Sciencemadness Discussion Board - N-Methyl-d,l Alanine

N-Methyl-d,l Alanine

Waffles SS - 23-4-2011 at 11:48

As you know alanine prepare by reaction of a-bromopropionic acid with ammonia:

Quote:

Slowly and with stirring, 100 g. (0.65 mole, 59 cc.) of cold (1–4°) α-bromopropionic acid is added to 3 l. (44.5 moles, 2700 g.) of cold (1–4°) concentrated aqueous ammonia (sp. gr. 0.9) in a 1-gal. glass-stoppered bottle, and the mixture is allowed to stand at room temperature for at least four days . The solution is concentrated to a volume of 300 cc., filtered, and concentrated further to 200 cc. The solution is cooled to room temperature and 1 l. of methyl alcohol added. After chilling overnight in a refrigerator (0–4°) the crystals are filtered with suction and washed with 250 cc. each of methyl alcohol and ether. The yield is 42–48 g. of crude alanine.
For purification the crude product is dissolved in 200 cc. of water (warming if necessary), 1 l. of methyl alcohol is added, and the mixture chilled overnight. After washing as before, the yield is about 38–42 g. (65–70 per cent of the theoretical amount) of purified dl-alanine, m. p. 295° (dec.) on the Maquenne block (Note 7). This product is free of bromide and contains only traces of ammonia. If an especially pure product is desired the material may be reprecipitated from methyl alcohol once more in the same manner.
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1...

and also this is possible to make N methyl d,l alanine by reaction of methyl amine (instead of ammonia) with a-bromopropionic acid.
But what about a- chloropropionic acid?(it is cheaper ,easier,safer to make)

Quote:

The use of α-chloropropionic acid gives a poorer yield (43–46 per cent of theoretical) and the product is more difficult to purify owing to the fact that ammonium chloride is less soluble than the bromide in methyl alcohol.

What is our problem in this reaction?(using a-chloro propionic acid)
Methylamine hydrochloride is more soluble in methyl alcohol than ammonium chloride

Dear cooker and amphetamine lovers,This topic isnt useful for you then please dont waste your time

[Edited on 23-4-2011 by Waffles SS]

GreenD - 23-4-2011 at 19:30

I don't understand the extreme ratios, 3L of conc. nh3 (ick) to 100 grams?
Then 200 ml h20 and 1 liter of meoh for recrystallizing 42 grams?

It just seems wasteful as hell...

If you are really asking "what is the problem" its because Cl makes a stronger bond to carbon than bromide does, but I don't think that is what your asking, is it?

I would assume slight warming would allow the equilibrium to shift slightly to the product, but as postart said you are going to get a mix of product - not that you care of course.

An uneducated guess; if you raised the pH to 8 you may see more product...

mr.crow - 23-4-2011 at 20:05

Cl is a much worse leaving group than Br so it is less reactive. The huge excess of ammonia is so primary amines are favored. If it was less then it would be more likely to produce secondary and tertiary amines.

Waffles SS - 23-4-2011 at 22:04

My question is about purify final product.
I think final product contain methyl amine hydrochlorodie,n-methyl d,l alanine, unreacted a-chloro propionic acid
and i am asking about n-methyl d,l alanine separation

In puryfing alanine ammonium chloride is less soluble than the bromide in methyl alcohol then this is difficult to purifing it if we use a chloro propionic acid. but in the n -methyl alanine we have methyl amine hydochloride,
it is more solube in methyl alcohol than ammonium chloride and purifying should be better.isnt it?

postart - 25-4-2011 at 07:51

Why doesn't SWIM use fractional chromatography. N-methyl alanine is available commercially but may be looked at as an ephedrine precourser.

SovereignSolip - 6-5-2011 at 10:39

I don't really understand all of these thread looking for amphetamine precursors. All of the commercially viable routes are known and highly watched. The ones that aren't watches, are not nearly as commercially viable. And if you really just wanted the stuff for personal use, there are quite a few syntheses that are relatively cheap for a home chemist.

