Sciencemadness Discussion Board - Alternative methylation reagents to form quat tryptamine salts?

Alternative methylation reagents to form quat tryptamine salts?

JJay - 11-11-2015 at 22:03

Methyl chloride and methyl bromide should be able to do it, but I suspect the reaction is fastest with methyl iodide. Methyl iodide isn't hard to produce, but I'm not sure how one would do it with chemicals that can be easily obtained... most syntheses would involve the use of elemental iodine or hydriotic acid, which are DEA List 1 chemicals.

Quatro - 12-11-2015 at 07:57

Well you could reflux H3PO4, NaI, and MeOH to do it, but that's besides the point. I was wondering if something other than the methyl halides could make the quat salt. (of course MeI does it the best, but I'm looking for alternatives?)

Could any of the ideas I listed be used? Anyone have any suggestions?

User123 - 12-11-2015 at 08:45

Methyl bromide would be the easiest for you to generate and use. It can be made by heating a mixture of sulphuric acid, methanol and sodium bromide. There is a preparation on orgsyn which you can follow. Search the forum, people have given links to it in the past. You can bubble the gas directly into the reaction mixture. Good luck.

Crowfjord - 12-11-2015 at 10:00

As far as I know, only alkyl halides or alkyl sulfates will quaternize amines. I don't think dimethyl carbonate or other weak alkylating agents will do it. Methyl bromide and methyl iodide are really not that bad, though. Just use proper lab practice.

I've made and used methyl bromide many times, using Painkilla's method. Rather than bubbling the gas through reaction mixtures, which is rather inefficient, I prefer to condense it in a coil of tubing or in a flask submersed in an ice-alcohol or dry ice-acetone bath. Then the liquid methyl bromide is poured into a swing-top beer bottle with the reaction mixture. The cap is clamped shut and the reaction allowed to proceed. The main downside is that one can't really stir this way. You have to swirl by hand. It works like a charm though, to methylate phenols.

Nicodem - 12-11-2015 at 11:09

Quote: Originally posted by Quatro

MeI, however, is extremely poisonous, and difficult to procure... I've been researching for hours on what types of reagent can methylate all the way to the quat salt... (avoid methyl halides, Dimethyl sulfate, etc)

Any sufficiently electrophilic methylating reagent will do. Dimethyl sulfate gives a methyl sulfate salt. The methyl sulfonates like methyl tosylate or methyl mesylate give the corresponding sulfonate salts (tosylate, mesylate).

Quote:

1. Dimethylcarbonate (DMC) is a much safer reagent for methylation, but not nearly as strong. Could this hypothetically form the quat carbonate salt or is that impossible?

Not as such. Dimethyl carbonate only efficiently methylates acidic functional groups. Of the amines it methylates (actually groups that form sufficiently acidic methyl carbamates (NHCOOMe), therefore mostly just primary aromatic amines.

Quote:

2. Does trimethylphosphate have any possible use?

It would give you a dimethylphosphate salt, though it would require much more forcing conditions that methyl iodide.

Quote:

3. (read this idea on a forum, doesn't sound possible BUT) could Dichloromethane (DCM) be refluxed with tryptamine to form the quat chloride salt? I know tryptamine is almost insoluble in DCM which would probably make the reaction slow?

That makes no sense. Dichloromethane does give quats by its reaction with tertiary amines, but tryptamine is a primary amine (and even if it would have been tertiary, it would not give the same quat cation as the methylating reagents do).

Quote:

4. Could Tetramethylammonium chloride possibly form the quat chloride salt?

There is not enough thermodynamic difference. Even if you would push from the initial equilibrium further on by removing the gaseous trimethylamine (a base would also be needed to regenerate the amine bases), the methylation would stop mainly at the dimethyltryptamine stage even with excess of tetramethylammonium chloride. Perhaps it would work, if you would use a tetramethylammonium salt having a nonnucleophilic anion (like a tosylate or some other sulfonate) and not heat too much (say at 120 °C).

Please read the forum guidelines. Open topics using a beginner's discourse only in the Beginnings section where I'm moving this.

