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dr. nick
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decarboxylation of phenylalanine
Hey! Not sure if this is the right forum, but as i'm definitely a beginner, here it goes:
Can any one give me some hints on the practical procedure of the decarboxylation of phenylalanine to
phenylethylamin?
Any reply highly appreciated, there's so much theoretical general stuff to find but nothing practical ...
Thanks!!
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Esplosivo
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First of, the reaction you mention is no decarboxylation. The addition of an ethyl group to the benzene ring is referred to as an alkylation, which is
usually carried out by Friedel-Crafts alkylation technique.
It basically involves anhydrous AlCl3 as a catalyst and chloroethane and refluxing. You may have some problems due to the oxidation of phenylamine and
also due to its decomposition at its boiling point. I would suggest working to your product by first obtaining ethylbenzene, nitrating this and then
reducing the nitro group ta an amine. This will produce the ortho- (2-) or para- (4-) methyl isomer though.
You could produce the meta- (3-) isomer by protecting the amine group. This can be done by reacting phenylamine with an acid chloride or an acid
anhydride producing the respective substituted amide. On this produt Friedel-Crafts alkylation could be carried out. Hope this helps.
[Edited on 23-1-2005 by Esplosivo]
Theory guides, experiment decides.
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sparkgap
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Uh, Esplosivo, you seem to be confused.
dr. nick was asking about the conversion from phenylalanine to phenylethylamine, or, as I prefer to call it, phenethyl amine (PEA).
That is a true blue decarboxylation:
Ph-CH2-CH(NH2)-COOH --> Ph-CH2-CH2-NH2
You most likely confused it with ethylaniline, from the synthesis you gave.
Matter of fact, something similar happens to both histidine and tryptophan, the first being converted to histamine; the second being converted to
tryptamine.
As to dr. nick's question, I am not at all aware of decaboxylation reactions for amino acids save enzyme-mediated ones. These, I am sure, were
the ones you found during your search.
Sorry for not of being much help.
sparky
(edit: misspelling)
[Edited on 23-1-2005 by sparkgap]
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JohnWW
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Amphetamine or benzedrine (a powerful stimulant, C6H5-CH2CH(CH3)-NH2) , mescaline (an hallucinogen, 3,4,5-trimethoxy-1-phenylethyl(2-amine)),
serotonin, adrenalin, and noradrenalin, along with LSD and opiates (with much more complex structures) like morphine and codeine and heroin, are all
derivatives of phenylethyl-2-amine, C6H5-CH2-CH2-NH2, which Dr Nick wants to make from decarboxylation of the amino-acid phenylalanine. Am I correct
in assuming that Dr Nick wants to use the phenylethyl-2-amine produced to make one of the above derivatives?
In practice, however, while decarboxylations are exothermic because of the stability of CO2, special groups usually have to be present in the molecule
for it to occur sufficiently readily to be useful in synthesis; for example, beta-keto-acids which form a ketone and CO2. Aromatic carboxylic acids
decarboxylate when their salts are heated with Cu and quinoline and an alkali, although these are very "forcing" conditions.
In the Hunsdiecker reaction, the Ag salt of a carboxylic acid is heated with Br2 in CCl4, resulting in the -COOH being replaced by Br, along with CO2
and AgBr. But then you would have to find some way to reduce the Br to H; reaction with Zn and aqueous acid should do it, taking advantage of the
exothermicity of production of ZnBr2.
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solo
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Ref: Decarboxylation
Here is a procedure from the Rhodium files.......solo
Decarboxylation of phenylalanines to phenethylamines
by Ritter
[ Back to the Chemistry Archive ]
Procedure
Mix 10g phenylalanine isomer of your choice in 50ml cyclohexanol. Add about 0.1 to 0.3ml cyclohexanone. Amino acid will not dissolve in cyclohexanol
until it is pretty hot. Bring mix up to about 140°C. Rapid and somewhat violent decarboxy-lation will start. The soln will bubble like beer (CO2
release) and slowly turn a light yellow. An interesting crackling noise is produced as temp gets up to reflux point (161°C) that sounds like popcorn
popping. It is actually pretty startling when done on a larger scale! When CO2 emission comes to a halt after about half an hour cool mix and extract
w/ dilute HCl. Basify HCl extract to isolate the pretty pure phenethylamine as a light yellow fishy smelling liquid. Yield unfortunately is variable -
anywhere from 4-8g has been isolated from this rxn. I'm sure other high BP solvents will work fine, cyclohexanol happens to be what was at hand.
[Edited on 23-1-2005 by solo]
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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Esplosivo
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Damn, sorry my bad. Thought it was phenylamine not phenylalanine. Sorry again.
Theory guides, experiment decides.
