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Author: Subject: Decarboxylation of L-tryptophan in DMSO
mr_bovinejony
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[*] posted on 13-11-2020 at 07:44


That's strange that you have a red oil, have you tried doing some hexane or naphtha pulls on it for further purification? That's how I did it at least, then decant the boiling hexane/naphtha off the oil and evaporate to leave the tan oil which can be easily crystallized
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ArbuzToWoda
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[*] posted on 13-11-2020 at 07:58


Total 15g of dry oxalic acid was added, no crystals appeared even after refrigerating it. Not sure how to fix it now, do another AB and hope for the best? Tiring.
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njl
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[*] posted on 13-11-2020 at 19:13


You should try to concentrate the solution first to see if you can get a crop without anymore workup.
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Benignium
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[*] posted on 14-11-2020 at 06:47


Quote: Originally posted by ArbuzToWoda  
@Benignium, how exactly did you do the oxalic acid purification? Just dumped it all into the methanol and heated up? And then it started crystallizing?


I tried dissolving the acid and the tryptamine (I'll just go ahead and call it that) in methanol at the same time but found dissolving them separately and then mixing the resulting clear solutions more pleasant. When dumped into methanol simultaneously, an instant slurry forms whereas combining ready-made solutions enables the growth of proper(ish) crystals. Concentration is very important and using too much methanol is a source of great existential dread. Also, I always make sure that my methanol is dry by distilling it from a suspension of anhydrous magnesium sulfate. I'm not sure how the presence of water in the methanol influences this particular procedure but it's definitely worth noting.

Equally important is to not add too much oxalic acid. I found that an equal weight of the dihydrate is more than plenty. Granted, this has some water in it and that may again have consequences. Water can be removed easily; just evaporate everything, dry the residue and start over with minimal boiling methanol. Excess oxalic acid on the other hand would require trying out different solvents, decomposition by hydrogen peroxide, precipitating as iron(II) oxalate or some other form of obscure fuckery.

I cannot recommend naphtha, hexane, heptane, petroleum ether etc. since in my case at least, the tryptamine is very poorly soluble in it even when kept at reflux for a while. Probably less than 0.1% solubility with 60-90 pet ether.

It's not a particularly relaxing process but don't give up trying! :)

[Edited on 14-11-2020 by Benignium]
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Benignium
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[*] posted on 1-12-2020 at 11:13


I attempted a method of formylating 1023 milligrams of the tryptamine by refluxing in ethyl formate for 24 hours. Once more I have no idea if I achieved the desired result. This is just a result.

The first photo is taken one hour into reflux. As a precaution I used foil to shield the process from light. Second one is taken after 24 hours of reflux. The procedure I am following describes the mixture as becoming "homogenous". Mine certainly didn't, but filtering through cotton resulted in a perfectly clear filtrate. Left behind was less than 100 milligrams of insoluble white impurity.




The filtrate was then stripped of solvent by first distilling in a 90 degree water bath, then detaching the distillation equipment and replacing solvent vapors in the flask with argon five times until the dark brownish red oily residue had mostly solidified.





When I manage to get LAH at a reasonable price I will attempt to follow through with the rest of the procedure. Until then, I have made some iodomethane which I aim to react with the rest of my tryptamine sample, followed by conversion of the iodide salt to chloride, and pyrolysis of said chloride to potentially yield very crude N,N-dimethyltryptamine which could be purified reasonably well and easily identified. I really hope that at least one of these approaches will work out.




[Edited on 2-12-2020 by Benignium]
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ArbuzToWoda
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[*] posted on 1-12-2020 at 11:23


Looks nice. Why did this route specifically catch your eye? I've heard only good things about NaBH4/HCHO. Also you don't need pyrolysis if you want to go via the ammonium salt, it's sufficient to just reflux it in ethanolamine. And that's much cleaner!
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Benignium
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[*] posted on 1-12-2020 at 14:12


Quote: Originally posted by ArbuzToWoda  
Looks nice. Why did this route specifically catch your eye? I've heard only good things about NaBH4/HCHO. Also you don't need pyrolysis if you want to go via the ammonium salt, it's sufficient to just reflux it in ethanolamine. And that's much cleaner!


Thanks! The procedure seems elegant, relatively non-toxic and particularly high-yielding (1.15 grams of N,N-dimethyltryptamine from 1 gram of tryptamine was reported - that would be 97.85% of theory!). I'm interested to see how reproducible it is. However, from what little I've read about the procedure I fully anticipate it to be full of surprises. Especially since I've been entertaining the thought of substituting 1,4-dioxane for THF, held at a temperature of 60-70 deg. C.

Thank you for the ethanolamine tip! That would indeed be way cleaner. I may purchase some THF, too. We'll see.