AvBaeyer - 13-11-2015 at 19:08

Quote:
2. Does trimethylphosphate have any possible use?

Trimethylphosphate on its own is not a particularly good alkylating agent. However, it is readily cleaved by NaI in acetone and methyl ethyl ketone to give methyl iodide and sodium dimethylphosphate. I can say that trimethylphosphate + catalytic NaI + potassium carbonate in acetone will cleanly methylate phenols. About methylating amines, I cannot say.

AvB

Quatro - 22-11-2015 at 06:24

Thanks Nicodem

In an old thread you mentioned how only MeCl is significantly less electrophilic than MeBr and MeI... Would it be difficult to get N,N,N-trimetyltryptamonium chloride to form by bubbling MeCl through an IPA/Tryptamine solution? Or would it just be a very slow reaction, and not efficient?

Also, I know that in the case of the quat IODIDE salt, refluxing in ETA transfers one of the methyl groups from the quat to the ETA. The mechanism is based on the fact that the ETA is present in excess over your quaternary amine, and thus the "extra" alkyl group is preferably transferred to the amine function of the ETA.

Would refluxing in ETA also work with the quat bromide, and chloride salt? Or would it not work with the chloride salt because it's not electrophilic enough? Or maybe you would just have to reflux longer and with higher temp?

[Edited on 11-22-2015 by Quatro]

byko3y - 22-11-2015 at 10:26

Nicodem, I can't seem to find the source of the quote "1. Dimethylcarbonate (DMC) is a much safer reagent for methylation, but not nearly as strong. Could this hypothetically form the quat carbonate salt or is that impossible?", is it deleted or the message edited?
Quatro, MeCl is less reactive, requiring something like 80°C to react with appreciable rate (60°C for MeBr, 50°C for MeI), but its reactivity is closely related to its safety and the reagents are cheap, you can use 10x stochiometric amount of MeCl without much problems.
You should use aprotic solvent to perform alkylation, otherwise nucleophiles will be shielded with solvent protons - this is a basic rule you should never forget. And luckily, many common aprotic solvents have high boiling point and are able to dissolve the MeCl gas well, thus you can actually heat the mixture up to 100-120°C and still have a fair amount of MeCl in the liquid phase, though the reaction will take more time than the one with MeBr or MeI (rate = [MeX]*[nucleophile], [MeCl] at atmoospheric pressure is obviously lower than [MeBr]). Autoclave is a good solutions, but not every person here has it, and it can be dangerous to work with.
ETA is ethanolamine.
I'd say the ammonium anion makes no difference for the dequaternization.

Quatro - 22-11-2015 at 12:01

Thanks for the info. Where are you getting those numbers that 50°C is necessary for MeI to react at an appreciable rate? It seems to react just fine at room temperature in IPA as a protic solvent. One example here and one here

MeCl appears to be miscible in acetone (aprotic solvent) but obviously acetone has a very low bp. What would you personally use?

I think Shulgin might have used IPA just because it makes it easier to filter out the formed ammonium salt.

byko3y - 22-11-2015 at 14:45

Quatro, 12 hours is a really long time for such a reactive halide as MeI, and the yields are low: 50% for the first case with 5x moles of MeI based on tryptamine, 30% for shulgin with 3.8x quantity of MeI. At reflux in aprotic solvent the same result could have been obtained in an hour. In 20 hours in acetonitrile tertiary amines using alsom stochiometric amount of alkylation agent (110%) are transforment into quaternary ammonium with 85-90% yield (US Patent 3,965,178); for Sn2 reaction with stochiometric reagents this means that half of this conversion will be achieved order of magnitude faster.
Common aprotic solvents are DMSO, DMF, acetonitrile, N-Methyl-2-pyrrolidone, though you can't use DMSO, because it will be methylated.
And yes, workup is much more easier for IPA, and i can't tell how to perform it with triptamine quaternary salt because I don't know its lipophilicity. Shulgin performed recrystallization in acetonitrile, but acetonitrile has a low boiling point.

