Sciencemadness Discussion Board - Isopropylamine and Diisopropylamine from Acetone

Isopropylamine and Diisopropylamine from Acetone

Eclectic - 7-9-2010 at 10:09

Does anyone have actual lab prep or direct experience making these using zinc dust as the reductant, preferably in aqueous system using an ammonium salt as the ammonia donor?

Nicodem - 7-9-2010 at 14:16

You could try using the method described in the Example 1 of FR971429 (reductive amination of cyclohexanone with NH3, using Zn + NiSO4), but having a lower NH3 vs. ketone ratio instead to promote the formation of the secondary amine. You would still get a mixture of isopropylamine and diisopropylamine, but these can be easily separated by distillation, and besides you say you want both.

Eclectic - 7-9-2010 at 17:42

Yes, both usefull ammonia like solvents at room temp

madscientist - 14-9-2010 at 11:58

You're likely aware of this, but aluminum amalgam does the trick. Dab a bit of HgCl2 on aluminum foil and drop it into the solution of acetone and ammonia. Your house will smell like a dead whale.

Anders2 - 14-9-2010 at 16:36

If I can make a suggestion, use NH2OH to form the oxime with acetone, then Zn/HCl. This should form the isopropylamine. As for Diisopropylamine, perhaps by making isobromopropane from the alcohol (see the topic "Iodomethane"), then reacting the bromopropane with isopropylamine.

If iso chloro propane is used instead of the bromo, it would have to be refluxed (in a sealed apparatus, under a fumehood)

Alternatively Propylene, the product of conc. H2SO4 on isopropanol, could be heated with either ammonia gas or propylamine gas, but this would be more difficult/dangerous.

leu - 14-9-2010 at 17:23

The easiest way for most members would be to form the oxime and reduce that to isopropylamine with amalgamated aluminum :cool:

[Edited on 15-9-2010 by leu]

mario840 - 15-9-2010 at 01:19

so what Hydroxylamine and acetone form oxime ? we must heat it under reflux ? how long ? give some more useful information and then amalgamated aluminum , and the product will be only isopropylamine with some besides product ? what yield ? is there patent for this ?

Hexagon - 15-9-2010 at 04:29

If you want monoisopropylamine, Roundup is the way to go, 3 or 4 euros per mole of iPrNH2 is too expensive?

Eclectic - 15-9-2010 at 06:56

Absolutely, compared to the cost of acetone and ammonia.

And it's for solvent use, not reagent or synthesis feedstock.

mario840 - 15-9-2010 at 10:20

so how to extract isopropylamine from roundup ? diethyl ether ? please tell me more about it

Hexagon - 15-9-2010 at 12:52

Havent done it, but roundup is a glifosate salt of isopropylamine (or ammonia, more rare) in aqueous solution, so add an excess of base (or titrate), saturate with NaCl and then boil the isopropylamine, just like one does with ammonia, witch can be dried with NaOH for example and condensed to obtain it pure or bubbled in what ever solvent you want. I think that from 1 liter of common roundup (4-6€ I think) one can obtain something like 1,5 moles of isopropylamine.

@ Eclectic: What kind of aplication you want the isopropylamine for? The only one I can think of you cant substitute it for a more common and cheap organic solvent is for some king of alkali metal solvating.

Eclectic - 15-9-2010 at 15:30

solvation and recrystalization of borohydrides. I have 100 kg LiH

How mad is that? Also 30 lbs Hg

I also want to make Hunig's base.

[Edited on 9-15-2010 by Eclectic]

madscientist - 15-9-2010 at 16:03

...that's a lot of LiH.

If you're going for Hunig's base the Al/Hg amalgam is your best bet - cheap and effective, and clearly someone also has no shortage of Hg.

Just use an excess of acetone and you'll be good to go.

Anders2 - 15-9-2010 at 17:47

Acetone spontaneously condenses with a solution of hydroxylamine to form the oxime, no heating required. (CH3)2C=NOH
Ammonia forms very transient amines =NH, but the equilibrium is very small.
Hydrazine condenses to form hydrazones =N--N= in very basic conditions, and then this hydrolyzes back to acetone and hydrazine once the pH of the solution goes back to normal. Hexagon, that roundup idea is good one.

madscientist - 15-9-2010 at 18:00

The *imine* (C=N-H) may not be stable but that's not an issue, as the reduction of imines to amines with Al/Hg proceeds smoothly, rapidly, and with relatively high yields. It's cheap and it's simple and all the materials are readily available.

