Sciencemadness Discussion Board

Hg/Al Reductive Amination w/Ammonia - Not Viable?

alking - 9-6-2017 at 11:50

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?

laserlisa - 9-6-2017 at 11:58

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.

alking - 9-6-2017 at 14:03

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.

Corrosive Joeseph - 9-6-2017 at 14:51

Can you post your experimental please..............?


/CJ

Melgar - 9-6-2017 at 16:22

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

alking - 9-6-2017 at 19:17

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]

alking - 10-6-2017 at 12:05

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.

Corrosive Joeseph - 10-6-2017 at 12:27

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

Melgar - 10-6-2017 at 12:33

You can make formic acid by distilling oxalic acid and glycerol, in the high likelihood that this reaction fails.

unionised - 10-6-2017 at 12:50

IIRC the reaction of ammonia solution with acetone is complex enough, even before you add alcohol and aluminium.

Corrosive Joeseph - 10-6-2017 at 12:58

Quote: Originally posted by unionised  
IIRC the reaction of ammonia solution with acetone is complex enough, even before you add alcohol and aluminium.



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

alking - 10-6-2017 at 13:27

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]

Corrosive Joeseph - 10-6-2017 at 13:37

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

alking - 10-6-2017 at 16:01

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.

alking - 11-6-2017 at 15:42

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.

alking - 11-6-2017 at 19:14

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]

Melgar - 11-6-2017 at 19:51

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.

alking - 11-6-2017 at 20:37

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]

Corrosive Joeseph - 12-6-2017 at 07:43

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]

alking - 12-6-2017 at 08:27

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]

alking - 12-6-2017 at 10:47

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]

Corrosive Joeseph - 12-6-2017 at 14:47

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

alking - 12-6-2017 at 16:30

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]

Melgar - 12-6-2017 at 17:17

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?

alking - 12-6-2017 at 18:04

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.

alking - 12-6-2017 at 18:56

Actually I am somewhat wrong after looking into it more. It does form the imine, but it's not part of the reduction, it forms first via the pathway Joseph mentioned. Then it is actually the imine that is reduced to form the carbonyl-amine condensation product, so the ketone itself should never actually be reduced.

Knowing that it would have likely been better to combine the ammonia and acetone first before adding the HgCl2, but at the time I did not know how vigorously it would react so I wouldn't have done it differently. As discussed there may not have been much imine formation without the aluminum to push it to the right though.

Melgar - 12-6-2017 at 23:50

You still seem to be confused as far as terminology. The imine is not reduced to form a carbonyl-amine condensation product, the imine IS a carbonyl-amine condensation product. And imine formation is not a redox reaction, since both before and after, the carbon is double-bonded to a more electronegative atom.

I'm concerned about your use of mercury just for screwing around, though. I would personally never use lead or mercury for any reaction that I wasn't already 99% sure of what the products would be. There are safer alternatives. Are you in the US? If so, I'll mail you some of this aluminum/gallium alloy stuff I've been experimenting with, for free. It'll reduce all the same things, at least it should. And if there are differences, they're differences that haven't been documented yet, so you'd be breaking new ground, scientifically. The only other research I'm aware of on this alloy is by a team at Purdue, that's only using it to generate hydrogen from aluminum.

If you save the wastes, you can reclaim gallium and whatever metals are more electropositive from it, then use the salts like you would mercury salts for a reduction. There are differences in procedure, but not not many. The last thing you need is to get lax with safety and accidentally discover a new synthesis for dimethylmercury or something.

alking - 13-6-2017 at 09:43

Quote:
You still seem to be confused as far as terminology. The imine is not reduced to form a carbonyl-amine condensation product, the imine IS a carbonyl-amine condensation product. And imine formation is not a redox reaction, since both before and after, the carbon is double-bonded to a more electronegative atom.


You're right. I did realize that and understand the mechanism/pathway now, but I did still use the wrong termonology in that sense. I did not mean that the reduction itself creates the condensation product just that after the reduction you have your target, reduced, condensation product.

