Mescaline Synthesis With Nitromethane. 1000g Scale.

[Mr Gonzo]

Hi with regards to the LAH is there something else thats is more easy to obtain and use in its place, or is there some way I could be instructed on how to buy the hydride from somewhere with minimal hassle? Tried a place in India and they was having none of if! I'm based in UK

 

[FredDurst]

Did you source some for the UK in the end mate?

 

[Rabidreject]

lol I did the exact same thing! I’m pretty scared to go near the LAH!

 

[Rabidreject]

Does the second bit of this synth work nicely scaled down to say a 5g starting nitrostyrene quantity? Or do the solvents scale differently? I’m about to try this…

 

[Rabidreject]

Oh one more thing, can I reduce the corresponding nitropropene for TMA in the same manner? It seeems okay but it would comfort me to know someone has done it!

 

[Rabidreject]

This is bugging me - I’m about to perform your reaction and have scaled everything down but I still find myself wondering this…

Why do you say to add the b-3,4,5-TMONS in portions as a powder, as opposed to dissolving it and adding dropwise?

Is it a scale thing that I’m missing because I have never worked on a scale even close to this?

 

[Swirly]

Dump in the nitrostyrene about 3 large spoonfuls at a time under crushed ice-salt-bit of water cooling. The sodium borohydride/IPA/h20 should be cooled to about 5 -8 celcius when you begin the nitrostyrene addition, as when you add a larger amount of nitrostyrene it does heat up some.

If you pour everything in at once it will be a runaway volcano, crazy action, too much heat.

Keep it under 26 - 28 C. Depending on the nitrostyrene and amount, addition might take over an hour. You will need to add more ice if taking a long time and working with lets say 100g.

If yours is a small amount, might be able to dump everything in at once without temp. spiking too much.

 

[Rabidreject]

Yeah I’m literally just testing on a 5g scale at the moment.

Iv been learning and due to the fact there is such a difference in the amount being added, I’m assuming I didn’t reflux it long enough.

I think I was expecting it to be way more exothermic than it was, due to the fact I did such a small scale reaction and therefore it was quite a bit cooler than the synth said upon addition. I don’t think I let it react for long enough at around 75c.

Im surprised by your temps to be honest but I guess as you say it differs depending on which styrene you are using? I dunno…it’s strange that it didn’t look like the organic solvent extracted anything out of the aqueous phase tbh.

 

[Swirly]

Yes, 2,5-DMNS seemed to give off less heat and did not react as vigorously as 3,4,5-TMNS at the same amounts. I was able to add the DMNS quicker and it fully dissolved, i.e. no orange/yellow was left. While I could not get the reaction mixture to go fully milky white with 3,4,5-TMNS, always a touch of yellow left.

I read elsewhere that temps are kept below 30 C during addition. Someone wrote that it increases yield or something. This was for 2,5-DMNS I believe, so I do this for 3,4,5-TMNS as well. Keep it all under the ice.

 

[Rabidreject]

Ahhh okay I get you.
That all makes sense…

Honestly, I used my first lot of the 3,4,5-NS in the first reaction and didn’t get squat out of it (5g scale). Not exactly sure where I went wrong but it certainly didn’t get too hot but I also didn’t let it react for very long at all….I just know when I went to extract the aqueous layer with DCM there was next to nothing in it…

Oh well, I often f up first go…so we’ll see but I also had to knock up more of the nitrostyrene as I can get more NM where as NE is more expensive and the 2,5- aldehyde I have less of as it’s more expensive compared to 3,4,5.

Oh I’m also going to write everything I do in the next reduction down lol

 

[Rabidreject]

I’m curious how after basifying, you are expecting the amine to be in the aqueous layer?
Surely you want to first acidify it to migrate it to the aqueous layer, and THEN basics, causing the amine to be deprotonated, causing it to crash out and THEN you can extract with something like DCM?

I just clocked this is very similarly written to a science madness post I just read, with stoichiometry altered for large scale.

I will admit I tried this before fully thinking it through.

The place that threw me was the straight to base and then expecting the amine to be in the aqueous layer to extract. It wasn’t and it didn’t lol

Also, I was told to just keep the temps low when doing it small scale, I can’t really comment on scaling reactions up, all I know is this didn’t work on a small scale and I imagine the going straight to base is why….or not even that - me being an idiot, basifying it and expecting the amine to be in the water layer. Should have picked up on it

Oh well, I made plenty more nitrostyrene for when I F it up again!

 

[Swirly]

After the reduction, most of the amine will be in the IPA, you can try to extract from the water with IPA, clean the combined IPA and and dry it. Then you drop in if you access to 20% H2SO4 in IPA. To pH 7 or 6.5 can't remember the specifics. You will create the mescaline hemisulfate so 2 mesc. molecules to 1 sulfuric acid. Or 1/2 mol amount of H2SO4 (calculated for a rough 80% yield from the nitrostyrene).

