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Nicodem
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If you have no better means you could search the patents like I already told you. There are several very simple methods there. Else you can search the
scientific literature at publisher's homepages.
Citrazinic acid is prepared by heating citric acid monohydrate with ammonia or preferably urea to 120-150°C (see the patents for details). The yield
is generally moderate (~50%) but this is irrelevant given how cheap and available both starting materials and potential solvent are.
As for its use, I don't know and you never said the product has to have any special use, but preparing a 2,4,6-substituted pyridine, even if such a
simple one, is a nice way to learn heterocyclic chemistry in its preparative aspects.
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ssdd
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Ok thanks, I managed to dig up some info where you said. Now I'm trying to figure out the best masses to use of each material (urea and citric acid).
The equation solver came up with it being an "impossible reaction." 
As to uses really anything, but I'll find something on my own to save the trouble. Thanks for being patient with me I know I can be a bit of a pain...
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Sauron
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citrazinic acid is 2,6-dihydroxyisonicotinic acid
Look at your citric acid, think about how ammonia (anibe groups) are going to add to it, and how the resulting intermediate will end up cyclized and
aromatic with a N in the ring adjacent to (surrounded by) a pair of hydroxyl substituents.
It's actually quite elegant getting from boring old citric acid (but not boring to a biochemist, think Krebs cycle) to an aromatic heterocycle in one
step with ammonia (urea) in a single step with just a little heat to give it a nudge.
Think amide -> keto/enol. The middle carboxylic group in citric acid is the one that ends up in the 4-position (sometimes called the
gamma-position) in the pyridine ring. The hydroxyl group eliminates as H2O giving rise to a pi bond that stabilizes the two enols. Ta-da! Let me know
if you still can't see it in your head and I will draw you a picture.
The overall reaction consumes one mol ammonia per mol citric acid and releases three mols water as steam.
So much for stoichiometry, I'd use urea. If you use ammonia you'll spend a lot of time eliminating the excess water. Dry distillation of the two
solids (citric and urea finely ground and intimately mixed) will work. I have used this for preps of succinimide and phthalimide from the dicarboxylic
acids. An alternative to urea is ammonium carbonate. Use whichever one is easier for you to obtain.
See the patent(s) for workup details. I have not read them. This is an easy mechanism to figure out.
Oh, since you start with citric acid monohydrate you drive off four mols water per mol citric acid.
As to use, I have found only one article in all of ACS journals dealing with its use (and none on its preparation).
Wiley and Kraus, J,Org.Chem 21, 757-758 (1956)
3-Arylidene-5-(-hydroxybenzylidene)-2,6-piperidinedione-4-carboxylic Acid -Lactones from Citrazinic Acid
I have that one if anyone wants it
An older British paper I have requested that hopefully details the preparation and workup of the acid.
LXXIII.—Studies on citrazinic acid. Part I
W. J. Sell and T. H. Easterfield, J. Chem. Soc., Trans., 1893, 63, 1035
DOI: 10.1039/CT8936301035
Here's my surmise on the mechanism. I am not suggesting that all of these intermediates are isolable, they are included for clarity. The last two are
the main tautomers.
[Edited on 2-5-2007 by Sauron]
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Nicodem
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An ancient RSC paper on citrazinic acid requested by Sauron in the Wanted references:
LXXIII.—Studies on citrazinic acid. Part I
W. J. Sell and T. H. Easterfield
J. Chem. Soc., Trans., 63, (1893), 1035 - 1051.
Attachment: Studies on citrazinic acid Part I.pdf (1.1MB)
This file has been downloaded 1369 times
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Sauron
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Why thanks @Nicodem, very obliging of you. I just found an even hoarier paper from Ber. pp 2681-2699 (1884) on the amides of citric acid and their use
in pyridine synthesis, and spent some time pulling up 20 pages one at a time in Gallatica and assembling them into a pdf. All the gory details are
there, for those who are not German-challenged. For those who are, including myself, I am sure the J.Chem.Soc. paper will be a welcome respite.
