So suppose you want to have your favourite alkaloid in salt form.

The most obvious answer would be to put it into water, add the acid of your choice and stirr until the salted amine is dissolved. But... now you face the problem of having to get rid of the water without burning your alkaloid. (I find rotovaps pretty crappy at removing water)

Next two ideas:
1) Dissolve the freebase in cyclohexane and add a molar equivalent of acid (preferrably not aqueous, or you end up in the same situation as before) and stirr for a while.
The salt should now crash out of solution and the cyclohexane can be evaporated off (or maybe even removed by filtrstion?? Or even recrystalization???)

2) Throw the freebase into an aprotic polar solven (maybe tetrahydrofuran??). And again add one molar equivalent of acid until the salted amine dissolves. Now, assuming you picked a solvent with a low enough boiling point, it should't be a problem to remove under vacuum.

Also, while I imagine that this works for weak acids, what about if you wanted to prepare something like the sulfate salt? I doubt it would fuck with the cyclohexane, but would it do somwthing to the THF?

Anyway, I curious to hear what you guys think and if you know of a more reliable, more streight forward method you'd be willing to share. (That doesn't require super fancy lab equipment

For me, the best way is FASA/FASI (fumaric acid saturated acetone or isopropanol)

It's really simple and effective.

To make FASI/FASA, just add excess fumaric acid to a container with some acetone/IPA, mix well and decant/filter your solvent away from the excess fumaric acid. Then dissolve your freebase alkaloid in another container with dry acetone or IPA, and once its dissolved you add your FASA or FASI slowly, wait for your crystals to form, then just filter to keep your crystals. Excess fumaric acid stays dissolved, which is great.

This process works best if you add FASA/FASI dropwise, very slowly, since it gives the opportunity for larger purer crystals to form, and they tend more to stick to the walls which makes it easier to pour the solvent out and leave crystals behind, or also filter easier if they are not stuck to the walls. The faster you add FASI or the more you shake/disturb the container as you do it, the smaller the crystals (less pure and harder to decant/filter)

As soon as the first drops start touching the acetone or IPA with your dissolved alkaloids, you'll see clouding happening, which is the precipitating alkaloids. When no more clouding occcur you can stop adding your FASA/FASI. Wait a couple of hours and add a few more drops to see if more cloudying occurs... If yes, keep adding. if not, you can prob filter/harvest your crystals already


Apart from ease of preparation, other advantages of this method are that fumaric acid is safe acid to use and consume, stable, and the resulting alkaloid salts are also very stable.

The Fumaric Acid salt / Fumarate is the only relevant salt for people here on the nexus:

Not only that it is food-grade, it is also at least thought to be antioxidative, as these double bonding would serve as antioxidant and would possibly react faster with any oxygen radicals. Nevertheless the *vulnerable* point of DMT is protected anyways, being the Amine in the form of any tertiary salt when salting. Also you are very correct about just filtrating stuff: If you just wait a little bit, all will settle and crystalize at the walls, so you can easily decant everything else. Using a minimal amount of solvent for the DMT and also for the fumaric acid may be super safe to reduce any substance loss. Also the FASA doesnt need to be saturated, but thats just a way to further decrease solvent usage. Fumaric acid takes quite a while to dissolve ... maybe throw excess amount in Aceton and wait for 1 day, then decant. Or put on hot plate at 60 °C, but cover the Aceton to not get any water inside and prevent evaporation.

If not using Fumaric Acid then you could use Maleic Acid, which has practically the same properties.
You could even use Ascorbic Acid - not a traditional acid, but strong enough to protonate DMT and also serving as antioxidant.

But these can only be used with polar solvents like Acetone, as Cyclohexan would only dissolve the DMT. Just even more polar solvents like DMT and DMSO would be bad, they may even dissolve salts of DMT.

Also: I would not use equimolar amounts of the acid, but use an excess. As long as it is fully dissolved (in case its solid in pure form) you will not get any of this in your product anyways. So better use excess of Acid to really get all of your DMT into salt. Otherwise you may loose stuff while decanting off the liquid.

