Sciencemadness Discussion Board

"Gassing" alkaloids out of nonpolar with acetic acid?

Hydropos - 21-5-2011 at 23:25

Many hobby chemists have found gassing (bubbling dry hydrogen chloride into a nonpolar solution) to be a great way to pull alkaloids without the god-awful goop that usually accompanies them. Now, with some alkaloids, hydrogen chloride acts as an electrophile and, well, eats them. Because of this, it seems advantageous to have an analogous procedure that utilizes a weaker acid. Therein lies the challenge. The alkaloid salts of weaker acids, namely organic acids, may be soluble in the nonpolar of choice. The procedure I envision would be adding some nonpolar with acetic acid dissolved in it (so no glacial is required) to the nonpolar alkaloid solution, then the resulting crystals are collected. So after doing my best to google for info and coming up with naught, I figured I should make an account here. Anyone know if this could work?

turd - 21-5-2011 at 23:48

Hm, yes I made the acetate of amines once or twice, though on cleaned product, not some crazy mixture. In one case I even detected dimorphism: recrystallization from IPA and treatment with neat AcOH followed by slow evaporation gave two completely different crystals of the same composition. There are many ways to skin a cat and you will have to optimize for the problem at hand. If possible, I would try to use glacial acetic acid, to avoid trouble with hydrates and solubility.

Generally, you will find derivation with organic acids are often made with picric acid (poisonous!), oxalic acid or, if intended for consumption, with fumaric acid. They are much more easily handled, since they exist as dry powders.

Hydropos - 22-5-2011 at 00:46

Quote: Originally posted by turd  
There are many ways to skin a cat and you will have to optimize for the problem at hand.
A good point, but what I was hoping for is an all-encompassing technique that could be used when one could not afford test batches to optimize a process.
Quote: Originally posted by turd  
If possible, I would try to use glacial acetic acid, to avoid trouble with hydrates and solubility.

The hope is that by having the acetic acid dissolved in nonpolar (less than 5% acid by weight) it would contain a nominal amount of water. Also, making a nonpolar with some dissolved acid is much easier than making glacial.
Quote: Originally posted by turd  
Generally, you will find derivation with organic acids are often made with picric acid (poisonous!), oxalic acid or, if intended for consumption, with fumaric acid. They are much more easily handled, since they exist as dry powders.
I thought of this a with while back citric acid (for availability's sake), but the issue was that it's hard to say how much to add, and if granules are added, if they will only react at the surfaces. I guess by weighing solids before and after, this could easily be tested, but no one ever got around to testing it, AFAIK.

GreenD - 22-5-2011 at 07:29

Someone on here gassed tryptamine with CO2, giving the carbonate salt. That was new as hell to me, but worth a shot.

so get some dry ice and make some concentrated CO2 gas, see if that works. Cheap as heck too.

thegardenman - 22-5-2011 at 10:53

nice. Ill be watching

Hydropos - 22-5-2011 at 11:05

Quote: Originally posted by GreenD  
Someone on here gassed tryptamine with CO2, giving the carbonate salt. That was new as hell to me, but worth a shot.

so get some dry ice and make some concentrated CO2 gas, see if that works. Cheap as heck too.
Wait, seriously? That would be pretty slick. Do you remember where I might find that post?

Nicodem - 22-5-2011 at 11:18

The prerequisite for any salt to form is in that the salt can form! Not all amines can form crystalline acetates. For example, not even all amines can form crystalline hydrochlorides and not all hydrochlorides are insoluble in nonpolar solvents. And hydrochloric acid over a billion times stronger acid than acetic (pKa of about -6 vs. 4.7), so it does not even have any issues in regard to N-protonation of aliphatic amines.
Quote: Originally posted by GreenD  
Someone on here gassed tryptamine with CO2, giving the carbonate salt. That was new as hell to me, but worth a shot.

