Denatonium
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Pyrazinoate from 2-acetylpyrazine
I'm interested in doing an OTC synthesis of pyrazinamide, mainly for the curiosity. I did a bit of research and found that 2-acetylpyrazine is
domestically available in bulk powder form as a food flavoring additive (FDA GRAS).
My first step would need to be to get rid of that methyl ketone by oxidizing it into a carboxylic acid. My first idea was to do a haloform on it, but
I think the nitrogens in the pyrazine ring would get in the way and I'd get unwanted side-products.
If there's anyone who can point me in the right direction in terms of finding oxidants that can cleave the methyl ketone without mangling the pyrazine
ring, or by finding a suitable (and OTC) way of protecting the nitrogens from the effects of whatever oxidant I'd use, I'd really appreciate the tips.
Bitter as always,
Denatonium
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jackchem2001
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| Quote: | | My first step would need to be to get rid of that methyl ketone by oxidizing it into a carboxylic acid. My first idea was to do a haloform on it, but
I think the nitrogens in the pyrazine ring would get in the way and I'd get unwanted side-products. |
I think the haloform reaction may have a good chance of success, as pyridine is said to function as a catalyst for halogenation reactions. The
electron withdrawing character of the ring likely makes that ketone even more enolizable, too.
The image is from Clayden Organic Chemistry, chapter 29, page 731
[Edited on 4-6-2024 by jackchem2001]
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Denatonium
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So I tried doing a haloform reaction with bleach containing 7.5% NaClO. My procedure was to first create a saturated solution of 2-acetylpyrazine in
water and add the bleach dropwise.
There was definitely a haloform reaction going on, judging by the smell of chloroform. The reaction mixture turned a deep reddish-brown color,
suggesting the formation of side products. Once I had added enough bleach, I then dumped in some ethanol to consume the excess bleach (to avoid a
green cloud) and acidified the product with hydrochloric acid.
When acidifying, I did get crystals crashing out in a foam-like manner. I'd guess there was pyrinazoic acid being formed.
I guess I now have an excuse to buy a melting-point apparatus.
Bitter as always,
Denatonium
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bnull
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@jackchem2001: It is pyrazine, with two N in the ring, one opposite the other (https://en.wikipedia.org/wiki/Pyrazine). Organic nomenclature is a mess.
@Denatonium: I think that hot permanganate will work with less side reactions.
The reddish-brown color may be due to a reaction of chloroform with the pyrazine ring in basic media. I had something similar happen after a
naphthalene chlorination with ethanol in water as solvent. After addition of NaOH, the color went from yellow to red.
[Edited on 4-6-2024 by bnull]
Quod scripsi, scripsi.
B. N. Ull
P.S.: Did you know that we have a Library?
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jackchem2001
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The point is the reactivity of the planar nitrogens in the ring
| Quote: | | The reaction mixture turned a deep reddish-brown color, suggesting the formation of side products. |
The most obvious potential side products are those from aldol condensations and subsequent dehydration. Does the same color arise from just aqueous
sodium hydroxide?
[Edited on 5-6-2024 by jackchem2001]
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Boffis
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@Denatonium; The reaction is perfectly feasible and the yield is reasonably good. I found that using 14% commercial hypochlorite bleach and adding the
finely powdered acetylpyrazine to the bleach is the simplest method. The reaction is very exothermic so a water bath is required to keep the
temperature between 60-70 C. Once the addition was complete I took away the water bath and adjusted the pH to 8 with 1:1 hydrochloric acid. I added
1ml of a mixture of active charcoal and kieselguhr and heated the slurry to 80 C. Because crystals started to form I eventually had to add a little
hot water to get complete solution. The mixture was filtered hot and the pale tea-coloured solution cooled slowly to 4 C. A small amount of almost
white silky sodium pyrazinoate crystallised slowly, this was filter off and dried. The filtrate was evaporated down a little but soon began to deposit
more sodium pyrazinoate and so was cooled in the fridge, were upon the solution almost solidified. The silky crystals were filtered off, drained and
dried; they're very soluble in pure water so I didn't was them. I haven't yet tried purifying them but an initial experiment reveals a fairly flat
solubility-temperature relationship in water so you only get a little of the sodium salt back by simply cooling the hot solution.
The final filtrate was acidified to just acid to Congo Red (pH ~2) with hydrochloric acid and chilled in the fridge again to give a small yield of
free acid.
The sodium saly gives an intense magenta-purple colour with ferrous ions.
If you want I'll dig out my notes and prepare a detailed write-up with quantities and yield.
I did a few experiements with acetylpyrazine. I tried reacting it with isatin in KOH solution which gives what I think is
2(pyrazinyl)-quinoline-4-carboxylic acid in reasonable yield. I am about to try condensing it with an aromatic aldehyde, possible benzaldehyde first
but the product with salicylaldehyde may be more interesting a a ligand.
I am thinking of trying to turn the acid into the amide and then try a Hoffmann degradation to pyrazinylamine as I am curious to know if it can be
diazotised.
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