Sciencemadness Discussion Board

Reductive amination and water

Geomancer - 29-4-2004 at 16:47

Reductive aminations are usually thought to proceed through reduction of an imine. But imines are easily hydrolysed. In general, what effect does the concentration of water have on the rate of reaction? Can one routinely use aqueous ammonia for primary amines? Are molecular sieves worthwhile?

Rhodium's site has a report that water has litttle effect on a certain class of compound (three guesses), but did not extend that observation to any other compounds. In particular, I'm somewhat interested in isopropylamines from acetone.

Trolf - 1-5-2004 at 01:20

I have thought about making this reaction too, but yes imines are very much sensitive to the pressence of water.

think u would have to use:
1. gaseous ammonia
2. A good compound to remove water from the reaction as it is formed from the reaction (MgSO4 ex.)

My question would be how do u reduce the imine (with something easily accessible)?

imine reduction

antibond - 23-11-2004 at 11:39

Problems during imine formation when water is present probably has alot to do with how highly substituted the ketone is and that is why silical gel and mol sieves are used during this step especially with usnsubbed ketone. Avoid polymerization by removing water and keeping the reaction cold during imine formation (0-5c) and reduction. Realize this runs contrary to popularized methods with unsubbed ketone but colder is better. Also, reduction via hydrogenation may be different in that water may not have to be removed (friefelder). But hydrogenation isn't a popular method for non-professionals. Using ammonia during imine formation is low yielding compared to monomethylamine. Have no idea how water affects the rate of the reaction but my guess would be that it wouldn't make too much of a diff. with desirable ketones.

Organikum - 24-11-2004 at 02:50

It depends on the method of imine reduction and the substrate.

Reduction with activated aluminium needs water to proceed, but usually gives results not better than 30% with unsubstituted substrates and ammonia in water, somehow better with substituted substrates like hydroxyphenylacetones which form stable, not easily hydrolized imines.

Ammonia in methanol with Rayney nickel under pressure of 40-100atm in a autoclave gives yields of 90%+. Without water is understood.


A good alternative is the Leuckard with ammonium formate and without any solvent done in the microwave. Fast and high yielding at least at a small to medium scale. Yields of 80% have been achieved with household microwaves, the dreaded "red tar" which made the Leuckard so unpopular for many was almost not present.

[Edited on 24-11-2004 by Organikum]

Mendeleev - 2-12-2004 at 22:34

This is very interesting, could you please elaborate on this leuckhard?

Edit: About catalytic hydrogenations, there is a patent, which has dissapeared from the US patent office website which details a catalyst which could potentially bypass the need for fancy and expensive catalysts made with rare metals like platinum, palladium, and rhodium. It is made by reacting copper sulfate pentahydrate with barium or calcium hydroxide to get a catalyst consisting of cupric oxide, and calcium or barium sulfate. The patent is US No. 2,828,343, but like I said, I couldn't find it on the website. I would like to know what kinds of pressures this catalyst requires andhow much of it is needed per mole of imine reduced.

[Edited on 3-12-2004 by Mendeleev]

Organikum - 3-12-2004 at 01:25

You find information on the microwave Leuckard on Rhodiums page, best you dl the .rar archive of Rhodiums page which mephisto uploaded to the ftp to look for this.

There have been several posts on the HIVE regarding this, I will look if I have them on disk somewhere and post it.

Your patent is here

[Edited on 3-12-2004 by Organikum]

ballzofsteel - 3-12-2004 at 02:47

Hi Org,

Cherry baby mentions a monomode microwave reactor in the post on Rhodiums.Did you modify your oven in any way?What Wattage used.?

Mendeleev - 3-12-2004 at 08:05

Crap, the CuO/CaSO4/BaSO4 catalyst requires 100 atm and 160 C, not very realistic.

Organikum - 3-12-2004 at 08:41

Hi bally! ;)

Read the original article and look at the amounts processed. The authors do some minimols in a 60W monomode micro.

Now you can easily see that interesting amounts are well to do in a 750W household-oven.
If the power is to much, some glassses with water scavenge a lot of MW-energy.
No monomode is needed, actually this monomode thingie is fairly overrated, mostly by those who dont know what it is.

micro?

antibond - 3-12-2004 at 08:52

what is a monomode micro?

Organikum - 3-12-2004 at 09:08

A microwave operating in monomode instead of multimode as standard household microwave ovens do.

Mendeleev - 3-12-2004 at 14:13

I already have Rhodium's archive, but the only thing about leuckart that I found was a very general article, which said it was the reduction of formamides or ammonium formate salts with a carbonyl compound. This seems very easy and versatile, given that formamide can have various groups subsituted to the amine part. However no microwave, do you perchance recall the title of the article? Or maybe it was a thread?

Ref: Microwave chemistry

solo - 3-12-2004 at 14:20

Here is something on the subject.....solo

http://home.ripway.com/2004-11/211899/amicrowaveofgooduseinc...