When these people get an inch, the try to take a whole mile.

leave drug-derailing out of the thread

Polverone - 6-5-2011 at 12:39

I don't know why Waffles SS wants to make this substance, but if you search the American Chemical Society journals for n-methyl amino acid synthesis it looks like a lot of other chemists are interested in the same topic. Amphetamines are simple enough molecules that, with a sufficiently jaundiced eye, a lot of mundane chemicals look like amphetamine precursors. The first post in the thread explicitly says that the author is not looking for advice on making controlled drugs. Don't spontaneously offer advice addressing the unasked and off-topic question "how can I easily make stimulant drugs?"

jon - 7-5-2011 at 07:29

that is one hell of an excess.
revealing the downsides of ammonolysis reactions the smaller the substrate molecule the larger the excess employed.
for example ammonolysis of methyliodide requires something like a 300 molar excess.
larger substrates that i've subjected to i could get by with 15 moles nh3.
i would suspect that would be suitable with a bulkier amine counterpart.

p.s. that equation is'nt balanced

[Edited on 7-5-2011 by jon]

smuv - 7-5-2011 at 08:01

This thread is full of so much bullshit. I don't care if you are making drugs or not; read more, post less.

Why is it hard to achieve good selectivity when alkylating amines? Generally as the number of alkyl substituents around the amine increases, so does its nucleophilicity. Therefore, when alkylating an amine you have lots of unreacted product and a fair amount of poly-alkylated product and then not much between.

There are many instances where amine alkylation is more stepwise; this is when alkylation produces an amine of lower nucleophilicity than the starting material. Essentially, these are cases where the alkylating agent has some electron withdrawing groups on it. In these cases amine alkylation becomes more stepwise.

The case of synthesis of a-amino acids is just this. Because the alpha-halo carboxylic acid has the electron withdrawing carboxylate group, it is possible to have higher selectivity for alkylations, because the formed amino acids are generally weaker nucleophiles than the starting amines.

The classic synthesis of glycine from chloroacetic acid and ammonia is one such example.

jon - 7-5-2011 at 10:06

no azo your not wrong it's just an impractical way to get alanine
and smuv good point there the formed amine would conjugate with the acid.
the only reason you would employ such an excess in a scheme like that is to prevent polyalkylation.
by surronding the substrate with ammonia molecules but since the product is rendered less reactive i don't see the point?

[Edited on 7-5-2011 by jon]

smuv - 7-5-2011 at 19:19

Some excess is still needed, N-methylaniline is only a little less nucleophilic than methylamine. That being said, I trust OS proceedures, but that +50 fold excess of ammonia seems excessive to me (but then again, I am just handwaving). Water is not a great solvent to use the lower nucleophilicity of amino acids to tune selectivity, something aprotic would be better. Also, the a-halo ester would probably allow for even greater selectivity for mono-alkylation than the a-halo acid (which is largely deprotonated in solution).

jon - 7-5-2011 at 20:49

doing ammonolysis on iodosafrole it only worked in isopropanol.
but it works really really well.
solvents play a big role in that reaction.
if methylamine were used you could use ethanol or methanol because it is a stronger nucleophile but still love ipa for those reactions
water kills those kind of reactions some water can be tolerated but not much more than 1%.
so it does'nt have to be bone dry.

[Edited on 8-5-2011 by jon]

Waffles SS - 11-9-2012 at 07:14

I think this is possible to make N-Methyl-d,l Alanine by Strecker amino-acid method
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1...
Am i wrong?

Jesse Pinkman - 25-9-2012 at 09:34

I have one idea:
1) Oxidation of lactic acid to the corresponding carbonyl compound
2) Reductive amination of the carbonyl compound to the desired amine

Waffles SS - 25-9-2012 at 13:00

somebody tried tetrahedron letter on N-methylation L-alanine by formaldehyde + Zinc?

I Like to test this method but i dont have detail for this reaction,this letter has little info about reaction detail

Attachment: Zn_HCHO_methylation.pdf (98kB)
This file has been downloaded 2440 times

Dr.Bob - 26-9-2012 at 12:06

Quote: Originally posted by Waffles SS

As you know alanine prepare by reaction of a-bromopropionic acid with ammonia:

and also this is possible to make N methyl d,l alanine by reaction of methyl amine (instead of ammonia) with a-bromopropionic acid.
But what about a- chloropropionic acid?(it is cheaper ,easier,safer to make)

The chloro group in -chloropropionic acid is just not as good of a leaving group as the bromo is in the a-bromopropionic acid. So it will react slower. That may help reduce di or tri aklylation of the nitrogen, but will also slow down reaction and lower yield, most of the time.

As for the large excesses used, this is an older prep, where they relied on crystallization to collect the product, so driving the reaction as far as possible with cheap reagents was normally done then. Also, it was harder to monitor reactions for completion, so again, going overboard was common.

If you just want the N-Me-(D,L)-alanine, this should work OK with N-methylamine, but I would expect that there are better ways to make the compound, especially if you want the chiral material. I would make the formamide of alanine and reduce it, as that can be done without racemizing, I believe.

