[foxfourfive]

So I'm trying to crystallize a sample of an amine ketone to a hydrochloride salt. The product is extracted with ethyl acetate (which I'm using as a substitute for diethyl ether), back extracted with dilute (10%) sulfuric acid, basified then extracted with DCM. This is then evaporated to yield a yellow/amber oil.

At this point I dissolved it in isopropanol, added concentrated HCl and was supposed to get crystals, but even after evaporation of solvent I get a yellow oil. I've tried filtering, washing and even using sulfuric acid to yield a sulfate but I ALWAYS end up with an oil regardless of whether it evaporates to dryness with heat or I cool the solution in the freezer then let evaporate at room temperature.

I left a solution of the freebase in ethyl acetate on a tray and this half evaporated to a crystal slurry. Both the freebase and acid should have a boiling point of 170-180°C.

Something worth mentioning is that in the original synthesis the base was distilled bulb to bulb after the DCM extraction, but this particular ketone is prone to dimerizing to a pyrazine, so I was cautious of this.

Can someone help me troubleshoot this? Every step until this point has seemed correct.

[discodermolide]

Obviously not cautious enough. An amino ketone as the free base is not stable.
Stick to an ether, diisopropylether is not bad and use HCL from the start. Why use sulfuric, then make the free base? Make the HCl salt directly.

[rolnor]

When you say concentrated hydrochloric acid, is that solution in water? I would dissolve the free base in ether and add anhydrous hydrogen chloride in ether. Also oxalic acid in ether can be used.

[foxfourfive]

Obviously not cautious enough. An amino ketone as the free base is not stable.
Stick to an ether, diisopropylether is not bad and use HCL from the start. Why use sulfuric, then make the free base? Make the HCl salt directly.

Thank you, when you say "not cautious enough" then make reference to sticking to an ether such as diisopropylether, are you suggesting the ethyl acetate is damaging or degrading the alkaloid extraction from the reaction mixture? I use sulfuric and basified as per the instructions I was given to obtain a pure product for testing.

[foxfourfive]

When you say concentrated hydrochloric acid, is that solution in water? I would dissolve the free base in ether and add anhydrous hydrogen chloride in ether. Also oxalic acid in ether can be used.

Yes, its a 33% aqueous HCl solution. I don't have ether on hand, would ethyl acetate be suitable or potentially as discodermolide pointed out diisopropylether?

[discodermolide]

Obviously not cautious enough. An amino ketone as the free base is not stable.
Stick to an ether, diisopropylether is not bad and use HCL from the start. Why use sulfuric, then make the free base? Make the HCl salt directly.

Thank you, when you say "not cautious enough" then make reference to sticking to an ether such as diisopropylether, are you suggesting the ethyl acetate is damaging or degrading the alkaloid extraction from the reaction mixture? I use sulfuric and basified as per the instructions I was given to obtain a pure product for testing.

As I said amino ketones are not stable, they tend to self condense. In these cases never isolate the free base but try and keep the amino ketone as a salt at all times. So instead of using ethyl acetate to do the extraction use an ether such as diisopropylether (a bit safer than diethylether) saturated with HCl. This should make the HCl salt directly which you should be able to crystallise.
Ethyl acetate can be a problematic solvent for several reasons. It is relatively reactive (aldol reactions) and if your amine is basic enough it can react with the amine. It is not usually very good for crystallisations, an ether is very much better, especially for amine salts.

[foxfourfive]

Obviously not cautious enough. An amino ketone as the free base is not stable.
Stick to an ether, diisopropylether is not bad and use HCL from the start. Why use sulfuric, then make the free base? Make the HCl salt directly.

Thank you, when you say "not cautious enough" then make reference to sticking to an ether such as diisopropylether, are you suggesting the ethyl acetate is damaging or degrading the alkaloid extraction from the reaction mixture? I use sulfuric and basified as per the instructions I was given to obtain a pure product for testing.

As I said amino ketones are not stable, they tend to self condense. In these cases never isolate the free base but try and keep the amino ketone as a salt at all times. So instead of using ethyl acetate to do the extraction use an ether such as diisopropylether (a bit safer than diethylether) saturated with HCl. This should make the HCl salt directly which you should be able to crystallise.
Ethyl acetate can be a problematic solvent for several reasons. It is relatively reactive (aldol reactions) and if your amine is basic enough it can react with the amine. It is not usually very good for crystallisations, an ether is very much better, especially for amine salts.

Thanks for the very informative reply. I've performed the synthesis again, this time extracting with diethyl ether, then back extracting with 10% Aqueous HCl. I've evaporated it however it's still an oil. The melting point should be 177°C so I'm completely at a loss as to why it's not crystallising. Until this point the synthesis always goes perfectly.

[foxfourfive]

It may also be worth noting that the acidic extract, although oily, does not phase-separate. It's more like a syrup, that won't crystallize in absolute alcohol at temperatures below 0°C or, when all solvent is evaporated off is a semi-sticky sweet smelling amber oil.

[orthoformate]

have you analyzed your oil at all? I would be curious to know what you are getting.

Also, I think it was noted earlier in the thread, it may be worth trying to use a water free acid.(e.g. PTSA, anhydrous HCl, etc)

[lb2]

Hi foxfourfive,

Ammonium salts can often be, but not always, very hygroscopic to the point that they become deliquescent. Sometimes you have to take extra special care to prevent them from absorbing even small amounts of water that can prevent them from ever becoming crystalline. If that is a problem (I'm not saying it is in your case, but it could very well be), often changing to a different salt (i.e., by changing the acid) can be helpful.

[discodermolide]

It may also be worth noting that the acidic extract, although oily, does not phase-separate. It's more like a syrup, that won't crystallize in absolute alcohol at temperatures below 0°C or, when all solvent is evaporated off is a semi-sticky sweet smelling amber oil.

Try azeotroping the oily HCl salt with toluene several times to remove any water. Then triturate the oil with diethyl or better diidopropyl ether.

[foxfourfive]

Hi foxfourfive,

Ammonium salts can often be, but not always, very hygroscopic to the point that they become deliquescent. Sometimes you have to take extra special care to prevent them from absorbing even small amounts of water that can prevent them from ever becoming crystalline. If that is a problem (I'm not saying it is in your case, but it could very well be), often changing to a different salt (i.e., by changing the acid) can be helpful.

Thank you!

[foxfourfive]

It may also be worth noting that the acidic extract, although oily, does not phase-separate. It's more like a syrup, that won't crystallize in absolute alcohol at temperatures below 0°C or, when all solvent is evaporated off is a semi-sticky sweet smelling amber oil.

Try azeotroping the oily HCl salt with toluene several times to remove any water. Then triturate the oil with diethyl or better diidopropyl ether.

This worked perfectly, glittering crystals with a fantastic yeild. Thanks again for all your information!

[foxfourfive]

have you analyzed your oil at all? I would be curious to know what you are getting.

Also, I think it was noted earlier in the thread, it may be worth trying to use a water free acid.(e.g. PTSA, anhydrous HCl, etc)

Not yet but I will be shortly. It seems it had absorbed substantial water and this was the problem.

[critzz]

So trapped water within the sample was the problem it didn't crystallize? Would you be able to re-crystallize it now?