Austin543
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Pyrazine Synthesis?
A few months ago, I stumbled upon a paper that described some copper complexes that exhibit a wide range of fluorescent colors, almost all the colors
in the rainbow in fact (https://pubs.acs.org/doi/abs/10.1021/ic0510359). However, one of the major ligands used is pyrazine or its derivatives. After doing some research
I've realized that such a simple molecule is a lot harder to synthesize than I would've imagined.
I've come across quite a few syntheses, all of which have disadvantages. The first one starts with ethyl acetoacetate and it seems like the best
method so far, however with many steps comes a reduced yield. I've posted the the pathway and the paper that it's from below. It forms
dimethylpyrazine, but according to another source I found, KMnO4 can be used to oxidize the methyl groups yielding a carboxylic pyrazine (bottom of page 8). In that source they
oxidized tetramethylpyrazine, but I don't see why it wouldn't do the same for the dimethyl version. From there you could do a decarboxylation similar
to the common pyridine synthesis from niacin (pyridine-3-carboxylic acid).
Another route involves the gas phase reaction of ethylene diamine over a copper catalyst. They mention copper chromite which is easily prepared as
shown by Doug's Lab, however it is a gas phase reaction, which makes the apparatus quite a bit more complicated. My idea for the apparatus would be
passing ethylene diamine vapor over a bed of catalyst similar to how Nile Red made SiCl4, but who knows how that would turn out.
I also thought of doing a simple ring forming reaction similar to the dioxane synthesis from ethylene glycol. Using glyoxal and ethylene diamine, but
it seems that it might make piperazine-2,3-diol among other things and sources are questionable.
Anyway, that's everything that I've come across regarding a piperazine synthesis and I wanted to hear your thoughts and see if any of you guys have
tried to make it before or know a better method 
Attachment: pyrazine from ethyl acetoacetate.pdf (212kB)
This file has been downloaded 207 times
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Pumukli
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I doubt if those two methyl groups would make a big difference as a ligand. Just do the synthesis and report what you find! :-)
Even if failed to luminesce the dimethyl-pyrazine synthesis in itself would be a worthy reading. I think no one attempted such a synth on
science-madness so far.
I can see that it was your first post, so welcome in the group. We need more budding amateur organic chemists, especially the ambitious type. ;-)
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Σldritch
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2,5-dimethylpyrazine route
I had a great idea how to make 2,5-dimethylpyrazine. It may even be possible as a one pot mix and leave synthesis but im not sure if the acetone
oxidation works in ammonia nor under what conditions the oxidation to pyrazine works. There should be a thread with more information on the acetone
oxidation somewhere on the forum. As for the oxidation to pyrazine, copper is a pretty good air oxidation catalyst in aqeous solution, even oxidizing
ammonia to nitrate. It may even be possible to cheap out on Copper Chloride by using it as a catalyst in step one with air. Workup should be a simple
distillation i believe, unless the presence of byproducts does not make it foam horribly (it probably will).
[Edited on 29-7-2020 by Σldritch]
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Austin543
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| Quote: |
I doubt if those two methyl groups would make a big difference as a ligand. Just do the synthesis and report what you find! :-)
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Thats a good point! It seems like most of these syntheses give dimethyl or trimethyl pyrazine so hopefully skipping the oxidation step would work.
| Quote: |
I had a great idea how to make 2,5-dimethylpyrazine. It may even be possible as a one pot mix and leave synthesis but im not sure if the acetone
oxidation works in ammonia nor under what conditions the oxidation to pyrazine works. There should be a thread with more information on the acetone
oxidation somewhere on the forum. As for the oxidation to pyrazine, copper is a pretty good air oxidation catalyst in aqeous solution, even oxidizing
ammonia to nitrate. It may even be possible to cheap out on Copper Chloride by using it as a catalyst in step one with air. Workup should be a simple
distillation i believe, unless the presence of byproducts does not make it foam horribly (it probably will). |
I did some research and found a french paper that describes what you're talking about with the aminoacetone but it says you'd also need to react it with a carbonyl compound in
order to isolate the cyclized ring. If you used formaldehyde it seems like you'd get trimethylpyrazine, which hopefully wont affect florescence, but
if it does I can try the permanganate oxidation step.
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Diachrynic
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2,3-Dimethylpyrazine synthesis
From my literature searching I figured the direct synthesis of dihydropyrazine from glyoxal and ethylene diamine would not work and produce other
compounds, see J. M. Edwards et al., Chem. Commun. (London) 1968, 1649-1650, https://doi.org/10.1039/C19680001649:
Attachment: edwards1968_glyoxal_ethylenediamine_cage_formation.pdf (117kB)
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However, diacetyl should work and indeed it does, producing a 2,3-dimethyl-5,6-dihydropyrazine which on oxidation can form 2,3-dimethylpyrazine.