You do not need to basify after all. No need to quench the reaction with NaOH. Better to quickly filter off the copper, extract 2x the aq. layer with IPA, clean the combined IPA with a 50% solution of K2CO3 two times. Then dry with magnesium sulfate, gravity filter off the magnesium sulfate. Then drop in the 20% H2SO4 in IPA (prepared from 98% clean concentrated H2SO4).

If you do not have any H2SO4, use HCl, in this case evaporate or distill off the IPA until you are left with freebase mescaline oil. Then drop slowly in an 80% mol eq. of HCl (rough estimate), diluted (rough estimate). Be careful as always when salting. For HCl maybe aim for pH 5 - 6. You can always do only half of the freebase oil at once, if you overshot the pH, I guess you can always pour some mesc. freebase back in to stabilize the pH.

Now I have only experience with mesc. hcl, at this point you need to once again evaporate off water to get this sticky nasty sludge of Mesc. HCl, you would need to freebase this with KOH to 10 - 11 pH and salt again with HCl to get a cleaner form. Extract 3x with DCM once you have basified with KOH, calculate amount of HCl. again and dilute the HCl. Drop in the HCl, watch carefully, past 7 pH it drops very quickly, one or two drops more is all you need sometimes.

Then distill/ evap off the DCM and then the water. You should have a cleaner product. Maybe an orange paste.

Now take this once mostly dry and under vacuum clean with cold ethyl acetate, then cold acetone. Copious amount of acetone.

Next time I will prepare the crude mesc. hemisulfate first. It should be much cleaner than the initial HCl. So will report back then.

No need to use DCM, initially you should salt the IPA layer directly. Most of the amine is there!

As for the actual reaction, I do not have trouble with it. Try to drop in the copper chloride all at once into the center of your reaction mixture. It is a violent reaction so if you are working with larger amounts remember to transfer to a large container JUST for the entire copper chloride drop. Maybe a 5 L or 20 L beaker, then pour everything back into your round bottom flask, and mix like crazy, heat a bit so it warms to 75 C. Ater you dropped in the copper chloride, spin for an 1 hour - 1h30min.

Also do not leave everything out for too long, think you need to run the reaction with the sodium borohydride and directly after with the copper at once.

 

[Rabidreject]

ahhh okay. Yes this makes more sense to me.
I will admit I tried it a couple of times and the first time got nothing, second time I got a small amount of V dirty looking freebase.

I ended up transitioning to try reducing using zinc/hcl…

I def got way more crude product out of it but then I also put a lot more effort into actually making sure the nitrostyrene was in solution before proceeding….anyway I’m about to try salting the freebase amine, so we’ll see.
Good to know it’s easier to use H2SO4 - I have both conc Hcl as well as H2SO4 so other than the dosage being different it makes no difference to me.

I have realised now that I actually had a load of insoluble contams from the initial Henry reaction - iv now sorted this and got much purer/cleaner looking crystals from that. Still though it seems to take a load of solvent to dissolve this 3,4,5-TMONS when compared with other styrene’s like 2,5-DMO.

Anyway I’m out at the mo but I’ll look over what you’ve said in more detail when I’m back and hopefully it’ll make it possible with that method.

Thanks a lot for the reply there - I assumed I was reading it wrong with that step where it tells you to basify then extract the aqueous layer. That is where I initially went wrong anyway.
Iv just found it to be a really messy horrible looking reaction mixture to the point it was hard to visibly see if the yellow was fading.
This was much easier with Zn/Hcl method so far but we will see!!

 

[Rabidreject]

Dammit I just tried this again and completely bloody forgot to cool.

It’s annoying, whenever I have done this reaction, just after adding the catalyst it starts going brown, then black and as I understand it, when phase separation happens, the black Cu is meant to stay in the aqueous layer but I’m finding it stays in the organic phase

I’m not going to lie the reason I forgot to chill it is because I thought I’d seriously messed it up last time until I realised I just simply couldn’t follow instructions regarding treatment of the different phases durin workup.
I abandoned this method to try the Zn/HCl reduction instead - needless to say I couldn’t manage that either!
I’ll try it again tomorrow - I’ll also let today’s sit and see if the Cu particles ‘settle’.

I have no idea what I’m doing wrong to be honest. On paper this is a really easy process and yet in reality I keep fucking it up!

 

[Rabidreject]

@Swirly

Hey man, when you were talking about the fact that with 2,5-DMONS you were able to get it to go fully white, and with TMO it was always slightly yellow, so you mean before you added the catalyst?

Obviously when you start adding the catalyst it starts going darker and darker so I’m assuming you meant before.

This is really annoying…I’m bloody determined to figure it out. I guess doing it on ice will be a start.

 

[Swirly]

Yeah it was not 100% milky white, very slightly yellow, need to slow down the addition and use ice for sure.