Quote:

I'm concerned about your use of mercury just for screwing around, though. I would personally never use lead or mercury for any reaction that I wasn't already 99% sure of what the products would be. There are safer alternatives. Are you in the US? If so, I'll mail you some of this aluminum/gallium alloy stuff I've been experimenting with, for free. It'll reduce all the same things, at least it should. And if there are differences, they're differences that haven't been documented yet, so you'd be breaking new ground, scientifically. The only other research I'm aware of on this alloy is by a team at Purdue, that's only using it to generate hydrogen from aluminum.

If you save the wastes, you can reclaim gallium and whatever metals are more electropositive from it, then use the salts like you would mercury salts for a reduction. There are differences in procedure, but not not many. The last thing you need is to get lax with safety and accidentally discover a new synthesis for dimethylmercury or something.


That's very kind. I am in the US so if you are offering I'll take you up on it, I was considering that some time back but did not pursue it.

I am relatively safe with the mercury, and I don't dump it down the drain or anything like that, but I'd definitely prefer not to work with it if possible. There are some alternatives that I have available, CuSO4/A and, Zinc/HCl come to mind, but I actually went with the Hg/Al because I was not sure if it would work.

Maybe that logic is backwards, but my thought was that if it doesn't reduce with Hg/Al, the most effective reducing agent I have, then it's reasonable to conclude a reduction is not viable. Yet if I tried with say CuSO4/Al and it did not work then all I can conclude is CuSO4 did not work but Hg/Al still may.

edit: Still grappling with the quote tags...

[Edited on 13-6-2017 by alking]

edit2: Actually I noticed you said above that you can 'use the [gallium] salts like you would Hg.' Are you saying that from experience or just theoretically? When I was researching Ga before the consensus seemed to be that you had to alloy it and creating an HCl or something is not very effective as it's hard to dissolve and I couldn't find any reports of someone actually using it that way.

[Edited on 13-6-2017 by alking]

Corrosive Joeseph - 13-6-2017 at 15:33

Quote: Originally posted by Melgar  
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.


Thank you for that quality piece of information, I didn't know that. I was wrong myself in thinking it wouldn't go well in water.
And this thread has interested me enough to look at this even closer..........

"The Al/Hg reduction system definitivly needs water, no water or not enough water - no reaction. It is mostly almost not possible to use to much water, for reductive aminations often 40% methylamine in WATER is used with excellent results." - Organikum

and from the same thread...........

"Anyway, the dissolving aluminium does not give a fuck about whether the proton donor is water, methanol, acetic acid or whatever else. The pKa of the proton donor will however influence the overvoltage at the metal surface. So, too acidic proton donors (like HCl, etc.) are no good since too much metal gets consumed by the reduction of H(+) to H2 and not enough acidic proton donors will slow down the reduction to a useless pace. Solvents like MeOH, H2O and conditionally AcOH are just OK for the dissolving metal reductions with aluminium amalgam. All there is to do is to adjust the solvent or combination of solvents to the substrate that is to be reduced." - Nicodem

"waterless al/hg?" - https://www.sciencemadness.org/talk/viewthread.php?tid=8452

also...........

"Pressurerized Al/Hg as on Rhodiums page but with ammomia in ethanol (94% alc. is ok). Yield: 50% to 60%
Add the amine in alcohol to the ketone and let sit for some hours. This should warm up on addition. Then do the Al/Hg under pressure (3 to 5 atm is ok).
Ratios amine to ketone 1 to 1,5 molar." - Organikum
" Reduction of carbonyl groups" - https://www.sciencemadness.org/talk/viewthread.php?tid=627

Never mind the pressure thing, Orgy seemed to like that one, just posting an example of forming the imine first for the OP...........


