Methaqualone

There is something delightfully attractive about things that are prohibited or otherwise challenging to obtain. Exclusivity. Perhaps the desire to feel special. I guess if you know you know. Oftentimes it is very motivating to work towards a product that you can't simply buy from any chemical supplier.

So here's me making drugs.

Reference.

9.63 grams of o-toluidine, 14.19 grams of anthranilic acid and 9.00 grams of glacial acetic acid were combined in a 250 mL Erlenmeyer. With strong stirring, 90 grams of hot polyphosphoric acid was added in 10-20 gram portions using a glass syringe. The mixture was heated to and kept at 185 degrees Celsius for three hours.

Degraded, stored-for-a-while o-toluidine.


PPA <--> o-T + AA


After adding all of the PPA.


Reaction taking place.


Cooled reaction mixture.


Once sufficiently cooled, the reaction mixture was poured in 400 mL of water and, after filtration, the solution was made basic using sodium carbonate. A grotesque mass separated from the aqueous solution and floated to the surface. The liquid was discarded and the solid(ish) mass melted and dried in the oven at 110 deg. C. This was then dissolved in in acetone and sufficient concentrated hydrochloric acid was added to precipitate out the product as the hydrochloride salt.

Reaction mixture being poured in water.


Some initial garbage caught in the filter.


Apparently, some people consume and even smoke this stuff.


Melted and sufficiently dry.


Precipitate containing crude methaqualone hydrochloride.


The crude product was collected by vacuum filtration and dried. At this point it looks deceivingly clean and weighs 9.63 grams. The solid was dissolved in minimal methanol, filtered and dried. Once dry the solid was washed with anhydrous acetone. This was then dissolved, dried and washed two more times in the same manner.

Crude product vacuum filtered.


Crude product dried.


Impurity exposed after redissolving and drying.


The now cleaner product was dissolved in acidified boiling water and treated with activated charcoal. There was some improvement. The treated solution was made basic, filtered and the solid base dried. The melting point range was determined to be 106-110 deg. C according to an interrupted alcohol-based thermometer. Actual melting point was likely a few degrees higher.

Product being dissolved in acidic water.


Hydrochloride solution before charcoal treatment.


Hydrochloride solution after charcoal treatment.


Methaqualone base.


Melting point test.


Melting point test. Still impure.


The product was once more converted to its hydrochloride salt. Recrystallization from the aqueous solution was attempted revealing more garbage. The solids were washed with acetonitrile, whose performance was very similar to that of acetone, dissolved in methanol, dried and washed with acetone.

Hydrochloride recrystallized from acidic water.


Getting there.


Finally, when no more color seemed to come off with acetone, the product was dissolved in minimal boiling methanol. An equivalent volume of MEK was added and much of the methanol was boiled off. At about the original volume of methanol, the still clear solution was taken off heat and a dash of acetone was added. This method of recrystallization is somewhat unreliable but affords decent crystals.

No matter what I tried - and I tried a lot of different things - some color always remained. Here are some of the purest crystals I could manage:






The whole project was a bit of a mess but I am still immensely happy with the fact that I managed as well as I did. All the reagents for this project, except for the phthalic anhydride which I purchased off Ebay, were sourced OTC which makes it all that much more special to me.

And now for a small rant. The workup was extremely frustrating. There was an incredible amount of colored impurity that followed the product everywhere and had to be leached out bit by bit. This is all well and good, but methaqualone has an incredibly obnoxious tendency to dissolve in solvents that it isn't soluble in if there is even a drop of water, alcohol, etc. in them. This makes it really hard to purify everything as you often have to go back a step and reclaim whatever you lost to unexpected dissolution. I might revisit the preparation and workup at a later date to see if using cleaner reagents and utilizing acetic anhydride makes for a cleaner product. For now, though, I've definitely had enough.




[Edited on 11-12-2020 by Benignium]

Quote: Originally posted by mackolol

It's even prohibited to do it here.