It seems the scheme I sketched above is off on stoichiometry. Three mols ammonia are required as the citric acid is converted to citramide before
cyclizing. The German paper includes preparation of that triamide as well as the diamide so one could if they wish do this in two stages, isolating
the citramide first.
Also turns out that the main use of citrazinic acid is as a component of Kodak's E-6 Ektachrome color process. Isn't that interesting?
Furthermore if you halogenate citrazinic acid at the 2 and 6 positions with, say, POCl3, and then reduce the resulting compound you obtain 4-picoline
(4-methylpyridine.) Probably the world's costliest picoline, because the stuff is cheap and there's little real point in making it from citric acid.
But it's nice to know it can be done. Most likely that reduction could be effected selectively (by judicious selection of reagent) to give
isonicotinic acid, which is much more interesting. This could save me a messy oxidation with permanganate, which is what I have a couple liters of
gamma-picoline sitting here for.
--------
After reading:
Damn, only 25% yield? That's rather discouraging. But apparently the ammonium hydroxide methods are even less efficient. I bet they'd go better in an
autoclave.
I have citric acid and urea aplenty (hence my interest) also ammonium carbonate. Maybe I will give this a try.
[Edited on 2-5-2007 by Sauron]
Attachment: Binder1.pdf (1MB)
This file has been downloaded 782 times
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Nicodem
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The US2752354 patent claims a 50-60% yield of citrazinic acid and similar yields for citrazinamide as well. From the little that I understood a couple
of Czechoslovak patents with essentially the same method also claim similar yields, so apparently it is possible to get to 50% with this procedure
using ethylene glycol as solvent.
If you want to use an autoclave and do the reaction in water solution with ammonia then there is the patent US2729647.
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Sauron
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Yes I just finished reading the Pfizer patent (aq ammonia, ammonium citrate, heat and pressure) and the followon patent on purification. I have not
seen the ethylene glycol solvent process yet but clearly, that bp makes all the difference.
I also found the Org Syn procedure for aconitic acid. Rather unsurprisingly from the structure it is similar to the procedure for acetonedicarboxylic
acid but weaker sulfuric acid is used albeit at higher temperature. <94% you get aconitic, 94% or higher, acetonedecarboxylic.
Unfortunately there is no Org.Syn entry for citrazinic acid, oh well. I requested parts II and III of that J.Chem.Soc. series plus an earlier one by
same authors. I am curious about just what acetanhydrocitric acid might be.
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Nicodem
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The other requested papers are cited bellow and attached in the Zip file:
V.—Studies on citrazinic acid. Part II
T. H. Easterfield M.A., W. J. Sell M.A., F.I.C.
J. Chem. Soc., Trans., 65 (1894) 28 – 31.
LXIV.—Studies on citrazinic acid. Part III.
W. J. Sell F.I.C., M.A. , T. H. Easterfield M.A.,Ph.D.
J. Chem. Soc., Trans., 65 (1894) 828 – 834.
LXXXIV.—Anhydro-derivatives of citric and aconitic acids.
T. H. Easterfield and W. J. Sell
J. Chem. Soc., Trans., 61 (1892) 1003-1012.
PS: Besides the aconitic acid at Org. Syth. there is also the procedure for the preparation of another simple derivative of citric acid, the itaconic acid and its anhydride which can be thermally isomerized to citraconic anhydride.
[Edited on by Nicodem]
Attachment: Some papers on citric acid derivatives.zip (1.1MB)
This file has been downloaded 680 times
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UnintentionalChaos
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I am currently following the procedure linked by nicodem 3 posts back. I am using glycerol (since they said it works) and the whole mix is being
heated in a somewhat temperature unstable oil bath. Fluxuations +/- 10 degrees celcius (which is within their acceptable range). Once the mix got up
to temperature, there is significant outgassing of ammonia (constant bubbling), though very little seems to be escaping the erlenmeyer. It has also
become a fairly dark brown color, probably from some of the glycerol breaking down. As far as I know, all the reagents were quite pure to start with.
USP glycerin, food-grade citric acid, and non-fertilizer urea that was snow white when added. I'd like to see if the glycol is a better solvent, but
I'm fresh out. I'll give you an update tomorrow on yield since it runs for 4 hours, followed by the necessity of drying the product. Going to
citrazinic acid from there will come later.
