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Author: Subject: Report on Decarboxylation of Tryptophan in various solvents
inertia
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[*] posted on 5-7-2014 at 09:00
Report on Decarboxylation of Tryptophan in various solvents


I've seen a few threads on this topic, but I'd like this to be a good reference to anyone trying to synth tryptamine.

3.0 g tryptophan in 100 mL toluene with methyl ethyl ketone catalyst (5 mL): Evolution of CO2 tapered by the 18th hour in reflux, ether extraction gave a 60% yield.

3.0 g tryptophan in 100 mL xylenes (o, m, p) with M.E.K. catalyst (5 mL): Evolution of CO2 tapered by the 5th hour in reflux, extraction gave 85% yield.

3.0 g tryptophan in 100 mL xylenes with acetophenone catalyst (5 mL): Evolution of CO2 tapered by the 4th hour in reflux, extraction gave 90% yield.

These were the most successful trials I had, most other solvents needed over a day of reflux and gave lower yields. If anyone has any better/different results, post away!
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Nicodem
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[*] posted on 6-7-2014 at 09:31


Quote: Originally posted by inertia  
These were the most successful trials I had, most other solvents needed over a day of reflux and gave lower yields. If anyone has any better/different results, post away!

Thank you for sharing, but do you mind sharing also a few more details, if available. What were the less efficient solvents tried? Did you characterize the product by any way (identity, purity, impurity profiles)? Did you try using any polar cosolvents, such as the addition of a small amount of DMSO (as reported to be beneficial on Hyperlab*)?

* In the Hyperlab post=570038 there is reported a decarboxylation with "90% yield, 94% purity in HPLC and 99% purity in NMR" using "L-tryptophan (51 g, 250 mmol), 5 mL of DMSO, 5 mL of caraway oil (containing 50% carvone) and 100 mL of turpentine".

Edit: I just noticed that you used a high dilution and catalyst loadings. Since tryptophan is poorly soluble in xylene even at reflux, this might explain your good yields (despite the absence of any cosolvent). Were the reaction mixture homogeneous from the start at reflux? Did you try with a lower amount of the solvent and/or different catalyst loadings?

[Edited on 6/7/2014 by Nicodem]




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quantime
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[*] posted on 6-7-2014 at 09:37
acetophenone


I was about to try this reduction in just acetophenone. Is that and idea you have tried? Acetophenone is a aryl keytone. Maybe the xylene is not necessary?

[Edited on 6-7-2014 by quantime]
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[*] posted on 6-7-2014 at 10:01


Acetophenone has been used with good results. See the other tryptophan decarboxylation thread.
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[*] posted on 6-7-2014 at 16:14


Thank you for sharing your notes!

I got also quite high yields, at least 80% after workup/purification via acid/base extraction followed by vacuum destillation with a cheap vacuum pump from ebay, when using turpentine as solvent and spearmint oil as catalyst (I think about 1 mL per 100 mL solvent if I remember well). I don't remember the clock but CO2 ceased also quite fast after only a very few hours, no reflux over night necessary. I don't know how much tryptophan I used anymore but I think much more than only 3 g/100 mL solvent, I think at least the double amount. The vacuum destillation left a some noteworthy dark tar which was not completly removable by acid/base extraction using CHCl3 as "defatting" solvent but final product was quite pure after destillation according to FTIR (compared to comercial p.A. tryptamine from Merck), only a few minor leftovers from both spearmint oil and turpentine could be seen which could removed by pulling them out of it under vacuum again while warming slightly if necessary.

Real turpentine is not everywhere easy to get though (locally here you can only buy synthetic subsitutes in most stores but I was able to order it in a paint store for 8€ per liter), but acetophenone and MEK are much harder to get here.

Though at least here you find oil from mentha spicata very easily OTC and it contains a lot (R)-(−)-Carvone which is a nice high yielding catalyst for this reaction.

PS: A friend of mine tried to use acetone as catalyst and xylene as solvent (both straight from local hardware store) but only got very low yields like maybe 20% after workup. He also got the same noteworthy dark tar left in the flask I got after vacuum destillation, he also wasn't able to remove completly by acid/base extraction. His product also showed visibly more impurities after vacuum destilation than my later attempt with turpentine+essential oil for some reason.

PPS: I heard that a great way to purify tryptamine(s), even better than vacuum destillation, is to dissolve them in an ether precipiate them with dry ice as carbonates.



[Edited on 7-7-2014 by Rabodon]

[Edited on 7-7-2014 by Rabodon]
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[*] posted on 8-7-2014 at 09:28


Okay this may be a silly question, but wouldn't the use of a pure ketone like acetophenone results in the formation of a whole bunch of junk? At those tempuratures aren't we looking at ideal conditions for a schiff-base condensation?
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[*] posted on 8-7-2014 at 09:56


^^^ Yes, I believe that this will be the major competing reaction. I suspect that the faster the decarboxylation can be completed the less tar will be produced. It is strictly an issue of the kinetics.