Actually, CO2 forms an ammonium carbamate (RNH3+ RNHCOO-) with most primary and secondary amines, rather than a carbonate or a bicarbonate. The reason is in that carbamic acids are more acidic than carbonic acid, and besides without water a carbonate can not form anyway (while a carbamate needs no H2O to form).

Hydropos - 30-5-2011 at 20:34

Quote: Originally posted by Nicodem  
The prerequisite for any salt to form is in that the salt can form! Not all amines can form crystalline acetates. For example, not even all amines can form crystalline hydrochlorides

:o

mind = blown

I was under the impression that any compound could form a crystal. So, if an acid reacts will a solvated amine to give an insoluble salt, but it can't form a crystal, does it form a glass? Or just a goop? Or not precipitate at all?
Quote: Originally posted by Nicodem  
and not all hydrochlorides are insoluble in nonpolar solvents.
You are just turning my world upside down. What kind of R3NHCl isn't polar enough to immediately come out of solution?
Quote: Originally posted by Nicodem  
And hydrochloric acid over a billion times stronger acid than acetic (pKa of about -6 vs. 4.7), so it does not even have any issues in regard to N-protonation of aliphatic amines.
Also, acetic may be a weak acid, but with a pKa of 4.7 it should even protonate aryl amines, no?
Quote: Originally posted by Nicodem  
Actually, CO2 forms an ammonium carbamate (RNH3+ RNHCOO-) with most primary and secondary amines, rather than a carbonate or a bicarbonate. The reason is in that carbamic acids are more acidic than carbonic acid, and besides without water a carbonate can not form anyway (while a carbamate needs no H2O to form).
How fast is the carbamate reaction? IE, if a given amine were to form a carbamate, then the corresponding amine carbamate salt could crystallize, would it have to be left with CO2 for weeks? Or just a few seconds?

Nicodem - 31-5-2011 at 08:16

Quote: Originally posted by Hydropos  
I was under the impression that any compound could form a crystal. So, if an acid reacts will a solvated amine to give an insoluble salt, but it can't form a crystal, does it form a glass? Or just a goop? Or not precipitate at all?

Usually it drops out as new liquid phase. Many salts simply do not crystallize no matter what, and some are liquid at room temperature.
Quote:
Quote: Originally posted by Nicodem  
and not all hydrochlorides are insoluble in nonpolar solvents.
You are just turning my world upside down. What kind of R3NHCl isn't polar enough to immediately come out of solution?

With hydrohalides this is quite common as many of them are well soluble in CH2Cl2 and sometimes even in acetone, ethyl acetate, toluene and so on. The most common example from lab practice is triethylamine hydrochloride or hydrobromide. Both are well soluble in dichloromethane. As far as I know, diethyl ether is the "safest" solvent for precipitating hydrochlorides, but not general! During my professional work I encountered a hydrochloride soluble in diethyl ether. Another thing that I encountered was a hydrochloride which had a partition coefficient much more convenient toward non-polar solvents, such as CH2Cl2, toluene and ethyl acetate, when compared to water (it was extracted from aq. solutions!). Some amine hydrochlorides have very poor solubility in water, but dissolve well in organic solvents.
Quote:
Quote: Originally posted by Nicodem  
And hydrochloric acid over a billion times stronger acid than acetic (pKa of about -6 vs. 4.7), so it does not even have any issues in regard to N-protonation of aliphatic amines.
Also, acetic may be a weak acid, but with a pKa of 4.7 it should even protonate aryl amines, no?

Barely, but many aryl amines have pKa < 4 and not all with pKa > 5 will form crystalline acetates. Also, the pKa values are totally different in non-water solvents. For example, aniline (or pyridine) and acetic acid dissolved in toluene or other comparatively non-polar solvents remain practically totally (un)protonated. The reason is in that the anilinium and acetate ions can not be efficiently solvated by non-polar solvents, which is reflected in their huge change of acidity/basicity in such solvents.
Quote:
Quote: Originally posted by Nicodem  
Actually, CO2 forms an ammonium carbamate (RNH3+ RNHCOO-) with most primary and secondary amines, rather than a carbonate or a bicarbonate. The reason is in that carbamic acids are more acidic than carbonic acid, and besides without water a carbonate can not form anyway (while a carbamate needs no H2O to form).
How fast is the carbamate reaction? IE, if a given amine were to form a carbamate, then the corresponding amine carbamate salt could crystallize, would it have to be left with CO2 for weeks? Or just a few seconds?