/CJ

[Edited on 13-6-2017 by Corrosive Joeseph]

Melgar - 13-6-2017 at 21:23

Quote: Originally posted by alking  
Quote:

I'm concerned about your use of mercury just for screwing around, though. I would personally never use lead or mercury for any reaction that I wasn't already 99% sure of what the products would be. There are safer alternatives. Are you in the US? If so, I'll mail you some of this aluminum/gallium alloy stuff I've been experimenting with, for free. It'll reduce all the same things, at least it should. And if there are differences, they're differences that haven't been documented yet, so you'd be breaking new ground, scientifically. The only other research I'm aware of on this alloy is by a team at Purdue, that's only using it to generate hydrogen from aluminum.

If you save the wastes, you can reclaim gallium and whatever metals are more electropositive from it, then use the salts like you would mercury salts for a reduction. There are differences in procedure, but not not many. The last thing you need is to get lax with safety and accidentally discover a new synthesis for dimethylmercury or something.


That's very kind. I am in the US so if you are offering I'll take you up on it, I was considering that some time back but did not pursue it.

U2U me your address, and I'll get it out in the mail. Just promise not to use mercury salts "just to see what happens", and only when you know exactly what you're doing, ok? This gallium alloy you can eat on your corn flakes and be fine, so use it for anything you can think of.
Quote:
I am relatively safe with the mercury, and I don't dump it down the drain or anything like that, but I'd definitely prefer not to work with it if possible. There are some alternatives that I have available, CuSO4/A and, Zinc/HCl come to mind, but I actually went with the Hg/Al because I was not sure if it would work.

Maybe that logic is backwards, but my thought was that if it doesn't reduce with Hg/Al, the most effective reducing agent I have, then it's reasonable to conclude a reduction is not viable. Yet if I tried with say CuSO4/Al and it did not work then all I can conclude is CuSO4 did not work but Hg/Al still may.

Well, in that case, the logic is wrong rather than backwards. Reducing agents aren't on a linear scale from strongest to weakest. I mean, there are stronger ones and weaker ones, but they all have their preferred functional groups for reducing. Sodium borohydride, for example, prefers to reduce ketones and aldehydes to alcohols, but will perform other reductions too, given enough time. All the PGMs have their own preferences too.

[Edited on 13-6-2017 by alking]
Quote:
edit2: Actually I noticed you said above that you can 'use the [gallium] salts like you would Hg.' Are you saying that from experience or just theoretically? When I was researching Ga before the consensus seemed to be that you had to alloy it and creating an HCl or something is not very effective as it's hard to dissolve and I couldn't find any reports of someone actually using it that way.

Original research that I haven't written up yet. Gallium dissolves just fine in HCl + H2O2, and will actually do its "angry dance" if conditions are just right and temperature rises to near the H2O2 decomposition temperature. That's where it's a melted ball, and bubbles are forming so quickly on its surface that it bounces all over the inside of the liquid in the flask. The trick is that you have to add gallium at a temperature well above its melting point, so like 50˚C.. This allows it to be reduced in localized spots on the aluminum, since reduction takes place much more quickly in areas where there's liquid gallium present. Otherwise, it deposits in scattered areas all over the surface, and doesn't form those localized liquid areas like mercury does. Once gallium is deposited, and you can see some bubbling, let it cool down before adding the indium chloride. You'll understand why I said to do that when you see the rapid increase in reactivity. Add indium chloride solution slowly, in any case, because you're sort of tuning the reaction at this point. Tin seems to be helpful as a catalyst, but it's hard to say for sure. I usually use the alloy containing all the different metals myself.

For rquote blocks, which are automatically added to your response, you need to end in a /rquote end tag. A quote bloc, on the other hand, has to always end with a /quote.
Quote:
I didn't know that. I was wrong myself in thinking it wouldn't go well in water.
And this thread has interested me enough to look at this even closer..........

Actually, you were right about how it would perform in water. Water needs to be removed from the reaction since it's a product of imine formation. Removing the formed water prevents the reaction from going backwards./

[Edited on 6/14/17 by Melgar]

Melgar - 14-6-2017 at 17:05

In my experience, the reason for the water is to react with the aluminum alkoxides to precipitate out the aluminum oxides. Aluminum alkoxides are gel-like and not very soluble in the alcohol, so they tend to coat the aluminum's surface. Water reacts with the alkoxides to give back the alcohol and a much denser, powdery aluminum oxide.

