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alking
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Hg/Al Reductive Amination w/Ammonia - Not Viable?
I thought this would work to form simple amines from ketones and aldehydes, however I'm currently trying to do so with acetone to make
diisopropylamine and I noticed that the ammonia seems to rather aggressively attack the foil which makes me question it. I've read reports of others
doing this, though most of it seems to be talk w/o any reports, however I really doubt it based on what I'm seeing here. Some amine may well form, but
there's no way the yields will be worthwhile as the ammonia seems to react much more quickly than the reduction. Am I wrong, or did I misunderstand
the procedure maybe? If not what would accomplish what I'm trying to do, would a salt of ammonia work perhaps?
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laserlisa
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I dont know if your procedure is likely to work but usually when making primary amines by reductive amination hydroxylamine is used instead of ammonia
to make an oxime rather than an imine.
Oximes are usually a bit more difficult to reduce though.
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Assuming this does work any advice on working it up as well? I'm thinking of extracting it directly from the reaction soup with some xylene and then
doing a fractional distillation from that. The boiling points are as follows:
Ammonia: -30C (or w/e it is)
Isoproylamine: 31-35C
Acetone: 56.5C
Diisopropylamine: 83-85C
Xylenes: 138-135C
There's a reasonable enough BP difference it should be a straight forward fractionation IF there are no troublesome azeotropes, however that I'm not
sure of and cannot find any references. I do know acetone forms an azeotrope with one or both of the amines, but I'm not sure about the xylene. There
should not be much acetone left though, if any, so that may not matter anyway. I'm hoping due to the high BP difference that xylene will not form an
azeotrope and just stay in the pot.
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Corrosive Joeseph
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Can you post your experimental please..............?
/CJ
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Melgar
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The standard reaction to accomplish this is the Leuckart reaction, which uses ammonium formate. Best of all, the formic acid acts as the reducing
agent, so you can dispense with the mercury salts.
https://en.wikipedia.org/wiki/Leuckart_reaction
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Yeah, that seems like it may be the best route all things considered, but since I don't have any formic acid or ammonium formate this was more viable
if it works. The reaction is almost over now, I'll probably wait to work it up until the morning though. Here's my procedure:
50g Acetone
50g Al Foil
60g ~25% Ammonium Hydroxide Solution
500ml H20
"Spatula tip" of HgCl2
Everything was combined in a 1000ml flask in an ice bath fitted with a reflux condenser, thermometer, and an addition funnel to introduce the acetone.
The ketone was dripped in rather quickly as it was not particularly reactive and probably could have been added at once. The solution was vigorously
stirred and maintained below 30C for the most part, though it did rise to 45C or so at one point when I got distracted by the internet. The total
reaction took approximately 7-8 hours.
edit: And to add to my previous post on the workup I forgot that there is likely to be some isopropanol in there too since I went light on the ammonia
to favor the secondary amine which may also pose an issue with the distillation. It's bp is rather close to diisopropylamine and I'm sure it forms an
azeotrope with, well, everything present actually. For now my plan is still to work it up the same way though, it will at least be more refined and
give me an idea of what I have. From there I can salt the amines away from any offending solvents if need be and re-distill to separate them..
[Edited on 10-6-2017 by alking]
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I'm in the process of working it up right now. I extracted it with ~200ml of Xylene, filtered off any suspended aluminium, and had about 240-260ml of
liquid that is currently being fractionated. Here's the fractions so far:
60-75C: 1-5ml
75-82.5C: ~8-15ml
83-85.1C: 15ml
They all smell ammoincal which is the only odor that can be detected. At this point it's hard to say if it was successful or not. The fractions are
what you would expect from a mixture of monoIPA, DIPA, and water, but it also could likely be some mix of ammonia, water, IPA, and Acetone. I'm going
to have to remove the ammonia, if present, before I can really determine anything. I assume relfuxing it will work to do that which is likely my next
step.
