Sciencemadness Discussion Board - Decarboxylation of AA's

Decarboxylation of AA's

Znoble - 12-12-2013 at 14:28

edit: It was pointed out to me that I didn't clearly state the intention of this thread when I posted it, so I'll state it here: I'm trying to design a one-pot reaction that will decarboxylate then dialkylate amino acids.

I plan on attempting the reaction on phenylalanine to begin with, then tyrosine, then proline. My focus is going to be on aromatic AA's. I'm purposefully avoiding tryptophan, as

#1. DMT is illegal.
#2. The indole skeleton would almost certainly guarantee
pictet-spengler formation, aka the reaction wouldn't work

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I had this nifty idea for a decarboxylation-alkylation reaction that I'd thought I'd run past you guys.

http://www.versuchschemie.de/upload/files2/96730940_2807.pdf

So this is a pretty nifty and green reaction IMO. I guess my question is, if the amine in question was a carboxylic acid, would the formation of the imine initiate decarboxylation? Or would some chemical property of amino acids prevent this from happening?

[Edited on 13-12-2013 by Znoble]

zed - 12-12-2013 at 16:27

As I recall, the imine is an intermediate in the decarboxylation reaction. The imine of an amino acid does not immediately decarboxylate. If it did, the procedure whereby amino acids may be racemized via refluxing with a ketone at ordinary temperature....well it wouldn't work.

Of course, I'm just hoofing it. Somewhere, in the dark remote recesses of my vast labyrinth of dusty books and papers, I have some interesting, long forgotten papers on the subject. I would be happy to share them when they are unearthed, but don't hold your breath. They have been buried since long before the age of Rhodium.

[Edited on 13-12-2013 by zed]

Znoble - 12-12-2013 at 20:29

Ya know what, I might just make this my first home experiment. I'll try it with phenylalanine first. If it doesn't work with a near stoichemetric quantities (like 1.5 eq) I might try forming the tertiary amine, as forcing it through the quaternary salt could give that carboxyl group the nudge it needs to decarboxylate.

Nicodem - 13-12-2013 at 06:41

Quote:

I guess my question is, if the amine in question was a carboxylic acid, would the formation of the imine initiate decarboxylation? Or would some chemical property of amino acids prevent this from happening?

It appears to me that you did not read the article (or its title?) or at least checked the examples, or else you would not ask this question: see examples 18-26 in Table 1 (they are all amino acids).
The formation of an imine from an alpha-amino acid does not automatically cause its decarboxylation, it only catalyses it. It still requires some activation energy. Even the beta-keto carboxylic acids do not decompose at room temperature, they require heating (they are isoelectronic to N-methylidene amino acids, at least in the relevant part).

Znoble - 13-12-2013 at 06:48

I'm aware that all the substrates in the article were AAs, and I wasn't planning on using the same conditions... I would probably try adding catalytic amounts of spearmint oil during the reaction, and, of course, higher reaction temps. I made that first post right before I had to go somewhere, so I was in a bit of a rush. Sorry for not clarifying.

Another problem that would pop up (esp. with phenylalanine/tryptamine) is the pictet-spengler formation.

Also, does anyone know what sort of effect pressure has on decarboxylation?

[Edited on 13-12-2013 by Znoble]

[Edited on 13-12-2013 by Znoble]

Nicodem - 13-12-2013 at 07:04

Please elaborate on what your talking about. I'm sorry, but I don't understand what it is that you want. You can edit the post above.

Znoble - 13-12-2013 at 08:23

http://www.erowid.org/archive/rhodium/chemistry/tryptophan.h...

About halfway down the page they talk about spearmint oil catalyzing decarboxylation. Their methodology was garbage, but still, it's a cool idea. I think they cite a russian article (IIRC), but I haven't read it.

And this: http://en.wikipedia.org/wiki/Pictet%E2%80%93Spengler_reactio...

It can happen with phenylalanine too, so its something to watch for. I need to do a bit more research for sure, but I'm glad to have some constructive criticism.

edit: I've been doing a bit more thinking...

http://www.beilstein-journals.org/bjoc/content/pdf/1860-5397...

This article details a reductive amination that occurs under BASIC conditions. This would discourage the formation of the pictet spengler product, and also encourage decarboxylation. However, it stops at the secondary amine. This problem could be solved by having the reaction be a two part, one pot reaction. The second part would involve adding an excess of an acid. This would encourage the formation of the tertiary amine.

