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Author: Subject: Synthesis of malonic acid
andyloris
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[*] posted on 25-10-2022 at 06:09


Then could this work with aspartic acid ?
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[*] posted on 25-10-2022 at 10:28


Since acrolein preparation is no joke and yields are not great in laboratory scale procedures as much tar is produced too, is making malonic acid via acrolein (which I assume you are looking at because it can be prepared from easily available glycerine and sodium bisulphate) really an amateur friendly route?

As andyloris points out there are several well explored routes from aspartic acid and also through beta-alanine. Both of which are cheap and degraded through well studied wet chemistry.

Also what's wrong with the route through 1,3-propandiol as this compound is now easily available online through hobbyist cosmetic ingredient suppliers, particularly in the US but they posted it to me in the UK without problem.
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[*] posted on 25-10-2022 at 10:46


What is the route from beta-alanine ?
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[*] posted on 25-10-2022 at 11:05


Perhaps you could try using a search engine instead of asking so many one-lined questions in rapid succession.



Come check out the Official Sciencemadness Wiki
They're not really active right now, but here's my YouTube channel and my blog.
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andyloris
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[*] posted on 25-10-2022 at 11:30


I searched on google but I only could find a source saying
Quote:

beta-Alanine can undergo a transamination reaction with pyruvate to form malonate-semialdehyde and L-alanine. The malonate semialdehyde can then be converted into malonate

However I thought a transamination reaction was the swaping of a ketone of a keto acid and the amine of an alpha-amino acid to form a new amino acid and a new keto acid. However beta-alanine is a beta amino acid, and this didn't make sense.

[Edited on 25-10-2022 by andyloris]
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[*] posted on 25-10-2022 at 12:07


Hi andyloris, give me a few days and I will track down the various references but I seem to recall that hypochlorite ions or their proxies such as the chlorimines like TCCA and NaDCCA convert b-alanine to hemialdehydo-malonate ion. I have several papers at home on these lines.
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[*] posted on 26-10-2022 at 02:29


Quote: Originally posted by andyloris  
Just got a random idea while looking at the strecker degradation wikipedia page:
Could serine undergo strecker degradation to form 3-hydroxypropanal and then be oxidised to malonic acid ?


I looked at this and I thought the number of carbons was right too :P
So easy to miscount.


Quote:

Since acrolein preparation is no joke and yields are not great in laboratory scale procedures as much tar is produced too, is making malonic acid via acrolein (which I assume you are looking at because it can be prepared from easily available glycerine and sodium bisulphate) really an amateur friendly route? As andyloris points out there are several well explored routes from aspartic acid and also through beta-alanine. Both of which are cheap and degraded through well studied wet chemistry. Also what's wrong with the route through 1,3-propandiol as this compound is now easily available online through hobbyist cosmetic ingredient suppliers, particularly in the US but they posted it to me in the UK without problem.


Yes, my primary motivation was based on the easy synthesis of acrolein from glycerol.
That's interesting, I wasn't aware of these routes, are they theoretical or are they suspected to work?

Indeed, there isn't anything particularly pleasant about acrolein, but, having read all of the threads I could find here regarding malonic acid, I couldn't see any practical routes avoiding cyanide; Even the oxidation of malic acid seems to be fruitless.

I would be much happier handling cyanides than acrolein, that's for sure, but cyanides are not easy to come by, and if I were to acquire some, I doubt I'd waste them on the synthesis of malonic acid, as you say, 1,3-propanediol is probably the most feasible route.

There has been much talk about the synthesis of cyanides using chloroform and ammonia, but very few positive results, so it seems quite unlikely to be successful.

I shall await your references! :)
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[*] posted on 26-10-2022 at 04:48


The route from aspartic acid is a random idea I got, but I see no reason why it wouldn't work.
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[*] posted on 26-10-2022 at 13:59




..... that is why some time ago I decided to order malonic acid directly from a manufacturer (PRC). Unfortunately, shipping costs almost doubled total price, giving ~40 $ per 1 kg of malonic acid in the end.
Earlier I made this acid by standard method (chloroacetic + cyanide), but without ether continuous extraction apparatus, preparing the free acid is highly problematic. Besides, using K/Na cyanide for this purpose is a waste. There are many better ways to utilize the cyanide ;)
Currently, malonic acid is cheaply (let us say ...) prepared in industry by fermentation methods.




