1 (1), 740:A / FT-NMR 1 (1), 1211:A / IR-Spectra (3), 430 / IR-Spectra
(2), 382:B / NMR-Reference 2 (1), 623:C / RegBook 1 (1), 867:F / Structure Index 1, 133:1
[Edited on 25-8-2008 by Sauron]
Attachment: JAmChemSoc1928p145.pdf (311kB)
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woelen
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Sauron, what reaction conditions do you suggest? Just drip some SOCl2 on malonic acid, or use a dilute solution in DCM? I also could dissolve the
malonic acid. Which is the best solvent for this?
I only can do this on a microscale in a test tube, because I only have 25 grams or so of malonic acid and don't want to use a lof of this for this
experiment (this stuff is expensive, and hard to obtain, I used it for oscillating reactions).
Btw. I cannot download the attached PDF, an error occurs, telling me that the document cannot be written to the cache. 
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DNA
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Working fine here the download...
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Sauron
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I get same sort of error message when left click any attachment on the forum, but downloads work fine when I right click and use Save Target As...
I do not get this error on other sites. So this is a forum sql or php quirk, one of many.
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Klute
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That article is a very good read (it read it directly at the ref forum).
I wondering of the possible uses of malonyl chloride.
It could be very usefull to form malonic esters with long alcohol chains if it was possible to mono-hydrolyse on of the ester functions after
alkylation and decarboxylate with affecting the remaing ester (react malonyl chloride with an alcohol, alkylate, mono-hydrolyse, decarboxylate: you
add 2 carbons and a long alcohol chain on a alkyl halide or other electrophile). Seems like a long shot though.
I don't suppose the acyl chloride can be dircetly alkylated, as the base required would react directly with the acyl chloride. I don't think any
alkylation will happen in neutral conditions?
The acyl chloride could be used to make malonyl amides, maybe mono-amination could be possible? that could lead to some cyclization.
Any more ideas?
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Sauron
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I'm still digging out literature.
Malonamide is commercial, as are the various half ester chlorides (ethyl malonyl chloride etc). There's a paper on preparing the half chloride of free
malonic acid and using it to make malonyl coenzyme A.
Another paper described prep of methylene di-isocyanate. Malonyl hydrazine is converted to malonyl azine (the acyl azide) by the Curtius method (with
references) and then carefully thermolyzed to the di-isocyanate. This was done under a contract from Office of Naval Research.
Malonyl chloride is related to diketene and also carbon suboxide.
Many papers relating to novel barbituric acids and related pyrimidine and pyrazine heterocycles involve malonyl chloride.
I've got a paper on the use of acid chlorides and acid dichlorides to cleave Si-N bonds forming amides under mild conditions and malonyl chloride was
one of three such reagents used.
Various alkylated malonyl chlorides such as dimethylmalonyl chloride and t-butylmalonyl chloride are described and employed.
So I guess finally I have a reason to make some SOCl2.
[Edited on 26-8-2008 by Sauron]
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woelen
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I now could read the document on another PC, just by clicking the link. I have the impression that the forum links do not work with certain
proxy-connections. The PC on which I am working now is connected to the Internet directly, the problematic PC is behind a proxy.
The article is very practical and interesting. I find it quite remarkable that the results are so erratic. I do not see a clear pattern in the
reaction of organic (poly)acids with thionyl chloride.
Also, the remark that SOCl2 is easier to handle than PCl5 surprised me. PCl5 is a solid, so isn't this easier to handle, or is there some property of
PCl5, which makes it extremely difficult to handle?
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Sauron
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It is risky to try to guess at the meaning of the author. Perhaps he was referring to the ease with which PCl5 hydrolyzes in air to POCl3. This would
mean wighing it out in a dry box and you'd still expose the box interior and scale to corrosive fumes.
Yes thionyl chloride is not the panacea people take it to be.
But then again - nothing is.
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woelen
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I did the experiment of adding thionylchloride to malonic acid. I took approximately 100 mg of malonic acid and added 0.5 ml of thionylchloride and
put this in a micro tube (small test tube, 6 mm diameter).