Anders2 - 15-9-2010 at 18:12

A better method might be to use NaOH on solid Aluminum.
Not only will this eleminate the requirement for Hg, but also the basic conditions will help to favor the imine equilibrium.
Obviously the solution should not be too concentrated with the NaOH, otherwise the ammonia may start bubbling out, Cooling the solution may help.

[Edited on 16-9-2010 by Anders2]

madscientist - 16-9-2010 at 07:27

Do you have any references pertaining to NaOH/Al reduction of imines? To my knowledge it does not work - not everything that produces hydrogen will result in a reduction. Be careful with speculation, it could lead others to waste valuable reagents or worse (accidents.)

Hexagon - 16-9-2010 at 12:13

In fact aq. sodium hydroxide works while activating aluminum on a microwave asisted pinacol coupling rxn, Don't know on a reduction like this...

The reference: http://nopr.niscair.res.in/bitstream/123456789/6173/1/IJCB%2045B(1)%20332-334.pdf

madscientist - 16-9-2010 at 12:19

Ah, yes, I was referring to imine reduction specifically. Thanks for sharing that reference though!

Eclectic - 16-9-2010 at 12:54

Ideal system would be water, acetone, ammonium chloride, and a dissolving reactive metal, with or without nickel..., scrap aluminum turnings would be great if it works, but I have zinc dust. I was just asking if anyone has actually DONE it, or has actual prep procedure.

mario840 - 16-9-2010 at 13:06

what about roundup ? there is 360SL 360 g salt per 1 liter for 5- 6 euro and I am really interesting about method isolation , we may add NaOH like Hexagon said or Na2CO3 to ph 10 and then extract with IPA ? will it works ? or destill directly from reaction mixture ? what do you think ?

Eclectic - 16-9-2010 at 13:12

It's probably reasonable if you want a few hundred grams, I'm thinking more in terms of liters....

mario840 - 16-9-2010 at 13:24

yes but i wonder if this "method" works , amine will form a layer on top (very low density) or what ? if form there will be easy to extract or separate withouth heating , i'm just asking that's all

Anders2 - 16-9-2010 at 18:37

Here is a relevent link:
http://www.organic-chemistry.org/synthesis/N1H/reductionsimi...

As you can see, plain imines are not used, an organic amine is usually used to form the imine, which becomes more resistant to hydrolysis, because the resulting condensate then lacks any N--H bonds, and becomes insoluble in the water that is produced.

Using just NH4OH, and doing reduction is likely to give very low yeilds, since the main reaction will be the reduction of free acetone (which dominates in the equilibrium) to Isopropanol, or even further to propane! Since the regents for this are cheap, however, it might be worth investigating, but a basic envirorment is definately required to get any workable equilibrium.

madscientist - 16-9-2010 at 18:43

That is not true - I performed a reductive amination on acetone in methanol/water 50/50 with Al/Hg amalgam and the yields were reasonable. This was 7 or 8 years ago so I can't throw out numbers but it does work and it works well.

A lack of a hydrogen bonded to the nitrogen is not going to pull it out of solution and cause this to somehow effect a reduction only in this case.

Anders2 - 16-9-2010 at 18:52

I meant if you used plain ammonia on a ketone, you would need a high pH, not if you used some other amine to form the imine.

"A lack of a hydrogen bonded to the nitrogen is not going to pull it out of solution"

Yes, but it may likely help the equilibrium. Another example is condensation of H2S with an aldehyde proceeds when the aldehyde has a very low solubility in water, for example PhCH=O

madscientist - 16-9-2010 at 19:31

I very much doubt it's going to have much of an effect on the solubility or the final yield. =NR is still going to be a hydrogen bond acceptor. Anyway, I need to get some sleep - 'night!

Panache - 17-9-2010 at 05:41

you could make nitro isopropane from AgNO2 and isopropyl iodide, this a convenient, easily performed reaction, especially at the multikg level, (anhydrous ether, no UV or visble light etc) then you could reduce the nitro to the amine using your zinc dust or maybe some tin and acid, the workup for this would be so simple, no insoluble crap everywhere at all!!
i should design custom synthesis for living i'm a natural.

Hexagon - 17-9-2010 at 05:41

Quote: Originally posted by mario840

yes but i wonder if this "method" works , amine will form a layer on top (very low density) or what ? if form there will be easy to extract or separate withouth heating , i'm just asking that's all

Yep if iPrOH separates, then iPrNH2 should separate too, better fully saturate the aq. phase with NaCl or something like that thogh. And yes, as long you want small ammounts of this amine, roundup is the way to go, it is the most widely used herbicide and you can find it easy on any farm supply store around the world AFAIK.

