Solvant-free Decarboxylation of Amino-acid

The standard decarboxylation method are not very good for L-tryptophan.

Refluxing in a high bp solvent with a ketone as catalyst give not really good yield and the reaction is long.

I never tried the chelate method but it seem to be not very interesting.

The best method I used is refluxing L-tryptophan in acetophenone (for 30 min to give 100% yield, no tryptophan formation) but the acetophenone is a problem : 1. formation of water dues to condensation of the amine/ketone imine formation. 2. Acetophenone is not easy to remove out from tryptamine.

But today, I had a new idea. I tried to heat 100mg of L-tryptophan on an aluminium paper in the same manner I did with lysine to form cadaverine when I was at school lol !
The CO2 is quickly envolved and it result a beautiful amber colored tryptamine crystal. The problem comes from the burner : the heat isn't steady and too high, this is the reason for black tar formation of some trial.

I'm thinking about a adjustable heater for gently decarboxylate the amino acid and easily collect the product as its liquid form.

Do you think is it possible to perform it to bigger amount of product ?

Quote:

Originally posted by manimal The uramido acid thus formed is converted to the hydantoin by evaporation to dryness with hydrochloric acid and the dry residue is dessolved in ether. The hydantoin crystallizes from the ether upon concentration. ....... A more efficient method of preparing the amino acid hydantoin would be useful, if anybody knows of such.

What do you suppose 'evaporation to dryness with HCl' means? One would assume its requires simply evaporating from an acidic medium of HCl?

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manimal - 30-6-2008 at 14:32

I guess it mean add some HCl and then let it evaporate.

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un0me2 - 17-6-2010 at 04:27

Quote: Originally posted by manimal

There is an old procedure in my book "Organic Preparations" by Conrad Weygand on how to decarboxylate alpha-amino acids: "The decarboxylation of a-amino acids can be carried out advantageously, according to Wada, through the hydantoins formed by reaction with urea. The hydantoins are hydrolyzed by concentrated alkalies or acids to form carbon dioxide and ammonia; thus, the basic primary amines are obtained in good yields according to the reaction: R*CH(NH2)*COOH + H2N*CO*NH2 --> H2N*CO*NH*CHR*COOH ---> R[ring](CH-NH-CO-NH-CO] + H2O ---> R*CH2*NH2 + 2CO2 + NH3 10 g of phenylalanine are boiled under a reflux for 35 minutes with an excess of urea (5 g) in 150 ml of water. The uramido acid thus formed is converted to the hydantoin by evaporation to dryness with hydrochloric acid and the dry residue is dessolved in ether. The hydantoin crystallizes from the ether upon concentration. The product (4.9 g) is refluxed for 10 hours with 70 ml of water and 20 ml of concentrated sulfuric acid. The solution is then made alkaline and extracted with ether. There are thus obtained 2.5 g of phenethylamine (80% of the theoretical amount) boiling at 189C. In place of urea, urethane, potassium cyanate, or phenyl isocyanate in neutral or alkaline solution may be used. Uramido acids or their salts are formed and these with dilute acids yield the hydantoins. Wada describes the decarboxylation of glycine, leucine, lysine, tyrosine, proline, tryptophan, arginine, cystine, aspartic acid and glutamic acid." A more efficient method of preparing the amino acid hydantoin would be useful, if anybody knows of such.

Manimal, could you please print the relevant pages (everything pertaining to the hydantoin route) out using primoPDF (or whatever) and then post the whole thing up here? I'd love to go through the basis of why he chose to do that and work out from there what exactly is going on.

Some of the old, particularly German (also Japanese) papers, dealing with decarboxylation, etc. to get interesting natural products are quite good reading... Have to keep brushing up on my German anyway (Rammstein is great for it)

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zed - 17-6-2010 at 21:26

The problems with high temp/ solvent free aminoacid decarboxylations, may be caused by a major side reaction.......polymerization.

In the ketone catalyzed reaction, the species decarboxylated is the imine produced by the reaction of the amino function and the ketone. Upon re-hydration, the resultant amine, and the solvent ketone are regenerated.

I would imagine the major competing reaction, would be the creation of complex polymeric amides. Peptide-ization. The reaction of the carboxylic acid and amino functions on adjacent molecules, may form amino-carboxylate salts. Heat then causes these salts to be dehydrated to amides. And on, and on, and on. In other words, it produces glop. Probably glop, that cannot be regenerated. Especially so, if it is well charred, because the hot reaction mixture, has not been protected from atmospheric oxygen.

Acetophenone works well. Why not use it? If you have trouble buying it......It's cheap and easy to make.