Quote: Originally posted by Benignium

The crude product was collected by vacuum filtration and dried. At this point it looks deceivingly clean and weighs 9.63 grams. The solid was dissolved in minimal methanol, filtered and dried. Once dry the solid was washed with anhydrous acetone. This was then dissolved, dried and washed two more times in the same manner. [Edited on 11-12-2020 by Benignium]

Quote: Originally posted by Corrosive Joeseph

Ludes went out of fashion with flares and platform shoes (the first time), I don't think anybody would be particularly interested in consuming the goods, or at least they shouldn't be. /CJ

Quote: Originally posted by mackolol

I wonder why. It's so easy to make them, yet practically nobody does so.

Unless they've watched wolf of wall street

Very good publication!
But why haven't you put this into prepublication directly?
It is more than worthy for this.

Also, a personal opinion, I consider the product rather boring and would always prefer thalidomide to which I grew a certain fondness over time
This does also not have the certain possible impurities that ruin the experience with their harmfulness... bladder cancer is a big issue with clandestinely produced methaqualone or so, I've heard.
Due to possible toluidine residues.

It might make for an interesting next project for you to try the preparation of thalidomide?

Quote: Originally posted by Amos

I'd love to know what your method for producing polyphoshoric acid is, and where you choose to stop the heating and finally use it. This is a reagent I'd love to try in a lot of different syntheses, particularly in inorganic chemistry. Also, can I assume you made the o-toluidine the usual home chemist way by mono-nitrating toluene, reducing everything with a metal and acid, then steam-distilling? Beautiful pictures and some very good chemistry on show in this post. This is the kind of scheduled substance post I can actually get behind.

Quote: Originally posted by zed

OK, I found a link..... https://www.sciencemadness.org/whisper/viewthread.php?tid=73...

Quote: Originally posted by karlos³

Also, a personal opinion, I consider the product rather boring and would always prefer thalidomide to which I grew a certain fondness over time This does also not have the certain possible impurities that ruin the experience with their harmfulness...

Quote: Originally posted by thors.lab

Excellent synthesis. The fact that this is all mostly OTC makes me question why street methaqualone is not more common than it is.

I would like to thank everyone who replied! I'm incredibly grateful for the positive response.

mackolol - To be frank I wasn't really too sure of this myself, but my interpretation was such that as long as my focus is on the chemistry it would be fine. I wish to keep posting here but in the future I will no longer make it as obvious if the subject is controversial. I've grown very attached to Sciencemadness and I would hate to do it harm.

As for your question, and I'm truly sorry it took me so long to get around to replying, the filtration in question was done just to get rid of any insoluble impurities that may be present.

I actually did try out the A/B approach but the line of inquiry took me a long time to finish. It worked out quite well and could in fact be used to significantly cut down on labor.

To some of the crude hydrochloride that was precipitated from acetone and redissolved in methanol, an approximated slight excess (2 grams) of oxalic acid dihydrate was added. The solution was concentrated for as long as it remained clear and water was added until no more precipitation was observed. The solution was decanted off and filtered. Dark brown solids remained in the beaker and on adding NaOH it was evident that no methaqualone was present.




The filtered solution was extracted once with 10 milliliters of DCM, which turned out to be enough to extract very nearly everything. The extract was stripped of solvent, redissolved in water and the aqueous solution made basic. Methaqualone base was filtered off and washed with water. The solid was dissolved in water by adding 48% hydrobromic acid dropwise. The water was removed by evaporation and the solid hydrobromide salt was recrystallized from minimal boiling methanol.



The hydrobromide salt seems to crystallize more readily and with significantly less impurity, affording very pale crystals even from a strongly colored mother liquor.

Pumukli - Steam distillation is a brilliant idea! I will definitely try it some day. Different melting points are reported for methaqualone ranging from 113 (Wikipedia) to 120 (PubChem) deg. Celsius. I have since repeated the melting point test with a proper thermometer and it seems consistent, with a sharp melting point range at 113-116. TLC plates are something I've been meaning to buy for ages now, but since it has not really been necessary until recently, I've just kept putting it off. Definitely going to need TLC going forward. Thank you!

