Leuckart synthesis impurities: PMA

[GC_MS]

It took a while, but finally the librarian could get his hands on two articles I requested:

[1] Forensic Sci Int 115 (2001) 53-67 - KP Kirkbride, AD Ward, NF Jenkins, G Klass, JC Coumbaros: Synthesis of 4-methyl-5-arylpyrimidines and 4-arylpyrimidines: route specific markers for the Leuckardt (sic) preparation of amphetamine, 4-methoxyamphetamine, and 4-methylthioamphetamine.
[2] Forensic Sci Int 127 (2002) 45-62 - D Blachut, K Wojtasiewicz, Z Czarnocki: Identification and synthesis of some contaminants present in 4-methoxyamphetamine (PMA) prepared by the Leuckart method.

I am not going to type out both articles, since they are much too long, and they both contain essential graphics which I cannot imitate in ASCII. I'll try to make a resume so you will understand the essentials of the texts.
Text [1] has been written by an Australian research team. If you follow the "Drug news", then you'd know that Down Under has been teased by PMA for several years now. I think "teased" is the correct word here, since there are Aussies selling PMA as MDMA, hereby endangering the lives of the consumers. Anyway, that is more an ethical approach of the problem, while I can only offer science for today... Article [2] has been written by Polish researchers. According to the text, several drug overdose deaths in Poland can be attributed to PMA intoxication.

When reading the two texts, the Australians conclude that clandestine PMA samples examined by them had been prepared using anisaldehyde as precursor, and using the Leuckart (they use "Leuckardt", but afaik, it still is "Leuckart". It is also how he names himself in the Berichte from the 1880s.) pathway to accomplish the amination of PMP2P (para-methoxy-phenyl-2-propanone). The Polish text mentions that PMP2P had been legally obtained at a chemical supplier shop, since it was not a regulated compound (at that time).

Australia:
anisaldehyde -> p-methoxyphenyl-2-nitropropene -> p-methoxyphenyl-2-propanone -> PMA
They explain this more in detail in one of their other papers ¹. Sadly, I don't have that article in my possession right now.

Poland:
PMP2P -> PMA
As simple as that, using the Leuckart reaction.

Both articles have similar conclusions: clandestine PMA samples confiscated in their countries seemed to have been prepared using Leuckart. Both teams use different chromatographic setups to prove this. The Australians use HSPME, which is a technique used to trace volatile compounds in samples. The Polish use regular techniques.
A difference in the two articles can be found in the type of impurities they are targetting. The Australian team is especially interested in demonstrating the presence of 4-methyl-5-arylpyrimidines and 4-arylpyrimidines. These two impurity types are very well know from the Leuckart synthesis of amphetamine and methamphetamine. Several articles on this topic can be found on Rh's site. These two impurity types are well known thanks to the work of a Dutch forensic team. Names as van der Ark, Sinnema and Verweij are regularly encountered names in the field ². The Australians synthesized the two impurities as they would appear in the synthesis of PMA and 4-MTA. When comparing their synthesized impurities with confiscated samples, they concluded that the PMA impurities were retrieved, and that as such, the clandestinely circulating PMA in Australia is prepared via Leuckart. They were unable to find similar impurities in 4-MTA, and as such they concluded that 4-MTA was prepared using another route, propably by reduction of the nitropropene.
The Polish found the forementioned pyrimidines as well, but aside that, they found a whole collection of other synthesis impurities as well. Actually, there isn't much new about it. It is the same story as for amphetamine and methamphetamine, just that the impurities in this case bare p-methoxy groups. They give details about impurities formed by condensation of PMA and PMP2P, its reduced analogue, and its N-formylated and N-methylated analogue. They also find the condensation product of anisaldehyde and PMA, and its reduced analogue. Furthermore, they found N-methylated (PMMA) and N,N-dimethylated PMA in their samples as well. For those interested in impurities and/or GC/MS, the Polish article is a most interesting read... The article also gives details about synthesizing PMA using Leuckart.

