Sciencemadness Discussion Board - Forming oxalte salts of amines

Forming oxalte salts of amines

Klute - 25-7-2009 at 11:14

Having problems with cristallizing sulfate salts of amines, which often result in gummy semi-liquid products, impossible to properly recristallize, I decided forming the mono-oxalate salt.

The amine freebase was dissolved in 5x its volume of dry IPA, and added dropwise to 1eq of anhydrous oxalic acid dissolved in IPA. In some case, no solid formed directly. 3x the volume of ether as added, and teh erlenmeyer placed in the freezer. An hour later, a voluminous fluffy white precipitate had formed. It was vacuum filtered, offering a gel like solid. It was triturated under ether, and dried by suction, then under vacuum. Recovery was between 60 and 95%.
Evaporating the filtrate gives an oily material, which crisatllizes when covered with ether and placed in the freezer. Recrysatllization with IPA:ether removes the last traces of oxalic acid.

This method should work with citric acid to form citrates, which would be less problematic if excess acid remains in the product: oxalic acid is toxic.

I always hated gassing with HCl, and this method seems like a very good alternative to this

entropy51 - 25-7-2009 at 12:05

Klute, that sounds like an alternative to hydrochloride salts, but the latter are often formed in almost quantitative yield. You can prepare HCl in Et2O without gassing as described in this paper:

Attachment: HCl in ether prep.pdf (486kB)
This file has been downloaded 1592 times

Klute - 25-7-2009 at 13:47

Interesting paper. I will try it soon. I don't know how much HCl will be lost with the MgSO4 though...

Paddywhacker - 25-7-2009 at 15:03

Salts are ionic compounds and forming them in anhydrous conditions is the exception rather than the rule.

As oxalic acid is a reasonably strong acid, I would expect it to hold even a very volatile amine as the mono salt. For example, monoammonium oxalate should be easy to make and crystallize from water.

From water though, you may get a hydrated crystal. But still, it gives you something to work with.

Klute - 25-7-2009 at 16:33

Unfortunaly, no. If you use the dihydrate, or wet solvents, you get a uncristallizable oil, even trituration under ether or leaving under vacuum for an hour doesn't help..
Amine salts are notably hydroscopic, some of them are even deliquescent.

[Edited on 26-7-2009 by Klute]

starman - 25-7-2009 at 17:34

Yes interesting paper.I find the wording of the last paragraph a little ambiguous however.Are they claiming anhydrous hydrobromic acid in ether can be prepared by this method? Also what would be the maximum concentration of HX in ether that could be attained?The example given is fairly dilute.

[Edited on 26-7-2009 by starman]

entropy51 - 25-7-2009 at 17:42

Quote: Originally posted by starman

Yes interesting paper.I find the wording of the last paragraph a little ambiguous however.Are they claiming anhydrous hydrobromic acid in ether can be prepared by this method?

Yes they are!

chemrox - 25-7-2009 at 17:49

thanks entropy for that. I wonder if sieves would work as well as MgSO4?

entropy51 - 25-7-2009 at 17:55

Quote: Originally posted by chemrox

thanks entropy for that. I wonder if sieves would work as well as MgSO4?

Why use sieves when MgSO4 is dirt cheap and doesn't need to be reclaimed?

I'm guessing the right sieves would work, but I've only tried it with MgSO4.

Klute - 26-7-2009 at 04:25

You've tried it out yourself? Hox concentrated was the anhydrous acid?

entropy51 - 26-7-2009 at 08:08

It's about 1 mol/L, which is not as concentrated as the Et2O solution made by saturating Et2O with HCl gas. The latter is about 6 or 7 mol/L at 20 C.

not_important - 26-7-2009 at 22:19

Quote: Originally posted by Klute

Unfortunaly, no. If you use the dihydrate, or wet solvents, you get a uncristallizable oil, even trituration under ether or leaving under vacuum for an hour doesn't help...

Have you ever tried azotropic dehydration? Suspend in say hexane/heptane, 1,2-dichloroethane, or chloroform, and distill off the solvent-water pair. Works for at least some amine hydrochlorides.

Klute - 27-7-2009 at 01:51

I tried it out wxith toluene but got notable decomposition, obtaining cristals contaminated with tar... guess low boiling alkanes would be a better choicre.