Oxidation with permanganate apparently produces 3-methylpyrazine-2-carboxylic acid fairly easily, which can decarboxylate to give 2-methylpyrazine.
But I am sure more harsh oxidation conditions could provide the dicarboxylic acid, which again easily decarboxylates.
Diacetyl was obtained as a perfume ingredient, but it seems to be no longer sold where I bought it. It has a lovely buttery aroma and is a yellow
liquid. It should also be possible to make by using methylethylketone and a nitrite ester, then hydrolysing the diacetylmonooxime obtained.
Ethylene diamine was obtained from a chemical supplier.
The first step of the procedure was taken from T. Ishiguro, M. Matsumura, Yakugaku Zasshi 1958, 78, 3, 229-231, https://doi.org/10.1248/yakushi1947.78.3_229:
Attachment: matsumura1947_dimethyldihydropyrazine.pdf (545kB)
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However, I deviated from their synthesis, which may have contributed to the low yield. I will repeat this at a later date.
Also of value was F. Jorre, "Synthese von 2,3-Dimethylpyrazin", Dissertation, Kiel 1897, urn:nbn:de:gbv:8:2-2889314. It's freely available at the link provided, but is too big to be attached here.
The oxidation was performed according to T. Akiyama, J. Agric. Food Chem. 1978, 26, 5, 1176-1179, https://doi.org/10.1021/jf60219a057:
Attachment: akiyama1978_dihydropyrazine_oxidation.pdf (415kB)
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Again, I deviated and should have used proper manganese dioxide and not battery crap, and also I should not have used denatured alcohol as there were
aldol side reactions.
2,3-Dimethylpyrazine has an entry in Beilsteins Handbuch der organischen Chemie, 4th edition, book 23 (1936), p. 95, available on archive.org here.
Experimental:
1.42 g of ethylene diamine (the paper uses 1.85 g of the hydrate, I used anhydrous) and 20 mL of diethyl ether were stirred in a 100 mL RBF in an
icebath. After it had cooled, a solution of 2.00 g of diacetly and 10 mL of Et2O was added dropwise via an addition funnel during 20 minutes. There is
a white precipitate appearing almost immediately. The diacetyl solution on the glass walls above the liquid turns a red color, but the solution itself
is almost colorless. After complete addition the ice bath was removed and the addition funnel replaced with a reflux condenser. It was stirred at room
temp. for 1 hour. The procedure stated to stir until it goes clear, which I didn't do. Then the solution was refluxed on a water bath for 30 minutes,
during which it cleared up. A slightly yellow ether layer and a reddish bottom layer was visible. 2.00 g of powdered KOH was added and the solution
stirred for 1 hour. The ether becomes more yellow.
Here I deviated from the procedure. The procedure now removes the ether layer and distills it under vacuum to obtain the
2,3-dimethyl-5,6-dihydropyrazine. Since I needed KOH for the next step anyways I figured I could get away without this. It might be part of the reason
for the bad yield.
The mixture of ether and KOH was distilled in a hot water bath of 50-60 °C until most of the ether, around 20 mL, was removed.
Then 40 mL of 95% EtOH (denatured but this is a terrible idea) and 12 g of crude manganese dioxide (again, use a higher grade) was added and the
solution refluxed for 4 hours. After cooling, filtration by gravity was extremely slow, but filtration by vacuum acceptable. The residue was washed
with 4x 10 mL of EtOH. The solution is dark red (presumably aldol side products). The EtOH was distilled off until only ~5 mL remained in the flask,
to which 10 mL of sat. NaCl-solution was added. This is extracted 2x with 10 mL of Et2O (I recommend doing more extractions). The yellow Et2O is
retained.
The Et2O extract is distilled and the ether collected. Distillate was obtained at 156-160 °C (large range due to small scale and large apparatus) and
amounts to 0.2755 g (11%).
The aqueous solution has a pH of 7-8, shows blue fluorescence and has a stale odor.
The boiling point of the 2,3-dimethyl-5,6-dihydropyrazine is reported as 162-165 °C, the 2,3-dimethylpyrazine as 156 °C. The solubility of the
2,3-dimethyl-5,6-dihydropyrazine is high in water and ethanol but much lower in ether, the solubility of the 2,3-dimethylpyrazine is high in water,
alcohol and ether. The 2,3-dimethyl-5,6-dihydropyrazine is reported to show a strongly basic reaction in water, the 2,3-dimethylpyrazine is supposed
to react neutral.