Amos - I actually made a small post on the preparation of PPA. Perhaps you have already found it, but in any case here you go! You're absolutely correct on the o-toluidine - I followed ChemPlayer's procedure.

karlos³ - Thank you so much! I'm going to have to look into the prepublications as I'm still unfamiliar with the concept. I like the idea of synthesizing thalidomide. I recently learned that thalidomide very nearly made it so I would not be born. It is an interesting compound.




[Edited on 27-12-2020 by Benignium]

Quote: Originally posted by Benignium

Degraded, stored-for-a-while o-toluidine.

Quote: Originally posted by Tsjerk

I believe the salts of toluidine are stable, so you could form for example the HCl salt and store it as a water solution. Before use you then freebase it, extract with a solvent, dry with sodium sulfate and evaporate the solvent.

Quote: Originally posted by zed

Question about Toluidine degradation. Freshly opened bottles of Aniline and Phenyl Hydrazine, contain a product that is colorless to yellowish, this product discolors quickly once the bottle has been opened. Exposure to oxygen, I suppose. When you revisit this bottle a few weeks later, the contents will be reddish, or reddish brown (though still clear). I can imagine a small amount of Toluidine in a fairly large bottle (lots of oxygen) could develop a molasses-like appearance pretty quickly.

Quote: Originally posted by Tsjerk

Yes, it is indeed oxygen which causes the coloring.

SuperOxide, I have no accurate yield to report. I started out with 9.63 grams of the crude. Beside impurities, a lot of the material ended up being tossed while investigating solubility and different methods of purification. Right now I have well over two grams of completely colorless material that I'm trying to get to form nice crystals.
The toluene is from a hardware store thinner. Fortunately for me it is quite pure - I have even made tosylic acid without much discoloration in the final product. I would highly recommend distillation as well as drying or separating any azeotrope, even if the MSDS states toluene as the only ingredient. However, some water isn't going to affect this particular nitration.

Thanks to zed, I figured out how to remove the remaining coloration. Treating the solution of methaqualone base in toluene seems to be the ticket here. It does not remove everything straight off the bat, however, and forming the hydrobromide salt after an A/B treatment using oxalic acid and recrystallizing it from methanol seems to be the most reliable way to get there.

Quote: Originally posted by Benignium

Thanks to zed, I figured out how to remove the remaining coloration. Treating the solution of methaqualone base in toluene seems to be the ticket here. It does not remove everything straight off the bat, however, and forming the hydrobromide salt after an A/B treatment using oxalic acid and recrystallizing it from methanol seems to be the most reliable way to get there.

I did actually try something like that. As the amount I was working with was too small for my only soxhlet apparatus, I folded a basket out of coffee filter, loaded it with a paste of methaqualone paste mixed with some sodium carbonate and suspended it over boiling 60-90 petroleum ether, under reflux. I let it go for 24 hours or so. The methaqualone did indeed accumulate on the bottom of the boiling vessel, but so did some of the brown color. The extracted material was a clear, exceedingly tough gel with a brown tinge. The filter paper was- Actually, I believe I have pictures...










[Edited on 19-1-2021 by Benignium]

Quote: Originally posted by Benignium

The toluene is from a hardware store thinner. Fortunately for me it is quite pure - I have even made tosylic acid without much discoloration in the final product. I would highly recommend distillation as well as drying or separating any azeotrope, even if the MSDS states toluene as the only ingredient. However, some water isn't going to affect this particular nitration.

Quote: Originally posted by njl

I though phenol was air/uv sensitive with respect to polymerization?

Quote: Originally posted by Benignium

I neglected to mention that the way I got rid of the last bit of color was by treating in toluene with activated carcoal. I should really learn to proofread my stuff properly.

I wonder if that would be enough to purify it without having to go through some of the various purification steps you mentioned you tried, some of which seem tedious or repetitive. Perhaps just treat it with activated charcoal in toluene, then recrystallize it using methanol.

I hope to get to try this in the near future. I have everything needed for it now, except for time and space

I appreciate the kind words, Amos!

Whenever there is the possibility of speeding up the process without the risk of losing product, I tend to go for it. I haven't utilized vacuum all that much thus far because my equipment lacks the necessary protection. Mostly I just heat the mixture near, or all the way to, its boiling point using either an oven, a water/oil bath or just a hotplate. I've also used PC fans to further encourage evaporation but lately that has fallen out of favor for no particular reason.