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Corrosive Joeseph
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Did you basify like regular Al-Hg.............? Although it's probably pretty basic already. Taken from another thread on ketone to amine-
"With small amines, an issue may be separating from aqueous phase, as eg freebase iPrNH2 is rather soluble in water whereas freebase cyclohexylamine
or amphetamine is not. If A/B sep is used some of the small amines may remain in water."
"It might just be a matter of using the right solvent.
Diisopropyl ether is particularly good at extraction of polar compounds from polar solvents."
/CJ
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Melgar
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You can make formic acid by distilling oxalic acid and glycerol, in the high likelihood that this reaction fails.
The first step in the process of learning something is admitting that you don't know it already.
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unionised
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IIRC the reaction of ammonia solution with acetone is complex enough, even before you add alcohol and aluminium.
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Corrosive Joeseph
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Quote: Originally posted by unionised  | IIRC the reaction of ammonia solution with acetone is complex enough, even before you add alcohol and aluminium.
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No alcohol mentioned in this one above but I think you are right.
I have yet to see a decent experimental procedure or reported yield from ANY reductive amination on acetone (Al/Hg, Zn/NiCl2 or Leukart).
30% tops
I'll see what I can dig up when I get a chance.
/CJ
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I did basify with NaOH for that reason, yes, although I only used 30g which is probably less than ideal. If I was confident it worked I'd have used
more to try to push it out, but I didn't want to waste it assuming it did not. I did notice that the extracted xylene had little to no smell of
ammonia yet as I was pouring the soup into the funnel to separate it the very bottom of the pot had a very strong smell of ammonia, I have no thoughts
as to why though. Would one of the amines sink to the bottom instead of going into the xylene or would the aluminum hold onto it for some reason?
Neither seem likely, but that's all I have.
In total I separated it into two fractions, each between 10 and 20ml, and the still head topped out at ~94C. The first smells very ammonical, the
second less so, and that is the only odor present in either. The majority of the first came over around 75C and the second 83-85C. My hunch is it's
simply unreacted ammonia and i-PrOH despite the favorable bp of the second fraction but we'll see. Either way the yield can't be more than 50% at this
point so even if it worked it's not particularly practical given alternatives.
[Edited on 10-6-2017 by alking]
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Corrosive Joeseph
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Freebase IPA boils at 31-35 degrees C and is miscible with water - https://en.wikipedia.org/wiki/Isopropylamine
There is a good chance it is still in the aqueous layer.
/CJ
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Perhaps so. It could be that when I smelled it the thin layer of xylene was poured off to the extent to allow the ammonia fumes to escape and it had
nothing to do with the bottom portion of the pot. There is ~20ml or so of liquid unaccounted for and there should be an insignificant amount water or
xylene in the two fractions.
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To give an update I combined my two fractions and neutralized it with some HCl. I used an unknown concentration of HCl and I didn't keep track of it
so I can't determine how many moles of NH4 were neutralized, but I'd guess a ballpark of maybe 10ml of 30% HCl was required. I also took the first
~50ml of Xylene that came over and washed it with some HCl until it came out acidic and combined that with the HCl amine solution.
From there I evaporated off most of the water, about 60ml maybe, until it seemed to become rather thick forming a solid mass once heating was stopped,
I was left with about 30ml of solid with an unknown amount of water. I assumed there was no solvent left at this point, but I'm unsure because of an
observation I'll get to momentarily, however no smell was detected of xylene, acetone, IPA, or ammonia. Also worth noting when the HCl was added the
previously colorless solution took on a yellow color that darkened to a red over the addition of the acid. Presumably this is from unreacted acetone
polymerizing. Based on the amount of color change I suspect there was only a minor amount of acetone present.
Next it was basified with ~10g NaOH in 15ml of dH2O which immediately changed the solution from a dark red to a brown. It was also noted that the
~40ml of solution (some water was added to transfer the solid to a flask) separated into two layer when the NaOH solution was added. The top about
10-15ml and the bottom about 30-45ml.