EDIT: The mix should really be kept at or just above 133C since that is the decomposition temperature of urea and the bubbling stops almost completely
5 degrees below that. I've tinkered with it and gotten it to stabilize at about 135C which isn't bad.
[Edited on 5-2-07 by UnintentionalChaos]
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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Sauron
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Just woke up and was pleased to find a further gift from @Nicodem to start off my day. Will go unwrap the package after this post. Last thing last
night read the Aries patent (which @UC is already running) and will be very interested in his results. While I just bought a nice stirred autoclave,
it is not of infinite capacity. So being able to work in glass at atmospheric pressure is a good thing. I'll also like to see if the oil bath is
really necessary or whether a well regulated mantle and a mechanical stirrer would serve as well.
@Nicodem, triple thanks again. I'll go unwrap it now. 
Grrr. The present did not unwrap. WinZip barfed on it and so did WinRAR. Not a valid archive. @Nicodem, would you mind attaching those three files,
one by one? You could do so in prior posts in this thread, if you wish, I will keep an eye out for them.
Thanks.
[Edited on 3-5-2007 by Sauron]
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leu
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There's nothing wrong with Nicodem's archive; if at first you don't succeed, try try again
Chemistry is our Covalent Bond
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Sauron
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Already tried, tried again 5 times. With both WinZip and Win RAR no go. Tried opening, tried saving, tried right clicking and Save As.
WinZip and WinRAR are working fine with other files.
I dumped cache, rebooted router, rebooted PC, changed HDD, changed from XP Pro SP2 to SP1. No go. "Invalid or corrupted" is the diagnosis of WinZip,
WinRAR and the file compression utility built into XP SP1.
As the one who requested these files, I'd rather like to get to see them. So I would appreciate it of someone would post them, one by one, in
uncompressed pdf form. I am NOT having any problem with zip files in general, just this one. I am NOT having problems with pdf's.
[Edited on 3-5-2007 by Sauron]
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UnintentionalChaos
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Ugh, something wen't terribly wrong with this synthesis. I expected some degree of burnt material/sideproducts, but the final reaction mix looks just
like motor oil. Upon acidification I got...nothing! I will let it sit for a while since it wouldn't be the first time something took a while to ppt
for me. The only compound in the mix that should have decomposed at the temperatures involved (including the worst fluxuations) should have been urea
and the chemicals I used seem to be of good quality. I will have to try this again with ethylene glycol and see If the same mess happens. Maybe
someone with a more stable heating system or guaranteed clean reagents could give it a shot. The hottest it ever got was @12 degrees over their 133
standard, though I quickly dropped the temperature when this occured. This is the result of trying to do this over flame since I don't have a
functioning hot plate at the minute. The oil bath was an attempt to stabilize rapid fluxuations in temperture since I was constantly raising and
lowering the burner to increase/decrease the temperature and maintain it in acceptable range. I failed to find a stabilized perfect temperature during
the entire 4 hours.
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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Nicodem
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| Quote: | Originally posted by Nicodem
V.—Studies on citrazinic acid. Part II
T. H. Easterfield M.A., W. J. Sell M.A., F.I.C.
J. Chem. Soc., Trans., 65 (1894) 28 – 31. |
I don't know if it is the Zip file that is corrupted (the copy on my HD is OK) but something certainly is wrong with the attachment either at the file
level or at the board level, because I'm unable to download it today while I'm able to download other attachments in the thread normally. I suspect
something went wrong yesterday when I tried to edit the post and instead it disappeared into a post containing only the attachment. I rescued the text
from the cache and reedited thinking the only thing damaged was the text of the reply. Maybe I hit some forum bug or whatever. Anyway, I'm reposting
the papers uncompressed one by one:
Attachment: Studies on citrazinic acid Part II.pdf (227kB)
This file has been downloaded 1232 times
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Nicodem
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| Quote: | LXIV.—Studies on citrazinic acid. Part III.
