TEK Ethyl acetate approach [CIELO]

[Transform]

I may be showing my unfamiliarity with mescaline again, but I think you'll get a sticky oil.

All the reports I've seen suggest the same. The melting point is recorded as 32-35°C, but it's said to persist as an oil at temperatures well below this.

The easiest way I've found to evaporate solvent is a water bath below the boiling point of the solvent, with air blowing on the solvent surface.

Just bear in mind, freebase mescaline is particularly noted for formation of a solid carbonate (or carbamate/bicarbonate - this is something I've been meaning to look into) by absorption of CO₂ and maybe water vapour from the atmosphere. This has the potential to throw any weigh calculations off by nearly as much as the uncertainties with the salt forms. Well, somewhere between 22 and 72 mass units on top of mescaline's 211, depending on the stoich«ometry, more if there's any additional hydration.

On the plus side, at least if it's not actually its own ipsocarbamate, the salt will be unstable and probably decomposes below 100°C, looking at NaHCO₃ as an analogy.

C₁₁H₁₅O₃NH₃⁺.HCO₃⁻ → C₁₁H₁₅O₃NH₂ + H₂O + CO₂

There's also a question of how hygroscopic this freebase might be, given its relatively high solubility in water. There' a certain amount of digging into the literature to be done in order to confirm whether there is any firm data regarding these points.

Investigating them practically for oneself would seem to require a few items of lab equipment, or at least the ability to creatively improvise them.

Don't be put off, however - I'm hoping that by providing some foresight it will help experiments to go more smoothly. It looks like 'simply' warming the carbonate-contaminated freebase under a controlled atmosphere and slightly reduced pressure should get rid of much of the CO₂ and moisture.

 

[aizoaceous]

Just bear in mind, freebase mescaline is particularly noted for formation of a solid carbonate (or carbamate/bicarbonate - this is something I've been meaning to look into) by absorption of CO₂ and maybe water vapour from the atmosphere.

Interesting complication, thanks. I'm pretty sure I did actually do this once and got the oil; but I might be lucky or misremembering, since the literature definitely reports that issue. Heffter, the first to isolate mescaline, reports that his freebase was a solid "melting around 150-160 C", implying that heating in free air won't decompose whatever he formed:

Heffter began his study of mescaline by preparing and analyzing salts, including the neutral sulfate dihydrate (C11H17NO3)2·H2SO4·2H2O. Surprisingly, he reported the free base as a solid softening above 100 °C and melting around 150−160 °C, which was not analyzed. As all subsequent work describes this alkaloid as a liquid at room temperature or as a solid melting at 35−36 °C, it seems likely that the solid mentioned was in fact a carbonate, as mescaline is known to readily absorb CO2 and water from the atmosphere.

https://shaunlacob.com/wp-content/uploads/2020/12/DC-MESCALINE.pdf

So perhaps it would be better to first dry the ethyl acetate, then add a weighed small excess of fumaric (or any other) acid, then evaporate and weigh? That addresses both the losses from material remaining in the mother liquor and the gains from atmospheric carbon dioxide.

There's still the question of gains from water, which evaporation in an open container on a water bath tends especially to promote. A long-necked container and strong air flow seem to help, as does foil or another barrier over most of the water surface. I'm saying this based on my experience with tryptamines and mesembrines though, which are probably less hygroscopic. The salt could also be dried in a warm oven, periodically recording the weight. Slow approach to an asymptote may indicate the desired drying, while linear loss of mass may indicate decomposition. I don't know what temperature is safe, and I guess that would be another interesting thing to learn. The literature reports vacuum distillation of mescaline base well above 100 C, but that's with minimal exposure to oxygen.

I'd guess the salt by evaporation would be at least partially amorphous, so the same weighing by subtraction would be required (and provides best accuracy even with perfect crystals anyways). If it's necessary to transfer the salt to a different container for weighing, then a solvent that dissolves it well (not ethyl acetate, maybe methanol?) should be used to rinse the old container. The salt could later be recrystallized.

 

[Loveall]

After extraction of the titration mixture, your ethyl acetate should contain mescaline base, some dissolved water, and some inorganic salts made soluble by the water. You could dry the ethyl acetate over anhydrous sodium sulfate, decant to separate the sodium sulfate, rinse the sodium sulfate a couple times with fresh ethyl acetate to recover mescaline from solvent trapped in the sodium sulfate, and then evaporate until the weight stops decreasing.