The Tett Letters paper is short on details, but they claim that running the reaction only 15 minutes generates the monoalkylated alanine in 85% yield. Not sure how you would purify that from the diMe easily without going further steps. It sounds pretty easy to test, and they give some basic conditions in their table.

[Edited on 26-9-2012 by Dr.Bob]

Waffles SS - 27-9-2012 at 00:42

Thanks Dr.Bob,
I tried this reaction by below ratio:
28 gr Sodium Di Hydrogen Phosphate ,12gr Formalin(37%),15gr Zinc dust,10gr L-alanine(i just have access to L-alanine) and 200ml water.
After adding all of these, tiny bubbles start to come(Hydrogen) and after 15 minutes you can see white powder on surface of Zinc dust(Zinc Phosphate). I dont know how can i separate N-methyl from solution.suggested solvent by letter(Chloroform ) didnt work because N-Methyl is soluble in water too.

I think another possible route for making N-methyl is also possible
First : Preparing 2-chloropropionic acid from L-alanine via diazotization in hydrochloric acid
(http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8...)

Second : Preparing alanine by ammonolysis of 2-bromopropanoic acid(also N-Methyl-alanine by Methylammonolysis of 2-chloropropanoic is possible)
(http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1...)
this article use bromopropionic acid and ammonia but as you know and mentioned on article ,ammonolysis of chloropropionic acid is possible(and also Methylammonolysis)

[Edited on 27-9-2012 by Waffles SS]

Rich_Insane - 28-9-2012 at 11:42

Quote:

I have one idea: 1) Oxidation of lactic acid to the corresponding carbonyl compound 2) Reductive amination of the carbonyl compound to the desired amine

I like this idea, but is it also possible to brominate lactic acid by reaction with HBr? I understand that in situ generation via H2SO4/Alkali bromide would create competition for the dehydration, but will lactic acid even brominate efficiently with HBr?

Waffles SS - 29-9-2012 at 23:40

I am confused.
I think L-alanine should be L(+)Alanine,(+)dextrorotatory,(s)eniantomer and Optical Rotation is +13.5° ~ +15.5° but in orgsyn mentioned (S)-Alanine Optical Rotation is −13.98 !!
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8...

Which one is correct?For making 2-ChloroPropionicAcid by diazotization and react it with Methylamine for making N-methyl-L-alanine Which alanine should be used?

Rich_Insane - 1-10-2012 at 08:25

Wouldn't it be best just to use racemic alanine?

Salmo - 1-10-2012 at 13:17

Quote: Originally posted by Waffles SS

I am confused.
I think L-alanine should be L(+)Alanine,(+)dextrorotatory,(s)eniantomer and Optical Rotation is +13.5° ~ +15.5° but in orgsyn mentioned (S)-Alanine Optical Rotation is −13.98 !!
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8...

Which one is correct?For making 2-ChloroPropionicAcid by diazotization and react it with Methylamine for making N-methyl-L-alanine Which alanine should be used?

Man I think you have to check the diazotization stereoselectivity, I think that diazotization shouldn't cause inversion of the chiral center, but i could be really wrong and I didnt check about the stereoselectivity about the reaction with methylamine even if I think that doesen't cause inversion too.. anyway I found this pdf for you, read pag 87.

Attachment: FULLTEXT01.pdf (1.8MB)
This file has been downloaded 2134 times

[Edited on 1-10-2012 by Salmo]

[Edited on 1-10-2012 by Salmo]

Waffles SS - 2-10-2012 at 11:57

Thanks salmo for your helpful text.according to this text diazotization dont cause inversion of the chiral center .this mean that diazotization of L-alanine cause R(+)2-ChloroPropionicAcid(am i wrong?)
I really dont know what Orgsyn wrote(Optical Rotation of (s)alanine is +13.5 not -13.5)

L-alanine(Synonyms : (S)-Alanine,L-(+)-Alanine,(S)-(+)-Alanine) OPTICAL ROTATION +13.5° ~ +15.5°
R(+)2-ChloroPropionicAcid OPTICAL ROTATION +14°

[Edited on 2-10-2012 by Waffles SS]

aliced25 - 6-6-2013 at 02:58

It can also be prepared by the reductive amination of pyruvate esters with the appropriate amine. I suspect other reductive approaches would work just as well.

I do wonder though, could that imine, which is very similar in structure to the one formed by the reaction of benzaldehyde with alanine esters, be alkylated directly at the 2-carbon giving a-methylphenylalanine directly (with reductive n-debenzylation).