The malonic acid does not react in the cold, but when the liquid is heated (not so much that the thionyl chloride boils), then there is a slow
reaction. Small bubbles of gas are produced at the crystals of malonic acid and the acid slowly dissolves. But things are going really slowly. Even
after 30 minutes, certainly half of the amount of acid still was not dissolved.
The resulting liquid is colorless, no red color at all could be observed. After some time, the liquid still is colorless. It might be that the red
color appears after days, but I did not store the test tube with this liquid (I cannot stopper these thin tubes with my rubber stoppers and stoppering
tubes with thionyl chloride is a bad thing anyway, the stuff really eats rubber).
Based on this experiment, I think that indeed making malonyl dichloride is a possible option, even for moderately equipped home chemists, provided one
has decent quantities of malonic acid and thionyl chloride.
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Sauron
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There's plenty of literature on malonyl chloride, malonyl monochloride, methyl and ethyl malonyl chlorides (half esters), various alkylated malonyl
chlorides, Malonyl chloride itself is commercially available.
SOCl2 is the only chlorinating reagent that will convert malonic acid this way. PCl5 makes malonic acid into the very interesting gas carbon suboxide
C=C=C=C=O which is related to diketene.
AND TCT does not react with malonic acid (go figure.)
I am also puzzled about the red color (what is it?) but they did not define the time needed to effect this. For all we know this could have resulted
from P or S contamination in the SOCl2, common in those days.
The chemical uses of malonyl chloride appear to be mostly barbiturates, pyrimidines, pyrazoles (heterocycles with a N-C-N structure); carbon suboxide
and duketene chemistry; malonyl coenzyme A biochemistry; and alpha-lactams. So it is interesting but not as versatile as oxalyl chloride.
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not_important
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If any carbon suboxide was formed during standing it can polymerise to yellow/orange/red/black substances. The red through black products are pretty
strongly coloured, not much would be needed to tint the main material.
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Sauron
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Thank, that is certainly plausible.
Now that Wiley's orgsyn.org server has gotten over its hiccups, I found two procedures there involving malonyl chloride.
One for ethyl t-butyl malonate and the other for di-t-butyl malonate. The latter includes prep of malonyl chloride from malonic acid and SOCl2.
Woelen, be happy with your succesful prep. Theirs takes THREE DAYS to dissolve finely powdered malonic acid in SOCl2, with heating. During that time
the mixture turns deep reddish-brown, However after workup and fractionation, product is pale yellow. Yield is same as in the JACS article, which
advised only a few hours for reaction.
Malonyl chloride also is formed from carbon suboxide and dry HCl. HCl is certainly evolved in this reaction and conditions are anhydrous.
Org Syn papers, combined into a single pdf, attached below.
[Edited on 27-8-2008 by Sauron]
Attachment: CV4P0261.pdf (310kB)
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Klute
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Thanks for those, Sauron.
It's a pity they don'tdescrib the preparation of ethyl malonyl chloride. Maybe it could be possible to prepare it from the alkylated mono-ethyl acid
and SOCL2? This could be a good way of introducing an acyl group with two more carbons, forming an amide for example, and decarboxylating the ester
off..
CH2-(COOEt)2 --RX/RONa--> RCH-(COOEt)2 --KOH--> KOOC-CHR-COOEt --HCl--> HOOC-CHR-COOEt --SOCl2--> ClOC-CHR-COOEt --RR'N/Et3N-->
RR'NCO-CHR-COOEt --KOH/HCl -CO2 --> RR'N-CO-CH2-R
I don't know if the amide could survive decarboxylation conditions from a practical point of view though, but you get the idea.
I guess you could just aswell perform the conventional malonic synthesis with diethyl malonate, and react the obtained acid with SOCl2 then with the
amine :S
Sauron, I take it the alkylated malonyl chlorides described in the litt where formed only by reacting the alkylated acids with SOCL2? Or is it
possible to alkylate malonyl chloride without affecting the acyl chlorides?
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Sauron
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The answers are in the lit. and I need to obtain some more full texts, all I have now are first pages.
The t-butyl ethyl malonate is clealrly just an assymetrical malonic ester, not alkylated, same for di-t-butyl malonate.
The article cited for ethyl malonyl chloride will have the prep of same and I am sure it is as you say, from monoethyl malonic acid and SOCl2. It is
also commercially available.