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[*] posted on 8-7-2014 at 10:25


There is information here and some intersting references ......solo


http://www.sciencemadness.org/talk/viewthread.php?tid=8574



Quote: Originally posted by solo  
Reference Information





One-pot Sequence for the Decarboxylation of a-Amino Acids
Laval, Bernard T. Golding
Synlett
2003, No. 4, Print: 12 03 2003.



Uploaded with ImageShack.us

Abstract
Treatment of an ?-amino acid with N-bromosuccinimide
in water at pH 5 or in an alcoholic-aqueous ammonium chloride
mixture, followed by addition of nickel(II) chloride and sodium
borohydride, effected an overall decarboxylation via an intermediate
nitrile to afford the corresponding amine in good yield.


[Edited on 26-7-2013 by solo]


[Edited on 8-7-2014 by solo]

Attachment: one pot sequence for the decarboxylation of alpha amino acids.pdf (66kB)
This file has been downloaded 837 times

[Edited on 8-7-2014 by solo]




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[*] posted on 8-7-2014 at 13:46


Quote: Originally posted by aga  
Zapata is Spanish for Shoe.

Of course Emiliano would prefer you to die on your feet, as he'll sell more shoes.


......not exactly a contribution to the topic "Report on Decarboxylation of Tryptophan in various solvents"

.....be creative and stay on topic, no need to insult .....solo




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[*] posted on 9-7-2014 at 12:40


Quote: Originally posted by Nicodem  

What were the less efficient solvents tried? Did you characterize the product by any way (identity, purity, impurity profiles)? Did you try using any polar cosolvents, such as the addition of a small amount of DMSO (as reported to be beneficial on Hyperlab*)?

[Edited on 6/7/2014 by Nicodem]


I attempted with pure MEK, which was a complete mess. From what I found, the higher boiling the solvent, the higher the yield and faster the reaction (as should obviously be expected). Poor results came from the use of acetone as a ketone catalyst or solvent, and the use of straight chain hydrocarbons, diethyl ether, THF, and ethyl acetate resulted in either no desired reaction, or i didn't have enough patience to see the reactions through.

Quote: Originally posted by Nicodem  

Edit: I just noticed that you used a high dilution and catalyst loadings. Since tryptophan is poorly soluble in xylene even at reflux, this might explain your good yields (despite the absence of any cosolvent). Were the reaction mixture homogeneous from the start at reflux? Did you try with a lower amount of the solvent and/or different catalyst loadings?


This was my thinking in setting up the reaction. In previous research I've done with low solubility reagents, I've had to use an extreme excess of solvent (research with large water-sensitive macrocyclic molecules). I didn't try a lower solvent to reactant ratio with this experiment, though. I wasn't particularly scientific about the amount of catalyst I used, but I kept it below 5 mL to eliminate any excess of side-products (particularly with acetone and MEK).

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[*] posted on 9-7-2014 at 13:08


Between my own experiments using the mineral oil/spearmint oil system and those of others I have corresponded with, I have also noticed that proper dilution provides good results. I believe that the more loaded the suspension (I have never really noted much, if any solvation of the tryptophan or tryptamine), the more likely di- and oligo-peptides and other byproducts are to form. The last time I tried, I proceeded as outlined in my posts in the other decarboxylation thread, but with 30 g tryptophan in 300 mL mineral oil with IIRC 3 mL spearmint oil. I also used 10% acetic acid in the extractions rather than 5%. The yield after workup was >90% based on tryptophan.
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[*] posted on 10-7-2014 at 03:50


Quote: Originally posted by inertia  

3.0 g tryptophan in 100 mL toluene with methyl ethyl ketone catalyst (5 mL): Evolution of CO2 tapered by the 18th hour in reflux, ether extraction gave a 60% yield.


I thought tryptamine was insoluble in ether. Or did you use another ether than diethyl ether?
Tryptamine properties Chemicalland
And toluene is also soluble in ether as far as I know.
Toluene properties
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[*] posted on 10-7-2014 at 10:11


I attached a patent regarding the purification via CO2.
DCM is used for tryptamine.

best regards
lullu

Attachment: US2943093.pdf (458kB)
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[*] posted on 13-7-2014 at 11:06


Quote: Originally posted by DirkDinkel  


I thought tryptamine was insoluble in ether. Or did you use another ether than diethyl ether?
Tryptamine properties Chemicalland
And toluene is also soluble in ether as far as I know.
Toluene properties


I removed toluene via vacuum and added diethyl ether to remove any remaining thryptophan/various other impurities and isolated the nondissolved solids.
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[*] posted on 14-7-2014 at 00:14


Quote: Originally posted by mnick12  
Okay this may be a silly question, but wouldn't the use of a pure ketone like acetophenone results in the formation of a whole bunch of junk? At those tempuratures aren't we looking at ideal conditions for a schiff-base condensation?