With all that said, I suspect the methaqualone may actually slowly break down into something yellow. The best indication of this was when converting colorless methaqualone base in toluene into the hydrochloride salt using hydrochloric acid while also applying heat. Of course, given that melting point tests are generally the most advanced analytical method in my arsenal, I cannot reasonably rule out the possibility of remaining impurities being the culprit.

Quote: Originally posted by Tsjerk

Phenol isn't air sensitive is it? Phenolates are though.

Quote: Originally posted by Benignium

[...] 9.63 grams of o-toluidine, 14.19 grams of anthranilic acid and 9.00 grams of glacial acetic acid were combined in a 250 mL Erlenmeyer. With strong stirring, 90 grams of hot polyphosphoric acid was added in 10-20 gram portions using a glass syringe. The mixture was heated to and kept at 185 degrees Celsius for three hours. [...]

Quote: Originally posted by karlos³

[...] Also, a personal opinion, I consider the product rather boring and would always prefer thalidomide to which I grew a certain fondness over time [...]

Quote: Originally posted by Pumukli

[...] - How thoroughly could you check the properties of the target compound? Do you know its solubility in various solvents? Could it be e.g. steam distilled? Sublimated? (You mentioned people used to smoke it. Well, it may be a good candidate for sublimation.) [...]

I was able to get this MQ synthesis a go as well (worked a treat thanks to OP's detailed post. So much in there that's not detailed anywhere else).

I decided to try the sublimation that was suggested by Pumukli. I took some photos of the process
Note: This was my first vacuum sublimation, so it's a rather sketchy setup, be gentle in your critiques, lol.

Summary: It does work ok. The crystals weren't nice and white like I was hoping, but they were definitely better than the crude product. Probably would have worked better with a higher vacuum and a better distributed heat source (eg: heating mantle instead of flame that needed to be moved around).

Here's a few of the photos of the crystals that sublimated onto the test tube:



[Edited on 3-5-2021 by SuperOxide]

Quote: Originally posted by Benignium

Thank you for trying the sublimation, SuperOxide! Very nice to see that it works. For resizing the embedded image, I recommend augmenting the BBCode: [img] -> [img=16x9] -- so width x height given in pixels.

Quote: Originally posted by Benignium

Thanks to zed, I figured out how to remove the remaining coloration. Treating the solution of methaqualone base in toluene seems to be the ticket here. It does not remove everything straight off the bat, however, and forming the hydrobromide salt after an A/B treatment using oxalic acid and recrystallizing it from methanol seems to be the most reliable way to get there.

Also thanks to Zed, I tried the same thing, and it seemed to work out perfectly.


It's not 100% white, it has a very small hint of yellow if you look at it at the right angle or under the right light, but it's by far the best I've done yet.

[Edited on 5-5-2021 by SuperOxide]

Quote: Originally posted by Mixe

Thank you both, and everyone else who participated, for this detailed and illustrating thread. I will most likely try this in the near future, but there's an elephant in the room that has been adressed but not sufficiently: the question of reaction time. 3 hours in OP:s work, 10 mins on Rhodium. And how long did you go for SuperOxide?

Quote: Originally posted by Uvxtal76

Quote: Originally posted by karlos³   Also, a personal opinion, I consider the product rather boring and would always prefer thalidomide to which I grew a certain fondness over time This does also not have the certain possible impurities that ruin the experience with their harmfulness... Thalidomide: As in the substance which caused this? https://helix.northwestern.edu/article/thalidomide-tragedy-l...

Quote: Originally posted by Nitrous2000

Quote: Originally posted by Uvxtal76   Quote: Originally posted by karlos³   Also, a personal opinion, I consider the product rather boring and would always prefer thalidomide to which I grew a certain fondness over time This does also not have the certain possible impurities that ruin the experience with their harmfulness... Thalidomide: As in the substance which caused this? https://helix.northwestern.edu/article/thalidomide-tragedy-l... Thalidomide was an excellent drug, just a disaster in women of childbearing age. There are many examples of drugs on the market today that can cause terrible birth defects if used in pregnant women.