Corrosive Joeseph - 15-6-2017 at 07:24

@ Meglar - Could you elaborate on that, I always thought it was aluminium hydroxide that was one of the end products..........?

"The presence of water in the solution is reportedly helpful—even necessary; the electron rich amalgam will oxidize aluminium and reduce H+ from water, creating aluminium hydroxide (Al(OH)3) and hydrogen gas (H2). The electrons from the aluminium reduce mercuric Hg2+ ion to metallic mercury. The metallic mercury can then form an amalgam with the exposed aluminium metal. The amalgamated aluminium then is oxidized by water, converting the aluminium to aluminium hydroxide and releasing free metallic mercury. The generated mercury then cycles through these last two steps until the aluminium metal supply is exhausted.[4]

The three reaction steps of the aluminium amalgam reaction. The first step reduces mercury ions to mercury metal. While the bottom two reactions continuously cycle until the aluminium supply is exhausted.

2 Al + 3 Hg2+ + 6 H20 --> 2 Al(OH)3 + 6H+ + 2Hg

Hg + Al --> Hg-Al

2Hg-Al + 6 H2O --> 2 Al(OH)3 + 2Hg + 3 H2"

Taken from - https://en.wikipedia.org/wiki/Aluminium_amalgam (Please excuse my terrible subscript and superscript technique, there isn't any)


And from this thread - "Aluminium amalgam" - http://www.sciencemadness.org/talk/viewthread.php?tid=20625

"And just a short note: if pure chemicals are used (abs. propanol) then no Al2O3 should form during this reaction."
I presume this means no water............?

and from the same thread -

"To see the stuff in your Al foil, soak it for about an hour in vinegar (we are trying to remove a plastic coating). Rinse and place in a container of aqueous ammonia. You will see tiny bubbles as the protective Al2O3 layer is circumvented by the rise in pH and the Al reacts with water forming H2 and a clear gelatinous Al(OH)3 (saturated with aqueous ammonia). In about a day or two, all that will remain is a black residue (Carbon or Silicon I suspect). "

The more I know, the more I realize I don't know (facepalm)


/CJ

Melgar - 15-6-2017 at 08:23

Aluminum hydroxide <-> aluminum oxide is also reversible. (2 Al(OH)3 <-> Al2O3 + 3 H2O) In an aqueous solution, hydroxide will dominate, but if not, the oxide will. This is convenient, since the oxide is denser and doesn't form a sludge. This is one of the reasons to avoid a mostly-aqueous solution. Additionally, like iron, aluminum can have mixed oxide-hydroxide compounds, which are virtually always found in products of aluminum reduction. In this case, it doesn't matter if it forms Al2O3, because by that point it's already in solution and not adhered to the aluminum surface.

Also, the one poster was right about Al2O3 not forming if the alcohol was pure. This is because it all becomes aluminum isopropoxide, and water is needed to turn that into the hydroxy compound, which would then be dehydrated to Al2O3, presumably due to the low water content.

Corrosive Joeseph - 19-6-2017 at 12:18

Oh-kay............. The whole reaction is very complex actually.......... I'm still trying to get my head round it but I can see it more clearly now........... Sheesh

I looked at this a while ago, in the hope of preparing primary amines from OTC ketones, but I never really saw anything very concrete.

Short chain aliphatic ketones (acetone and MEK) just don't seem to do well in any reductive amination from what I have read.
Here is another one -

"Most of the yields reported in preparations of primary amines from simple aliphatic ketones are better than 50%. The
yields from acetone and methyl ethyl ketone, in preparations carried out with hydrogen and a nickel catalyst, are only about 30%.
However, methyl n-propyl ketone 12 and methyl isopropyl ketonex are converted to the primary amines in yields of 90% and 65%, respectively.
The yield of cyclohexylamine from cyclohexanone is about 80%."

