Question Why The Leuckart?

[Blammo]

I'm just wondering why the Leuckart is used for large scale for amphetamine production in general.

I assume a few things. Cheap reagents (formic acid, ammonium formate/methylamine) and simplicity (basically simply heat the reaction).

My question is, unless there is some magic method to increase yield (I've read there are catalysts that can increase yield somewhat, magnesium chloride maybe?), the yields are low, better for unsubstituted amphetamines, maybe like 50%? Idk exactly. But low for mdma, like 30%.

Why not scale up say an aluminum amalgam? Or precious metal catalyst on carbon, say a catalytic transfer hydrogenation using potassium formate or the like?

All the papers I've read say amalgam and the leuckart are the dominant production methods, and these are papers put out regarding synthetic drug production in the netherlands.

 

[GnarleyBarley]

aluminium amalgam doesn\t scale well (but be my guest and try it), it gets very hot and also so much dirty shit water from the NaOH neutralization, a pain in the ass to filter, A lot of hydrogenation is done industrially (for other processes) so should not be a problem here either, but you would need a source of hydrogen (like tanks of hydrogen), hydrogenation is more risky, many of those catalysts are pyrophoric and shit but I can't really speak about hydrogenation as I have never used it in a home lab.e

You can get better yields with leuckart 80% and maybe more, just not a lot of people who have posted about their yields and researchers many times don't run the reactions long enough for whatever reason (either to not help improve the process of clandestine chemists by showing higher yields or because they are limited by time (work))

 

[Blammo]

I have read the leuckart, at scale, needs to be slowly heated and ran for 2 to 3 days. Does this sound right?

I've never heard anything close to 80% outside of one off reports, especially for mdma. If it is possible it makes sense.

I've always theorized that hitting a leuckart reaction with an ultrasonic cleaner type thing would greatly speed up the reaction and yield. Likely not worth it for criminal groups though, they are expensive.

 

[Blammo]

Also, even the guide on here to do the leuckart for meth and mdma has yields of about 30%.

I don't really think people are hitting 80% unless you know some secret they dont.

 

[GnarleyBarley]

Never done the leuckart, was planning to do it but decided not do. Seemed messy and dirtier than what I am comfortable with. I have heard about the high yields both on forums, in private messages and 50-60% in journal articles.

You may find information of both bad yielding (i.e. may contain information on conditions that result in bad yields [saw one with just 18%, think it was for 4-methoxyphenylacetone], may help you decide on conditions you may want to avoid, contrast this with the better yielding ones to find out what you have to do for better yields) and good yielding leuckart from scientific journals in the following articles (These are articles in my zotero directory labeled leuckart):