1. Amino Acid + Aldehyde + zinc -----basic conditions--->secondary amine

2. secondary amine + aldehyde + zinc -----acidic conditons---> secondary amine

[Edited on 13-12-2013 by Znoble]

[Edited on 13-12-2013 by Znoble]

Nicodem - 13-12-2013 at 08:52

Not that. I did not ask what a decarboxylation and the Pictet-Spengler reaction is.
I can't figure out what is it that you want to do. If it is about a specific experiment, please describe it, explain what it is about and what your goal is. I thought you were asking if decarboxylation would occur when applying the Tetrahedron Lett. 48, 7680–7682 method on alpha-amino acids, but that would be a question too stupid as the article already reports such experiments. But if that is not what you are asking, then I know nothing about what the topic of this thread is supposed to be. So for the last time, please explain so that there can be any discussion here.

Znoble - 13-12-2013 at 08:55

Oh, my bad, I didn't understand what you were asking for. Basically, I want to design a one pot reaction that begins with an amino acid and ends with an N,N dialkyl amine.

I plan on attempting the reaction on phenylalanine to begin with, then tyrosine, then proline, then maybe histidine. My focus is going to be on aromatic AA's. I'm purposefully avoiding tryptophan, as

#1. DMT is illegal.
#2. The indole skeleton would almost certainly guarentee
pictet-spengler formation, aka the reaction wouldn't work

[Edited on 13-12-2013 by Znoble]

I Like Dots - 13-12-2013 at 11:21

As for decarboxylation and solvent/catalyst pairs and Pictet-Spengler, see the article Nicoderm posted here. https://www.sciencemadness.org/whisper/viewthread.php?tid=99...

They don't have Acetophenone listed, what are the chances of a ring closure happening here?

Its pretty obvious he is looking to create a one-pot DMT synthesis.
Oh, maybe you are not. I spoke too soon. Even if you were, its not taboo. It is all theory anyway.

[Edited on 13-12-2013 by I Like Dots]

Znoble - 13-12-2013 at 11:40

Quote: Originally posted by I Like Dots

As for decarboxylation and solvent/catalyst pairs and Pictet-Spengler, see the article Nicoderm posted here. https://www.sciencemadness.org/whisper/viewthread.php?tid=99...

They don't have Acetophenone listed, what are the chances of a ring closure happening here?

Its pretty obvious he is looking to create a one-pot DMT synthesis.

For the record, I am not going to synthesize drugs, and even if I did, I understand that open discussion is not welcome on this site. I do intend to confirm any theories that may develop on this site through legal methods, and would be happy to share the results with the general community. I think that I've shown in the above discussion I have a legitimate interest in chemistry, and I hope that you will appreciate that and let me try to contribute to this community.

Quote:

Oh, maybe you are not. I spoke too soon. Even if you were, its not taboo. It is all theory anyway.

Thank you. I appreciate the clarification that theory is welcome.

[Edited on 13-12-2013 by Znoble]

killer_lapin - 13-12-2013 at 13:00

You can decarboxylate AA with high boiling point ketones in PEG or high alkane without acids or base. it has been done with Phe, Tyr, Trp and so on... The schiff base of the decarboxylated AA was found along the free amine. From what i understood from the paper, zed is right and the imine is just an intermediate. And if you use a high alkane like kerosene with a dean-stark you can remove the water and promote the imine formation.

Also last year i looked for pictet spengler reaction and it seems that if you're not using formaldehyde the reaction is not really fast. But it's hard to find good information on this reaction.

zed - 13-12-2013 at 17:46

So, are you suggesting, dimethylation of the amino function of an amino-acid, followed by decarboxylation. Sure, why not? But, don't expect it to be easy. You are on unfamiliar ground.

These amino-acid decarboxylations, proceed via the imine. To my way of thinking, your dimethyl-amino-acid, cannot form an imine. So Ketone catalyzed decarboxylation, cannot proceed. At least, not at comfortable temperatures.

Of course, a bacterial enzyme system could perform the decarboxylation easily. But, that's not really fair. Bacteria can do anything.

Doable, but I don't know how.

Znoble - 13-12-2013 at 21:04

Quote: Originally posted by zed

So, are you suggesting, dimethylation of the amino function of an amino-acid, followed by decarboxylation. Sure, why not? But, don't expect it to be easy. You are on unfamiliar ground.