Oh, and the NaBH4/HCHO method - I was under the impression that the aldehyde will mostly get reduced before it has time to form the imine intermediate. I did also read about performing the reaction at very low temperatures with simultaneous dropwise addition of NaBH4 and 37% formalin (or perhaps methanol solution?) to the reaction mixture. I haven't investigated any further, though I would love to hear any additional details you might have! :)

[Edited on 1-12-2020 by Benignium]
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ArbuzToWoda
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[*] posted on 1-12-2020 at 15:14


Oh yes, I have researched it quite a bit.
Here are some places you could gather information from.
Vespiary threads:
1. https://www.thevespiary.org/talk/index.php?topic=1954.40
2. https://www.thevespiary.org/talk/index.php?topic=16470.40

Hyperlab threads (a shit ton to read, a lot of info too)
1. https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
2. https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...

There are some threads here also. You should be able to find them just fine. Even that:

Quote:

From SciMad, applicable to plain old tryptamine:
"5-Methoxy-N,N-dimethyltryptamine, 5-MeO-DMT
5-methoxy-tryptamine freebase (12.5 g, 63 mmol, 95% pure) was dissolved in MeOH (250 mL) and the solution was cooled to 0 °C with a ice/salt bath. There was then added, while controling the temperature to not go above 5 °C, in six portions espaced by 15 min : 5 g of 36% HCHO solution in MeOH (39% m/v) followed after 10 sec by NaBH4 (1.2 g, powder). Hence in total during 1h30 there was added 6 x (5 g 36% HCHO in MeOH + 1.2 g NaBH4) = 10.8 g HCHO (360 mmol, 6 eq) and 7.2 g NaBH4 (189 mmol, 3 eq). After each addition an exothermic reaction occur and the temperature must be controlled to stay under 5 °C. The conversion of 5-MeO-T to 5-MeO-DMT was complete under these conditions. The solvent was evaporated, water was added followed by NaOH until pH 12 and the residue was extracted with CH2Cl2. Drying over Na2CO3, filtration, washing with CH2Cl2 and recrystallization from boiling hexanes yielded pale yellow crystals (8.5 g, 62%), >99% pure by NMR and HPLC."

And from a patent I dug up about substituted tryptamines:
"A solution of 35% aqueous formaldehyde (140 ml in 70 ml of methanol) and sodium tetrahydroborate (10 g in 140 ml of water) is added dropwise at the same time to the reaction mixture at the temperature of 10-15°C during 1 hour. The mixture is then stirred at the temperature of 30 °C for another 6 hours. 1 g of activated charcoal is added and after 10 mins the mixture is filtered through diatomite. Then, pH of the solution is adjusted to ca. 9 by addition of 10% aqueous Na2CO3. After that, MeOH is removed by distillation and the product is extracted with ethyl acetate (3 x 100 ml). The solution of the crude product is concentrated under reduced pressure. The evaporation residue is dissolved in ethanol (20 ml) and added dropwise to a solution of fumaric acid (4 g) in ethanol (80 ml). The mixture is stirred at the laboratory temperature for 1 hour. The separated crystals are filtered and washed with ethanol."

If you're scared of the HCHO reduction you could try using sodium triacetoxyborohydride, some people think it's superior as it reduces imines more readily. I don't know if it's true, although I have seen reports claiming success with both this and other methods. Especially the one presented in "Hamilton's Pharmacopeia" in the episode "Wizards of DMT". I think you'd find that one very ellegant ;)
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[*] posted on 2-12-2020 at 02:36


Ethanolamine doesn't work, at least for me.
Nobody has really reported success with this way and there are as many threads that tell that ethanolamine doesn't work as those who tell that it does.
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Benignium
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[*] posted on 18-3-2021 at 13:35


So I did some more reading.

As rather smugly put by Nicodem, there really is nothing to this. There are plenty of tried and tested approaches that seem often overlooked. Inspired, and feeling personally attacked, I chose to try the following:

Commercial "100%" L-tryptophan (25 g), acetophenone (5 g), DMSO (5 mL) and xylene (75 g) were placed in a 250 mL Erlenmeyer equipped with a Claisen adapter to which were attached a gas line that lead to the mixture surface as well as a condenser. On top of the condenser was attached a gas inlet adapter with a stopcock. The apparatus was purged with argon, a plastic bag filled with argon was fixed to the gas adapter and the stopcock was closed. The argon cylinder was replaced with a hose leading to mineral oil in a test tube. With strong stirring the mixture was heated to reflux for 20 hours. The reaction seemed essentially complete after 10 hours, but unreacted tryptophan had accumulated on the walls and refluxing was continued for ten more hours in hopes that the tryptophan would get flushed down and decarboxylated. This did not happen, in fact it appeared that only decomposition of the product had taken place during the last ten hours.

Heating was ceased and the stopcock opened to allow argon from the bag into the apparatus as it cooled.