Mendeleev - 3-12-2004 at 15:00

Does the leuckart give better yield with formamide or ammonium formate?

Organikum - 4-12-2004 at 00:33

The standard Leuckard with formamide is haunted by the production of the dreaded "red tar". Ammonium formate seems to be better but yields generally dont exceed 50%, there was a post of antoncho on the HIVE where yields of 95% were claimed, but nobody seemed to be able to reproduce this. :(

formic %

ballzofsteel - 4-12-2004 at 07:49

I know I should know...but my memory fails me.

Is 70+-% formic acid, like the homemade stuff, useable in such a Leukart,
seeing as these hydroxyketones form stable imines and all?
This would be nice, as formic is hard for me to aquire.
If not (sorry to stray off topic btw)any tips on dehydrating 70%?



THis is practice not only theory yeah?
The Luekart on PAc I mean.
This would be fantastic!
Amination being the missing link and all...:(

Cheers.

[Edited on 4-12-2004 by ballzofsteel]

Mendeleev - 4-12-2004 at 13:48

You don't actually use formic acid in the leuckard, you synthesize ammonium formate or formamide. Bubbling ammonia or mixing an amine with formic acid should form the ammonium formate, after that, just boil away the water under vacuum or something. I believe 88% formic acid is obtained by fractional distillation under vacuum, but I don't know the exact vacuum/temperature this should be done at, so does anyone here know?

Edit: Why does the red goo form?

Edit2: If I have a supplier of formic acid, is there any risk in ordering it? It's not scheduled as a precursor, but it was mentioned that it is watched on Rhodium, so what do you risk by ordering it?

[Edited on 4-12-2004 by Mendeleev]

[Edited on 4-12-2004 by Mendeleev]

ballzofsteel - 4-12-2004 at 17:26

Thanks Mendeleev .The Leukart-Wallach then:D

Organikum - 5-12-2004 at 00:18

The red tar is polymerisation products - the temperatures in the Leuckard are rather high.

Formic acid is watched.

Al/Hg under pressure with alcoholic ammonia gives decent yields on l-PAC. (ammonia in denat. alc. is ok)

question about preparing the needed reagents

Mendeleev - 5-12-2004 at 11:11

Can the ammonium formate or alkylammonium formate in a leuckart be prepared by simply adding store-bought 5% ammonia solution to acqueous formic acid, then boiling off the water? Or does the reaction have to be dry? Also, is purity a huge concern with the leukart? How pure does the ketone have to be?

[Edited on 5-12-2004 by Mendeleev]

S.C. Wack - 5-12-2004 at 13:06

From what I've read, no, it isn't that easy. Perhaps you could get the formate to precipitate with addition of acetone to conc. soln. But IMHO the most practical way to make this (and the acetate) is by adding ammonium carbonate to the dry acid.

It isn't difficult to purify (methyl) ketones as you know, so might as well.

Mendeleev - 5-12-2004 at 14:49

Why won't the method using dilute acid and amine work? Is it because formic acid is not a srong enough acid? I know that mixing 5% ammonia with HCl yields ammonium chloride on evaporating. This is the experimental procedure for the leuckart, given in a 1939 JACS article:



In a distilling flask fitted with a cork bearing a thermometer extending nearly to the bottom is placed 4 moles of alkylammonium formate prepared by adding the proper amine to cold formic acid. The temperature is raised slowly to 180-190°C and this temperature maintained as long as water distils. After cooling, 1 mole of ketone is added and the mixture heated until boiling begins; water, carbon dioxide, and amine distil and are collected in concentrated hydrochloric acid. In case any ketone distils over, it is returned to the flask at intervals. The temperature of the boiling mixture is 190-230°C, which is maintained for four to eight hours, after which the mixture is cooled and diluted with 3-4 volumes of water, giving oily and aqueous layers. The aqueous layer, mixed with the hydrochloric acid used in collecting the distilled amine, is concentrated to give the hydrochloride of the excess of amine used. The oil is refluxed for several hours with 150-200mL of hydrochloric acid per mole of ketone taken, and after the hydrolysis is complete water is added, the solution filtered through moist paper to separate resinified material and the filtrate, if not clear, extracted once or twice with ether. In some experiments the amine hydrochloride crystallizes on cooling. The aqueous solution is made alkaline with ammonia, extracted with ether, the ether solution dried with sodium sulfate and saturated with hydrogen chloride to give the amine hydrochloride. The product is purified further by dissolving in absolute alcohol and precipitating with absolute ether.



It says the alkylammonium formate was prepared by adding the proper amine to cold formic acid, does that mean they had to use anhydrous formic acid and anhydrous amine, or did they use something to catalyze the reaction?