Would be a short route to a-methylphenylalanine if it could

Attachment: Crouch.Holden.Weaver.Reductive.Amination.of.Pyruvate.Esters.A.Microscale.Synthesis.of.N.Benzylalanine.Esters.pdf (53kB)
This file has been downloaded 886 times

phlogiston - 6-6-2013 at 04:07

Quote:

28 gr Sodium Di Hydrogen Phosphate ,12gr Formalin(37%),15gr Zinc dust,10gr L-alanine(i just have access to L-alanine) and 200ml water.

You don't say anywhere if you desire a racemic mixture or not, but if you do I found an easy method to quickly obtain a racemic mixture of most amino acids is to heat them with pyridoxal-5-phosphate (vitamine B6) in an alkaline environment.
I only occasionally need small amounts for analytical purposes. Last time I took about 40 ul of a 25 mM solution of L-amino acid + 250 ul 25% ammonia + 10 ul 100 mM PLP. This was heated in a glass vial with a screw cap to 95 deg C and kept at this temperature for 1 hour, resulting in complete racemisation and 90% recovery.
If you need to get rid of the PLP and its products you can use W50 cation exchange resin.
It works well for most but not all amino acids.

The following fragment (from wikipedia) may clear up the confusion regarding the optical rotation:

Quote:

The D/L labeling is unrelated to (+)/(−

; it does not indicate which enantiomer is dextrorotatory and which is levorotatory. Rather, it says that the compound's stereochemistry is related to that of the dextrorotatory or levorotatory enantiomer of glyceraldehyde—the dextrorotatory isomer of glyceraldehyde is, in fact, the D- isomer. Nine of the nineteen L-amino acids commonly found in proteins are dextrorotatory (at a wavelength of 589 nm)

Waffles SS - 6-6-2013 at 05:39

Quote: Originally posted by phlogiston

Thanks @phlogiston,
Can you put reference for this method?

Quote: Originally posted by phlogiston

You don't say anywhere if you desire a racemic mixture or not

No different.

Somebody ever tried separation of amino acid by Isoelectric Point?I tried L-alanine and glycine but i failed.
I dissolved 10 gram L-alanine in 100cc water and set PH to isoelectric point of alanine and then cool solution to 4-5c for 24 hours but no crystal appeared.!

Somebody ever tried to resolution racemic mixture by Chiral Column Chromatography?

[Edited on 6-6-2013 by Waffles SS]

phlogiston - 6-6-2013 at 07:50

I don't think I have a real reference for that method. I just improvised it based on a single line in a paper. I don't remember the paper in detail but I do recall it did not provide a detailed experimental procedure for that. but I'll have a look if I can find that paper again.

I actually do chiral separation by LC almost daily because my research work revolves around the functions and metabolism of D-amino acids in humans (yes, in contrast to what most textbooks will tell you we do make and use D-amino acids, as neurotransmitters and for regulation of certain hormones).

I devised a method which is based on derivatisation with an enantiomerically pure reagent. I can then separate the derivatised enantiomers (which are diastereoisomers) of the different amino acids on a simple non-chiral C18 UPLC column (UPLC=essentially just HPLC but with even smaller particles/higher pressures).
For preparative purposes, it would probably be easier to use a chiral column (or you would have to undo the derivatisation somehow). Alternatively, you can sometimes degrade/remove the L-enantiomer enzymatically to obtain pure D-enantiomer.

However, all this may be a bit difficult in an amateur setting. chiral HPLC columns, purified enzymes etc are probably not easy to acquire.

aliced25 - 6-6-2013 at 13:47

Waffles, try tartaric acid or naproxen (tartaric acid first) and get the hang of that.

Waffles SS - 7-6-2013 at 08:17

I think resolution of amino acids by tartaric acid is not possible

Quote:

Vogel Practical Organic Chemistry 5th, P.815

This method should be effective for resolution of N-methyl Alanine too.am i wrong?
@phlogiston,
This is possible to use Chiral Column chromatography for resolution of Amino Acids?(not HPLC )

[Edited on 7-6-2013 by Waffles SS]

questions - 11-7-2013 at 00:33

I can do the original method to make n=methylalanine but how do I get it out of the solution ? ? ? ? ? ? ?

phlogiston - 11-7-2013 at 03:56

For amino acids, I have only used HPLC-based methods, but in principle I don't see any reason why it could not be done.

There are stationary chiral phases available for this kind of work. See for instance:

Preparative chiral chromatographic resolution of enantiomers in drug discovery
Journal of Biochemical and Biophysical Methods
Volume 54, Issues 1–3, 31 December 2002, Pages 11–23

I'd be happy to mail you the pdf if you can't get it without a subscription.