These amino-acid decarboxylations, proceed via the imine. To my way of thinking, your dimethyl-amino-acid, cannot form an imine. So Ketone catalyzed decarboxylation, cannot proceed. At least, not at comfortable temperatures.

Of course, a bacterial enzyme system could perform the decarboxylation easily. But, that's not really fair. Bacteria can do anything.

Doable, but I don't know how.

I think that decarboxylation followed by alkylation would be a much better order.

The conditions that decarboxylation and reductive amination occur under are pretty different, so I think that it would probably be necessary to have two steps. I was thinking the first step would be zinc mediated alkylation under basic conditions. I'm pretty sure that the basic conditions coupled with the formation of the imine and high temperatures should be enough to initiate decarboxylation, but if not, I could always try spearmint oil or a ketone.

source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170205/

Step two would involve neutralizing the base, then adding an acid to drive the secondary amine to the tertiary amine.

killer_lapin - 13-12-2013 at 21:39

You can still decarboxylate the AA and then from the residual decarboxylated imine add the zinc and acid to reduce the imine. From that you could add an other ketone and form asymetric tertiary amine from an other imine intermediate.

solo - 13-12-2013 at 21:57

Reference Information

One-pot Sequence for the Decarboxylation of a-Amino Acids

Laval, Bernard T. Golding
Synlett
2003, No. 4, Print: 12 03 2003.

Attachment: aminoacid.decarboxylation.pdf (66kB)
This file has been downloaded 571 times

[Edited on 15-12-2013 by solo]

Znoble - 15-12-2013 at 11:23

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.

[Edited on 15-12-2013 by solo]

Not quite what I'm looking for... Thank you though. This type of reaction is very much so charted ground. I would like to avoid hydrides too, and stick to "green", sustainable reagents. Yeah, I'm a bit earthy, get over it

I think zinc has some very interesting reductive properties that could be useful to this sort of reaction, so I'm going to keep delving into the lit and seeing what pops up...

[Edited on 15-12-2013 by Znoble]

killer_lapin - 15-12-2013 at 14:33

There is this paper about decarboxylation of amino acids with ketones( with isolable imines

), it's in french tough.
La décarboxylation thermique des alpha-acides aminés

I'm in my finals now so I don't have time to translate it, but I could do it after if you want. I think sciencemadness community would also appreciate.

solo - 15-12-2013 at 17:15

.....at a lost what you are looking for , but here is some more info......solo

http://www.erowid.org/archive/rhodium/chemistry/trp.decarbox...

Znoble - 15-12-2013 at 17:22

Quote: Originally posted by killer_lapin

There is this paper about decarboxylation of amino acids with ketones( with isolable imines

do you know of an article that clearly states what the mechanism of decarboxylation is? I wonder if an aldehyde could substitute... I'm a first year college student, so I haven't taken anything past basic chem yet.

Znoble - 15-12-2013 at 18:27

Quote: Originally posted by solo

.....at a lost what you are looking for , but here is some more info......solo

http://www.erowid.org/archive/rhodium/chemistry/trp.decarbox...

I'm trying to do original research on an OTC and safe method of producing tertiary amines from amino acids. I'm putting the research on this site because I know there are kindred spirits out there who share interests in this type of reaction.

solo - 15-12-2013 at 18:30

.......I guess they haven't thought you how to do research,....you better learn, here is some basic info on decarboxylation....solo

Attachment: decarboxylation reaction.pdf (111kB)
This file has been downloaded 4539 times

killer_lapin - 15-12-2013 at 19:12

I think in the same paper there is a part about the possible mechanism. But it sure passes by an imine. because dialkylated AA can not be decarboxylated.

Znoble - 15-12-2013 at 19:59

Quote: Originally posted by killer_lapin

I think in the same paper there is a part about the possible mechanism. But it sure passes by an imine. because dialkylated AA can not be decarboxylated.

I've tried to say this before, but clearly I'm not being clear: I understand that a tertiary amine cannot be decarboxylated. I've been busy with finals, wrapping up my semester (grants n wutnot), and my job, so yeah, I haven't had a lot of TIME for research. I'm intending on buckling down over winter break and figuring out the nitty gritties of whether a reaction like this (decarboxylation followed by reductive amination, with zinc as the reductive agent) would work. I understand that research involves a good deal of legwork, I just haven't had time for anything but big ideas with little substance. I shall hasten.