If you really must proceed with heat only, consider using a system that helps to prevent polymerization. Try to keep the individual molecules of aminoacid away from each other. Sometimes, heating very finely powdered material, well dispersed in white sand, will do the trick. Vacuum distillation from the hot reaction mass may be in order. Don't be surprised if you obtain solids or semisolids, when you were expecting liquid amines. Remember, the side products of this reaction will be H20 and CO2.....and THEY may combine to produce carbonic acid. Carbonic acid may then combine with your amines, to produce analogs of ammonium carbonate.

[Edited on 18-6-2010 by zed]

[Edited on 18-6-2010 by zed]

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gardenvariety - 18-6-2010 at 02:09

Regarding the workup with acetophenone, does it form a bisulphite adduct?

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Nicodem - 20-6-2010 at 13:40

Quote: Originally posted by un0me2

Quote: Originally posted by manimal   There is an old procedure in my book "Organic Preparations" by Conrad Weygand on how to decarboxylate alpha-amino acids:... Manimal, could you please print the relevant pages (everything pertaining to the hydantoin route) out using primoPDF (or whatever) and then post the whole thing up here? I'd love to go through the basis of why he chose to do that and work out from there what exactly is going on.

The hydrolysis of the alpha-amino acid derived hydantoins gives back the starting amino acid. Due to the weirdness of the claims, a group of researchers actually went so far as to repeat Wada's work and confirmed no decarboxylation occurs. I don't remember in which paper I read about this (and don't really have the time and will to again do a literature search), but it was when doing a literature search for the post here.

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Bolt - 29-11-2010 at 14:34

Here is Wada's publication (obviously in German).

I am quite interested in the work of the researchers who attempted to reproduce the decarboxylation. This would be an easy method of preparing valuable amines, if it works. Can anyone provide a reference for the more modern attempt?


Eine neue Methode zur Darstellung von Aminen aus Aminosäuren
Wada, M
Biochemische Zeitschrift 1933 pp. 47-51

Attachment: decarboxylation amino acid.pdf (1000kB)
This file has been downloaded 1506 times

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Bolt - 29-11-2010 at 19:33

In fact, I have looked up this reference in scifinder, and it shows no citing articles.

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Ozone - 29-11-2010 at 19:48

Very cool, Methyl.

Have you confirmed the identity/purity of your product? This could be a fairly big deal which would explain quite a bit about the anomalous color formation (e.g. Maillard reaction) which occurs in bulk raw-sugar processing.

I will, when I have time (God help me), give this a shot, and i'll run it on the MS. A source of (relatively) highly reactive amine would help to explain a good deal.

Cheers,

O3

[Edited on 30-11-2010 by Ozone]

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Sedit - 29-11-2010 at 20:00

On the reference that Bolt attached would any of our
German speaking bretheran care to translate Example 8 on page 4 title: Indolathylamin aus tryptophan. Perhaps theres something missing in modern reproductions or translations.

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Bolt - 30-11-2010 at 01:32

The following is a table of "easily" decarboxylated acids from March's Adv. O. Chem., 6th ed., p. 836.



The decarboxylation mechanism requires alpha atom to draw electron density from the carboxylate group. If the alpha atom is not electronegative enough on "its own," as is the nitrogen in the case of [carbamic] acids (R-N-C(=O)-OH), the beta atoms should be electronegative or at least electrophilic, as in the cases of the trihaloacetate example from the table and beta keto acid decarboxylation, respectively. The beta - gamma bond is often of an order greater than one (even if it is not a full two). See the beta,gamma-unsaturated acid example from the table. That example illustrates that inductive effects are only part of the mechanistic explanation, and the labile electron density in the pi bonds must have a similar result (decarboxylation). Note that the imino species that decarboxylates in the ketone catalyzed amino acid decarboxylations is not mentioned as an "easy" acid to decarboxylate.

In light of these observations, an acid of the structure R1-C(=O)-N-CH2-C(=O)-OH is also likely to be able to be decarboxylated due to the electronegative nature of the nitrogen atom as well as the partial double bond character of the beta - gamma bond. This molecule probably does not decarboxylate as easily as a molecule with a beta - gamma bond of two, as in the imino species. I wonder if that is the intermediate through which an "uncatalyzed" alpha-amino acid decarboxylation occurs - condensation with one of its own kind and then decarboxylation.

[Edited on 1-12-2010 by Bolt]

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Mush - 30-11-2010 at 03:14

Somebody somewhere translated that paper. Thanks for that!!

M. Wada - Biochem. Z. 260, 47, 1933

"Here's a translation of the interesting parts for non-German speaking chemists:


"It is known that, when amino acids are heated with urea, urethane (ethyl carbamate), potassium cyanate or phenylisocyanate, either in neutral or in basic solution, like a Ba(OH)2 solution, uramino acids are formed (1), which by the action of diluted acids easily form their anhydrides (hydantoins).