Also its told to add the Fumarate slowly to prevent the creation of Mono-Salts. This is not really a problem, but then you cant really measure it easily - regarding DMT-content. Still, its not known if there is a real *problem* with mainly causing Mono-Salt precipitation if adding your stuff too fast. It will look like this.


Now regarding other salts:



Sulfate:

Dissolve DMT in Acetone and then add concentrated H2SO4 (95 %+). The H2SO4 should be diluted maybe down to 10 % or 5 % in Acetone before to not do a Rambo-precipitation.


HCl:

Normally the oldschool method is to generate HCl gas and bubble it through a solution. Of course laborious and dangerous. You can create HCl in situ by dissolving Trimethylsilyl chloride in IPA and heat this a little for 30 min. This will create HCl dissolved in IPA. Then add our DMT - but dissolve it in IPA first and slowly drip it in. Always make both stuff dissolved and not throw in solid DMT into an acidic solution.

Acetate:

Dissolve DMT in Aceton and just add glacial acetic acid. Much easier than dissolving DMT in Acetic Acid and then boiling all off.

Carbonate:

A common method for Tryptamine separation in literature seems to be the generation of the Carbonate salt. Do this by bubbling CO2 through your solution - this is already enough to precipitate your Stuff as the Carbonate.


It seems all of these lower salts either pull moisture or are a little oily on its own - very crappy to handle ... not recommended by anyone it seems.

The THF, while a little more reactive than the cyclohexane, would still be sufficiently resistant to sulfuric acid at room temperature. But you don't need to do that anyhow.

AFAIK, no-one has tried FASA/I precipitation from THF. Therefore all the relevant solubility characteristics are relatively unknown.

If you happened to have a solution of freebase alkaloid in cyclohexane which you then wanted to precipitate using FASA/FASI it would be worth testing whether or not adding FASA/I to the pure cyclohexane alone produces a precipitate. A while back it was reported that, when FASA was added to naphtha, fumaric acid appeared to precipitate out of solution without necessarily reacting with any freebase, leading to fumaric acid contamination of the product. There's a possibility that this might occur with cyclohexane also, due to its similarity to naphtha.

A few tests demonstrated that the precipitation of fumaric acid could be suppressed by spiking the naphtha with acetone before the FASA treatment. Perhaps this would work for cyclohexane too.

Thank you for the tip! I always wondered why I see so much of the fumarate salts around. So i guess the answer is that you can readily form it by the method you just described, and it's even an antioxidant! One thing though is that in my experience (strangely) acetone doesn't dissolve either freebases nor salts very well... Methanol dissolves both. But maybe my acetone had absorbed moisture from the air. Fortunately, anhydrous MgSO4 can be easily made with only epsom salts and an oven.

Thanks for the tip about using excess acid. I guess the same would go for the other direction if you want to make the freebase from a salt. Tried this a while back with alkaloid.HCl and equivalent amount of KOH. Pulled it into ether which was evaporated off to give a pretty ... oily ... result.

Also just out of curiosity, if you add HCl to an alcohol like IPA, would't you substktute Cl for at least some of the OH ?

Ah ok, didn't concider the fact that acids being polar would't dissolve well in cyclohexane...
(AlthoughI once put some H2SO4 into d-limonene which immediately started to percipitate black gunk, lol. (Also thd boiling point of d-limonene is a lot higher than water)

I haven't looked at whether THF can dissolve the freebase, but I guess my hope is that it's nonpolar enough to do so, while still being polar enough to dissolve the acid and later the salt.

Regarding the ether:

So did you evaporate the Ether by using a rotavap like from a chemistry lab? I guess it was just regular evaporation.

This will mostly result in an oil ...