Lots of universities have videos on YouTube that show the liquid-liquid extraction and drying. The easiest way I've found to evaporate solvent is a water bath below the boiling point of the solvent, with air blowing on the solvent surface. This avoids splashes from vigorous boiling that could cause injury, fire, or lost product. Professional labs use a similar method to evaporate vials and other quantities too small for the rotovap. I don't know what temperature is safe for mescaline, but 50 C is common, because it's safe for most alkaloids and also safe to briefly touch. I use an aquarium air pump, but a fan or blower would work too. The fumes must of course be exhausted outdoors, and present both a toxic and explosion hazard otherwise.

I may be showing my unfamiliarity with mescaline again, but I think you'll get a sticky oil. If so then you'll need to weigh it in the container where you evaporated it, by weighing the empty container and subtracting. If your container is too heavy for your milligram scale, then evaporate most of the way, transfer to a smaller container, then rinse the big container with fresh ethyl acetate and transfer and repeat.

I believe this would be more accurate than comparing crystallized salt to crystallized salt, since it removes the uncertainty of the remaining weight dissolved in the mother liquor. The freebase mescaline can be redissolved in ethyl acetate (or another solvent) and then salted as usual to recover crystals.

The water should be salted with something insoluble in EA or something that evaporates. Otherwise a fraction of the excess organic acid will partition into the freebase and be there after evap. Something like HCl or Vinegar? Vinegar may be best.

 

[Loveall]

I haven't done anything with it yet! I'd meant to reply to your earlier comment on yield and re-acidifying to fumarate; that I'm currently planning on adding excess NaCl (kosher) and pulling with ethyl acetate, then re-salting citric acid to compare weight vs 400mg fumarate. I've never isolated freebase mescaline before I don't have a clue offhand how to do that to weigh it for comparison .

To do another repeat titration I'd have to extract more or re-x I think because I've only got roughly 50mg of this sample left that was IPA re-x'd, and i don't trust my other stock as like a reliable normal CIELO example; it's a mix of normal extracted fumarate from CIELO, water re-x'd, and a big part of a result of a maximum water:EtAc experiment I did which turned out pretty chunky (attached).

But 50mg is ideal for a dilute titration
Use same volumes for the solutions, titrate with .05ml steps of a 0.01M solution only (no adjustments or drops). Keep track of the added weight when practical

 

[Transform]

Interesting complication, thanks. I'm pretty sure I did actually do this once and got the oil; but I might be lucky or misremembering, since the literature definitely reports that issue. Heffter, the first to isolate mescaline, reports that his freebase was a solid "melting around 150-160 C", implying that heating in free air won't decompose whatever he formed:

https://shaunlacob.com/wp-content/uploads/2020/12/DC-MESCALINE.pdf

So perhaps it would be better to first dry the ethyl acetate, then add a weighed small excess of fumaric (or any other) acid, then evaporate and weigh? That addresses both the losses from material remaining in the mother liquor and the gains from atmospheric carbon dioxide.

There's still the question of gains from water, which evaporation in an open container on a water bath tends especially to promote. A long-necked container and strong air flow seem to help, as does foil or another barrier over most of the water surface. I'm saying this based on my experience with tryptamines and mesembrines though, which are probably less hygroscopic. The salt could also be dried in a warm oven, periodically recording the weight. Slow approach to an asymptote may indicate the desired drying, while linear loss of mass may indicate decomposition. I don't know what temperature is safe, and I guess that would be another interesting thing to learn. The literature reports vacuum distillation of mescaline base well above 100 C, but that's with minimal exposure to oxygen.

I'd guess the salt by evaporation would be at least partially amorphous, so the same weighing by subtraction would be required (and provides best accuracy even with perfect crystals anyways). If it's necessary to transfer the salt to a different container for weighing, then a solvent that dissolves it well (not ethyl acetate, maybe methanol?) should be used to rinse the old container. The salt could later be recrystallized.

Yes, maybe I was overstating the likelihood of carbonate formation, but the point was more that even a partial conversion to carbonate would throw the calculations, if only by a little.

This game can get quite fiddly

 

[Loveall]

Yes, maybe I was overstating the likelihood of carbonate formation, but the point was more that even a partial conversion to carbonate would throw the calculations, if only by a little.

This game can get quite fiddly

We know the citrate salt structure well, so maybe we can get that from the titrated solution to compare.

 

[aizoaceous]

We know the citrate salt structure well, so maybe we can get that from the titrated solution to compare.

Do we know how much mescaline will remain in the mother liquor after crystallization of the citrate though? That's the uncertainty I was hoping to remove, though the freebase adds new uncertainties per above.