The author has now observed that these hydantoins by the action of concentrated acidic or alkaline solutions are converted to the corresponding amines.

Using this reaction the author has obtained phenethylamine, tyramine, methylamine, isoamylamine, histamine, putrescine, cadaverine, tryptamine, aminoethyldisulfide, pyrrolidine, beta-alanine and GABA from their corresponding amino acids. In every case the reaction was performed smoothly, and very good yields are obtained. Especially recommendable is this reaction for diamino acids, tryptophan, cystine etc."

Experimental part

Phenylethylamine from phenylalanine
10 g phenylalanine and 5 g urea (molar excess) were dissolved in 150 ml water and refluxed for 35 minutes. To convert the uramino acid to the hydantoin the solution was acidified with HCl, evaporated partly, and extracted with ether. After evaporation of the ether the hydantoin of phenylalanine was obtained as thin, long plates.

4.9 g of this hydantoin was refluxed with 70 ml water and 20 ml conc. H2SO4 for 10 hours, after cooling basified with KOH and extracted with ether. After evaporation of the ether phenethylamine was obtained as shiny plates, yield 2.5 g (80%), mp 189°C.


Methylamine from glycine
10 g glycine and 15 g urethane (molar excess) were dissolved in 50 ml 0.25M Ba(OH)2 and heated for 2 hours. After precipitating the baryta as the carbonate by passing CO2 through the solution, the filtrate was acidified with a couple of drops of HCl and the solution was evaporated. The hydantoin was not isolated, yet 50 ml conc HCl was added and this was refluxed for 10 hours, after which the major part of the solution was evaporated.

This caused the hydantoin to completely transform into methylamine, so that by addition of ethanol no hydantoin was precipitated, and the characteristic reaction (2) of amines with sodium nitroprusside and acetone was obtained.

The solution was decolorised with animal charcoal and picric acid was added. After evaporation the picrate was obtained as brightly yellow plates with mp 215°C. Yield: 29 g picrate (84%)


Tryptamine from tryptophan
1.3 g tryptophan, 0.5 g urea and 0.1 g Ba(OH)2 is heated in 10 ml water for 3 hours. A bit of HCl was added and the solution was evaporated in vacuo. The residue was again heated with 1.4 g Ba(OH)2 and 10 ml water for 1 hour. After precipitating the baryta as the carbonate by passing CO2 through the solution, the obtained tryptamine can be isolated as the picrate salt as dark red needles, mp 239-242°C. Yield: 1 g picrate (40%)


Beta-alanine from aspartic acid
2.2 g aspartic acid, 1.5 g urea and 2.2 g Ba(OH)2 were dissolved in 50 ml water and refluxed for 3 hours. It was then acidified with HCl and heated for 2 hours on the waterbath. To the solution was added 7 g Ba(OH)2 and this was heated for 1 hour, the baryta was precipitated as the sulfate, the filtrate was acidified with HCl and evaporated. Beta-alanine hydrochloride precipitates as small plates, mp 122°C, yield: 1.6 g (77%)


GABA from glutamic acid
10 g glutamic acid, 5 g urea and 10 g Ba(OH)2 were heated in 50 ml water for 2 hours. The baryta was precipitated with sulfuric acid, the filtrate acidified with HCl, evaporated and the residue was heated with 80 ml 30% H2SO4 for 8 hours. After removing the excess sulfuric acid with Ba(OH)2 the obtained GABA was isolated as the HCl salt. Feather-like crystals were obtained, which are slightly soluble in water. Yield: 7.8 g (82%), mp 135°C.

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fractional - 30-11-2010 at 04:46

Quote: Originally posted by Mush

Somebody somewhere translated that paper. Thanks for that!! M. Wada - Biochem. Z. 260, 47, 1933 "Here's a translation of the interesting parts for non-German speaking chemists: "It is known that, when amino acids are heated with urea, urethane (ethyl carbamate), potassium cyanate or phenylisocyanate, either in neutral or in basic solution, like a Ba(OH)2 solution, uramino acids are formed (1), which by the action of diluted acids easily form their anhydrides (hydantoins). The author has now observed that these hydantoins by the action of concentrated acidic or alkaline solutions are converted to the corresponding amines. ... Experimental part ... Tryptamine from tryptophan 1.3 g tryptophan, 0.5 g urea and 0.1 g Ba(OH)2 is heated in 10 ml water for 3 hours. A bit of HCl was added and the solution was evaporated in vacuo. The residue was again heated with 1.4 g Ba(OH)2 and 10 ml water for 1 hour. After precipitating the baryta as the carbonate by passing CO2 through the solution, the obtained tryptamine can be isolated as the picrate salt as dark red needles, mp 239-242°C. Yield: 1 g picrate (40%) i]

There is a mistake in the translation of preparation No. 8, Tryptamine from tryptophan (see above): Obviously the reaction of tryptophan, urea and baryte does not directly form the picrate. The original text states that: "... the thus formed indolethylamine was then transformed into its picrate (salt)..."