Reason:

Ether is partially soluble with water and will take up water while evaporating. Even worse: Ether is evaporating at very low temperatures, so it will cause an intense cooling while evaporating. This forces additional water into your mixture, as it is now a surface of lower temperature, which will also cause condensation of water into that ether mix.
So in the end you will always result in an oily mess with ether :/
There is even a 3rd reason: If you did an extraction with ether you would normally do 2 steps afterwards:
1. *Backextraction* with saturated salt water aka. Brine which *extracts* the residual water off from the ether. Water is soluble with ether in a low amount, so as soon as it had water contact, it will already include water.
2. Use MgSO4 or Na2SO4 to throw into that mix and stirr it to get rid of even the last bit of water. These 2 are binding water like crazy, forming a complex with 8 and 12 water molecules.
3. Then the ether needs to be evaporated like with a rotavap and only then you have 0 water left in your mix :/


Regarding the reaction which I mentioned:

Trimethylsilyl chlorid (TMS-Cl) is basically HCl, but here the H+ is replaced with a *bigger* H, which is the TMS+. It is a heavy electrophile and will do substitution reactions with any nucleophil. So with the IPA: The R-OH attacks this big thing, releasing Cl- and attaching TMS+ to the alcohol, while getting rid of the H+.
In the end you have this:



So this is a method to generate HCl in a water-free environment. But the HCl does not attack any alcohol. Maybe it will partially Form R-OH2+, but this is quickly dissociating back to R-OH ...

And the R-OH and TMS-O-R are inert to DMT. If you let all the TMS-Cl and IPA react before putting in the DMT, then there is no TMS-Cl left to react with DMT.

But thats a lot of Blabla, it could be a method to generate the DMT*HCl-salt, but well why would anyone want that? As far as I know its quite hygroscopic. But again that's just something that I read once so I may test this somehow?




Yes in this case Cyclohexan is no problem: The more polar solvent has to be used when you have an acid that is solid normally and needs to be dissolved first:
Fumaric Acid, Maleic acid, Ascorbic acid for example

but glacial acetic acid / sulfuric acid will mix with Cyclohexan



I'm pretty sure it will dissolve that and also it will not dissolve the salt. Buuuut I mean you could also just use Acetone when doing the salting ... THF is not quite healthy - it's actually toxic, really no idea why, it looks to harmless ... So I think there is no real reason to use this over anything like Acetone / IPA / normal Ether / Methyl ethyl ketone

I suppose it depends on what freebase you are talking about.. Harmalas freebase don't dissolve well in acetone, but DMT freebase is VERY soluble in acetone. You can try isopropanol and FASI instead if it dissolves better.. I've never played around but ethanol/FASE will prob work too if you can get dry ethanol.

You can also use FASA/FASI in other non polars to precipitate alkaloids, for example if you have freebase alkaloids dissolved in xylene or limonene, you can then use FASA/FASI to precipitate them.

Methanol wont work well though because the fumarate salts are often still at least partly soluble in methanol so some (or all) wont precipitate.

So you are mostly on the right track, the only problem is with the choice of solvents, both cyclohexane and THF are not good choices and I will explain why, and not because of their reactivity.

When choosing a solvent for the freebase, you want something polar enough to dissolve the freebase with ease as well as remain miscible with the acid solution. If you use something like hexanes or cyclohexane you need to use a lot more solvent just to dissolve the freebase. You also don't want the salt to be so immiscible that it instantly precipitates as a fine chalky powder, this will trap more acid, be difficult to filter and definitely need to be recrystallized. Cyclohexane is pretty much the only thing more non-polar than hexanes, and it can't even be used for freeze precipitation because it has a melting point of 6 °C. (on a side note, the properties of cyclohexane makes an excellent solvent for recrystallization of DMT freebase) Limonene is a bad choice because it has a fairly reactive double bond, will definitely react in the presence of strong acids. Limonene is not a typical laboratory solvent for that reason among many others. It is not a very 'clean' solvent. Despite smelling like oranges. Oxidation products of limonene (epoxides) that could occur during an extraction can be quite toxic to the liver and body.

like cyclohexane, THF is also a bad idea for a few different reasons. THF dissolves salts very well because it can form complex with metal ions (part of toxicity as well). It is also very difficult to remove by evaporation compared to something like acetone, diethyl ether, or methanol. It is also not necessary to even use an aprotic solvent if you plan to evaporate. In that case, methanol is the primary solvent of choice. Filtration is of course better because it gives a purer product, both methods filtration or evaporation should be followed by recrystallization to get a product free of acid traces as well as produce a more crystalline product.