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[*] posted on 28-10-2022 at 10:58


While I agree that malonic acid is one of those simple organic building blocks that is best bought I can't help but feel that the challenge has a certain attraction for masochists :).

So a few days ago I decided to try a route from beta alanine. First I tried just dissolving 10g of beta alanine in a molar equivalent fairly strong sodium nitrite solution (7.75g in 50ml of water) and then gently warmed it. When the temperature reached about 60-70 C a slow evolution of nitrogen began but it was very slow so I added a molar equivalence of 50% nitric acid fairly quickly. The rate was chosen so that the gas remained colourless (hopefully therefore nitrogen), too rapid an addition caused the gas to become brown. The temperature rose to about 90 C and the evolution of gas was vigorous. When the reaction subsided I evaporated the solution down to about 20-25ml on a steam bath and let it cool. About 6g of sodium nitrate rhombs crystallised out, they were filtered off but weighed damp. The filtrate was warmed to about 70 C and the 40ml of 50% nitric acid added dropwise. It took quite a while before any reaction started but when it did the mixture boiled steadily throughout the addition, much brown NO2 evolved. When the reaction subsided it was cooled in an open bowl to allow further evaporation. The pale orange yellow liquid was chilled overnight but no crystals formed so it was neutralised with 50% NaOH solution, still no crystals formed so the solution was evaporated from about 40ml to 20ml; copious colourless crystals appeared as evaporation occurred. When no further evaporation appeared to occur the slurry was cooled and then filtered, The cake comprising almost colourless crystals weighed 6.47g is yet to be investigated and a viscous orange-brown solution which is currently being evaporated further on a hotplate.

The reaction of nitrous acid with beta-alanine yield 3-hydroxypropanoic acid and nitrogen but without a mineral acid it is very slow. The former dehydrates easily to acrylic acid but I am not sure how easily this occurs in aqueous solution or how important this is given that the intermediate product wasn't isolated but th reaction temperature at times reached boiling point. However, the viscosity of the final filtrate suggest that some polymerised acrylate like material is present. My work-up plan is to treat the latter crystals with a little nitric acid, evaporate to dryness on the steam bath and leach out any malonic acid with alcohol. Watch this space.

I may try this reaction again using beta alanine and 50% nitric acid with just a catalytic amount of sodium nitrite to generate the initial nitrous acid. I am also going to try Magpie's 1,3-propanediol method now I have the diol.

[Edited on 28-10-2022 by Boffis]
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[*] posted on 31-10-2022 at 12:18


Well the proposed nitric acid oxidation of beta alanine with a trace of nitrite to act as catalyst seems to work nicely, although I haven't characterised the product yet. I tried various methods but the best seems to be to moisten 10g of beta-alanine with a few ml of water and warm it on a steam bath in a ceramic bowl. When it is hot to the touch, c 70 C, remove from the heat and add 11-12ml of conc. nitric acid slowly, drop by drop at such a rate that the frothing is manageable and only the slightest brown NO2 is generated and the temperature runs at around 90 C. Have a bowl of cold water available to cool the reaction if it gets too frisky. When the addition of nitric acid no longer provokes vigorous effervescence the reaction is done. Return to the bowl to the steam bath and steam for a couple of hour to drive of most of the remaining water to leave a viscous yellow liquid which solidifies completely on cooling.

I am currently researching the recrystallisation of malonic acid; has anyone got any experience of recrystallisation solvents for this acid. I have checked out "Purification of laboratory chemicals" but they recommend water, acetone or a complex mixture of benzene etc.? Water would be nice but the solubility is so high a lot will be left in the filtrate. Anyone got experience of acetone?
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[*] posted on 1-11-2022 at 22:34


Quote: Originally posted by Boffis  

I am currently researching the recrystallisation of malonic acid; has anyone got any experience of recrystallisation solvents for this acid.


