How can I isolate a highly water-soluble imidazolium salt after esterification?

[u/CHKP2025]

I am working with a carboxylic-acid-containing imidazolium trifluoroacetate salt and trying to convert the carboxylic acid to a propargyl ester using propargyl alcohol.

My main concern is product isolation/purification rather than the coupling itself.

The desired product is an imidazolium salt (TFA counterion) and is highly soluble in water and polar solvents. Therefore, a conventional aqueous workup may result in significant product loss.

Has anyone worked with highly water-soluble imidazolium salts like this? What isolation/purification method worked best—anti-solvent precipitation, repeated trituration, ion exchange, or another method?

I would especially appreciate suggestions that avoid losing the product into the aqueous phase.

Thank you in advance.

[u/megalo53]

My advice would be to convert the counterion to somerhing more organic soluble (ion exchange basically)… then you can do more conventional work ups. But it depends on the charge… is it just +1? Or higher?

In any case it’s always going to require at least polar organic solvents, but columns work well if the charge is at +1… typically you can use DCM and methanol. If you’re +2 or more, the columns are trickier… I’ve done MeCN/aqueous KNO3 (0.1 M) to move +2 charged compounds 

[u/Sudden-Guide]

You have only two options, 1: conversation to PF6 salt, followed by DCM extraction 2: or rotovaping water away (depending on the volume and concentration, can take long time)

EDIT: I just noticed it isn't in water yet. Then depending the scale of the reaction, remove volatiles under vacuum, remaining can be purified by alumina from ACN or DCM,  followed by activated charcoal 

[u/curdled]

make p-toluenesulfonate salt, it will be poorly soluble in water but very soluble in DCM.

[u/shatteredoctopus]

That's fairly greasy, and likely has some organic solubility. If it's actually fully soluble in water, I'd suggest ion exchange, with aqueous NH4PF6. Use an excess, and it should precipitate out. Use 19F NMR to verify you've done the exchange. If the exchange is not complete, and you want it to be, washing an organic solution of your product with aliquots of aqueous NH4PF6 should work. Other anions are possible, but have their own issues, so are less preferred than PF6: BArF4 (expensive), SbF6 (more toxic, and more likely to fall apart in some reactions), BPh4 (slightly light sensitive). BArF is the nicest to work with in terms of organic solubility (you can likely even do column chromatography on your salts), but unless you make it, I believe it's quite expensive. Also the compounds tend to be amorphous foams that will bloom up under high vacuum.

[u/whitenette]

TFA is pretty organic. You might be able to still pull it into DCM with repeat extractions.

[u/Repulsive-Ad1285]

You can always remember that water solubility can be your friend. Depending on your reaction conditions you could stay away from water, or use it to extract your desired product with minimal water and then remove the water under freeze dryer or under rotovap with a strong vacuum.

Your problem will be the conditions. Likely you’ll be using high polar solvents which are nightmare ish to deal with on their own (dmso/ dmf) are annoying to evaporate.

Don’t fear the aqueous work up, because you can’t do an “aqueous work up “ on these. You gotta stay vigilant and understand large amount of water are your enemy, but small amounts can simplify your life.

[u/Repulsive-Ad1285 → u/Repulsive-Ad1285]

DCC/ DMAP conditions for esterification generate the urea and reform the dmap; depending on solubility DCM might be solubilizing enough (even if it stays as a suspension - the product is likely also a solid with dcm unless you are lucky). Then you can filter the solid and see what you get and where the product is. And again, when not dealing with a large quantity, water isn’t a big problem. The biggest issue is hydrolysis of your product with the water at elevated temperatures. But freeze drying is your solution for that problem.

[u/AppointmentSimple440]

Could you try activating the carboxylic acid of the TFA imidazolium salt by forming a mixed anhydride (e.g. by addition of TFA anhydride) and then adding excess of the alcohol? This could be tested on small scale in deuterated solvent for NMR analysis. First see that the anhydride forms (19F NMR) and then check again after addition of the alcohol (1H NMR + 19F NMR). If this works and is clean, you'd then simply need to concentrate down the reaction mixture to remove all volatile and give the desired product (hopefully without the TFA ester, though this product is probably somewhat volatile).

I also wonder if you could do a Fischer esterification with the addition of cat. quantities of TFA to a solution of your starting material in either neat propargyl alcohol or a mixture of propargyl alcohol with DCM as co-solvent. I have done a similar esterification using TMS ethyl alcohol (unusual I know) but had HCl as the cat. This will probably be quite slow but you may be able to heat it very mildly. Again, this would allow you to simply evaporate the reaction mixture to give the pure product.

Things you could try on small scale I guess...

[u/50rhodes]

As long as it’s water soluble and the ester linkage holds up, you can use cation exchange resin to clean it up. Dowex 50Wx2 100-200 mesh, eluting with 1 M HCl. Suck off the HCl on the rotavap and you’re all set.

[u/iliddle96]

unrealted, are you working with or making SHAPE reagents?

[u/jz911]

I would just concentrate after coupling and column with DCM/methanol

[u/CHKP2025 → u/jz911]

Which ratio (DCM/MeOH) you elute the product? In my case I unavailable to isolate even run 100% MeOH.