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dr. nick
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hey, cool!
thanks all!!
but i guess cyclohexanon can not be substituted with anything else, right?
that's why i love this part of chemistry, one never get's in danger because one never comes to a reaction, every time one problem is solved
another 2 turn up
that's what i would call "built in safety", arrr  
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enima
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the cyclohexanone can be replaced with any other ketone, it acts as a catalyst, acetone or methyl ethyl ketone can be used here.
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trilobite
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The acetone or MEK might reside mostly in the vapour phase at that temperature.
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dr. nick
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Hey all, thanks for the hints!
it's some time gone meanwhile, and after talking to some other interested people the procedure was changed in so far, that Paraffinum Liquidum
was used instead of Cyclohexanol and the whole thing was started in a micro test run:
2g of l-Phenylalanin, 10ml of Paraffin Oil and 0.5ml Cyclohexanon where heated in a test tube with a thermometer over an open flame in an "oil
bath" (some oil in a tin cup). Even at over 160 C the Phenylalanin did not resolve. The Liquid became pretty yellow, but the phenylalanine seemed
to be still on the bottom of the tube ...
Also there was nothing like crackling noises - everything was dead silent 
Don't know what to think now - is that normal? Or is there something wrong with the Paraffin Oil? Hm ...
any hints anyone?
Thanks!
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dr. nick
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now same was tried with cyclohexanol instead of paraffine oil, everything went like in the write upbut - the PA still didn't dissolve ...
No Clue, no end in sight. The work up is also still a riddle to swim ...
Maybe the reaction can not be scaled down like dr. nick did?
darn, it's all so confusing. Can Phenylalanine become old?
After the reaction just acidify with diluted HCL? How? Adding some drops of it? Adding watery solution with a ph of 7, 6,5 ... ? What's the sense
of this step? Salting out the wanted PEA.hcl? After that one can simply evaporate the water? What about the cyclohexanol - it is water soluble, not
very much, but still ... And then? Basifying? What for? To get the freebase again? How to get that freebase out of the lye water? With non polar
solvent?
arrr, swim's cracking ...
Help, please, if anyone can ...
Every hint very welcome, swim don't get it anymore ... *sob*
Also that smell of toluen and stuff makes swim sick. rather sniffing acetone than this all the time. toluen smell has something of
sugar-sweet-smelling-dog-shit ... bwaark
[Edited on 23-6-2005 by dr. nick]
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dr. nick
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ooouh pleeease - does really noone have any idea?!?
please help a stupid newb before his weak blockhead
pops up at the wall ... err, if you get what i mean ...
Any hints on isolating or every others step in this procedure very welcome, also interested in the theorectics behind this! I'm sorry, no clue
what i could offer for a hint,
i maybe could dance around on the street on one leg one finger in every nose hole, chanting "bah-bah, white sheep" or what ever may please
my potential saviour ...
(argh, forgive me, going nuts, trying and trying. maybe it's also that f***ing toluene ... ) Where ever swim searchs there's no practical information to find (at least not practical for swim) and noone
seems to know anything on this. is this really that much off key/uncommon/dumb?
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Cloner
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i think dissolving stuff is pretty necessary in any reaction. If molecules don't meet each other, they don't react and for this reason you
need the stuff somewhat soluble in the chosen liquid.
I don't know the reaction but it looks like you need only two things: a high boiling ketone and a high boiling solvent that dissolves both the
ketone and the phenylalanin. Perhaps other solvents will do a better job, like diglyme, DMSO, even glycerol?
Dissolving phenylalanin wil also be PH influenced. Would it help dissolving in a minimum amount of water and then adding to cyclohexanol?
The HCl step is meant for getting the HCl salt of the product. It is an amine, which is not soluble at all in water by itself but when ionized to
ammonium form, it is very soluble. So the product enters the water phase and after one or more extraction steps you don't seem to need to boil it
out at all since simply basification will make it insoluble in water again. No nonpolar liquids, it will come out of the water by itself. You might
extract the water afterwards just to be sure you got it all though.
[Edited on 4-7-2005 by Cloner]
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dr. nick
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Wow, Cloner - Thank you!!
I was about to get nuts with this!
Thanks!
(If swim will ever have any success with this he will post ist, even if he don't knows if anybody at all is interested in it ...)
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dr. nick
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another try - another failure
- the phenylalanine (2g in 10ml of dh2o) is still insoluble, even when boiling it.
- on the other hand it is pretty good soluble in strongly basified water (dh2o with naoh)
Now what swim is wondering about is:
Couldn't one basify the phenylalanine first in naoh solution and then put it to the desired amount of NP, in this case cyclohexanol?
Shouldn't the phenylalanine go into the np then?
Or dose this only work with amines? maybe i got this wrong, but as there aren't much docs on this swim got to the most related (he thinks) -
meth!
He believes that he has l-phenylalanine.hcl. (it's a white, small-shardy powder). if he bases it in naoh solution it should become the free base,
he thinks, which can then go into the np ...
after that the reaction could be done as in the write up ...
is this completely wrong?