[Edited on 22-11-2015 by byko3y]

Quatro - 22-11-2015 at 15:42

Well I think the low yield probably has to do with the positively charged amine hydroiodides that form due to the HI made by the reaction. I don't think the yield is being affected by the use of an aprotic or protic solvent, but rather that just effects the time it takes to react? I could be wrong.

I think it would be better to keep using IPA for the simple work up and maybe just add heat and or pressure to continue the reaction faster?

[Edited on 11-23-2015 by Quatro]

byko3y - 22-11-2015 at 16:01

You are right, there should be a base for a regular amine alkylation. Clearly, the examples you gave are unoptimized. Once medium turns acidic - alkylation is slowed down. It's strange they've managed to obtain more than 30% yield. BTW, the first paper uses shulgin's procedure.
IPA is just as low boiling as acetonitrile, and can dissolve less MeCl because IPA is protic, while MeCl is aprotic.

Quatro - 22-11-2015 at 16:40

I had this same discussion with my friend Crowfjord. Although maybe Hunig's base could be used, strong bases can actually cause 1-methylation on the indole. So I'm not sure if it would be a good idea or not. Maybe Hunig's base isn't strong enough though to cause that to happen.

byko3y - 22-11-2015 at 20:15

Hunig's base does not allow quaternization, so the product will be N,N-dimethyltryptamine.
For quaterniation you can use carbonate and bicarbonate, which are poorly soluble in IPA or acetonitrile, but amine salt has good solubility in water, so amine salt will go into water layer full of carbonates.
Although I have no idea whether it can interfere with quaternization, mainly because I have no idea about what is alkylammonium carbonates, how soluble they are in different solvents, how they react with alkylation agents.

JJay - 23-11-2015 at 05:28

N,N-dimethyltryptamine was a controlled substance last time I checked. I should probably figure out what we are talking about making before I accidentally tell someone how to make some illegal drugs.

Crowfjord - 23-11-2015 at 08:45

Quote: Originally posted by byko3y

Hunig's base does not allow quaternization, so the product will be N,N-dimethyltryptamine.

I think you have this mixed up, byko3y. The sterically hindered base itself does not get quaternized, not easily at least. By what mechanism would it prevent another, non-hindered amine from being quaternized?

My advice to Quatro to use a hindered base comes from J. Org. Chem., 1970, 35 (5), pp 1558–1562. This reference says that hydroxides or carbonates may also be used, but "under these heterogeneous reaction conditions prolonged heating is needed leading to numerous side reactions and low yields." Though the N,N,N-trimethyltryptamine salt may not be so unstable. I will go ahead and post the paper here.

Attachment: Alkylation of Amines. A New Method for the Synthesis of Quaternary Ammonium Compounds from Primary and Secondary Amines. (624kB)
This file has been downloaded 1510 times

Quatro - 23-11-2015 at 11:02

JJay, this is Nicodem's quote from a different thread

Quote: Originally posted by Nicodem

Quote: Originally posted by hkparker

Isn't the goal of this thread to make a psychedelic drug? Don't we frown upon that? Even though the discussion here is really interesting and higher level.

No we do not frown upon that. That is not the forum policy, as far as I know. What we frown upon are kewls, greed and malice.
"We" as the forum collective are supposed to be (amateur) scientists, so we are supposed to behave scientificaly as long as the discourse is kept on a scientific level without the annoying tweaker's delirium, expressions of greed, kewlishness, SWIMing, street slang, pretending idiotism, spoonfeed requests or recipe questions. If you see any post that does not conform, please use the report button.

Besides, anyone who is intelligent enough to understand the discussion here is intelligent enough to make drugs. No one is spoon feeding anyone, and an average teenager would never be able to pull off a DMT synthesis. (An extraction yes, a synthesis no)

[Edited on 11-23-2015 by Quatro]

JJay - 23-11-2015 at 11:35

Quote: Originally posted by Quatro

JJay, this is Nicodem's quote from a different thread

Quote: Originally posted by Nicodem

Quote: Originally posted by hkparker

Isn't the goal of this thread to make a psychedelic drug? Don't we frown upon that? Even though the discussion here is really interesting and higher level.