I read 30% EVERY time, with EVERY method.

That was taken from 'The Preparation of Amines by Reductive Alkylation' in 'Organic Reactions Vol. 4',
It is in the SM library - http://library.sciencemadness.org/library/books/organic_reac... -

Much great information in that chapter, but all reduction methods are hydrogenation and metal catalyst (usually Ni)
Modern researchers seem to prefer NaBH3CN............ Pfft..........!!

Al-Hg on cyclohexanone to cyclohexamine looks much more promising.
Does anyone have any experience with this or know of any reports..........?

In the middle of all my digging, I found this -
" The Al/Hg gives 85% and more and workup is not bad if done right and no unnecessary excess of Al was used (in cases the product steamdistills workup is cake anyways)."

[EDIT] - Just realized this is with alkylamine and not ammonia........ Grrrr

Taken from - "wet aminative reduction" - http://www.sciencemadness.org/talk/viewthread.php?tid=19587

Anyways, out of useful information for now. Where's my shovel...........


/CJ


Attached - Reductive Amination of Aldehydes and Ketones - Mechanics and Selectivity


Attachment: Reductive Amination of Aldehydes and Ketones - Mechanics and Selectivity.pdf (256kB)
This file has been downloaded 486 times

[Edited on 19-6-2017 by Corrosive Joeseph]

[Edited on 19-6-2017 by Corrosive Joeseph]

Corrosive Joeseph - 20-6-2017 at 20:49

Please excuse the double post...........

For the OP - Taken from the attachment above -

"The initially formed primary amines can, in their turn, behave as aminating agents for carbonyl compounds to afford secondary
amines.
It was proposed as well that primary amines react with imines, forming an addition product, which can directly be reduced to the secondary amine. The secondary amine would react similarly with either the carbonyl compound or the imine to give the tertiary amine through hydrogenation of the corresponding carbinolamine or gem-diamine intermediate (Scheme 2).[7]

However, a kinetic study on the reductive amination of acetone with NH3 revealed that both isopropylamine and diisopropylamine are obtained through hydrogenation of the imine intermediates formed from acetone and NH3 or acetone and isopropylamine, respectively.
A separate study of the reaction of acetone and isopropylamine showed that the diisopropylimine equilibration reaction is acid catalysed (Scheme 3).[8]"

Still found no report of a Leuckart on acetone, except a post from Leu -

"You will need a pressure vessel to carry out a leuckart reaction using formamide with acetone, as acetone is a vapor at the temperatures that a Leuckart reaction occurs at atmospheric pressure :) One might be able to use an alternative such as CTH or catalytic hydrogenation, but LAH is what was used in the published papers :P "
https://www.sciencemadness.org/whisper/viewthread.php?tid=56...

Hmmm.......... Makes sense I guess

There is an excellent chapter on the Leuckart in Organic Reactions 5 - http://library.sciencemadness.org/library/books/organic_reac...

The only mention of acetone is -
Acetone + a-Naphtylamine + Methyl Formate ---> N-Isopropyl-a-naphthylamine
No stated yield........ Only a Ref #

And no mention of MEK.


Over and out


/CJ

[EDIT] - Still looking for a reported Al-Hg on cyclohexanone and ammonia...... Nothing yet





[Edited on 21-6-2017 by Corrosive Joeseph]

[Edited on 21-6-2017 by Corrosive Joeseph]

Melgar - 21-6-2017 at 00:29

Pressure reactions are easy to do at a small scale. Little one-ounce glass bottles can hold at least 100 psi if they have a good enough lid. Ive reacted fairly substantial quantities of aluminum with iodine in 10-mL bottles, and despite the purple and brown storm going on inside, it held. The smaller the vessel, the higher pressures it's capable of, typically.

Most cyclohexylamine is produced by hydrogenating the ring on aniline (which is formed by perhaps the easiest reduction in organic chemistry from nitrobenzene). You can probably do this with the room-temperature Birch reduction variant that uses amines rather than ammonia. Or a regular Birch reduction, if you have that capability.