Also, it is not always a good thing to avoid the presence of water completely, in some cases having a bit of water in the mix can actually be beneficial for the formation and precipitation of certain salts (stable hydrates). The presence of an alcohol, water, or the use of a more polar solvent causes the precipitation to slow down and will become more crystalline, this product is more pure and is easier to filter and dry. The problem people have that they usually blame on water is when a salt doesn't crystallize and instead forms a goo, this is actually more commonly a result of excess acid, then it is about excess water. For instance, most salts are many times more soluble in ACIDIC water than they are in neutral water. So if the salt was titrated with the acid and and slowly neutralized, it is more likely to form crystals. If it is added too quickly or in excess, then it forms a goo.

Good solvents to use at home are ones that can double as extraction solvents (less evaporation). Diethyl ether is usually preferred, but it has a low extraction efficiency as well, similar to hexanes. So sometimes I would extract with a more efficient solvent like DCM, then dry with MgSO4 or K2CO3 (i prefer k carb for drying freebase amines in solution vs MgSO4) then evaporate the DCM to yield the freebase amine oil, then re-dissolve it in dry ether or dry acetone. This is easiest with a rotovap, but simple distillation works fine too.

Alternatively, polar aprotic solvents like ethyl acetate are great choices for salt precipitation as well, it can double as extraction solvent, saving a step. Toluene and xylene can be used this way as well. However, dissolving the freebase after extraction in is probably the best choice at home because you can use acetone, which is less stinky.

The method you are using of course can change based on the salt you want to produce and the amine you are using, but this is the most general method I use for converting most freebase amines into salts.

Having the freebase dissolved in acetone or ether, I usually add the acid dissolved in an alcohol, methanol, ethanol or isopropanol, or just pure ether. These all come with their certain trade-offs as well.

For h2so4, I prepare the mixture by mixing conc. 98% h2so4 with ethanol or isopropanol (10-20% by volume), both are cooled in freezer prior to mixing. This mixture cannot really be stored as it is very hygroscopic and also catalyzes the dehydration of the alcohol. having H2so4 and alcohol anhydrous is not very necessary either because most sulfate salts are poorly soluble in water and alcohols compared to hcl salts.
For recrystallization as well i prefer to use aqueous ethanol (80%). With h2so4 it is imperative to titrate the neutralization and perform it slowly with good mixing. It is recommended to do the addition with magnetic stirring, but i prefer to do it by hand out of habit. As long as you maintain the mixing with every drop and testing of the solution pH. Titration should end before the pH drops below 7. H2SO4 can form bisulfate salt if added too quickly, and excess is not easy to remove.

with fumarate, the same process carried out but with fumaric acid instead of h2so4. Practically any acid can be used here, maleic, benzoic, phosphoric, citric etc. Not all will result in stable salts. I recommend NOT adding excess with fumaric acid because it will not stay fully dissolved if you are using a less polar solvent (certainly not cyclohexane). If you are using the same solvent (like acetone) then it would stay dissolved BUT you are also pushing the equilibrium of hydrofumarate, it is more common than you might think I would wager that most people using excess FASA or FASI have a significant amount of it. Having a mixture of fumarate and hydrofumarate will interfere with crystal formation, resulting in a amphorous solid or gel, usually it can still be separated by decantation but requires further purification. There is no reason not to titrate, it simplifies things and gives a better product.

With HCl, often these salts are hygroscopic so anhydrous is more important but not strictly necessary in some cases. TMSCl is a great laboratory method, far superior to generating HCl gas and trying to bubble it into alcohol or ether. The resulting alcoholic HCl can be stored as well. I don't use TMSCl but instead just acetyl chloride : AcCl + EtOH -> EtOAC + HCl, in roughly a 20% ratio as well. The only byproduct is ethyl acetate, which is nice if your freebase solvent is also ethyl acetate.
In some cases, you can get away with simply diluting concentrated aqueous HCl with isopropanol. (10mL of 37% HCl and 90mL of 99% IPA), this would be easiest to carry out at home, but it is not suitable for all hydrochlorides. Another way is adding ether to conc. aq. HCl, then mixing and pipetting the top ether layer, which will contain some HCl. This is suitable for small amounts (less than a gram) Addition of a drying agent can be done as well, however not usually with the alcohols. In some cases this can work with IPA but usually it gets contaminated and you will end up adding inorganic salts to your amine. HCl salt is not really suitable for DMT but it is for most phenethylamines.