At first I assumed this top layer is probably my amine(s) being pushed out by OH ions, but I'm not so sure. For one it did not smell as strongly of
ammonia as I would have expected, it definitely smelled of NH4, but not as strong as I would expect. Perhaps DIPA is not as volatile as amines I'm
used to working with, but my thought is more likely that that top layer is xylene which is holding it down. When it was refluxed for ~30min with a ~0C
condenser I also had effectively no ammonia escape. A very faint smell of NH4 could be detected, but appreciably none. This made me think perhaps it
is higher boiling amines, but it also could be that the water is holding onto the ammonia better than expected.
The last observation that makes me think the top layer is xylene is that when the solution began to boil the bottom layer would boil off and the
bubbles would immediately get trapped in the top layer indicating that w/e the bubbles are boil at a lower temp than that top layer. If those bubbles
were water then the only product I'm aware of that could be is xylene. It may be that it was some Ammonia, acetone, or IPA and the top layer was DIPA,
but I don't know. I would have thought I'd smell the xylene if any were present and I also would have expected it to form another layer before the
NaOH was added too. My next step is to distill and see what fractions I get, but I'm taking a break for now.
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So I fractionated it and it came over in a single fraction, ~22ml, boiling between 74.6 and 75.0. It smells ammonical for sure, but the bp doesn't
match anything expected. Any ideas? I'm not sure what to do from here.
It does smell more amine like than ammonia to me, or in other words it smells much more strongly of fish which I associate with amines, but that's
hardly identifying nor does it exclude ammonia. Due to the amount of HCl required to neutralize it if it were ammonia though it should smell much more
and be significantly more volatile so at this point I'm confident I have at least made some proportion of the two amines, primary or secondary. Any
suggestions on what to do from here?
[Edited on 12-6-2017 by alking]
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Melgar
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The ammonia-smelling sludge may contain metal-ammine complexes. Really, it's all but certain to be the case, given the composition of commercial aluminum alloys.
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Reynold's aluminum foil was used as the aluminum source. It's supposed to be 99.985% aluminum or something like that (pulling that from memory). So
there's definitely some complexes in there, but it shouldn't be a significant amount as far as the product is concerned. Maybe itas far as my nose is?
Of course I wouldn't be surprised if Reynold's lies either.
[Edited on 12-6-2017 by alking]
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Corrosive Joeseph
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Quote from a post by Nicodem in this thread - 'Isopropylamine and Diisopropylamine from Acetone'
https://www.sciencemadness.org/whisper/viewthread.php?tid=14...
"That is a common oldfashioned reductive amination of ketones. It gives shitty yields when using ammonia instead of the more nucleophilic alkyl
amines, but basically it can work to some degree. So if madscientist says he got reasonable yields, it may just be so.
The work-up will obviously involve a distillation from the postreaction slurry, followed by acidification of the distillate with HCl(aq), rotavap,
basification of the residue with conc. NaOH(aq), phase separation and again distillation, this time with a distillation column."
/CJ
[Edited on 12-6-2017 by Corrosive Joeseph]
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That's pretty much the exact workup I followed except for phase separation, although my bp does not match any target product (bp ~75C, products ~33C
and ~83C respectively). I also extracted from the soup instead of distilled as I did not want to worry about mercury fumes so that very likely lead to
a loss, likely of the primary amine.
The phases did separate, but I distilled out of both of them instead of taking the top alone. The top was what came over by the way and it did have a
lower bp than the water so the bubbles from the bottom that then became trapped in it must have been some ammonia or something, perhaps it became
bound due to a higher attraction from the amines present in the top layer?
[Edited on 12-6-2017 by alking]
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I'm thinking that the solution is likely an azeotrope or otherwise a composition of the primary and secondary amine, likely with ammonia, isopropyl
alcohol, water, and possibly traces of acetone as impurities. I would assume these impurities are quite minor, the ammonia should have mostly been
boiled off or consumed, the acetone should have polymerized, the i-PrOH should be minimal, and due to the bp little water should have come over.