[Edited on 17-9-2010 by Hexagon]

madscientist - 17-9-2010 at 06:51

The isopropylamine won't separate, it's miscible in water.

Hexagon - 17-9-2010 at 07:53

Quote: Originally posted by madscientist

The isopropylamine won't separate, it's miscible in water.

True, but isopropanol is miscible in water too and if you saturate the water of that mixture with a salt like NaCl, you'll obtain a biphasic mixture, azeotropic iPrOH being on the top of it (with just a little bit of salt) and brine at the bottom of it (with just a little bit of isopropanol in it) I think it's a safe assumption that isopropylamine will behave similar, or at least it'll be extracted by the IPA.

Even ethanol will salt out with potassium carbonate or ammonium sulfate. Hell, why do I like so much the salting out process?

mario840 - 17-9-2010 at 09:06

so better add alone NaCl to solution or previous saturated aq. solution NaCl and then add to the reaction mixture or it doesn't matter ? But when i extract solution with IPA the first will came out isopropylamine (boiling point much lower then IPA) , so i think why waste of IPA just boil to 40 - 50 C in water bath etc. and evaporate. Another question how to dry this amine ? MgSO4 or Na2CO3 will work ?

mario840 - 18-9-2010 at 03:57

i have also thinking why not isolate glyphosate too , if Roundup is aqueous solution so we need to add 6 M HCl to ph = 3 and we have insoluble in water glyphosate crystals and very soluble in water isopropylamine*HCl , next step is take over water layer and make whole solution base to pH = 10 (with 3M or 6 M NaOH) and amine SHOULD form upper layer in strong base solution (in neutral it is miscieble with water also acidic) if NOT just evaporate amine (32 C) .. so we have 2 chemicals from 1 product and Roundup have very strong product containing up to 45% salt

is this method really possible ??

zed - 24-9-2010 at 22:33

Hunig's base? The method of Heinzelmann might work quite nicely. Requires hydrogenation, but nowadays that is easily achieved, via the method of Brown, using a stir-bar.

Heinzelman produces a methyl-di-isopropylamine, rather deftly from methylamine and two moles of ketone. Should be readily adaptable to large scale synthesis of Hunig's base.

Heinzelman J.Am.Chem. Society 75, 921 (1953)

As I recall, the procedure is given in the above document, though it is possible, it is in a subsequent paper. Sorry, I no longer have the paper on hand.

[Edited on 25-9-2010 by zed]

Lambda-Eyde - 13-12-2010 at 02:46

Quote: Originally posted by Nicodem

You could try using the method described in the Example 1 of FR971429 (reductive amination of cyclohexanone with NH3, using Zn + NiSO4), but having a lower NH3 vs. ketone ratio instead to promote the formation of the secondary amine.

I was unable to locate that patent using Google web search and patent search. Could you provide it for me if you have it?

If I were to prepare monoisopropyl amine, would the method the thread starter proposes work?

I'm thinking of using acetone, water, zinc dust, Ni++ and HgCl2 catalysts, and an ammonium salt in aqueous solution. But I'm not sure if it would work; if the process calls for free ammonia, a strong base would be needed. However, that would also precipitate the metal salts. I suppose if an ammonium salt would work, aqueous ammonia would be just as good.

However, this is all speculation based on the thread starter's assumptions and partly on what I know from the description of the patent you mentioned. Is there anything to it?

Quote: Originally posted by madscientist

You're likely aware of this, but aluminum amalgam does the trick. Dab a bit of HgCl2 on aluminum foil and drop it into the solution of acetone and ammonia. Your house will smell like a dead whale.

Does this eliminate the need for the nickel catalyst? If this is a simple preparatory procedure, my only concern will be the work-up.

Quote: Originally posted by Eclectic

Ideal system would be water, acetone, ammonium chloride, and a dissolving reactive metal, with or without nickel..., scrap aluminum turnings would be great if it works, but I have zinc dust. I was just asking if anyone has actually DONE it, or has actual prep procedure.

Quote: Originally posted by madscientist

That is not true - I performed a reductive amination on acetone in methanol/water 50/50 with Al/Hg amalgam and the yields were reasonable. This was 7 or 8 years ago so I can't throw out numbers but it does work and it works well.