W. J. Sell F.I.C., M.A. , T. H. Easterfield M.A.,Ph.D.
J. Chem. Soc., Trans., 65 (1894) 828 – 834. |
Attachment: Studies on citrazinic acid Part III.pdf (377kB)
This file has been downloaded 880 times
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Nicodem
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| Quote: | LXXXIV.—Anhydro-derivatives of citric and aconitic acids.
T. H. Easterfield and W. J. Sell
J. Chem. Soc., Trans., 61 (1892) 1003-1012. |
Attachment: Anhydro-derivatives of citric and aconitic acids.pdf (584kB)
This file has been downloaded 876 times
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Nicodem
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Weird! Now I'm able to download the Zip, but it does not open as a Zip file. After inspecting the file content in notepad I noticed that it is not
even defined as a Zip since it does not even start with the "PK" declaration as it should.
The moral of the story is that from now on I will avoid editing the posts containing attachments. 
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Sauron
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Thanks, @Nicodem. It was making me crazy all morning.
You reckon the archive was corrupted by editing the post it was attached to? Must be part of the new improved MySQL I guess...better inform
@Polverone.
Of those last three articles, so far as I can tell from a quick look the most interesting is the earliest one preceeding the three part series.
"Acetanhydrocitric acid" is obtained from citric acid and acetyl chloride. As soon as I finish studying this paper I will report.
Okay, anhydrous citric acid is treated with 4 mols acetyl chloride per mol, and warmed on steam bath for two hours under reflux. This gives a nearly
quantitative yield of what Sell and Easterfield called acetanhydroacetic acid, but what I would call acetylcitric anhydride and what IUPAC names as a
substituted tetrahydropyran. I base my choice of acetylcitric anhydride on the fact that Sell and Easterfield treated this substance with water and
obtained acetylcitric acid.
When treated with concentrated ammonium hydroxide at 130-140 this substance gives 30-40% citrazinic acid on workup. We know from the teachings of
later workers that if this reaction is run in an autoclave, thus precluding loss of ammonia, much higher yields could be expected.
As we have elucidated the facile preparation of acetyl chloride and acetic anhydride by a variety of routes (TCT, benzoyl chloride, phthaloyl chloride
etc) the reagent presents no great difficulty. This may be an alternative in case the urea method as taught in the Aries patent (plyhydroxy solvents)
proves difficult.
[Edited on 3-5-2007 by Sauron]
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Sauron
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Sorry about the double post.
@UC, heads up. See following from Ullman's. This might throw some light on your problem and cast doubt over the Aries patent.
"Citric acid is easily esterified with many alcohols under the usual conditions in the presence of a catalyst, such as sulfuric acid,
p-toluenesulfonic acid, or an acid ion-exchange resin; esterification with alcohols boiling above 150 °C requires no catalyst.
Benzyl chloride and sodium citrate yield di- or tribenzyl esters. Trimethyl, triethyl, and tributyl citrate are used as plasticizers in food-packaging
materials.
Dihydric alcohols, dihydric phenols, and polyhydric alcohols, such as mannitol, sorbitol, and glycerol, form polyesters with citric
acid. In some cases the esterification reaction can be stopped before completion, leaving at least one of the carboxylic acid moieties free
to form a salt; the resulting polyester may be soluble in water."
So citric acid esterifies polyhdric alcohols (that would include ethylene glycol, glycerol, and mannitol as mentioned in patent) and alcohols in
general having a bp over 150 C, without catalyst. Presumably, this occurs at or above that minimum bp. You are operating close to that especially when
fluctuations are taken into account.
So, did you make poly(ethylene citrate)? Wouldn't that maybe be a lot like...motor oil?
Personally I would look for a solvent that is inert, dissolves both urea and citric acid, and boils above the rxn temperature.
But polyhydroxy compounds may not be inert enough.
[Edited on 4-5-2007 by Sauron]
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UnintentionalChaos
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At least it all washed off nicely and was a small scale test. There weren't any carbon deposits, just an extremely dark brown/black mess. I suppose it
was glycerol-tricitrate or something. Since each citric acid has 3 carboxyls, crosslinking is highly possible. I have some DMSO on hand, but 1: its
power to dissolve everything may be an issue when seperating products 2: I've heard it tends to decarboxylate things and citric acid has everything to
lose and 3: I haven't used it yet (recent acquisition) and have no idea what kind of side reactions can occur. If you think it's still plausible, I'll
run the experiment, since the solvent (in both cases) is more expensive than the other reagents and none of it was particularly pricey.