THANKS!
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dr. nick
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sorry, question was already answered. *sigh*
[Edited on 18-7-2005 by dr. nick]
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dr. nick
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oh, oops - sorry, thought i already wrote this, but anyway - here it goes:
In the end it worked - the only problem was, that the reaction times in the Rhodium-File did not fit for dr. nick - after around the double time (1
1/2h, as far as i remember)
everything was done. Some A/B, and so on and voila ...
The only thing since then is: what to do with that crap ??? :
anyway, thanks for all the help!!!
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Vitus_Verdegast
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Your phenylalanine doesn't have to be completely dissolved. It is strong stirring that is absolutely necessary to drive this reaction forward. Even
when the aminoacid substrate is completely dissolved in the solvent, without strong stirring the decarboxylation will take forever and a day to
complete.
At least that is what my grandmother told me about her attempts to decarboxylate tryptophan on a +-10gram scale.
Possible uses for phenethylamine: excessive methylation will give a N,N,N-trimethyl-phenethylammonium salt, which could be an interesting
phase-transfer catalyst.
Or you can diazotise it in an attempt to obtain phenylethanol, which smells like roses and should be more desirable to the smell of fish.
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nitroglycol
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| Quote: | Originally posted by enima
the cyclohexanone can be replaced with any other ketone, it acts as a catalyst, acetone or methyl ethyl ketone can be used here.
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There's a procedure from JCS 3993(1965) for decarboxylation of tryptophan that uses no ketones; in this procedure 10 g of TRP are dissolved in 500 mL
Ph20 and refluxed for an hour under nitrogen. I've never tried this procedure; I wonder if it would work for PHE-->PEA?
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dr. nick
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hey - thanks-thanks-thanks a lot!!!
at least a use for this!!
amino alcohols are good, someone told me - don't know what for, but well ...
On the stirring: may really be right, swis used only 5g of it without stirring, and it already took almost the double time as it should - thought he
got low quality reagents, but it might also have been from lack of stirring!
Swis used Cyclohexanol as it took him a lot of time to get it
Oh, and last but not least because he did not need any apparatus, like stirrer, reflux and so on which he does not have available ...
Was going to try it again with paraffin and turpentine oil, but not yet ...
Thanks!!
ps.: diazotisation?? got to look that up, i fear
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dr. nick
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Hi there,
been away for a long time, now i thought it was time to take a look again at this thread - the possibilites of getting interesting things from amino
acids ar far too interesting to forget about it.
Since the repeated tries lead to success (and the2-pea is pretty useless itself)
i try to find out more about opiat-synthesis outgoing from amino acids or 2-pea,
but all i could find where contradictory sources that say opiates where from the thyrosin-type, others say it was from tryptamin type and, last but
not least, some dark murmurs on a corey-fuchs synthesis from phenylalanin to morphin with 10% results.
Not really thinking of trying this in practise but still very interested to understand as swid is kind of a chronic pain patient and opiates and
analgetica are around all time.
can anyone give me a hint leading to the right path on this, regarding opiat precursor, amino acids and so on?
there's so much information out there i can not find a way through it ...
Thanks!
[Edited on 9-9-2006 by dr. nick]
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solo
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Reference Information
Recent Progress in the Synthesis of Morphine Alkaloids
Josef Zezulaa, Tomas Hudlicky
Synlett 2005: 388-405
Abstract
Recent accomplishments in the field of total synthesis of morphine alkaloids are reviewed. Approaches to the skeleton of morphine are included as are
various efforts towards related medicinally important agents. The literature coverage begins after the publication of our last update in 2000 and
continues mid-way through 2004.
1 Introduction
2 Total Syntheses of Morphine
2.1 Taber
2.2 Trost
2.3 Ogasawara
3 Approaches to the Morphine Skeleton
3.1 Vollhardt
3.2 Ogasawara
3.3 Cheng
3.4 Passarella
3.5 Hudlicky
3.6 Hudlicky
4 Unnatural Analogs and Mimics
4.1 Rice
4.2 Grauert
4.3 Trost
4.4 Ohno
4.5 Schmidhammer
5 Conclusions and Outlook
Key words
morphine - total synthesis - alkaloids - approaches to morphine skeleton - morphine analogs and mimics
[Edited on 9-9-2006 by solo]
Attachment: Recent Progress in the Synthesis of Morphine Alkaloids.pdf (451kB)
This file has been downloaded 5454 times
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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dr. nick
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Thank you very much!
domo honto ni arigato gozaimashita, or so
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2bob
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try this, I have been meaning to get around to it, but UNI shit keeps getting in the way!!!
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dr. nick
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we-hell, after reading the info i could find yet i'd love to take a closer look,
but do you maybe have any practical advice?
All i found yet was too theoretical for me ...
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