The citation is:
A New Synthesis of β-Keto Esters of the Type RCOCH2COOC2H5
Jacs 66 1286-1288 (1947)
I have requested it.
I have a reference to dimethyl malonyl chloride that sounds like it is actually alkylated.
I do not have a clear idea yet of the precise synthetic utility of all these derivatives, but I can tell you the point of the assym. t-butyl malonic
esters is to be acylated, then the t-butyl eliminated as isobutylene (isobutene) using a catalytic amount of p-TsOH since t-butyl esters are very acid
sensitive. This is a very facile route to beta-keto esters otherwise difficult to prepare. The ethyl t-butyl malonate is prepared from ethyl malonyl
chloride and SOCl2 in presence of a tertiary amine, the resulting ethyl t-butyl malonic ester is reacted with magnesium ethoxide then acylated with an
acyl chloride. The acylated ethyl t-butyl malonic ester is then treated with cat.p-TsOH and isobutylene evolves on warming. I will post the paper when
received.
[Edited on 27-8-2008 by Sauron]
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tapira1
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MalCl2
Preferred method for the synthesis of malonyl chloride
In a 250-ml. Erlenmeyer flask fitted by a ground-glass joint to a reflux condenser capped with a calcium chloride drying tube are placed 52 g. (0.5
mole) of finely powered, dry malonic acid and 120 ml. (about 1.65 mole) of thionyl chloride. The flask is warmed for 3 days in a heating bath kept at
45–50°C. During this period the mixture, which is agitated occasionally by gentle swirling, gradually darkens to a deep brownish red or sometimes a
blue color. Finally the mixture is heated at 60° for 5–6 hours. After cooling, it is transferred to a 125-ml modified Claisen flask and distilled
at reduced pressure (water aspirator). A calcium chloride guard tube is inserted between the vacuum line and the apparatus, and the flask is heated
with a bath rather than a free flame. After a small fore-run of thionyl chloride, the malonyl chloride distils at 58–60°/28 mm. The pale yellow
product amounts to 50.5–60 g. (72–85% yield).
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Sauron
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Thanks. that is verbatim as recited in one of the Org.Syn.monographs posted above.
The JACS article on use of t-butyl alonyl esters to prepare beta-keto esters is attached. It details the conversion of diethyl malonate to the
potassium salt od ethyl hydrogen malonate, then the free acid, and finally ethyl malonyl chloride by use of our old friend phthaloyl chloride, rather
than the expected SOCl2.
The question is, can phthaloyl chloride be used to prepare malonyl (di)chloride? The old lit.suggests that thionyl chloride was the "only" reagent
capable of thi, since PCl5 gives only carbon suboxide. Also, SOCl2 is cheaper than phthaloyl chloride, where it is available at all. So could SOCl2
have effected the chlorination of this half ester? One would expect so.
I cannot buy SOCl2, and am not yet ready to prepare it. I can buy phthaloyl chloride, and have some on hand.
Those of us who can't purchase phthaloyl chloride, do not despair. It is made by reacting phthalic anhydride and benzotrichloride with a small amount
of anhydrous ZnCl2 -- see Kyrides cited in this paper, and posted previously by me.
The author of the present paper explains that phthaloyl chloride turned out to be superior to the action of thionyl chloride on either ethyl hydrogen
malonate or the dotassium salt. He cited an unavailable paper from Bull.Soc.Chim. and a readily available one from Ber. for the SOCl2 procedures. The
question of phthaloyl chloride on malonic acid per se remains open.
For discussion of the application of the t-butyl ester prepared from ethyl malonyl chloride, see the text. It does look like a useful extension of the
malonic ester synthesis.
[Edited on 28-8-2008 by Sauron]
Attachment: ja01236a022.pdf (416kB)
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Klute
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That article is a very good read.
I'm thinking the t-Bu half chloride could be used to prepare b-ketoamides: react the half chloride with amine (should be quantitiative and clean),
alkylate the methylene, decarboxylate with cat. TsOH, wihtout affecting the amide.
Now that several steps, and the ttoal yield might not be worth the effort compared to direct aminolysis of the b-ketoesters, even though it's a pretty
dirty reaction with lots of impurirties (stable chelated enamines, thermal decompositions, etc)
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