I always titrate these neutralizations with pH papers, they can be monitored visually and also easily calculated if you know the quantity of freebase. Having excess acid can cause the salts to become like a gel or paste or liquify after solvent removal, even in the case of easy to remove acids like HCl. Adding an equimolar amount, in a slow controlled dropwise manner with adequete mixing, will result in better crystal growth, a purer product that is easy to remove by filtration. There are no advantages to using excess acid, only disadvantage. The only reason someone should use excess if they are not confident in their ability to titrate, or lacking pH papers, and so add excess to ensure precipitation, or that they accidently add too much. Excess can be removed without too much difficulty, but it creates complications without offering any real advantages and should be avoided if possible.

After addition is complete, filtration can be carried out by vacuum or gravity, both are very fast if the precipitation was carried out correctly. Then you can wash with a bit of fresh acetone, or with more crude products, you can boil them in some fresh acetone and ether before filtering again, this would be a good way to remove excess fumaric acid as well , for instance.

You mean forming an alkyl chloride? (CH3)2CHOH + HCl -> (CH3)2CHCl + H2O ?

No, not without a Lewis acid catalyst. C-OH bond strength is weaker than C-Cl, more importantly Cl is just far superior leaving group ( ability to stabilize a negative charge), just compare it in terms of acidity, Cl- is a far weaker base than H2O, for example. A bronsted acid isn't near enough to make oxygen a better leaving group in this case. (Lewis acid is though) It is more due to size of the oxygen atom, making it a bad leaving group, similar to fluoride.



Acetone doesn't dissolve salts but it does definitely dissolve freebase very easily, which makes it a good solvent for salt precipitation. Freebase dissolves in acetone even faster than isopropanol, methanol dissolves both freebase and inorganic salts very well... perhaps your freebase is contaminated with some inorganic salts?

What I have been wondering for a long time is whether the bulk (or perhaps all) of the water solution could be boiled off in a microwave. This would cap the maximum temperature at less than 100C which is well below the point where dmt salts start to vaporize.

I'd imagine being that microwaving is a step during acidification in some teks, it would not hurt to microwave the final water alkaloid mix.

I've got no knowledge of chemistry or microwaves so this is all speculation.

well its very easy to do this with a stable salt like FASA. a microwave is probably a bad idea though because when it gets near dry it will probably pop and splatter DMT all inside your microwave. Not the best approach.

The better approach is to simply mix your equimolar freebase DMT and fumaric acid, 1 to 1 equimolar, mix with a few mLs of water in a pyrex pie dish. Then simply place the pie dish above a boiling pot of water (steam bath). The steam will nicely heat the dish no higher than 100C, while the convection current will carry away all the water vapor. Some people seem to confuse the fact that the steam is also water, that it will not dry the water in the dish, but this is not the case due to thermodynamics. Steam bath has been used by chemist for more than 100 years to drive off water

Well I was playing around with these salts on Thursday and thus I didnt read about optimal processing with Titration

That kind of made things worse, as overshooting with these kind of acids even caused the precipitation to either dissolve again (H2SO4) or not occur at all (HCl). So TMSCl + IPA works to generate pH < 0, but impossible to guess the actual HCl content for equimolar addition of course ...

But if added slowly in correct amount the 2DMT*H2SO4 salt was retrieved in correct amount (64 mg from 50 mg). Still that thing is only solid shortly after evaporating residual Aceton, then it turns to goo after 2 h ...

But I made a cool video of that precipitation step, comes quite voluminous! Sadly shrinks like hell when evaporating the Aceton

Also tried to evaporate this stuff to see if you can also get vapors from it like from the Acetate. But it seems this hard ions will just bake into the hot plate to a black cake like probably expected ...

The HCl content can be calculated precisely, as long as the temp is kept low during addition of TMSCl, the HCl will remain dissolved. So 1 mol eq. TMSCl = 1 mol eq. HCl.

DMT sulfate may be similar to DMT HCl, in that it does not form a stable salt, or one that quickly absorbs water and liquifies. So even if it is performed correctly it still may not be a solid salt.