1. Umar Q, Luo M. A Brief Review: Advancement in the Synthesis of Amine through the Leuckart Reaction. Reactions. 2023;4(1):117-147. doi:10.3390/reactions4010007
2. Umar Q, Luo M. A Brief Review: Advancement in the Synthesis of Amine through the Leuckart Reaction. Reactions. 2023;4(1):117-147. doi:10.3390/reactions4010007
3. Renton RJ, Cowie JS, Oon MCH. A study of the precursors, intermediates and reaction by-products in the synthesis of 3,4-methylenedioxymethylamphetamine and its application to forensic drug analysis. Forensic Science International. 1993;60(3):189-202. doi:10.1016/0379-0738(93)90238-6
4. Braun U, Shulgin AT, Braun G. Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine). Journal of Pharmaceutical Sciences. 1980;69(2):192-195. doi:10.1002/jps.2600690220
5. Kunalan V, Nic Daéid N, Kerr WJ, Buchanan HAS, McPherson AR. Characterization of Route Specific Impurities Found in Methamphetamine Synthesized by the Leuckart and Reductive Amination Methods. Anal Chem. 2009;81(17):7342-7348. doi:10.1021/ac9005588
6. Kunalan V, Nic Daéid N, Kerr WJ, Buchanan HAS, McPherson AR. Characterization of Route Specific Impurities Found in Methamphetamine Synthesized by the Leuckart and Reductive Amination Methods. Anal Chem. 2009;81(17):7342-7348. doi:10.1021/ac9005588
7. Ingersoll AW, Brown JH, Kim CK, Beauchamp WD, Jennings G. Extensions of the Leuckart Synthesis of Amines. J Am Chem Soc. 1936;58(9):1808-1811. doi:10.1021/ja01300a089
8. Ingersoll AW, Brown JH, Kim CK, Beauchamp WD, Jennings G. Extensions of the Leuckart Synthesis of Amines. J Am Chem Soc. 1936;58(9):1808-1811. doi:10.1021/ja01300a089
9. Błachut D, Wojtasiewicz K, Krawczyk K, Maurin J, Szawkało J, Czarnocki Z. Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method. Forensic Science International. 2012;216(1-3):108-120. doi:10.1016/j.forsciint.2011.09.005
10. Błachut D, Wojtasiewicz K, Krawczyk K, Maurin J, Szawkało J, Czarnocki Z. Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method. Forensic Science International. 2012;216(1-3):108-120. doi:10.1016/j.forsciint.2011.09.005
11. Ostovari H, Zahedi E, Sarvi I, Shiroudi A. Kinetic and mechanistic insight into the formation of amphetamine using the Leuckart–Wallach reaction and interaction of the drug with GpC·CpG base-pair step of DNA: a DFT study. Monatsh Chem. 2018;149(6):1045-1057. doi:10.1007/s00706-018-2145-7
12. Błachut D, Wojtasiewicz K, Czarnocki Z. Some pyridine derivatives as “route-specific markers” in 4-methoxyamphetamine (PMA) prepared by the Leuckart method. Forensic Science International. 2005;152(2-3):157-173. doi:10.1016/j.forsciint.2004.07.018
13. Crossley FS, Moore ML. STUDIES ON THE LEUCKART REACTION. J Org Chem. 1944;09(6):529-536. doi:10.1021/jo01188a006
14. Kochana J, Wilamowski J, Parczewski A, Surma M. Synthesis of standards of the most important markers of Leuckart p-methoxymethamphetamine (PMMA). Forensic Science International. 2003;134(2-3):207-213. doi:10.1016/S0379-0738(03)00163-4
15. Webers VJ, Bruce WF. The Leuckart Reaction: A Study of the Mechanism. J Am Chem Soc. 1948;70(4):1422-1424. doi:10.1021/ja01184a038

Edit: I just noticed the many duplicates in my directory, (just ignore the duplicates)

 

[LabPsycho]

Last time I did the Leuckart (few years ago) with P2P + formamide + formic acid + ZnCl2. Heated just 8 hours 30 min. Temp: 140-150 C and for last two hours at 160-170 C, I got 75% molar yield of N-formyl amine. I just quit it all, because I just failed and failed with basic hydrolyzations and was interested more to do something else.

 

[Blammo]

Was the zinc chloride anhydrous?

What scale?

 

[LabPsycho]

I want to also make clear that every reagent was made by myself.
Zinc chloride was anhydrous. I followed basic chemistry procedure from zinc sulfate ---> zinc carbonate ---> zinc chloride. I used always small scale syntheses. In this reaction, from 16.48 g of P2P to 15.96 g N-formylamine (~75% molar yield). Everything was always very good, yield wise, but then it didn't matter if I calculated my acid or base (0.5 molar to ketone), or hydrolyzing 1 to even 8 hours, in the right temperatures, did get always fockin' BLACK reaction mixture! Using acid or base hydrolysis with different experiment conditions was always so frustrating, because I had to work and learn to make that P2P... Fuck, I got angry even now! hhaha.. Any ideas? So I learned to make the real N-formyl derivative in couple of tries, but my projects crashed always in the hydrolysis. In this my last reaction I went through acid hydrolysis with 34.17 g of ~ 18% hydrochloric acid bought from hardware shop, and I got black mixture again. I basified it to pH: 10-12, and it went to black and thick, clumpy mess not soluble in water anymore. I extracted it with 3 portions of xylenes (didn't have options but xylenes should work). Then I washed it twice with excess of pure water, and it gave much shit out of xylene-extract, but still. BLACK! Many people say that yes, you can do the Leuckart with impure P2P. I think the only thing can be that my P2P is just very VERY impure. It is clear but dark orange colour. But if problem is my too impure P2P, I must do the bisulfite purification, BUT I can only have and I have the reagent even now, witch is potassium metabisulfite. When I make solution from it it will turn potassium bisulfite (read this info from many sites) and even G. Patton said potassium metabisulfite will work. OK. But I only have sodium carbonate and KOH as bases. If it has to be carbonate, will sodium carbonate work to bisulfite product made with that potassium bisulfite solution to free the diethyl ether purified P2P potassiumsulfate? Or has it to be potassium carbonate? I live in place that even planning to do these kind of syntheses is jail time!