I do not have such experience, but there are many papers giving solubility of malonic acid in many solvents and their binary mixtures (THF, IPA, ethanol, EtAc, dioxan, MeCN, acetone... etc)
For example here:
https://doi.org/10.1002/ceat.201700227




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[*] posted on 3-11-2022 at 11:08


I could not resist and tried to make malonic acid via the nitric acid oxidation of malic acid.
Well, it was a failure as far as I can tell.

No oxidation took place, at least nothing obvious (no NOx development), though I tried to "boost" the process with a few milligrams of NaNO2 too. :)
The acid was not concentrated, only around 50-55%, but the temperature was above 70 Celsius.




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[*] posted on 5-11-2022 at 14:25


Quote: Originally posted by Boffis  
Well the proposed nitric acid oxidation of beta alanine ....

I made some literature research, no procedure I found describes formation of uniform product in case of oxidation of aminoacids.
Becuse strong acid is used, the first step is formation of ammonium salt, formation of some diazo compound in this case is highly doubtful and if even, it does not explain further reactions.
Besides, oxidation of some organic compounds by HNO3 gives N2O as product of nitrogen reduction - it may be mistaken with N2.
As I said earlier, formation of complex mixture of products, even if more malonic acid is formed, makes further work up cumbersome.
And the more HNO3 is used in higher temperatures, the more (COOH)2 is always formed.




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[*] posted on 8-11-2022 at 14:56


@ kmno4; Well I have something to report but I am not quite sure what!!

I ran a 20g batch of beta-alanine and obtained a workable amount of beautiful colourless crystals up to 30mm long. It melts without decomposition if heated carefully to a clear liquid and then as the temperature climb gives of gas an decomposes. I heated quickly on foil it melts then suddenly puffs away. I have set up a melting point jig so I'll run a more accurate test tomorrow but the Mp appears to be <90 C. (beta alanine 207, Malonic acid 135)

My original idea was that the presence of nitrous acid or a proxy would replace the amine group with a hydroxy group producing 3-hydroxypropanoic acid would could them be oxidized by the nitric acid. The production of reduced nitrogen oxides as the oxidation proceeds would convert more beta alanine to the hydroxy acid and so the reaction should be self-sustaining until the amino acid is used up. However, the product does not appear to be malonic acid.

In my searches I came across a couple of interesting examples of nitric acid oxidation of simple esters (eg ethyl acetoacetate) to produce furazan or furazan-2-N-oxide derivatives. These compounds often have fairly low Mps and are often energetic.

Other possibilities are things like tartronic acid (hydroxymalonic acid Mp 157) but the Mp is too low.

By the way if you try these experiments don't try recovering the wash acetone from the recrystallisation. When the acetone is distilled it results in a violent decomposition rather suddenly in spite of the fact that free nitric acid has been almost totally removed. The impurity in this reaction is a water soluble yellow oil that deflagrates quite readily!!

The plot thickens!
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[*] posted on 9-11-2022 at 02:04


Oxidation of organic matters by HNO3 has free-radical mechanism and is not very selective. Of course, same HNO3 is not responsible for hydrogen abstraction from the organic molecule (as it happens usually), but its oxides do this (because NO or NO2 acts as radicals, but N2O does not). Additional complications is nitration and nitro-esters formation when too concentrated HNO3 is used. Usually, concentration below 20% is used, to avoid such reactions. Very common is 10% HNO3 as oxidation agent.
Of course, there are many organic compounds giving large yields of desired oxidation products even when conc. HNO3 is used.
But the dependency of oxidation-nitration properities of HNO3 (depending of its concentration) is well established.
As I wrote above, -NH2 group is protonated under acidic conditions and becomes partly inert. For example, reaction of phenylalanine with aq. HNO3 gives p-nitrophenylalanine in rather good yield, -NH2 is retained.