If you're only trying to make it because a certain Dr. Shulgin was fond of using it, you can use pretty much any high-boiling primary amine that's relatively stable. Decarboxylate phenylalanine to get phenethylamine, for instance.

Corrosive Joeseph - 21-6-2017 at 01:19

Thanks Melgar, that was all I had dug up so far....... Most of it posted for the OP and the benefit of the others in the future

I found MANY routes to Cyclohexylamine but nearly all of them are out of my reach.
Cyclohexanone is OTC at the local auto parts store/motor factors and mercury and aluminum foil are cheap......!!

I just thought it interesting. And nobody seems to have done it.
Every other reductive amination method I found yielded around 70% on Cyclohexanone.
Much better than acetone or MEK, that's for sure......

Regarding Sasha, he was most fond of using ammonium acetate, which, by all accounts, is a woeful Knoevenagel catalyst.
The man was a genius but he didn't half use some unorthodox methods.

I just want low MW amines, not the crazy ones he was making.......!!
Thanks for the heads up on the PEA


/CJ

Melgar - 21-6-2017 at 05:33

I think he only used cyclohexylamine because of how cheap it is to purchase for chemists, industrially. It's a precursor to one of the most common artificial sweeteners used in Europe, cyclamate, and it's easily made from aniline, which is bought and sold by the train-car. In bulk, it costs about the same as isopropanol or acetone. When I realized how cheap it was as an industrial chemical, I realized it was probably one of his throw-away chemicals, and his choice to use it was probably similar to the choice you or I might make of what to use to rinse an oily organic residue out of some glassware.

alking - 21-6-2017 at 07:27

What is cyclohexamine sold as in autoparts stores? That's one I'd like to add to my list.

Cyclohexylamine is cheap but so are other more effective amines and the products shulgin was losing to a reduced yield were not cheap.

Melgar - 21-6-2017 at 13:48

Are you sure you're not thinking of cyclohexane or cyclohexene? "Cyclohexamine" isn't a real chemical.

Corrosive Joeseph - 27-6-2017 at 11:00

Quote: Originally posted by alking  
What is cyclohexamine sold as in autoparts stores?


Check my post again, it is Cyclohexanone that is sold as a specialist thinners here...........

Anyways, I decided to look into this again. I am fascinated by the fact that one reaction needs water removed and the other reaction needs water to happen.

This is before one considers the many other competing reactions going on at the same time. Anyways, more research - Taken from 'Ketones and Aldehydes' attached below......

"Formation of Imines (Condensation Reactions)

Under appropriate conditions, primary amines (and ammonia) react with ketones or aldehydes to generate imines.
An imine is a nitrogen analogue of a ketone (or aldehyde) with a C=N nitrogen double bond instead of a C=O.
Just as amines are nucleophilic and basic, so are imines.
(Sometimes substituted imines are referred to as Schiff's bases).
Imine formation is an example of a condensation reaction -
where two molecules join together accompanied by the expulsion of a small molecule (usually water).


The mechanism of imine formation starts with the addition of the amine to the carbonyl group.
Protonation of the oxyanion and deprotonation of the nitrogen cation generates an unstable intermediate called a
carbinolamine.
The carbinolamine has its oxygen protonated, and then water acts as the good leaving group.
This acid catalyzed dehydration creates the double bond, and the last step is the removal of the proton to produce
the neutral amine product.
The pH of the reaction mixture is crucial to successful formation of imines.
The pH must be acidic to promote the dehydration step, yet if the mixture is too acidic,
then the reacting amine will be protonated, and therefore un-nucleophilic, and this would inhibit the first step.
The rate of reaction varies with the pH as follows:

[See graph in attachment 'Ketones and Aldehydes]

The best pH for imine formation is around 4.5."

and from the same document -

"Under acidic conditions, weaker nucleophiles such as water and alcohols can add.
The carbonyl group is a weak base, and in acidic solution it can become protonated.
This makes the carbon very electrophilic (see resonance structures), and so it will react with poor nucleophiles.
E.g. the acid catalyzed nucleophilic addition of water to acetone to produce the acetone hydrate.
Summary
The base catalyzed addition reactions to carbonyl compounds result from initial attack of a strong nucleophile, whereas the acid catalyzed reactions begin with the protonation of the oxygen, followed by attack of the weaker nucleophile."