Maybe dry the ethyl acetate, evaporate to ~10 mL, re-wet, add a known small excess of citric acid, let it crystallize and weigh the crystals, evaporate the mother liquor and weigh the residue? That would put most of the mass in the well-characterized citrate crystals, and also let us correct for the remaining dissolved amount. By drying we remove sodium fumarate, hydroxide, or chloride in the dissolved water, which otherwise makes the weight after evaporation hard to interpret. By minimizing the volume of solvent when crystallizing, we minimize the losses in that. I believe the re-wetting is necessary since the citrate is a hydrate.

If crystals are weighed, then accuracy may still be improved by weighing the crystals by subtraction in the container where they were crystallized, carefully syringing off the mother liquor instead of filtering. The monobasic fumarate yields only 1.22x the mass per unit of mescaline base vs. the dibasic, so we need accuracy within a few percent to confidently distinguish.

 

[Loveall]

Do we know how much mescaline will remain in the mother liquor after crystallization of the citrate though? That's the uncertainty I was hoping to remove, though the freebase adds new uncertainties per above.

Maybe dry the ethyl acetate, evaporate to ~10 mL, re-wet, add a known small excess of citric acid, let it crystallize and weigh the crystals, evaporate the mother liquor and weigh the residue? That would put most of the mass in the well-characterized citrate crystals, and also let us correct for the remaining dissolved amount. By drying we remove sodium fumarate, hydroxide, or chloride in the dissolved water, which otherwise makes the weight after evaporation hard to interpret. By minimizing the volume of solvent when crystallizing, we minimize the losses in that. I believe the re-wetting is necessary since the citrate is a hydrate.

If crystals are weighed, then accuracy may still be improved by weighing the crystals by subtraction in the container where they were crystallized, carefully syringing off the mother liquor instead of filtering. The monobasic fumarate yields only 1.22x the mass per unit of mescaline base vs. the dibasic, so we need accuracy within a few percent to confidently distinguish.

Good point.

Another option is to split the titrated solution in half.

The first extraction will "condition" the EA, in the sense that after regeneration, any un-precipitated mescaline will remain in the EA (as a freebase).

The second extraction (using the regenerated EA) will yield more if the conditioned EA carried any un-precipitated mescaline.

Finally, for additional thoroughness, the second extraction EA can be regenerated and evaporated. The would yield a freebase mass if present.

Whey you say hydroxyde above, what do you mean? I don't think any hydroxyde ions are in the EA.

 

[Transform]

Good point.

Another option is to split the titrated solution in half.

The first extraction will "condition" the EA, in the sense that after regeneration, any un-precipitated mescaline will remain in the EA (as a freebase).

The second extraction (using the regenerated EA) will yield more if the conditioned EA carried any un-precipitated mescaline.

Finally, for additional thoroughness, the second extraction EA can be regenerated and evaporated. The would yield a freebase mass if present.

Interesting ideas. Do we have a reasonable estimate for the [maximum) solubility of freebase mescaline in EA yet?

When you say hydroxyde above, what do you mean? I don't think any hydroxyde ions are in the EA.

Freebase mescaline will generate hydroxide ions in the presence of dissolved water in the EA.

 

[Loveall]

Interesting ideas. Do we have a reasonable estimate for the [maximum) solubility of freebase mescaline in EA yet?

Freebase mescaline will generate hydroxide ions in the presence of dissolved water in the EA.

No , don't know the maximum solubility.

Ok, so simply from the alkaloid doing it's weak base thing in any water present. I was ignoring that and out of my mind since after neutralization the pH strips are neutral, but it should be happening to some degree, but I think less than in pure water. Not sure though.

 

[Loveall]

How about this way to minimize lab work and chances for errors and experimental simplicity.

Extract the titrated 400mg citrate solution (0.93 moles) into EA. Salt with 120mg of fumaric acid (1.03 moles to have excess). Collect product (x mg) and evaporate the EA to a obtain residue (y mg).

Note: Wash the product and add the wash to the salted EA to move any traces of fumaric from the product to the spent extract.

I'm going to ignore any small amount of freebase mescaline losses from any mescaline remaining in the titrated solution or other places (e) for now.

Mass balance in residue (as y in moles) is the simply the original moles of fumaric minus the fumaric moles that moved into the product x, plus the moles of fumarate salt that did not crash (if any)

y/116 = 120/116 - x/(211+116)+ 0.93-x/(211+116)

Under the dimescaline fumerate hypothesis,

y/116 = 120/116 - x/[(211+116+211)/2]+ 0.93-x/[(211+116+211)/2]

The measured x and y will fall near one of two lines. There is separation between them (see image - the factor that @aizoaceous mentioned which gets smaller as y increases, but not by much).