EDIT: I've read all of the articles you posted trying to help me understand what decarboxylation is: I do understand. If it's on rhodium, trust me, I've read it.

I understand that oxidative conditions initiate decarboxylation, (and that ketones oxidize the amine to the imine, initiating decarboxylation). The order of the reaction will be decarboxylation, then reductive amination. I'd like it to be one pot, and to only use very accessible reagents. Obviously, some of you understand what the end goal of this project, and I would like to clarify that if at any time I am no longer welcome on this forum, a mod can PM me and I'll leave.

[Edited on 16-12-2013 by Znoble]

killer_lapin - 16-12-2013 at 13:36

One pot doesn't always mean that you mix all the reagent and turn te heat on. What we've been trying to say is that you add the reagent to decarboxylate and then you do the reduction, without a purification in between. That is still called a one pot synthesis.

[Edited on 16-12-2013 by killer_lapin]

I Like Dots - 18-12-2013 at 09:56

What would reduce an Amine, but not a Ketone? Sodium triacetoxyborohydride? Sodium cyanoborohydride?

solo - 18-12-2013 at 10:59

Quote: Originally posted by I Like Dots

What would reduce an Amine, but not a Ketone? Sodium triacetoxyborohydride? Sodium cyanoborohydride?

.....reduce an amine to what?...solo

I Like Dots - 18-12-2013 at 12:38

I am not sure if "reduce" was the correct terminology, but I was meaning add an alkyl group to form a secondary or tertiary amine. a nucleophilic aliphatic substitution may be what im trying to say.

solo - 18-12-2013 at 13:27

....then look for methylation of amines to secondary or tertiary whichever you are seeking on google.....or here on the search function ....solo

turd - 18-12-2013 at 13:50

Then you want to reduce an imine or an enamine intermediate.

And yes, sodium cyanoborohydride is the classical reagent for this and the reason why it is for example used in the MDA synthesis:
https://www.erowid.org/library/books_online/pihkal/pihkal100...

Trialkoxyborohydrides are the more modern versions.

But since you know these reagents and this is even detailed on their wikipedia page and there are reviews freely available on the net - why do you even ask?

I Like Dots - 18-12-2013 at 15:31

Quote: Originally posted by turd

... why do you even ask?

Im getting to that

Znoble is trying to decarboxylate and alkylation using a one-pot approach. From what i've been reading decarboxylating in Acetophenone seems good due to its high boiling point and high conversion rate. But the high boiling point plus the fact it wont form a bisulfite addition makes purifying your amino acid hard.

Unless you could just drop in some sodium cyanoborohydride, and MeOH and call it a day.

Nicodem - 19-12-2013 at 06:33

Quote: Originally posted by I Like Dots

But the high boiling point plus the fact it wont form a bisulfite addition makes purifying your amino acid hard.

Unless you could just drop in some sodium cyanoborohydride, and MeOH and call it a day.

Please have the decency to at least read some basic level chemistry textbook before you clutter threads with nonsense. Or better yet, have the dignity of not posting on topics you don't have the slightest clue. Don't threat this forum as a trash bin.

I Like Dots - 19-12-2013 at 07:29

Oh, sorry. I was thinking of something I read, but I had the info wrong.
Anyway, I don't like how you make all these assumptions about me. I am interested, and I do try.
Don't you think that was a little harsh?

Anyway, I read http://www.sciencemadness.org/talk/viewthread.php?tid=23682 and wondered if you could use acetophenone instead of THF. But no, that's wrong because the formalin is not miscible with it.

zed - 19-12-2013 at 17:47

Dialkylated amino-acids CAN be decarboxylated. But, perhaps not by the means with which we are most familiar.

As I recall, the gas-gangrene bacteria can perform this little wonder easily. Though I may be recalling incorrectly.

Might try heating up such an amino-acid, under vacuum, just to see what happens. Since there are no hydrogens available on the amino function, amides cannot be formed. So, dialkylation should also prevent polymerization.

solo - 20-12-2013 at 08:22

Quote: Originally posted by zed

Dialkylated amino-acids CAN be decarboxylated. But, perhaps not by the means with which we are most familiar.

As I recall, the gas-gangrene bacteria can perform this little wonder easily. Though I may be recalling incorrectly.

Might try heating up such an amino-acid, under vacuum, just to see what happens. Since there are no hydrogens available on the amino function, amides cannot be formed. So, dialkylation should also prevent polymerization.

......good idea I might just give it a shot, ....solo