Oh dear, I presume just like acetone and NH3 (mentioned above), the mechanism for di-imine formation is also acid catalyzed.........

I also found that Cyclohexanone to Cyclohexanol reduction with Al-Hg in THF:H20 (9:1) yields 95%, and seems to be VERY favourable.
See 'Selective Cycloalkanone Reductions using Aluminum Amalgam' attached.

But when the same reaction is done in DCM, it yields 55% of a Pinacol coupling product (From 'Reductions in Organic Chemistry' by Hudlicky Pg. 118)


Okay, the big question............. If one was to attempt this should the imine be formed first and dripped on the amalgam, or should the Cyclohexanone be dripped in the soup and the imine reduced as it is formed.........?

I was always under the impression that acidic Al-Hg prevents dimerization (this is a double bond after all)

Has anyone any advice............? There is a lot going on here.........


/CJ

Attachment: Ketones and Aldehydes.pdf (2.5MB)
This file has been downloaded 523 times

Attachment: Selective Cyclohexanone Reductions using Aluminum Amalgam.pdf (221kB)
This file has been downloaded 446 times

Melgar - 27-6-2017 at 22:11

Quote: Originally posted by Corrosive Joeseph  
Anyways, I decided to look into this again. I am fascinated by the fact that one reaction needs water removed and the other reaction needs water to happen.

There are quite a lot of reactions like that, especially reactions that say they need strict anhydrous conditions, but actually need very slight quantities of water to initiate. Far too small for that to ever be a concern for a chemist, but interesting nonetheless.

In this case, it's actually one of the reasons that this reaction is used though; since one of the reactions' products feeds into the other, and vice versa, this keeps the reaction controlled intrinsically. For some reason, the nearest parallel I can think of is the fact that internal parasites virtually always require two host species. The reason for this is that parasites are stupid, and would (and often do) kill their hosts if their population got out of control within an individual. By needing two species as hosts within their life cycle, their populations are intrinsically limited by the interaction between the species, and both species' populations. It's sort of the same with two reactions that feed into each other. Sort of a yin-yang type of thing going on.
Quote:
Okay, the big question............. If one was to attempt this should the imine be formed first and dripped on the amalgam, or should the Cyclohexanone be dripped in the soup and the imine reduced as it is formed.........?

I was always under the impression that acidic Al-Hg prevents dimerization (this is a double bond after all)

Has anyone any advice............? There is a lot going on here.........


/CJ

Neither! Do you know WHY dimerization occurs? Because of how readily primary amines undergo reductive amination! Considerably better than ammonia, for sure. That's actually the primary use of reductive amination; to make a secondary amine from a primary amine and an aldehyde or ketone. When making a primary amine, hydroxylamine will actually be used rather than ammonia, because of how much EASIER it is to REDUCE the resulting OXIME. You'll notice that the three words I've capitalized are not often seen in the same sentence... (Sorry for channelling Dr. Cox from Scrubs there for a minute.)


The same problem that you get if you try to monoalkylate primary amines with alkyl halides, will get you if you try to monoalkylate ammonia with reductive amination and an aldehyde or ketone. If you're hell-bent on reductive amination rather than a Leuckart reaction or something, you could possibly form the imine under anhydrous conditions, isolate it, and then reduce it, but of course, that precludes the use of Al/Hg, which for some reason, everyone is a huge fan of except me.

[Edited on 6/28/17 by Melgar]

Melgar - 29-6-2017 at 20:07

Oh, for anyone needing cyclohexylamine, I assume you've already decided against just buying it.