The x value is constrained to a maximum of all the mescaline precipitates,

For the monomescaline salt,

x/(211+116) = 0.930, or x= 304mg (max)

x/[(211+116+211)/2] = 0.930, or x=250mg (max)

If the above is correct, there a decent separation in the x and y plane.

Won't be perfect because we always lose some mescaline, so x may be shifted to the left and y will be shifted up, but thankfully that should not decrease the separation in the plane to first order.

Here is the Wolfram Alpha link to generate the plot,

plot (y/116 = 120/116 - x/(211+116)+ 0.93-x/(211+116), y/116 = 120/116 - x/[(211+116+211)/2]+ 0.93-x/[(211+116+211)/2], x=304, x = 250, from x = 200 to 310 and y = 0 to 50) - Wolfram|Alpha

Wolfram|Alpha brings expert-level knowledge and capabilities to the broadest possible range of people—spanning all professions and education levels.

www.wolframalpha.com

 

[aizoaceous]

Extract the titrated 400mg citrate solution (0.93 moles) into EA. Salt with 120mg of fumaric acid (1.03 moles to have excess). Collect product (x mg) and evaporate the EA to a obtain residue (y mg).

Isn't that backwards from the current situation, since @starbob's solution was made from a known mass of fumarate and should thus be converted to the citrate plus residue? I agree with the basic idea though.

As to solubility of mescaline citrate in ethyl acetate, this thread says <0.11 mg/mL in dry ethyl acetate and a reply seems to imply it's also low in wet ethyl acetate. That would suggest my concern about losses in the mother liquor is unfounded, and e.g. crystallization of the citrate from 40 mL ethyl acetate would lose <1% of our mescaline here. Weighing of the evaporation residue would still be a nice double check though.

Freebase mescaline will generate hydroxide ions in the presence of dissolved water in the EA.

True, though I think we also have significant excess lye since the titration was continued to pH >12. For completeness I guess we also have carbonate from atmospheric carbon dioxide, and that effect may explain the slight dips in the titration curve when @starbob paused work.

Also is basic hydrolysis of the ethyl acetate a concern? I'd expect that sodium acetate would be mostly removed if the ethyl acetate is dried, but that ethanol would remain in the ethyl acetate. I guess that would be fine unless dissolved ethanol greatly increased the solubility of the mescaline citrate, and we at least seem to know dissolved water doesn't. The timescale for that hydrolysis is probably minutes, so perhaps it's beneficial to work quickly while extracting?

For anyone coming late to this thread, I should emphasize that the effects we're discussing are second-order, relevant primarily because we're trying to calculate the yield within a few percent to confirm identification of the salt. They are probably negligible in most normal work.

 

[Loveall]

Isn't that backwards from the current situation, since @starbob's solution was made from a known mass of fumarate and should thus be converted to the citrate plus residue? I agree with the basic idea though.

As to solubility of mescaline citrate in ethyl acetate, this thread says <0.11 mg/mL in dry ethyl acetate and a reply seems to imply it's also low in wet ethyl acetate. That would suggest my concern about losses in the mother liquor is unfounded, and e.g. crystallization of the citrate from 40 mL ethyl acetate would lose <1% of our mescaline here. Weighing of the evaporation residue would still be a nice double check though.


True, though I think we also have significant excess lye since the titration was continued to pH >12. For completeness I guess we also have carbonate from atmospheric carbon dioxide, and that effect may explain the slight dips in the titration curve when @starbob paused work.

Also is basic hydrolysis of the ethyl acetate a concern? I'd expect that sodium acetate would be mostly removed if the ethyl acetate is dried, but that ethanol would remain in the ethyl acetate. I guess that would be fine unless dissolved ethanol greatly increased the solubility of the mescaline citrate, and we at least seem to know dissolved water doesn't. The timescale for that hydrolysis is probably minutes, so perhaps it's beneficial to work quickly while extracting?

For anyone coming late to this thread, I should emphasize that the effects we're discussing are second-order, relevant primarily because we're trying to calculate the yield within a few percent to confirm identification of the salt. They are probably negligible in most normal work.

Oops, yes I got it backwards. We started with fumaric and are salting with citric.

Anyway, extracting, salting with well measured excess to get x and evaporating to get y, should give us a data point with separation between the two hypothesis and (should) confirm monomescaline fumarate.

What I remember from hydrolysis is that NaOH can do it, other weaker bases cannot, and it is not very fast at room temp - but ai could be wrong and don't have the sources handy.