Klute - 27-7-2009 at 03:06

The MgSO4/HCl/Ey2O works wonders! I folowed the article's indications, although more than 13g of MgSO4 was required to absorbed the lower layer, and HCl bubbling into the tehreal layer was visible. I placed the stoppered erlen in the fridge to complete drying an ansure all the HCl stays dissolved... The obtaine dsolution was then used to titrate a amine freebase in ether, with the immediate precipitation of a chunky white solid, very easy to filter (much more so than the oxaltes), currently drying under vacuum...

Very nice find! No more gassing for me...

EDIT: bad news: it didn't work out well for the amine which I was having problems with... Triethylamine formed a beautifull salt though

SO back to oxalate/citrate... I will be trying the citrate with the hydrated acid...

[Edited on 27-7-2009 by Klute]

entropy51 - 27-7-2009 at 16:06

Klute, certain amines offend the chemistry gods.

It has worked for all the amines that I've tried. Keep the Et2O cold while adding the MgSO4.

starman - 27-7-2009 at 18:24

Be interesting to see how the citrate experiments come out Klute.I've read that some amines can give high,clean yeilds with phosphoric acid as the monobasic phosphates.

Arrhenius - 27-7-2009 at 19:38

Mind sharing what the amine is you're trying to form a salt of?

Klute - 28-7-2009 at 00:53

Of course, 2-(N-methyl-N-phenethylamino)-N-phenyl-propylamine.

The citrate worked pretty well, but was hard to crysatllize: I dissolved 1eq of citric acid in 50mL MeOH, added the amine disssolved in Et2O, no solid formed. I added 100mL ether, causing the mixture to turn milky, and placed the erlen at -18°C. A few hours after, a colorless goo had formed. Decanting the ether and addign fresh ether didn't help, so the goo was place duner vacuum (0.1torr) overnight, forming a sugar-like foam. At first the material was very sticky, like cake icing, sugar-like, but once the foam was bone dry it formed a fluffy crunchy white solid. I will try using anhydrous citric acid next time.

grind - 28-7-2009 at 04:05

Some methods to obtain anhydrous HCl salts of amines with aqueous HCl (avoiding dry HCl-gas method):

1. Add all at once 1,1 eq. of 37% HCl to the neat amine (if it is liquid) with very good stirring and without cooling (except for sensitive amines), stir until the mixture is cold or solidified. Apply vacuum and heat on the water bath until the mass is constant. In many cases you get a nearly pure, anhydrous HCl-salt of the amine. To obtain pure, nice crystals, crystallize the salt from ethanol/ether or IPA or IPA/IPE or acetone or whatever is suitable.

If this fails (salt becomes not anhydrous and/or fails to crystallize):

2. like 1., but with solvent. Suitable solvents are lower alcohols, THF, DCM, CHCl3, toluene. After the addition of the aqueous 37% HCl stir a few minutes, then remove the solvent at normal pressure. Especially toluene, DCM and CHCl3, but even THF and absolute ethanol remove the water in the mixture during the distillation.

If even 2. fails:

3. Dissolve the amine in toluene, add an excess of aqueous HCl and heat the mixture in the flask, which is connected with a dean-stark-trap. This method removes water reliably. Not suitable with sensitive amines.

only suitable for amine HCl-salts, which are soluble in DCM or CHCl3:

4. Dissolve the amine in DCM (or CHCl3), add an excess of conc. HCl, shake thoroughly, separate the layers. Extract the HCl-layer with DCM, combine the organic layers, dry with MgSO4 or Na2SO4. Remove the solvent at normal pressure. The nearly pure, anhydrous HCl-salt remains.

Other acids which often form nice, crystalline salts with amines are maleic acid, succinic acid, fumaric acid, malic acid, tartaric acid, picric acid (toxic) and so on...

Arrhenius - 28-7-2009 at 07:28

I would bet that your material is not pure. I would try forming the salt by any of the above methods and then trying to salvage the resulting oil/glass. I've seen several hydrochlorides that are glasses. Adding DCM and repeatedly stripping the solvent on the rotovap sometimes induces crystallization. Using toluene or ethanol in the same manner is a good option if you think there's water. For some reason azeotroping off the water seems to work far better than just pumping on the flask with a vacuum pump. One other option is to add hexanes and let it sit a few days.

Klute - 28-7-2009 at 08:40

Thanks for the tips Grind!