Was this the mono- or diisopropylamine? Is the methanol crucial to the reaction, and could ethanol fit as a substitute? Do you remember how you performed the work-up?

Does anyone have an actual paper on this reaction, and not just anecdotes and patent references? Thanks.

madscientist - 13-12-2010 at 05:32

Sorry, I don't recall, it's been too long.

solo provided a paper a while ago detailing reductive amination using nothing but 10% NaOH and zinc dust to effect the reduction. Might be worth a try since the reagents are cheap.

Nicodem - 13-12-2010 at 14:38

Quote: Originally posted by Lambda-Eyde

I was unable to locate that patent using Google web search and patent search. Could you provide it for me if you have it?

You should search patents where they are supposed to be and not in secondary sources. The obvious place for a French patent is the European patent office site.

Quote:

I'm thinking of using acetone, water, zinc dust, Ni++ and HgCl2 catalysts, and an ammonium salt in aqueous solution. But I'm not sure if it would work; if the process calls for free ammonia, a strong base would be needed. However, that would also precipitate the metal salts. I suppose if an ammonium salt would work, aqueous ammonia would be just as good.

I don't see what role would HgCl2 have there. The electrons are transferred from Zn to Ni and from there to the imine, so you don't need any amalgamation of Zn as this would allow direct transfer of electrons from Zn to the organic substrate and this would be counter productive in regard of imine vs. ketone chemoselectivity.
I also don't understand what do you mean by "precipitate the metal salts" in regard to ammonia. Which metal salt would be precipitated by ammonia and why? Ni(II) surely would not as ammonia is a good ligand for Ni2+ cations, Zn is metallic, while Hg(II) was never suggested originally anyway.
Besides, ammonium salts of strong acids are nonnucleophilic so they can't form imines until they are neutralized first.

Quote:

However, this is all speculation based on the thread starter's assumptions and partly on what I know from the description of the patent you mentioned. Is there anything to it?

Yes, don't bother with speculations when you have no reason to do so. Just follow the instructions of the patent. It was tested on cyclohexanone and it gives amines from it, so it is not worthless.

Quote:

Quote: Originally posted by madscientist

You're likely aware of this, but aluminum amalgam does the trick. Dab a bit of HgCl2 on aluminum foil and drop it into the solution of acetone and ammonia. Your house will smell like a dead whale.

Does this eliminate the need for the nickel catalyst? If this is a simple preparatory procedure, my only concern will be the work-up.

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.
I don't really understand your question about nickel catalyst. There is no Ni involved here. This is a different reduction system.

Quote:

Does anyone have an actual paper on this reaction, and not just anecdotes and patent references? Thanks.

As far as I know there is something on Ni/Zn couple for reductive aminations in the scientific literature as well, though perhaps there is much less written about it when compared to the Ni/Al couple. In any case, it is always wise to do a literature search before engaging in any experimental work.

Magpie - 15-3-2012 at 19:04

I have extracted isoproylamine from Shore-Klear, an aquatic variant of the herbicide Roundup. I selected an aquatic variant vs Roundup as these do not contain a surfactant. Whether or not this is important I do not know, it just seemed prudent.

I tested my process on 5mL up to the distillation step and it seemed successful so then proceeded to a 100mL batch. My procedure consists of 4 steps:

1. Acidify with ~75 mL of 6N HCl. This causes the insoluble gyphosate to precipitate as a heavy (sp gr 1.7) white solid. The isopropylamine (IPA) hydrochloride stays dissolved in the clear aqueous supernate.

2. Separate the glyphosate from the IPA HCl by use of a separatory funnel. Recover more IPA HCl from the glyphosate fraction by centrifugation. Discard the glyphosate.

3. Basify the clear supernate with about 65mL of 6M NaOH. The IPA is now dissolved in the water as a free base. You will know this by the smell. It is important if not essential that you do this outside or in a good hood because of this smell.

4. Distill over the IPA (bp 33-34C) using a fractionation column. I used broken glass packing as I have seen several references to IPA reacting with metals. Much to my surprise there is no azeotrope and the distillation is easy with the stillhead thermometer locking on at 33-34C.

Yield = 13.4g, or 19.4mL. %yield = 76.0%. (Basis = 105mL).

My plan was to use stoichiometric amounts of HCl and NaOH, but due to a calculation error I used quite a bit more than that. I suspect that stoichiometric amounts would have worked just as well. My choice of molarities was arbitrary.