Since I think the target temperature of 130-133 was to allow the decomposition of urea, but minimize esterification (if possible), the use of another
solvent may make that narrow temperature gap obsolete, as long as the temperatures dont approach the decomposition point of the citric acid itself.
Then again, high heat might lead to more side products, so I'll just keep it where I had it. I imagine the formation of the tri-amide is the major and
unavoidable byproduct that keeps yields low.
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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not_important
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If the ZIP file in question is "Some papers on citric acid derivatives.zip" I just downloaded it again and opened it without trouble, which suggests
the problem isn't simple.
Regarding the citric acid - urea - polyol solvent, perhaps adding technical xylene and running at reflux would work, if there's enough xylene the
temperature should stay around 140 C.
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UnintentionalChaos
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I don't think it is really a temperature issue. I am sure that it was darkening before it even got that hot. By the time it hit 130 it was starting to
brown. Sauron mentioned that "esterification with alcohols boiling above 150 °C requires no catalyst," so i would assume that any decently elevated
temperature will lead to rapid formation of esters. The problem in the reaction is that it is operating above the boiling point of water and therefore
the formation of an ester (or the desired amide, which are both dehydration reactions) become irreversible since the water is immediately removed. I
think an alternative solvent is definetly the route to go here.
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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chemrox
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| Quote: | The other requested papers are cited bellow and attached in the Zip file:
V.—Studies on citrazinic acid. Part II
T. H. Easterfield M.A., W. J. Sell M.A., F.I.C.
J. Chem. Soc., Trans., 65 (1894) 28 – 31.
LXIV.—Studies on citrazinic acid. Part III.
W. J. Sell F.I.C., M.A. , T. H. Easterfield M.A.,Ph.D.
J. Chem. Soc., Trans., 65 (1894) 828 – 834.
LXXXIV.—Anhydro-derivatives of citric and aconitic acids.
T. H. Easterfield and W. J. Sell
J. Chem. Soc., Trans., 61 (1892) 1003-1012.
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I get an error message trying to open the zip file.
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not_important
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Ah, but
RCO2R' + R"NH2 <=> RCONHR" + R'OH
standard amide preparation, goes faster left to right and an excess of amine can drive it that way.
And I just tried the download for the 3rd time with success. What filesize are you getting?
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Sauron
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Having slept on the matter I have come to think there are two possibilities.
1. My initial reading of the Aries patent was cursory. If as I took it, the polyols are just intended to be high boiling solvents or diluents then
indeed maybe they were poor choices and in that case the xylene suggestion may be an excellent one.
2. On the other hand, both the Aries patent and the Pfizer patent in discussing the background of the art, make mention of the prior art use of
citrate esters rather than citric acid, in reaction with aqueous ammonia, to give citazinic acid via citrazinamide.
In light of that, a more thoughtful reading of the Aries patent might indicate that the selection of polyols like glycol and glycerol and mannitol
might not be only, or even chiefly for bp but, rather, to form citrate esters in situ and react them at appropriate temp. with urea or its
decomposition products, NH3 etc. Again proceeding through citrazinamide to citrazinic acid.
Maybe?
Additionally I would like to try using ammonium citrate as suggested by the Pfizer patent and ammonium carbonate as suggested by Vogel in prep of
phthalimide as alternative to either urea or ammonium hydroxide. Having done phthalimide all three ways I don't see why this would not work.
Furthermore, @UC, just to get back on track why not try the dry method? Citric acid and urea. Acidify not with sulfuric but with acetic acid.
Citrazinic acid does not fluoresce in water unless alkili is present. Solubility in water is very low but freely sol in base. Expect about a 25-30%
yield of a yellow solid with greenish tinge.
The Aries and Pfizer patents after all are just attempts at upping the yield. (Doubling ot.)
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