Decarboxylation of l-alanine, various musings

nyarlothotep · Fri Apr 15, 2005 6:42 am

Swin has been looking at this bugger.
Swin went thru that tantalizing idea in the nitroethane synth compilation ala Rhodium, and found why it was doomed to failure.

Swin sees the problem as such:
It's that fucking carbocation waiting to be formed.
Problem is, the alpha location of the amine gives it very little staying power.....during the decarboxylation under oxidative situations, that blasted N and it's happy pair of electrons goes skirting off willy nilly to seek its own destiny as a Free Gas in the realms of Atmosphere.

Now, dissuading Swinself from hunting amine protective groups (altho that would work), he proposes the following reagents for scrutiny:

Cu[II](something or other):
Based off of both biological theory (most decarboxylases have a central transition metal atom as their active core, quite often copper) and the tryptophan decarboxylation techniques described here: https://www.synthetikal.com/Rhodiums_pdfs/chemistry/tryptophan.html

Swin would propose an attempt to be made with, firstly, cupric acetate, and possibly other copper[II] compounds......sulfate working in this regard would be a glorious dream.

Ketone catalyst:
While not having found exact mechanisms proposed for this, it appears to be a versatile and fairly safe decarboxylation method.....clues as to how it proceeds would be welcome.

Looking at both l-tryptophan and l-alanine in some depth, Swin can't quite see any serious stabilization effects coming from that adjacent ring.......and would love to hear others views on that analysis(seeing as he is quite rusty in that regard)
Differences in logged decarboxylation temperatures between the two compounds suggest some action, however.

The damned amino acid will decarboxylate with sufficient heating.....problem is, that temp is ~60 degrees higher than the sublimination temperature, which makes for serious problems for amature chemists, or those not in a well equipped lab.

Swin thinks this is possible, altho will not be able to test for some time, due to unavoidable circumstances, but thinks these options hold enough merit to bring to light.

Thoughts?

IndoleAmine · Dreamreader Deluxe

I think if you want nitro(whatever) from an amine, you will have to oxidize it anyway, and this makes the use of protection groups unnecessary. Same applies for decarboxylation of an amine: no need to do it that way round, so why?

i_a

nyarlothotep · Sat Apr 16, 2005 4:38 am

l-alanine is an extreme example of an amino acid.
That nitrogen group will fall off under nearly any oxidative pressure. There's simply no reason for it to stick around.
And unlike glycine, which will retain the amine and oxidize it to the nitro group, the addition of the second carbon onto the chain allows for enough stabilization of the cationic form that's involved for the nitrogen to go skirting away.
So oxidative situations for inducing decarboxylation are out.
Even mild bleach solutions will torch it down to nothing useful, if there aren't any substituents other than hydrogen on the nitrogen.
Thermal decarboxylation of the straight amino acid takes place at too high of a temp.....shit subliminates lower than that temp.

Now, as was mentioned, Swin hasn't spent all that much time trying to figure out how a ketone would affect the group, but they have been used in the past for decarboxylation catalysts.
this article:
Chem Soc [Perkin 1]. 1968;4:406-10.

Schiff bases. I. Thermal decarboxylation of alpha-amino-acids in the presence of ketones.

al-Sayyab AF, Lawson A.

Is absolutely VITAL to the endeavour, but swin can't seem to find the fucker, as he is no longer within reach of any decent library, and askance of undergraduate friends for assistance has led to dead ends.

He's also spent some time reading over the book Java kindly provided on organocopper chemistry, but it's geared more towards actual reagents, and nothing all that specific on how the chelating process would take place.
That type of thing is a bit further than he's ever gotten in his home reading.
Finding a viable way to do this would be a great leap forward towards formation of ethylamine, and from there to nitroethane, if one were so inclined.

So unclear knowledge has led him to ask for views on the subjects, prior to his figuring it out himself.