The next best idea I have is to prepare some 2-bromopropane and throw in an equimolar amount of K2CO3 to alkylate it. Assuming a mix of mono and di
isopropylamines that should convert it all to the secondary amine. Tri-isopropylamine is too sterically hindered to produce via alkyation so it should
stop there and using an excess of BriPr should ensure the reaction goes to completion w/o increasing the formation of side products.
From there I would be left with a solution of diisopropylamine, if any ammonia is present it too should actually be converted to diisopropylamine
(perhaps I should have just tried that from the start?), potassium bromide, likely some amine carbonates, and w/e solvents were used or initially
present (i-PrOH, acetone, and water). I assume the solvents would not likely be prone to alkylation and should remain largely intact, or am I wrong?
Lastly another fractional distillation should, at least in theory, yield relatively pure DIPA assuming there's not a significant amount of solvents
present that would cause an issue with the separation.
edit: If I go that route I'm unsure of how long to let it react or a way to monitor the progress however, any ideas? I have TLC plates, but no way I'm
aware of to visualize the amines, and taking a sample to check the BP or whatever is not practical for a variety of reasons. If I can't get any input
I'm thinking my best bet would be to combine everything in a stoppered flask, wait 2-3 days, and hope for the best.
[Edited on 12-6-2017 by alking]
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Corrosive Joeseph
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I have been interested in low MW amines for a while now. I really wish I knew more. But what I do know..........
"Imines are typically prepared by the condensation of primary amines and aldehydes and less commonly ketones:
RNH2 + R'C(O)R → RN=C(R')(R) + H2O
In terms of mechanism, such reactions proceed via the nucleophilic addition giving a hemiaminal -C(OH)(NHR)- intermediate, followed by an elimination
of water to yield the imine. (see alkylimino-de-oxo-bisubstitution for a detailed mechanism) The equilibrium in this reaction usually favors the
carbonyl compound and amine, so that azeotropic distillation or use of a dehydrating agent, such as molecular sieves or magnesium sulfate, is required
to push the reaction in favor of imine formation."
"The most important reactions of imines are their hydrolysis to the corresponding amine and carbonyl compound." -
https://en.wikipedia.org/wiki/Imine
"Hydrolysis usually means the cleavage of chemical bonds by the addition of water. Hydrolysis can be the reverse of a condensation reaction in which
two molecules join together into a larger one and eject a water molecule. Thus hydrolysis adds water to break down, whereas condensation builds up by
removing water."
I don't know how stable acetone imine is but it looks like it was never going to go well in water.
I did wonder earlier why you didn't use an alcohol solvent............?
Ammonia is a shit nucleophile, yields were never going to be above 30% from what I have read.
I did also wonder if any isopropylamine formed would condense with your acetone.
It might go better if the imine was formed first in alcohol and then dripped into your amalgam in solution.
Hopefully someone who knows more will comment. I also found these -
"Reductive amination and water" - https://www.sciencemadness.org/talk/viewthread.php?tid=1938
"Reduction Al-Hg" - https://www.sciencemadness.org/whisper/viewthread.php?tid=92...
/CJ
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Simply combining ammonia and a ketone/aldehyde is all it takes to form the imine? That is worth considering next time if so, it should increase the
yields at the very least. Reading the wikipedia article on imines it also says they can be hydrolysed to amines, what would it take to do that? Is
simply added water enough? Refluxing with a strong base?
I believe reductive amination would create an imine anyway, water present or not. The double bond on the carbonyl is reduced, the nitrogen binds to it
and pushes off the oxygen creating an intermediate imine. The imine is then further reduced/hydrogenated to form the amine.
Water is required for an Aluminium reduction as it uses it as a proton source, otherwise I believe the product gets reduced but not hydrogenated so it
would stop at the imine stage and likely go on to form side products. Theoretically alcohols should work via alkoxides, but ime it doesn't seem to. I
also was using an ammonium hydroxide solution and the acetone was not dry so water was present anyway. If I have to then I do, but drying the acetone,
alcohol, and creating gaseous ammonia is certainly more work than I had initially planned for.