Acetophenone at least used to be among the preferred solvents for the thermal decarboxylation of substituted pipecolic acids under reflux, affirming the kinetics.
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[*] posted on 5-9-2014 at 05:42


Quote: Originally posted by Chemosynthesis  

Acetophenone at least used to be among the preferred solvents for the thermal decarboxylation of substituted pipecolic acids under reflux, affirming the kinetics.


I have used Acetophenone and it works great. Decarb starts around 150C which is much farther away from the decomposition point of tryptamine than the 200C that is needed for the mineral oil method. It runs less than and hour and no catalyst is required. That said, it is hard to get, is much more expensive than mineral oil or turpentine, and has an overpowering sweet almond smell that if spilled will be around for a few days.
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[*] posted on 17-4-2017 at 07:53


Quote: Originally posted by mnick12  
Okay this may be a silly question, but wouldn't the use of a pure ketone like acetophenone results in the formation of a whole bunch of junk? At those tempuratures aren't we looking at ideal conditions for a schiff-base condensation?


Probably, but ketimines are very hard to form even when trying to. See my post on my struggles trying to make these compounds. Schiff bases form easily from an aldehyde but even an aromatic ketone is hard to persuade to condense XD

The xylene and MEK route seems inexpensive so I'll definitely be giving that one a try, but a quick question: I'm planning on getting my tryptophan from nutritional supplements, should I extract the pure tryptophan before attempting the decarboxylation? I assume leaving in the fillers/binders would lower the yield but it may be more cost efficient than running an extraction.
Where did you guys get your tryptophan from out of curiosity?
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[*] posted on 17-4-2017 at 13:15


Has benzophenone been tried as catalyst? It's my understanding that this is more accessible than acetophenone but it is not enolizable which may pose some difficulty.

Quote:
Treatment of an ?-amino acid with N-bromosuccinimide
in water at pH 5 or in an alcoholic-aqueous ammonium chloride
mixture, followed by addition of nickel(II) chloride and sodium
borohydride, effected an overall decarboxylation via an intermediate
nitrile to afford the corresponding amine in good yield.

In some refs NBS will oxidize indole to oxindole; is that going to be a problem here?

https://en.wikipedia.org/wiki/Indole#Oxidation_of_indole
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[*] posted on 17-4-2017 at 13:49


@clearly_not_atara, why do you think it plays a role if the ketone is enolizable? The biocatalytic equivalent is pyridoxal phosphate - an aldehyde and cofactor in L-amino acid decarboxylases. Long time ago I've performed a successful decarboxylation of phenylalanine in pure benzaldyde at around 150 °C. Yield was almost quantitative after acid base extraction. I contribute this just because benzaldehyde is not reported as far as I know. For tryptophane there might be a risk of condensation giving beta-carbolines.

edit: I think I got you wrong, I didn't realize you actually talk about enamine, not enol. Anyhow, the aromatic ring delivers resonance stabilization.

[Edited on 17-4-2017 by Alice]
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[*] posted on 15-9-2020 at 14:31


Does the decarboxylation of tryptophan produce Skatole as a side product? I'd like to try this reaction but cannot afford the stank of shit to linger in the surrounding area.
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[*] posted on 15-9-2020 at 22:25


Many claim that it does. I did it a couple times and it stank, but I don't think it was feces-like. It's a characteristic, lingering smell. Neat acetophenone decarb limits the smelly compounds well, I believe.

According to this paper (which you have probably seen a hundred times) indole based side products are produced.

Attachment: brandt2006.pdf (596kB)
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[*] posted on 16-9-2020 at 09:22


It does produce something "shitty". :-) Not too much, not too bad but I could definitely smell something.
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[*] posted on 23-9-2020 at 05:10


I've had good and bad yields with neat acetophenone. My most recent run was with 200 mls and 40 g of tryptophan. I ran it overnight and after workup I didn't get shit, but left in the boiling flask is a nice pretty layer of tar that won't come off even after 2 days of soaking in an NaOH bath. My advice to everyone is hold the reflux below 180 until the sound of frying food stops, then do the usual a/b extraction once its cooled. There's is definitely decomposition products that form but what surprised me is that the boiling flask will look as if everything is normal until it cools, and then the tar comes.
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