It is also of interest that the 2,3-dimethylpyrazine is steam volatile.
Overall this leaves much to be improved, but I will give this another attempt.
[Edited on 6-9-2022 by Diachrynic]
[Edited on 6-9-2022 by Diachrynic]
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Boffis
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Interesting synthesis Diachrynic, I am interested in pyrazine compounds too. I would be interested to hear how you get on if you have another go. One
point is that using MnO2 as an oxidizing agent in a strongly alkaline situation seems strange. Usually there is at least some acetic acid added to
remove the Mn2+ formed and keep the reaction chugging forward. In an alkaline medium where does the Mn2+ go? Or do you end up with an Mn-pyrazine
complex (the red colour?).
Some years ago I found saw 500g of piperazine hydrate for sale on ebay and bought it. My cunning plan is to try and oxidise it to pyrazine or perhaps
to try to de-hydrogenate it with palladium or raney nickel. I don't know if this would work and I haven't had time to try it yet.
By the way that German dissertation; can it be downloaded in one go or is it just page by page?
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Lionel Spanner
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The first scheme in the OP is a Gutknecht synthesis, which is a good general method for making pyrazines that are inversely symmetrical about the
nitrogens. If memory serves, the second step in the original reaction reduced the oxime using tin and hydrochloric acid as opposed to zinc and caustic
soda - not sure if this would improve the yield.
Industrial chemist rediscovering the practical pleasures of pure chemistry.
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Diachrynic
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Quote: Originally posted by Boffis  | | One point is that using MnO2 as an oxidizing agent in a strongly alkaline situation seems strange. Usually there is at least some acetic acid added to
remove the Mn2+ formed and keep the reaction chugging forward. In an alkaline medium where does the Mn2+ go? Or do you end up with an Mn-pyrazine
complex (the red colour?). |
I assume that Mn2O3 is formed, but the paper doesn't talk about it. The reaction mixture after filtration was indeed red, but I
assume that is merely from aldol condensations from using denatured ethanol since Mn(II) is not stable in basic conditions I think. A rerun using
ketone-free alcohol should tell if this assertion is correct or not.
Good luck on the piperazine oxidation, I got the impression that piperazine is fairly hard to aromatize while searching for pyrazine procedures. But
then again I never looked too much into it since I don't have any. Piperazine citrate, a dewormer that used to be OTC in some places, seems to be
phased out by now.
It can be downloaded in sections, but I haven't found the button to download it all at once. Navigate into the section you want, then go to "Zitieren
und Nachnutzen" > "Kapitel" > "PDF". It should redirect you to the following links: Title page, introduction, experimental, curriculum vitae.
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Boffis
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Many thanks Diachrynic; I successfully downloaded the thesis.
By the way have you seen "the chemistry of heterocyclic compounds" series, specifically volume 41 Pyrazines? They can be downloaded from Libgen but
its a big file, about 28 MB. Apparently it is possible to dehydrogenate piperazine to pyrazine by distillation with lime and zinc dust; sounds brutal
and inefficient but I might try something like MnO2 and acetic acid or lime and sulphur.
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Diachrynic
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Thank you for the book recommendation!
| Quote: Originally posted by Boffis | | Apparently it is possible to dehydrogenate piperazine to pyrazine by distillation with lime and zinc dust; sounds brutal and inefficient but I might
try something like MnO2 and acetic acid or lime and sulphur. |
I was reading in Houben-Weyl
IV/1a p.125 today and found a reference for the preparation of pyrazine from piperazine using CuO at 300 °C with a yield of 94%.
The reference is S. P. Yurel, A. A. Anderson, M. V. Shimanskaya, Khimiya Geterotsiklicheskikh Soedinenii 1974, 1414-1419.
This is available in translation: S. P. Yurel, A. A. Anderson, M. V. Shimanskaya, Chemistry of Heterocyclic Compounds 1974,
10, 1241–1245, https://doi.org/10.1007/BF00470173.
Attachment: BF00470173_pyrazine_from_piperazine.pdf (403kB)
This file has been downloaded 2 times
I thought you might be interested.