The Leuckart synthesis of 4-methoxyamphetamine
In a two-necked round bottom flask equipped with thermometer and reflux condenser, 25 g (0.152 mol) of 4-methoxyphenylacetone, 64.8 g (0.9 mol) of anhydrous ammonium formate was refluxed for 7h at 185C. To the cooled mixture, 80 mL of concentrated HCl was added and the reflux was continued for 3h. The reaction mixture was then cooled down, combined with 350 mL of water and carefully made alkaline with 30% NaOH solution. The resultant basic mixture was extracted with methylene chloride (3x100 mL). The extracts were combined, dried over anhydrous sodium sulfate and evaporated yielding dark brown oil. Crude amine, without further purification was converted to its sulfate salt by treatment with 25% sulfuric acid in EtOH. The beige crystalline product was filtered off, washed with cold EtOH:ether 1:1 and dried. Crystallization from EtOH gave white precipitate of sulfate salt of PMA (9.1 g, 28%), mp 210-212C.

In short: there are some fucks out there, synthesizing PMA and selling it as MDMA. Also, these fucks use a 100+ year old method which is proven to be rather insufficient in the majority of cases, and it is also known that the Leuckart method yields many impurities. That the found impurities are Leuckart-specific is also demonstrated in both texts. Just one remark. It's odd that anethole is not mentioned in neither both texts. Only the Polish make a small reference to it, but do not elaborate it. Would't you use anethole as precursor if you intended to make PM(M)A? Anyway, I hope you enjoyed the read.



References:
[1] JC Coumbaros, KP Kirkbride, G Klass. Application of solid-phase microextraction to the profiling of an illicit drug: manufacturing impurities in illicit 4-methoxyamphetamine. J Forensic Sci 44 (1999) 1237-1242
[2] (just as example, since there are many more:) AM van der Ark, AMA verweij, A Sinnema. Weakly basic impurities in illicit amphetamine. J Forensic Sci 23 (1978) 693-700

[Osmium]

> The Leuckart synthesis of 4-methoxyamphetamine
> Crude amine, without further purification was converted
> to its sulfate salt by treatment with 25% sulfuric acid
> in EtOH. The beige crystalline product...

Nice example of how scientists often produce the results they already expect to find. Note the absence of a simple A/B or a distillation. While this is probably justified to simulate a worst case illicit drug synth and assures sufficient impurities to be present to be easily found in product analysis this writeup shouldn't be used for actual production. Higher-yielding, more gentle procedures are available (although I still don't like the Leuckart, it's a pretty dirty reaction). A simple A/B after the acid hydrolysis would have greatly reduced contamination, and even better purity can of course be achieved by distilling the product.

> It's odd that anethole is not mentioned in neither both
> texts. Only the Polish make a small reference to it, but
> do not elaborate it. Would't you use anethole as precursor
> if you intended to make PM(M)A?

Professional chemists think differently. When they want to do a reaction they grab their Aldrich catalogue and look what's available, especially when they are research chemists. They make $50-100K a year working in a lab building which cost a few million to build, using equipment every day which cost even more. Ordering 100g of an obscenely overpriced chemical from Aldrich will cost next to nothing compared to the usual everyday expenses. Synthing something yourself is simply not worth it anymore as long as it is available for sale somewhere. Those 100g will also allow them to pretend to be busy and doing valuable research for the next few months resulting in a paper or two, so its price is totally justifiable for them.

They also have no idea what acquisition problems underground chemists have to deal with. All they know is that chem suppliers usually only deal with companies or institutions, so they assume that every drug cook either has to do without real chems whatsoever or can order MeO-P2P by the kilogram just like them without questions asked.

Maybe they looked up anethole prices from Aldrich, but since it was similarly overpriced and they didn't bother to check for real world prices they just shrugged it off and ordered the easier precursor. That's common behavior for research types, money doesn't matter much especially since they are told daily that reagent grade methanol or acetone costs $20 per liter, production chemists are much more aware of real world costs of bigger scale synthesis since they have to convert lab findings into industrial syntheses, that's where money is made by cutting costs.

[pHarmacist]

(2S )-1-(4-Methoxyphenyl)-N-[(1R )-2-(4-methoxyphenyl)-1-
methylethyl ]-2-propanamine in Crude p-Methoxyamphetamine(PMA) Produced by the Leuckart Method

Full-Text:

http://www.znaturforsch.com/57b/s57b0593.pdf

[GC_MS]

It's written by the same authors and deals with only one impurity type, one which they deal with in the Forensic Sci Int article as well. I find the FSI really interesting, MS-wise. The Z Naturforschung is interesting as well, but more from a real chemical approach.