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[*] posted on 9-11-2022 at 11:18


Well, carried out a Mp test on my white crystals and got a figure of 93-93.5 C; the compound melted sharply and without decomposition. Any ideas? The sharp melting point suggests a pure compound and it is obtained in high yield; 20g of beta-alanine gave 31g of product and after recrystallisation and washing in acetone 26g, this is far too high for any simple oxidation product it must incorporate some part of the nitric acid. Clearly this is a very complex reaction but worthy

By the way if you think furazan derivatives (Oxodiazoles) or furoxans (Oxodiazole-N-oxides) are not that likely check out some of the threads on SM and in particular a reference posted by Dany:

1] Snyder, H. R., & Boyer, N. E. (1955). The Synthesis of Furoxans from Aryl Methyl Ketones and Nitric Acid1. Journal of the American Chemical Society, 77(16), 4233-4238. doi: 10.1021/ja01621a021

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[*] posted on 10-11-2022 at 18:32


Quote: Originally posted by Boffis  
Well, carried out a Mp test on my white crystals and got a figure of 93-93.5 C; the compound melted sharply and without decomposition. Any ideas?

I can be everything (almost).
But if you like furoxan-like matters, here you are a candidate:
furoxancarboxylic acid (I am not sure if it is correct name)
https://archive.org/download/crossref-pre-1923-scholarly-wor...
.... and find page 66. The structural formula is not fully correct in this old paper: the oxygen bridge is not good.




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[*] posted on 11-11-2022 at 12:15


Hi kmno4, thankyou for the paper, I haven't seen this one before but I have looked at, and indeed translated several others on "glyoxime peroxides" as part of my investigation into fulminic and fulminuric acid.

I have found online a book on the furazan and furoxan heterocyclics and there are lots of examples of nitric acid oxidation of various ketones and keto-acids. I have attached a copy of the Synder paper.

beta-alanine to furoxan.gif - 20kB

Looking at the published literature there are two possible reaction routes but neither is quite applicable to a beta-aminoacid. In one route the nitrogen oxides attack the amino group and somehow generate a nitrile oxide rather than a diazo compound. I can't find any info on the furoxan-diacetic acid. My original idea was that a transient diazo compound formed that then hydrolysed to the hydroxy acid which was then simply oxidized to a second acid group is not tenable in view of the results.

In the second, more likely, route nitrous acid from the nitrite attacks the alpha carbon to the carboxylic acid group forming a isonitroso group while the amine is oxidised to a nitroso group that rearranges it the isonitroso form and is then oxidised and cyclotises to the furoxan carboxylic acid. I prefer this latter route.


Attachment: The preparation of furoxans by oxidation of methylketones with nitric acid JACS 1955.pdf (640kB)
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[Edited on 11-11-2022 by Boffis]
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[*] posted on 12-11-2022 at 00:01



The "diaceto" derivative would have higher m.p. than the monocarboxylate furoxan, at least I think so.
You may do some NaOH titration of your compound and/or make some tests described in this article from Annalen. The most possibly your preparate is purer and gives higher m.p. than noted there (89-91 C). The Ag salt is "explosive", as noted elsewhere, but many Ag salts of "nitrogen-acid" do so.

I would name your reaction as "Boffis reaction", but somehow I have impression that it is too simple and someone must have done it earlier. However, I think that making something new, a reaction or a compound, is not very difficult even at "home-chemistry" level.
The chemistry is the endless sea of possibilities ;)

P.S. I am going to do some additional literature research, but maybe SciFinder or similar tool would be more helpful (I have no access now)

[Edited on 12-11-2022 by kmno4]




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[*] posted on 12-11-2022 at 07:46


I agree with you kmno4 about the mp of the diacetic acid and I find this route rather implausible too. Apart from Synder's paper I have read many papers that produce what are clearly furoxans, although usually referred to as glyoxime peroxides, with nitric acid including the original paper by Propper and several by Ulpiani. Unfortunately other interesting paper by Ponzio and Quilico are in issues of Gaz. Chim. Ital that are not readily available (up to 1923 is available at archive.org but these two latter authors mostly published around 1926 to 1938. I don't have access to scifinder either, any volunteers out there that do?

I have just been preparing salts of the compound and got some weird results that suggest the compound is not furoxan carboxylic acid. It does not appear to be decomposed by the amount of NaOH required to neutralise it and the resulting solution can be evaporated on a steam bath. There is no ppt with either ammoniacal silver nitrate or 2M silver nitrate solution with either the free acid or the neutralised acid and the barium salt is also very soluble.