Arrhenius, what makes you say my material is not pur? I will be doing an H NMR soon so we will be sorted out.. The oil was colorless, and gives a beautifull white fluffy powder. Considering the llenght of vacuum required to get an solid, azeotroping with a solvent would have taken ages, if it even worked sufficently. And my amine salt is soluble in DCM, even an extraction with 150mL of 10% HCl didn't extract it from the DCM layer, to my surprise. It got rid of some residual triethylamine though.

Paddywhacker - 28-7-2009 at 15:49

Here is a method attributed to Kilomentor that discusses purification of organic amines by precipitation as a salt or adduct.

Attachment: Embonic Acid.txt (15kB)
This file has been downloaded 1365 times

Arrhenius - 28-7-2009 at 19:32

Klute: Try using toluene or ethanol some time, it really should be pretty fast. I only say your material may not be pure because often times when it's difficult to crystallize something you know ought to be crystalline this can be due to purity issues. Color means almost nothing in terms of purity. I have tan/beige products that are 99% pure by LC, pure by 1H-NMR and nearly pure by 13C-NMR. **Do note that 1H-NMR is NOT a very good measure of purity**Conversly I have plenty of impure white products or clear oils. DCM usually dissolves salts to some extent. I've observed the same phenomenon. When I do acid/base workup of amines I usually wash the acidic layer with ether, and extract the basic layer with DCM to avoid salt solubility issues. If you partition the free base into organic solvent and wash with water you should be able to get rid of the triethylamine. It will also come off under high vac if it's triethylamine free base.

Opylation - 16-6-2021 at 17:11

I know this is an old thread, but I found the conversation intriguing and wanted to add a little bit of knowledge that I’ve gained dealing with HCl salts that’s retain water or HCl, and/or form a glassy amorphous solid. I’ve found that boiling the mass in ethyl acetate quickly dehydrates HCl salts a couple of ways. The first most likely is the ethyl acetate water azeotrope. The second, is if there is left over free HCl trapped within the salt along with water, the ethyl acetate will hydrolyze and the left over ethanol, acetic acid, and HCl acid are carried away with boiling ethyl acetate. Agitating the mass with a spatula helps speed up the process

Edit: I’ve tried this with other solvents, like DCM, and nothing comes close to ethyl acetate. You can see the salt dehydrate in seconds to form a white powder. Really cool to see

[Edited on 17-6-2021 by Opylation]

Panache - 26-8-2021 at 04:51

Quote: Originally posted by Opylation

I know this is an old thread, but I found the conversation intriguing and wanted to add a little bit of knowledge that I’ve gained dealing with HCl salts that’s retain water or HCl, and/or form a glassy amorphous solid. I’ve found that boiling the mass in ethyl acetate quickly dehydrates HCl salts a couple of ways. The first most likely is the ethyl acetate water azeotrope. The second, is if there is left over free HCl trapped within the salt along with water, the ethyl acetate will hydrolyze and the left over ethanol, acetic acid, and HCl acid are carried away with boiling ethyl acetate. Agitating the mass with a spatula helps speed up the process

Edit: I’ve tried this with other solvents, like DCM, and nothing comes close to ethyl acetate. You can see the salt dehydrate in seconds to form a white powder. Really cool to see

[Edited on 17-6-2021 by Opylation]

That is a good idea, vogel suggests something similar for drying organic acids and this is well not an organic acid but the an acid conjugate of an organic base and well actually not similar at all. Ok vogels is irrelevant this is fresh! Nic3 one!

AvBaeyer - 26-8-2021 at 18:34

Using ethyl acetate to dry HCl salts is a very old trick - it is nice to see it reinvented! I learned this from some old hands when I was a bench chemist a very long time ago. In fact, one of the best ways to make HCl salts is to dissolve the amine in cold ethyl acetate and pass dry HCl gas into the solution. The resulting solid-liquid mixture is concentrated and the solid salt taken up in ethyl acetate and reconcentrated one or two more times. In order to avoid having to use HCl gas for every reaction we kept a stock solution of 4M HCl in ethyl acetate stored in the refrigerator. This is a very stable solution unless it is allowed to absorb too much moisture.

If you have a wet solid or gummy hydrochloride salt, acetonitrile works equally well to remove moisture. It actually works quite well for a variety of amine salts.

AvB