Sciencemadness Discussion Board

N-Mono and N-Di-Alkylation of Phenylalanine?

vaprizz - 31-8-2009 at 08:54

Hello there!
I've some lonely phenylalanine lying around here.
I like to mono- and di-N-alkylate this amino acid because I like to try an reductive amination just for fun, on something which is not illegal :P. I have also some histidine lying around here.

I heard of reductive amination via Zn/weak acid with the amino acid and formaldehyde in water - but does that also work with other aldehydes?
Which acid I could use?
And most important, how to workup that mixture to get something pure?
Isoelectric focusing sucks in home labs. Destillation would end in decomposition/ at least decarboxylation...

Are there any other good tested ways to geht some alkylated amino acids, for example via NaBH4, CTH or alkyhalogenides?

Has anyone done something similar with another amino acid?
Any suggestions?

Sorry for my bad english!


[Edited on 31-8-2009 by vaprizz]

[Edited on 31-8-2009 by vaprizz]

[Edited on 31-8-2009 by vaprizz]

Klute - 31-8-2009 at 14:18

For the mono-N-alkylation I would suggest the route I used for N-methylphenethylamine, forming the aldimine with benzaldehdye, alkylating with alkyl halide other alkylating agent, and hydrolyzing.. Very good yields, no side products (tertiary or quaternary), and easy to get reagents..

Otherwise, ceasium mediated alkylation using cesium carbonate and alkyl halide would be the second best option..

For dimethylation, I think paraformaldehdye/zinc or CTH/hydrogenation should work well. There has been some articles posted on the subject in various threads, I suggest UTFSE.

not_important - 31-8-2009 at 19:40

For dimethylation the paraformaldehyde+oxalic acid method could be useful, as it is fairly mild and doesn't over-methylate. Again it's detailed in previous threads.

Nicodem - 31-8-2009 at 23:58

Apparently the Eschweiler-Clarke reaction does not give N,N-dimethylphenylalanine when applied on phenylalanine. Instead it gives a certain pyrrolidinone derived from the condensation of phenylalanine with phenylpyruvic acid (itself formed from N-methyleneimine of phenylalanine decomposition). See J. Am. Chem. Soc., 55 (1933) 4571-4587 (attached).
Otherwise, the most common method for phenylalanine N,N-dimethylation is hydrogenation in the presence of formaldehyde using Pd-C (just one of the several examples: Journal of the Chemical Society (1950) 1342-1345; DOI: 10.1039/jr9500001342).
Methylation with dimethyl sulfate is not suitable as it does not stops at the tertiary amine and gives the N,N,N-trimethyl derivative instead (see Chemische Berichte, 45 (1912) 838). Reductive alkylation with HCHO by using NaBH4 should work, because it works on p-nitrophenylalanine (see Helvetica Chimica Acta, 86 (2003) 3601 - 3612, DOI: 10.1002/hlca.200390305).
Quote: Originally posted by vaprizz  
Hello there!
I've some lonely phenylalanine lying around here.
I like to mono- and di-N-alkylate this amino acid because I like to try an reductive amination just for fun, on something which is not illegal :P. I have also some histidine lying around here.

Claiming that you are not up to something illegal where there is nothing illegal in the first place, is a great way to make you appear as being up to something illegal. Experience told us this is one of the most effective ways to upset lots of members. Next, time spare us your apologetics and stick to the science. Also, keep in mind that opening threads without providing a single reference is generally only tolerated in the Beginnings section where I'm moving this thread any way. Saying "I heard of..." is not the same as providing a reference. Members don't know what and where you heard, but need to know if they want to give you a comprehensible answer.

Attachment: The Action of Formaldehyde on Amines and Amino Acids.pdf (1.2MB)
This file has been downloaded 4809 times

vaprizz - 1-9-2009 at 08:27

Thanks to all! And by the way I'll spare apologetics and search for references next time
Now I like to try dimethylation.
To Klute - aren't there some side reactions when benzaldehyde is added to an amino acid? (->Akabori)


ITTFSE and Google but I can't find anything experimental on CTH reductive alkylation, except http://www.erowid.org/archive/rhodium/pdf/redamin.cth-pd.pdf... only with H2 under pressure. And nothing about alkylation of amino acids. I have some nice 10% Pd/C here which I've never used before and I would like to test it. I have also some grams of potassium formate and 100ml 37% aq. formaldeyhde. How to workup this mixture?
How to do this exatly? Only mixing everything togther with a little excess of the aldehyde and formate in EtOH? How to workup this mixture?


[Edited on 1-9-2009 by vaprizz]

zed - 9-9-2009 at 21:51

Keep in mind, that the formation of your phenylalanine Imine, will probably de-isomerize your L-phenylalanine. When you form the imine, expect that the Imino double bond will shift back and forth between the two carbon skeletons.

Since that shifting, will momentarily remove the center of asymmetry on the L-phenylalanine molecule......it will be lost forever. You will end up with an N-substituted D,L-Phenylalanine.

What this resonance form looks like I do not know, but I assume it exists. Treating an aminoacid with an aldehyde or a ketone, is a well known method, for de-isomerizing aminoacids.
If sufficient heat is applied, the aminoacid will be de-carboxylated.

If you wish to produce a pure D, or a pure L product, it might be possible to do so thusly.......Diazotize and de-amineate your aminoacid, to convert it to an alpha- Halogenated-phenylpropionic acid. This will maintain the center of asymmetry perfectly. You can then react your halogenated acid, with whatever amine you wish.

This seems likely to produce a pure isomer. Though I may be mistaken.

There is a procedure for the production of such halo-acids from amino-acids in Organic Synthesis Online.

[Edited on 10-9-2009 by zed]

[Edited on 10-9-2009 by zed]