It is very fast. Try bubbling CO2 in a solution of Et2NH or some other secondary or primary amine in some nonpolar solvent like toluene or ethers. See also the thread mentioned earlier in this thread in regard to this topic.
The ammonium carbamates when dissolved in water end up forming an equilibrium with the carbonates (e.g., like the equilibrium of "ammonium carbonate" in aq. solutions).

Sedit - 31-5-2011 at 10:50

If one made the acetate of an amine would it not undergo H2O elimination under prolong mild heating to yeild the N-acetyl derivative?

Hydropos - 3-6-2011 at 07:53

Quote: Originally posted by Nicodem  
See also the thread mentioned earlier in this thread in regard to this topic.
I never got a link to this thread, or even a title. How do I find it?

not_important - 3-6-2011 at 12:46

Also usable are sulfates and phosphates, both generally of lower solubility in organic solvents than the hydrochlorides. Oxalates are often good.

And there there's using an acidic ion exchange resin to grab onto basic components of a mixture, followed by washing them out with KOH in an alcohol.

here is the paper you are after

antibody - 10-6-2011 at 13:31

@ Hydropos - here is the link you are looking for
http://www.sciencemadness.org/talk/viewthread.php?tid=8574&a...

here is the paper he references in that post, but I'm not sure how stable the carbamate is for long term storage.

If you want to use fumaric acid to precipiate amines as a salt it is very simple. Create a saturated solution of fumaric acid in acetone (it is soluble in acetone), then dissolve your amine in the minimum amoumt of acetone required to dissolve it and then add the saturated fumaric/acetone solution dropwise until the salt stopped falling out of solution.

You will get better results if you isolate your amine before salting it with fumaric acid. Fumaric acid can be purchased online for cheap from a cooking/spice store if you google it.

Attachment: US3131221.pdf (231kB)
This file has been downloaded 620 times

[Edited on 10-6-2011 by antibody]

l0k1 - 14-11-2012 at 14:09

this oxalate precipitation thing - what nonpolars does it dissolve best in? naptha, pentane, hexane, heptane, toluene, xylene?

would this work:

with dried nonpolar with alkaloid freebase dissolved, add dry oxalic acid of appropriate quantity and then filter/settle out and dry formed oxalate. (of solvent). perhaps even wash a few times with clean solvent to remove as much as possible of any oily gak that might remain.

then add the oxalate salt to a solution of sodium chloride with the appropriate number of moles and a minimum amount of water. sodium oxalate would then form which is 37g/L solubility at 20 degrees C and insoluble in alcohol. the source of that information did not specify *which* alcohol but i presume that isopropyl would be better than ethanol because of its' lower polarity and availability in 99% concentration and better.

The solution is then dehydrated and the desired hydrochloride salt is extracted and the sodium oxalate remains undissolved.

for an amount of let's say 2mol of a suitable alkaloid, 90.03g of oxalic acid is used. we would then need 116.88g of sodium chloride which is soluble to 357g/L at 20C so using brine at 20C we would need 325.57ml, or you could use the number of the solubility of the end product hydrochloride salt, let's say we are extracting ... hm... something or other alkaloid, and this other alkaloid is say 1.8g/ml with molar mass 303g that's 336ml of water.

it occurs to me that this might be made a little easier by using calcium chloride instead of sodium chloride, but it bears repeating that it is a moderately toxic substance and should be handled carefully.

[Edited on 14-11-2012 by l0k1]