(that and the fact that once swin has his mental teeth into an idea, he'll shake it till it either dissolves completely or gives up the goods) Twisted Evil

IndoleAmine · Dreamreader Deluxe

So (just for my understanding) alanine can't be oxidized to a nitro-carboxylic acid and then decarboxylated to a nitroalkane afterwards, because the nitrogen will be split off when oxid. is attempted, is this the problem that makes decarboxylation of the amine necessary? And are you sure about that?

nyarlothotep · Sat Apr 16, 2005 6:18 am

Absofuckinglutely.
Failures at all oxidative decarboxylation attempts that are performed on l-alanine are all that is in the literature, and various vain attempts to prove otherwise have met with utter failure.

EVERYTHING swin has read and everything he's pieced together about the reaction indicate that it is so. The reaction under oxidative conditions gives ammonia, carbon dioxide, and acetaldehyde.
The germ that sent him on this witchhunt was refuted by the contributer over at WD in a certain thread regarding nitroethane synths.
He's not ready to give up yet tho.

The hope placed in the two mentioned ideas lies in (with the chelating) some stabilization of the nitrogen by the copper atom (lots of decarboxylases use it)

He can't quite see how the ketone works (that ref previously posted would clear up that idea right fucking quick) but he assumes it to be some type of protecting group.
That reference has been requested of someone who can probably get it, but he's got licensing tests this weekend, so curiosity remains ravenous.

IndoleAmine · Dreamreader Deluxe

Suggestion: when you look up the requested article, be so kind and seach also for a synthesis of 2-nitropropanoic acid starting with alanine - there MUST be a way to oxidize the amine without effecting decarboxylation at the same time. Just in case your chelating plans fail, you know... Very Happy

(Maybe the carboxyl has to be protected somehow during oxidation?

Esterification? hm, ethyl-2-nitropropionate, sounds eazy.. Idea

)

greets

i_a

IndoleAmine · Dreamreader Deluxe

Or maybe start looking for a good yielding ethylamine synth, its maybe easier after all..
Laughing

i_a

nyarlothotep · Sat Apr 16, 2005 8:28 am

Heh....esterification might be interesting, but swin has no bloody clue how stable the nitro group would be as compared to the amine....suspects the same problems would arise upon attempted decarboxylation.
If neither of these two ideas pans out, protective groups are all that have a fighting chance, unless there is some amazing shit in the rarified atmospheres of acadamia that he hasn't come across yet. Sad

Can't find an entry for 2-nitropropanoic in MERCK, altho he did try.

At this point with alanine, it's not so much about finding something that works (altho that would be fucking great) as exhausting all possibilities so the idea can be layed to rest and exorcised from swins mind. Shocked

He didn't spend ~25 or 30 hours on this crap just to let the last few routes he can concieve slip away.
GOT TO KNOW Evil or Very Mad

Guest · Sat Apr 16, 2005 8:49 am

From what has been reported about the decarbox of alanine, it does seem that there are poor results being obtained,

I am not surprised, but dissapointed at the same time,
PPA goes through a decarbox , to form PEA, but I fear from little feedback that this is met with low yields aswell,

The decarbox of Glycine to Methylamine, works in theory, yet is so hard to reproduce in the lab, is the same fate destined for l-alanine as well?

syn

IndoleAmine · Dreamreader Deluxe

Decarbox is only a problem when oxidative rxn conditions are employed to turn NH2 into NO2 as far as I understand it.

And alanine is also called alpha-aminopropionic acid. To my knowledge, amino groups are inert to esterifications of carboxyl groups to esters.

So I think we can conclude that if propanoic acid can be esterified with 1-butanol to n-butyl propionate (cas# 590-01-2), it can also be done with L-2-aminopropanoic acid (l-alanine) to give butyl-2-aminopropionate, right? (note: propanoic is the same as propionic)

And then the amino group could be oxidized without affecting the COO- moiety, then one could hydrolyze the butylpropionate ester back to the carboxylic acid (with aequ. HCl?) to get nitropropionate, decarboxylate somehow, and voilà! - nitroethane...

