AlbertChemist said:
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 :d
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.