[Edited on 13-6-2017 by alking]
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Melgar
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Imine formation is reversible. Typically, the reaction is driven in a particular direction by either adding or removing water. If you want the imine
to preferentially form, you need to remove water. Since aluminum amalgam reacts with water, that's usually how it's done.
| Quote: | | I believe reductive amination would create an imine anyway, water present or not. |
Reductive amination does not create imines, it transforms them into amines, by definition.
| Quote: | | The double bond on the carbonyl is reduced, the nitrogen binds to it and pushes off the oxygen creating an intermediate imine. |
When a carbonyl oxygen is reduced, that gives a secondary alcohol, which is no longer capable of forming an imine. You're getting everything
backwards!
| Quote: | | The imine is then further reduced/hydrogenated to form the amine. |
"Further" reduced?
| Quote: | | Water is required for an Aluminium reduction as it uses it as a proton source, otherwise I believe the product gets reduced but not hydrogenated so it
would stop at the imine stage and likely go on to form side products. |
Water, or virtually ANY OTHER PROTIC SOLVENT. Methanol, ethanol, and isopropanol are all popular. This sentence might actually fall under the
category of "Not even wrong". If it doesn't work, it's certainly not because you aren't using enough water!
Is anyone else worried that alking is apparently in possession of mercury salts?
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| Quote: | I don't have all night to figure out these quote tags, I don't know where the hell I have messed this up, but instead of deleting this in rage I'll
post it as is and let you guys deal with it.
| Quote: | Imine formation is reversible. Typically, the reaction is driven in a particular direction by either adding or removing water. If you want the imine
to preferentially form, you need to remove water. Since aluminum amalgam reacts with water, that's usually how it's done.
| Quote: | | I believe reductive amination would create an imine anyway, water present or not. |
Reductive amination does not create imines, it transforms them into amines, by definition. |
Through an intermediate, yes, in this case an imine. Someone correct me if I'm wrong. It's an amination because you run the reaction to completion and
probably with some exceptions it's difficult to stop at the imine stage. If I am wrong I know it doesn't just magically become an amine, there is most
definitely at least one intermediate formed.
| Quote: | | The double bond on the carbonyl is reduced, the nitrogen binds to it and pushes off the oxygen creating an intermediate imine. |
| Quote: |
When a carbonyl oxygen is reduced, that gives a secondary alcohol, which is no longer capable of forming an imine. You're getting everything
backwards! |
If you did not have the amine present , yes, you would get an alcohol. In the presence of an amine though the nitrogen bonds to the carbon center
instead forming an imine.
| Quote: | | The imine is then further reduced/hydrogenated to form the amine. |
"Further" reduced? |
Yes, you realize an imine is in a higher oxidative state than the corresponding amine, right? That double bond can be reduced, the nitrogen
hydrogenated, and you get an amine.
| Quote: |
| Quote: | | Water is required for an Aluminium reduction as it uses it as a proton source, otherwise I believe the product gets reduced but not hydrogenated so it
would stop at the imine stage and likely go on to form side products. |
Water, or virtually ANY OTHER PROTIC SOLVENT. Methanol, ethanol, and isopropanol are all popular. This sentence might actually fall under the
category of "Not even wrong". If it doesn't work, it's certainly not because you aren't using enough water! |
Just because they're protic solvents doesn't mean they work. I said as much myself that they should but in practice they don't, it's better to use
water. That is pretty common knowledge in fact for Hg/Al reductions, sometimes alcohol is fine, sometimes just water is fine, but generally w/e your
solvent you're likely going to get a better result if at least some water is present.
| Quote: |
Is anyone else worried that alking is apparently in possession of mercury salts? |
I may be wrong about some things, but at least I am aware of that and I'm not ashamed to admit it. We're all here to learn and teach one another, if
you're going to be rude and insult someone for not understanding something at least make sure you know what you're talking about first and explain how
they are wrong. Making snide remarks and name calling accomplished nothing. If I am wrong then what is the correct pathway? The way you seem to act is
that it just magically happens and there is no pathway at all which makes me think you don't actually understand what's going on yourself.
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