(man how lucky I am to be able to buy this stuff!)

nyarlothotep · Sat Apr 16, 2005 9:31 am

It's the damned alpha position. That's the entire problem.
PhenylAlanine (meant that, right? Wink

) is a prime candidate for a chelation procedure.....assuming the interaction of a nearby aromatic ring to be crucial, as it might be.

Glycine to methylamine is just an ugly little peice, but swin'd be willing to assume most of the problems had are due to inadequate control of reaction conditions......don't wanna get that permanganate over excited......might tear the place apart.

Swin's not giving up, but first he's gotta get some of the Cu[II]acetate (seems best idea, if that works, he'll run analagous reactions with the sulphate) then run down some good sources, and then some DMSO or higher(!???) boiling solvent.....
He's currently hoping ferverently for that article to come thru, as it is a serious PITA to find, apparently.
Any and all asistance towards that or the aquisition of the references regarding the ketones as catalysts and chelations in the tryptophan decarboxylation reference would be MUCH appreciated.
Don't give up yet. Still a few things to look at and try.
If it's possible with anything easily aquirable, swin will find out.
And if it's not, well, he'll probably buy a case of beer and return to more trodden fields for a time. Mad

IndoleAmine · Dreamreader Deluxe

Yay, if it works out for trp decarbox via copper chelating agent, this would be a handy dandy route to tryptamine too (a topic that has given many bees grey hair already I guess Very Happy

)...

(*hope*)

Did you already request in "wanted refs"? Even if noone would be willing to get his ass up to the library for a nitroethane synth: I bet they would for a decent route to tryptamine from tryptophan... Wink

i_a

nyarlothotep · Sat Apr 16, 2005 10:20 am

Well, swius U.S. bees can't get none of that either.
But the rhodium document contained quite a few links to uploaded .pdf articles that are still freakin missing, but swin hasn't asked for them specifically, he was wasting time ruling out other ideas.

Both the chelation and the ketone catalysts do work according to vaguely remembered anecdotal reports, and they're straight ripped from the literature.
But lo and behold, the one regarding the chelation was never uploaded, and swin never had need of it prior to now, being more interested in the phenyls......got nice easy self-synthing ways to a decent variety of tryptamines that grow near him.

Besides, the decarboxylation as described with the chelation leads to some shitty yields. (~40%) the ketone catalyst seems to be the best idea, if it'll work.
But swin would prefer to know HOW it would go about working prior to his just blindly attempting it....call him academic, if you must.

nyarlothotep · Tue Apr 19, 2005 5:16 am

http://synthetikal.com/synthforum/viewtopic.php?p=3612#3612

Well, that is an interesting article. Seems that the addition of a aromatic, substituted ketone does some wonderous things in regards to decarboxylation.

In regards to alanine, the closest they came was leucine.....but here's how Swin sees the reaction taking place.
Since all the reactions that were entirely decarboxylative took place with "electron donating groups" (looking at methoxy, hydroxy) at ortho or para positions, he's got to think that there is a semblence of a bond formed between the carbonyl component and the nitrogen, stabilizing that, while the presence of a group that's prepared to donate electrons will assist in pulling off the carboxyl group.
Throughout the paper, it's always the ortho groups that result in the corresponding amine with no deamination.
So, looking at alanine's apparent desire to lose that nitrogen group, thoughts lean towards an ortho- or para-methoxy group on a benzealdehyde.

Now to find that other paper that the ketone catalyzed decarboxylations referenced in the Tryptophan synth come from.......this shit will probably work, albiet in some high boiling solvents and with some considerable experimentation. *if* it can work with a non-aromatic ketone (which seems unlikely) that would be amazing.

Any of you dreamers out there see any flaws?

java · Consumer

There was a study documented in the Pharmaceutical Society of Japan in 1954 , actually six articles , I was able to secure the last two in which they verify the claims of earlier articles . the title of the study "Reactions between Aromatic Aldehydes and alpha-Amino Acids" by Takagi, Ensaka, Mangyo and Sawai, unfortunately the articles are in Japanese but have some good illustrations.

I will scannn them and upload them in the hope that someone finds help in translating these articles..........java