I originally thought that it might be a compound oxidised in the central carbon like tartronic acid or mesoxalic acid but the former melts at 157 and the latter is so unstable that it can't be isolated in solid form but could it be a nitrate ester of either tartronic acid or 3-hydroxypropanoic acid?

I am also becoming interested in the yellow energetic, water soluble oil that accompanies it after reading that many of the furazan and furozan compounds are viscous liquids. I am being sent overseas with my work soon so I will loose access to my lab until Christmas so I am running out of experimental time.
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[*] posted on 13-11-2022 at 07:58



OK.
As a matter of fact, it is really hard to guess correct structure of the product without elemental analysis, IR spectra.... etc.
I would make a test with NaHCO3 sol. to see if your substance is acidic (carboxylic) at all. The crystal form may also suggest some oxime, many of them form large long crystalline needles. Possibly a test with Ni salts (in alkaline conditions) would also show something. Besides, its Ag or Ba salt can be water soluble, who knows....

BTW, the yellow oily matter can be also whatever: some nitro derivatie, nitrate ester, nitrosoamine ... etc, also in multisubstituted versions.

[Edited on 13-11-2022 by kmno4]




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[*] posted on 19-1-2023 at 13:05


Hi kmno4. I haven’t replied to this thread earlier as when at home over the Christmas period I was rather ill and didn’t really feel like doing any chemistry and I am now overseas again for a while. However, I have been doing some reading into this subject and found some old but rather interesting papers. You are quite right, I am just guessing about the identity of the my mysterious compound but not having access to physical measurements other than melting point my method of working is; “guess the identity then check the literature for its properties, do they match; -yes, whoopee –No, back to the guessing game” technique.

You might think that every possible C3 derivative of propanoic and malonic acids has been prepared but much of the information on these compounds is very old and many have not been isolated in a satisfactory solid form. One such compound is the theoretical 2-oxime of mesoxalic acid semialdehyde.


Van Slyke developed a method1,2) for the determination of amino-acid amino groups by treating the acids with sodium nitrite in acid solution. Some amino acids give slightly anomalous results and during a follow-up investigation by Schmidt4) it was found that beta-alanine reacted like a normal amino acid and rapidly de-aminated, presumably to beta-hydroxypropanoic acid though this isn’t expressly stated. The reaction is essentially complete in 3-5 minutes. So if 1,3-propandiol is oxidized by nitric acid to malonic acid one would expect the hydroxylpropanoic acid to be an intermediate and yield the same product, in fact this is expressly stated in von Richter’s textbook of carbon compounds. So I would expect malonic acid to be the end product of nitric acid oxidation. However, in my final experiment I didn’t add any sodium nitrite so the oxidation route is much less clear. One slight complication is that beta-hydroxypropanoic acid, which is a well-studied intermediate for bio-polymers(see Wikipedia), readily dehydrates to acrylic acid and this may react differently towards nitric acid too. A further problem I see is that an oxime group in the 3 position allows it to cyclotise to an oxazolone derivative.

When I am home next I will try nitrous acid de-amination of beta-alanine then nitric acid oxidation in separate stages to see if I get the same material. I may also try repeating Magpie’s procedure to see what I get.

I also intend to try treating the product with hydroxylamine to see if it has any carbonyl groups in it.

While rummaging through the old literature I came across another paper investigating the reason for the excess nitrogen by Austin3) in which he concludes that one of the products of de-amination of glycine with nitrous acid are things like methazonic acid and fulminic acid and that the polymerization and decomposition of these material leads to the formation of excess nitrogen. Incidentally this paper has been posted before, I think it was on chemplayer’s thread on "essence of smirf" which is described in the latter part of this paper.

1 The reaction of alpha amino acids and related with nitrous acid JBC Van Slyke 1911 v09 p185
2 Quantitative determination of aliphatic amino groups JBC Van Slyke 1912 v12 p275
3 Deamination of amino acids by nitrous acid JCS A T Austin 1950
4 The reaction of nitrous acid with certain amino acids at 45 C JBC C L Schmidt 1930 v82 p587

References 1,2 and 4 are available from the Journal of biological chemistry web site freely.

Attachment: 3 Deamination of amino acids by nitrous acid re methylnitrolic acid & fulminates JCS A T Austin 1950.pdf (205kB)
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