Before reaction


10 hours into the reaction


After 20 hours



To the cooled reaction mixture was added an equivalent volume (~125 mL) of 5% acetic acid, and the mixture was stirred for some hours with mild heating (<50°C). After this arbitrary period of time the mixture was gravity filtered through cotton twice and the layers were separated. The organic layer was extracted with a small portion of water and discarded. The aqueous layers were combined, filtered through cotton and heated to 65°C during which NaCl (50g) and water (50 mL) were added, and a clear solution was obtained. This was then refrigerated and slow crystal growth was observed over 2-3 days. After vacuum filtration and air drying 10 grams of tryptamine hydrochloride was obtained. The solution was concentrated to a volume of 200 mL by gentle heating and refrigerated to yield 5 more grams of product. The remaining solution was basified and extracted with ethyl acetate. The extracted product was taken up in dilute hydrochloric acid and the aqueous solution evaporated to dryness on a 75°C hotplate overnight which caused the product (approximately 2-3 grams) to decompose to an unknown extent. The decomposed material was discarded.

One gram of the obtained hydrochloride was dissolved in water with the help of microwave radiation and combined with 10 mL of 10% NaOH solution in a 25 mL beaker. A heavy amber colored oil separated and, after washing it with water, crystallized to a light brown hard, waxy mass. A portion of the solid material was placed in a test tube under mineral oil and the test tube was placed in a 116°C propylene glycol bath, causing the solids to melt completely.

Filtered aqueous solution


Tryptamine hydrochloride


Melting point test



The melting point test isn't perfect, but still leads me to believe that I've succeeded. The yield of obtained hydrochloride corresponds to 62.3% which isn't too bad, and will doubtlessly be improved by cutting the reaction time in half and being more careful during work up in order to obtain the last few grams from the salt solution.

During the reaction, I kept an eye on the escaping carbon dioxide by leading it through mineral oil. Based on approximate bubble size and frequency, I had estimated the reaction to take as long as nearly 200 hours. Fortunately this wasn't the case, but I can't help but wonder what happened to the carbon dioxide that was definitely evolved but didn't make it out of the system. My best guess is that it reacted with the imine and tryptamine carbonate was formed. To be perfectly honest, I have no idea if that's even possible.

The reaction proceeded nicely, the workup was great, the reagents were cheap the product was significantly cleaner. Overall this method is superior in every way compared to the one I opened this thread with.

I attempted the formylation route outlined by Shulgin, and it failed. This may be due to degradation of the intermediate during storage, as a dramatic change in appearance was observed.
I also attempted the reductive amination utilizing triacetoxyborohydride that was demonstrated in Hamilton's Pharmacopeia I did not have DCE, so I tried to replace it with a mixture of DCM (to better dissolve the supposed tryptamine) and THF (to act as the carrier for the reducing agent where the use of DCM resulted in a thick, unusable foam). After arbitrarily calling it, a definitely DMT-like sticky wax was effortlessly fished out from the reaction solution, that roughly corresponded to the expected product by mass. However, this material degraded on heating when it had been reacted with fumaric acid and dissolution in isopropanol was attempted. It may still have contained N,N-dimethyltryptamine, but the amount had to have been negligible. This may be due to stopping the reaction too early (NMT?) as the solvent system definitely wasn't ideal, or due to impure starting material.
Going forward I can finally utilize thin layer chromatography, and I've also placed an order for dichloroethane.

Another approach I want to try is the more direct approach to reductive amination using formaldehyde and borohydride at 0-5°C.

I will most probably dedicate a thread to the alkylations of tryptamine and, with any luck, 5-methoxytryptamine.


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ArbuzToWoda
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[*] posted on 18-3-2021 at 13:39


Looking forward to it. You're a godsend in matter of experimental observartions.
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[*] posted on 19-3-2021 at 16:26


I was thinking of this same reaction out of a list i want to do.
I have the DMSO, Acetophenone, acetonitrile and l-tryptophan.

Thanks for the writeup that i can use as a guide and I love your clever solvent extraction method because DMSO is a challenging one to use sometimes.

I will have tryptophan, doing the same reaction to see the results and i may post it if i am not lazy. It sounds like a fun experiment.

image.jpg - 1.3MB image.jpg - 1.4MB



[Edited on 20-3-2021 by ChemichaelRXN]




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[*] posted on 20-3-2021 at 06:23


Melatonin is not an amino acid, it can't undergo this reaction.



Reflux condenser?? I barely know her!
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ChemichaelRXN
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[*] posted on 20-3-2021 at 09:49


Sorry for the error, for some reason thinking melatonin had that carboxylic acid. You would need 5-Methoxy-L-tryptophan (CAS 25197-96-0) *
I will just start with mexamine if I needed it. I am still messing around with the Eschweiler-Clarke Reaction.

Have a nice weekend.




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njl
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[*] posted on 21-3-2021 at 07:26


Melatonin is nice because the hydrolysis is easy and clean, leaving fairly pure mexamine with just NaOH/H2O/Heat.



Reflux condenser?? I barely know her!
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