Experimenting with salting out using NaCl did not yield a phase separation of IPA and water. IPA is miscible with water, alcohol, and ether. That is the reason I went to distillation. I had also read an article in I&EC describing an industrial separation using distillation.

[Edited on 16-3-2012 by Magpie]

[Edited on 16-3-2012 by Magpie]

[Edited on 17-3-2012 by Magpie]

Magpie - 19-3-2012 at 09:38

I thought I should post the results of further experimentation in the isolation of isopropylamine from Shore-Klear (re: previous post).

The basis for my last batch was 200mL of Shore-Klear. A stoichiometric amount of 6M HCl was used. This brought the pH to ~5. The resulting ppt of glyphosate settled well, better than before. This was easily removed by Buchner vacuum filtration, so no need for any tedious centrifugation. Yield was about the same, ie, 72%.

The waste byproduct glyphosate could be recovered as a very nice white solid, probably quite pure. Does anyone know of any use for this in mad science?

Glyphosate-2D-skeletal.png - 4kB

glyphosate

Dr.Bob - 20-3-2012 at 08:16

Quote: Originally posted by Magpie

The waste byproduct glyphosate could be recovered as a very nice white solid, probably quite pure. Does anyone know of any use for this in mad science?

You could use it to kill some weeds near your science laboratory? :-)

Not much that I can think of to do with it other than that.

Scr0t - 20-3-2012 at 15:08

Quote:

I have extracted isoproylamine I selected an aquatic variant vs Roundup as these do not contain a surfactant. Whether or not this is important I do not know, it just seemed prudent.

The surfactant(s) do not appear to matter. I used Round-up Biactive 360 (more expensive but it's what I had to hand).
I simply distilled a 50% NaOH solution with the Round-up (100% excess of NaOH) and dried the distillate over an equal volume of NaOH before re-distilling to yield ~80% iPrNH2.
No problems with foaming... pretty straight forward.

Magpie - 20-3-2012 at 15:47

Quote: Originally posted by Scr0t

I also thought that it might not be necessary to remove the glyphosate first. It's good that you have verified what is likely the most simple method. What was your yield?

AndersHoveland - 26-5-2012 at 02:33

Another simple route to making isopropylamine is the Leuckart–Wallach reaction, where acetone is made to react with ammonium formate.
http://en.wikipedia.org/wiki/Leuckart%E2%80%93Wallach_reacti...

Adas - 26-5-2012 at 06:07

Quote: Originally posted by AndersHoveland

Another simple route to making isopropylamine is the Leuckart–Wallach reaction, where acetone is made to react with ammonium formate.
http://en.wikipedia.org/wiki/Leuckart%E2%80%93Wallach_reacti...

Shame that I only have ammonium acetate :/

barley81 - 26-5-2012 at 06:34

Formic acid can be bought for $12 a liter from Dudadiesel. React with standardized ammonia, and you're set!

ciro - 26-5-2012 at 06:38

Maybe it works by reducing the imine formed by acetone and ammonia with sodium borohydride in acetic acid.
This paper: http://www.erowid.org/archive/rhodium/pdf/nabh4.carboxylic.a... in 2.2. N-Alkylation of amines, describes the alkylaton of aniline to give N-ethylaniline, but also with acetone and a variation in the conditions (temperature), it gives N-isopropylamine.

[Edited on 26-5-2012 by ciro]

Diisopropylamine via Isopropylamine alkylation

Scr0t - 28-8-2013 at 13:07

16.8g iPrNH2 and 43g iPrBr (1.2 eq) in 100ml IPA was refluxed for 36hrs.
Crystals began to form in the hot solution at about 15hrs.

About 25ml of liquid was distilled off removing some left over iPrBr/iPrNH2. After cooling the solids were filtered, rinsed with a little IPA and air dried to yield Diisopropylammonium bromide as white platelets (61% based on iPrNH2).

Evaporation of the filtrate gave a couple grams more of the product.

Treatment of the salt with strong NaOH solution followed by separation and distillation yields the free-base.

The iPrNH2 used was extracted from Roundup.

The Taiwanese reference given by Entropy51 in
https://www.sciencemadness.org/whisper/viewthread.php?tid=12416&page=2#pid155929

involved reflux for a shorter time (15hrs) in EtOH and obtained a 43% yield.

----------------

Several attempts to use a Zn-Ni couple in a similar fashion to
FR971429 to prepare this secondary amine from Acetone gave no workable amounts even when adding an excess of iPrNH2 into the reaction rather than in-situ generation with NH3.

I've had no success isolating secondary amines using this reagent.