While reading another large review article (Y. Yamamoto et al., Science Of Synthesis, Hetarenes and Related Ring Systems, Product Class 14,
Pyrazines 2014, 751, https://doi.org/10.1055/sos-SD-016-00919) I came across the mention of the reaction of 2,3-diaminopropionic acid with glyoxal, followed by air
oxidation, to give pyrazine-2-carboxylic acid. A procedure for this can be found in british patent GB1016468A:
Attachment: GB1016468A_pyrazine_carboxylic_acid_diaminopropionic_acid.pdf (333kB)
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Now 2,3-diaminopropionic acid isn't easy to make in itself. I had plans for this some time ago as a potential way to make ethylene diamine. Briefly,
alanine would be chlorinated in concentrated sulfuric acid to produce 3-chloro-2-aminopropionic acid (J. Kollonitsch, A. Rosegay, G. Doldouras, J.
Am. Chem. Soc. 1964, 86, 9, 1857-1858, https://doi.org/10.1021/ja01063a045) which should then react in some way with an excess of concentrated ammonia (which is presumably the nail in
the coffin for this reaction - the literature uses very concentrated ammonia and uses glass tubes, melted shut, to withstand the pressure when the
mixture is heated...) to form 2,3-diaminopropionic acid. The low solubility of its oxalate could possibly be exploited for purification. (E. Klebs,
Z. Physiol. Chem. 1894, 19, 22, https://doi.org/10.1515/bchm1.1895.19.4-5.301). But unless a less suicidal way of doing the substitution is found this won't be viable.
Another approach would be to use fumaric or maleic acid, dibrominate it and replace the bromides with amines (either maybe via ammonia or in two steps
using benzyl amine, followed by deprotection with hydrogen and Pd/C, for this way see W. Wenner, J. Org. Chem. 1948, 13, 1,
26-30, https://doi.org/10.1021/jo01159a004 and H. McKennis, A. S. Yard, J. Org. Chem. 1958, 23, 7, 980-982, https://doi.org/10.1021/jo01101a010). This provides 2,3-diaminosuccinic acid which can condense with glyoxal in much the same way as mentioned
above to form pyrazine-2,3-dicarboxylic acid. (A. V. R. Rao et al, Indian J. Chem., Sect. B 1984, 9, 850, I could only find
the ChemInform version under https://doi.org/10.1002/chin.198452235.)
I looked more into the literature and here are the methods for oxidation of dihydropyrazines to pyrazines which I have found so far:
FeCl3 in EtOH (WO2000025791A1; P. J. Steel, G. B. Caygill, J. Organometallic Chem. 1990, 395, 359-373, https://doi.org/10.1016/0022-328X(90)85299-E)
DDQ (A-C. Chen, Tetrahedron 2008, 64, 37, 8907-8921, https://doi.org/10.1016/j.tet.2008.06.054)
Nickel peroxide (T. Kobayashi, J. Chem. Soc., Perkin Trans. 1 2001, 12, 1372-1385, https://doi.org/10.1039/B101330K)
NaOEt in MeOH under N2 (What is going on with this one?) (Experimental of compound 16 in M. Isbera et al., Synthesis
2019, 51, 23, 4463-4472, https://doi.org/10.1055/s-0039-1690678)
KOH, EtOH, O2 (C. M. Fitchett, P. J. Steel, ARKIVOC (Gainesville, FL, U. S.) 2005, 218-225, https://doi.org/10.3998/ark.5550190.0007.318)
Sulfur (A. Ohta, J. Heterocyclic Chem. 1984, 21, 103, https://doi.org/10.1002/jhet.5570210122)
MnO2, CuO (T. Akiyama, J. Agric. Food Chem. 1978, 26, 5, 1176-1179, https://doi.org/10.1021/jf60219a057)
Fehlings reagent, potassium ferricyanide (F. Jorre, Dissertation, Kiel 1897, urn:nbn:de:gbv:8:2-2889314)
Chloranil (This supposedly gives near quantitative yield, is much faster than MnO2, and uses stoichometric amounts: N. Furuta,
Heterocycles 2009, 77, 2, 1079-1088, https://doi.org/10.3987/com-08-s(f)87) (Axt has prepared chloranil from paracetamol, having done this myself I should warn that the reaction is indeed vigourous, foams a lot, and makes a cloud of
nitrogen dioxide, if the nitric acid is added at once.)
HNO3 in AcOH (The derivative is described as being very easy to oxidize so this may not generalize, A. Hildesheimer, Ber. Dtsch.
Chem. Ges. 1910, 43, 3, 2796-2805, https://doi.org/10.1002/cber.19100430338)
HNO2 (Again, this substrate seems easy to oxidize, S. Gabriel, Ber. Dtsch. Chem. Ges. 1908, 41, 1, 1134, https://doi.org/10.1002/cber.190804101223)
Some seem to be easier to oxidize than others (it seems especially phenyl substituted ones) so not all of these methods will work for the ones at
hand. But maybe there are some useable ones that are less messy than the ones already mentioned.
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