PPA via Akabori of benzaldehyde and dl-alanine

[DRIVEN]

Hi everyone,

D was very excited to see Bandils' success with the synthesis of 4-MAR with the use of KOCN.  D is deeply intrigued by this substance and would like to dream up its existence and was wondering if someone could possibly offer some advice about the production of the precursor, dl-PPA.  Though it may seem more appropriate to derive PPA from the reaction of nitroethane and benzaldehyde, it would be nice to derive dl-PPA through the Akabori rxn of benzaldehyde and dl-alanine for practical reasons.  If this direction seems futile, please by all means speak your mind and D will get off the train here as he doesn’t have any experience with this reaction.

IOC performed a run by combining 100g BnZ and 40g l-alanine, heating the mixture to 140 (until fizzing stops),extracted the post reaction with H2O, concentrated, then cleaned up the crude product (how it was cleaned wasn’t specfied). In this case there was 15 % yield - which was low but for D, 15% yield would suffice if properly purified.  Given PPA is produced, D thinks the next issue is to determine the nature of side products and how to separate them from the target especially when they are likely to be in large quantities from a low yielding reaction.  According to Takagi et al (1): When BzH and DL-alanine are heated directly; PhCH2NH2, PhCH(OH)CHPhNH2 (2 dl-compds.), AcH, and CO2 are formed.

D searched for the physical data on PPA and these side products.  These (incomplete) data are indicated below (2).

Proposed cleanup (a work in progress):  After extracting the post reaction with water, it would be expected that at least benzylamine (PhCH2NH2), being water soluble, would travel along with the PPA. Since the bp of benzylamine, 182 - 185 deg C (760mmHg), is about 80 degrees higher than PPA base then the mixture could be distilled to collect a fraction at 100-105 deg C containing PPA base and water.  D is unsure about how to subsequently separate the PPA base from water given their bp’s are so close. D had difficulty finding the bp or solublity data for 2-amino-1,2-diphenylethanol (PhCH(OH)CHPhNH2) so D is still unsure about how to predict its removal.

My questions are:

1) It is assumed that the post reaction will be basic and therefore PPA in its base form, is this correct?
2) Could one separate PPA base from water by acidifying it (making PPA-HCL which has a higher bp than water) and concentrating the mixture?
3) Does anyone know where to find the solubility and bp data for the 2-amino-1,2-diphenylethanol contaminant?
4) Can benzylamine be removed from the reaction mixture as proposed above?
5) What does "AcH" abbreviate?

Any input, directions and comments would be much appreciated!

Take care

DrIvEn

References and Data:

(1) Reaction between aromatic aldehydes and a-amino acids. I. New facts on the Akabori reaction. Takagi, Eiichi. J. Pharm. Soc. Japan (1951), 71 648-51.

(2) Physical Data of Various Chemicals Produced by the Akabori Reaction of Benzaldehyde and dl-alanine

Phenylpropanolamine (racemic mix of d- and l-norephedrine)
 
Base  Bp: 101-101.5°
HCl Bp : 190-194°
HCl (+)-form Bp : 171-172°

PhCH2NH2 is benzylamine:

Physical State:
Liquid Appearance: clear colorless to slightly yellow
Odor: ammonia-like
pH: Not available.
Vapor Pressure: 0.6 mbar @ 20 deg C
Viscosity: mPas 20 deg C
Boiling Point: 182 - 185 deg C @ 760.00mm Hg
Freezing/Melting Point: 10 deg C
Solubility in water: > 500 G/L (20°C) IN WATER
Specific Gravity/Density: .9810g/cm3


d,l-PhCH(OH)CHPhNH2 is 2-amino-1,2-diphenylethanol:

This compound has several racemic forms, (1R,2R)(1S,2R)(1RS,2RS),(1RS,2SR)

For example: (1R,2R)-(+)-2-Amino-1,2-diphenylethanol:

Product Number 523704 CAS Number 88082660 Formula C14H15NO Formula Weight 213.3 APPEARANCE WHITE POWDER MELTING POINT 143.8-146.8 DEGREES CELSIUS INFRARED SPECTRUM CONFORMS TO STRUCTURE. PROTON NMR SPECTRUM CONFORMS TO STRUCUTRE. TITRATION 99.1 % (WITH HCLO4) OPTICAL ROTATION +7.5 DEGREES (C=0.6198%, ETOH)

[Aurelius]

Hey DRIVEN, take a look.

Post 422067 (missing)

(Aurelius: "Ephedrine Compilation", Stimulants)

Just about anything you ever wanted to know about the subject.  If you've read all of this, let me know and I'll help you out with your questions.

1. Yes, the mixture begins basic, probably ends that way too.  Depends on the reaction conditions mostly.

2 & 4.  You should clean the reaction mixture by first acidifying the mixture with 10-30% HCl until strongly acidic to litmus.  Then filter the whole mess twice to remove any nastiness that we don't want.  extract the mix twice with 2x50ml of DCM (or other suitable non-polar) and Separate any layers present and keep the aqueous layer.  slowly add NaOH solution (10-30%) until stongly basic to litmus.  Extract the mixture with DCM 4x50ml and keep the extract.  Combine the extracts and remove the solvent.  Fractionally distill the remainder. 
benzylamine will be removed when you fractionally distill.

3. try the merck, lang's handbook, CRC handbook, or any of the other very common handbooks with chemical data.  It'll be in at least one of them, if not all.

5. AcH is just another way to write Acetic acid. It is more commonly abbreviated as AcOH.

[DRIVEN]

Thanks for being so helpful Aurelius.

Your awsome!

[Rhodium]

Ac is most often an abbreviation for acetyl { CH₃(C=O)- } - not acetoxy { CH₃(C=O)O- / AcO- } nor acetate { CH₃COO^- / AcO^- }.

For example, Ethyl Acetate is properly abbreviated EtOAc (and not EtAc) as its structure is CH₃CH₂O(C=O)CH₃.
EtAc is the abbreviation of CH₃CH₂(C=O)CH₃ - methylethylketone (MEK)!

From the above follows that AcOH is a correct designation for CH₃COOH, or acetic acid, and that the often incorrectly interpreted AcH really designates { CH₃(C=O)H / MeCHO } - acetaldehyde, or etanal!

[Aurelius]

I'm not going to say you're wrong, but given the large number of newbees around here, I still think that the abbreviation was probably meant to be understood as acetic acid.

Driven, could you please post the article in which you found the abbreviation and use a colored markup to point it out? (surround the word with [ r e d ] word [ / r e d ]  But without ANY of the spaces and you get word.

[Rhodium]

The earliest mention of AcH] at the hive together with Akabori discussions is in the abstract in the first CA citation in

Post 227827

(foxy2: "Re: P2P - 100% OTC !?!", Chemistry Discourse) - The reaction seem much more likely to produce acetaldehyde than acetic acid.

PhCHO + CH₃CH(NH₂)COOH -> PhCH₂NH₂ + PhCH(OH)CH(NH2)Ph + AcH + CO₂

My main point wasn't to only correct this instance of possible Ac-nomenclature confusion, but also to write a post which to refer back to in the future, should confusion happen again. Regardless of what newbees may write by mistake, it is imperative that we teach them the correct nomenclature now, before we cannot find anything we can be sure of in the archive...