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Klute
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Forming oxalte salts of amines
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
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entropy51
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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 1472 times
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Klute
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Interesting paper. I will try it soon. I don't know how much HCl will be lost with the MgSO4 though...
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Paddywhacker
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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.
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Klute
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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]
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starman
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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]
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entropy51
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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!
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chemrox
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thanks entropy for that. I wonder if sieves would work as well as MgSO4?
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entropy51
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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.
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Klute
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You've tried it out yourself? Hox concentrated was the anhydrous acid?
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entropy51
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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.
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not_important
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| 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.
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Klute
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I tried it out wxith toluene but got notable decomposition, obtaining cristals contaminated with tar... guess low boiling alkanes would be a better
choicre.
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Klute
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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]
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entropy51
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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.
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starman
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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.
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Arrhenius
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Mind sharing what the amine is you're trying to form a salt of?
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Klute
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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.
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grind
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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...
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Arrhenius
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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.
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Klute
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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.
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Paddywhacker
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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 1271 times
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Arrhenius
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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.
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Opylation
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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]
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Panache
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| 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!
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