Quatro, I'm not saying that I think that it is always morally wrong to make DMT or that I'm averse to willfully and publicly discussing methods for making it, but I might want to link to my profile for professional purposes at some point, and accidentally helping people make illegal drugs is not something I am trying to do.

Should it be legal to make or consume DMT? I don't pretend to have the answer to that question, but the fact is, making it is probably both illegal and not terribly interesting. Making DMT quat compounds... is possibly both interesting and legal, so it's something I would like to discuss.

Quatro - 25-11-2015 at 07:43

I completely understand where you're coming from JJay, I respect your opinion.

The synthesis of these quat salts seems very simple at first glance. I think that getting 33% yield is always very simple.

But if you want a high yield, it's a bit harder. Hunig's base is pretty expensive. Sodium carbonate could neutralize the formed acid but it might make the separation of everything more difficult, because there's a salt and some water added to the mix.

Nicodem - 25-11-2015 at 10:36

Quote: Originally posted by Quatro

The synthesis of these quat salts seems very simple at first glance. I think that getting 33% yield is always very simple.

Well, a reaction in the absence of the base is different, so a 33% yield calculated on what you would get by the trimethylation of all of the amine, actually represents a 99% yield according to the actual stoichiometry. For example, Shulgin gives a procedure that provides N,N,N-trimethyltryptammonium iodide in an 88% yield in his book TIHKAL.

Quote:

But if you want a high yield, it's a bit harder. Hunig's base is pretty expensive. Sodium carbonate could neutralize the formed acid but it might make the separation of everything more difficult, because there's a salt and some water added to the mix.

Then use a two step synthesis and avoid the cleaning of the methiodide. You can synthesize N,N-dimethyltryptamine from tryptamine by any of the many methods in the literature or from the Internet forums (there are simple methods using formaldehyde and NaBH₄ posted on the Hyperlab forum, and even one methiodide based route which was posted recently). You can then react this with methyl iodide in alcohols or acetone which gives a nicely crystalline N,N,N-trimethyltryptammonium iodide directly from the reaction mixture, pure from any inorganic salts, because the quaternization from a tertiary amine consumes all the starting amine even in the absence of any added base.

Quatro - 25-11-2015 at 12:55

Well what I was trying to say is, in the absence of a base an 88% - 99% yield should be accomplished pretty easily. Shulgin uses a huge excess of MeI which I think is a little wasteful. I would think that using the standard 3 molar equivalents of MeI would produce the same yield, but maybe it would just take longer to complete. Or maybe he could have added heat and a condenser to avoid evaporation.

Just out of curiosity, can you link me to the "methiodide based route which was posted recently"?

And I don't think the N,N-dimethyltryptamine synthesis is nearly as simple as you are making it sound. Well it may be simple in principle, but it utilizes significantly more expensive reagents like formaldehyde and NaBH₄. Would you actually go that route if you intended to make the quat iodide salt?

Shulgin's method seems to get a good yield, and he simply washes with IPA to isolate the quat salt. It would be far easier and cheaper to do that procedure a couple times, than making DMT first with NaBH₄. And I bet the product is quite pure just from the IPA washes. If you wanted you could even recrystallize in acetonitrile like he did.

MeI is also by far the most expensive methyl halide. Like Crowfjord suggested, MeBr would be a good idea. MeCl would be cheapest, but slightly less efficient at methylation, but I doubt it would be a problem?

I haven't found much information on synthesis of MeCl. I assume it's simple, however, and all you would need to do is drip H₂SO₄ onto NaCl, an bubble that dry HCl into boiling methanol. I think ZnCl₂ catalyst might be important, because I read somewhere that the reaction of aqueous HCl and MeOH is EXTREMELY slow and will not get you anywhere.

byko3y - 25-11-2015 at 21:49

Quatro, 3.3 eq. MeI, 1.25 eq. K2CO3, 18 h at rt in ethanol.