Following Sedit's request I have only read and translated preparation No. 8 (see below).
If there is an interest I can try to review the translation also for the rest of the paper.



Attachment: A new Method for the Preparation of Amines from Amino Acids.pdf (9kB)
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Bolt - 30-11-2010 at 14:23

So, I guess all that remains is experimentation..

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Nicodem - 1-12-2010 at 00:13

Quote: Originally posted by Nicodem

The hydrolysis of the alpha-amino acid derived hydantoins gives back the starting amino acid. Due to the weirdness of the claims, a group of researchers actually went so far as to repeat Wada's work and confirmed no decarboxylation occurs. I don't remember in which paper I read about this (and don't really have the time and will to again do a literature search), but it was when doing a literature search for the post here.

Quote: Originally posted by Bolt

Here is Wada's publication (obviously in German). I am quite interested in the work of the researchers who attempted to reproduce the decarboxylation. This would be an easy method of preparing valuable amines, if it works. Can anyone provide a reference for the more modern attempt? Eine neue Methode zur Darstellung von Aminen aus Aminosäuren Wada, M Biochemische Zeitschrift 1933 pp. 47-51

I'm surprised there is so much interest in something that makes no sense mechanistically. Basic hydrolysis of hydantoins might not be as well known as their enzymatic hydrolysis, but it is well known to give back amino acids rather than primary amines. In fact Ba(OH)2 is quite often used for this purpose! Don't you think that if it would give primary amines as end products, this would be mentioned by those many who reported the use of Ba(OH)2 for the hydrolysis of hydantoins? Yet nobody here bothered to check the literature before wasting further time:

An investigation of Wada's method of converting α-aminoacids into 2-substituted ethylamines.
H. Burton and P. F. Hu
J. Chem. Soc., 1949, 181-182
DOI: 10.1039/JR9490000181

Checking the literature is the first thing any researcher does, but apparently some forum members still believe doing this is a waste of time and prefer to waste time otherwise and to others.

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Bolt - 1-12-2010 at 04:09

Quote: Originally posted by Bolt

In fact, I have looked up this reference in scifinder, and it shows no citing articles.

Actually, I did check for citing articles using scifinder, but it showed none. Also, you claim that the decarboxylation makes no sense mechanistically. Lemme read the paper to see if it sheds any light on your attack.

Edit: Having read the article, I believe that all we can currently say is that the method failed in the hands of those authors. They say that the method is bunk 1) because they couldn't get it to work and 2) because the Rimini rxn could give false positives for the success of the reaction. Wada actually used mass spectroscopy and the melting points of the compound in question and often its picrate derivative to characterize his products.

No, I don't think we can throw out this method without further experimentation.

[Edited on 1-12-2010 by Bolt]

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Nicodem - 1-12-2010 at 09:12

Quote: Originally posted by Bolt

Quote: Originally posted by Bolt   In fact, I have looked up this reference in scifinder, and it shows no citing articles. Actually, I did check for citing articles using scifinder, but it showed none.

You can not rely on that. Those articles were abstracted way before citations were integrated into SciFinder (or WoS). Such a search would only give you recent articles citing the old one, but not also an old article citing an even older article. When you search the literature you really need to do it properly. Shortcuts like that are useless.

Quote:

Edit: Having read the article, I believe that all we can currently say is that the method failed in the hands of those authors. They say that the method is bunk 1) because they couldn't get it to work and 2) because the Rimini rxn could give false positives for the success of the reaction.

Well, the problem is that they are not the only ones who report that method does not work as described, though they are probably the only ones who directly evaluate it and say it explicitly. If you bother to search the literature for the hydrolysis methods from hydantoins into the corresponding amino acids, you will find plenty of more or less comparable reactions using all kind of hydroxides or carbonates as bases. Examples of acidic hydrolysis are harder to find though. The hydrolysis of hydantoins is simply too well known to give amino acids, while Wada was the only one ever reporting it giving primary amines. So either he was wrong or all later researchers (and even industrial processes) are wrong.

Quote:

Wada actually used mass spectroscopy and the melting points of the compound in question and often its picrate derivative to characterize his products.

Mass spectroscopy in the year 1933? There is no mass spectroscopy there. He only gives melting points and N elemental analysis. Besides, if you check, already the first experimental makes no sense. He claims the product was 2-phenylethylamine, yet what he obtained was a solid with the m.p. of 189 °C.

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Bolt - 1-12-2010 at 15:23

^ Oops, you're right, he just gives the N elemental analysis. And that "melting point" is a little strange.. maybe it's the boiling point? or the melting point of a salt or derivative? :\

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