Edit: Just found this posted in the preparation of cyanides thread by madscientist:

"PREPARATION OF AMMONIUM FORMATE ( [HCOO-][NH4+] )
Formic acid is added to an aqueous solution of ammonia ( [NH4+][OH-] ). The remaining solution is evaporated; the crystals left are ammonium formate crystals. Crystals should weight about 64 grams if you have been achieving 100% yields. "

[Edited on 5-12-2004 by Mendeleev]

Ref: Water and reductive alkylation

solo - 5-12-2004 at 18:02

I would say got to the hive and read bariums work on the use of water......I however found the 64 posts on the matter so read about it......solo



[Edited on 6-12-2004 by solo]

Attachment: a really wet redfuctive alkylation (barium).html (205kB)
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S.C. Wack - 5-12-2004 at 20:17

If anyone has a chemistry book, encyclopedia, or journal that says that the normal ammonium formate or acetate can be crystallized by evaporation from dilute ammonia solutions + acid, I'd love to see it.

Solutions of the formate or acetate lose significant amounts of ammonia in air. The more water to evaporate and/or the higher the temperature, the more ammonia is lost. Some of the acid volatizes as well. So you get a solution of acid salt. Both the acid and normal salts are very soluble in water.

Even when made from a more concentrated ammonia solution, the yield of normal formate crystallizing out of the acid formate sol'n is low. If you try to make the acetate from vinegar and grocery store ammonia you may have a hard time getting anything to crystallize.

In industry, NH3 or ammonium carbonate is added to the concentrated sol'n of acid ammonium formate.

PS - AFAIK all journal preparations of the last 100 years use NH3 on the acid to produce a crystalline product. Before that, I doubt that anything but an ammonium carbonate or NH3 was used.

[Edited on 6-12-2004 by S.C. Wack]

Mendeleev - 6-12-2004 at 13:21

Okay then, thanks, that helps a lot! To me formamide would be a better candidate, but could someone please tell me more about this red goo? What conditions cause it and can it be avoided?. Aslo would this amination work with halogen derivatives of carbonyl compounds, such as chloroacetone? And if it did work with chloroacetone, would it be possible to use that amino chloroacetone in a friedel crafts alkylation?

[Edited on 6-12-2004 by Mendeleev]

Baphomet - 3-4-2009 at 18:12

Quote: Originally posted by S.C. Wack  
If anyone has a chemistry book, encyclopedia, or journal that says that the normal ammonium formate or acetate can be crystallized by evaporation from dilute ammonia solutions + acid, I'd love to see it.


I know this is an old thread but this week I had some first hand experience and thought I'd share.

Ammonium Acetate left nothing at all, even upon evaporation out of direct sunlight. It is a phantom above all phantoms ;)

On the other hand it was possible to concentrate a solution of Ammonium Formate over a water bath. Upon cooling, clumps of needle-like crystals appeared spectacularly. This was placed in a dessicator for further drying.

Cheers..

Baphomet - 13-4-2009 at 19:05

As a follow-up to the last post:

After a week in the dessicator with plenty of CaCl2, the crystals are still not dry.

Should I conclude that this dessicant is not particularly strong, and another should be sought?

Strangely the Amm. Formate crystals 'climbed' up the side of the container, spreading further over time.

If someone knows the best way to dry this, please share it :D

chemrox - 13-4-2009 at 21:38

This thread started with a question about water removal during imine formation involving a ketone. I've made them in toluene with a Dean Stark to remove the water and let me know when the reax was complete. A crystal or two of P-toluene sulfonic acid and 48-72 hours were needed. I have to add that I was using anilines and believe that ammonia and Meam may be harder to work with. Then there was a digression regarding the Leukart and the statement was made that formic acid is a watched compound. I wish people would state what country when they say things like that. I'm in the US where formic is not watched. However there's a group that thinks everything here is watched including LAH.

Paddywhacker - 14-4-2009 at 01:26

Quote: Originally posted by Baphomet  
As a follow-up to the last post:

After a week in the dessicator with plenty of CaCl2, the crystals are still not dry.

Should I conclude that this dessicant is not particularly strong, and another should be sought?

Strangely the Amm. Formate crystals 'climbed' up the side of the container, spreading further over time.

If someone knows the best way to dry this, please share it :D
Ammonium formate widd dissociate, giving off ammonia that will react with calcium chloride. Maybe replace the CaCl2 with NaOH crystals.

solo - 14-4-2009 at 18:31

Quote: Originally posted by Mendeleev  
This is very interesting, could you please elaborate on this leuckhard?

Edit: About catalytic hydrogenations, there is a patent, which has dissapeared from the US patent office website which details a catalyst which could potentially bypass the need for fancy and expensive catalysts made with rare metals like platinum, palladium, and rhodium. It is made by reacting copper sulfate pentahydrate with barium or calcium hydroxide to get a catalyst consisting of cupric oxide, and calcium or barium sulfate. The patent is US No. 2,828,343, but like I said, I couldn't find it on the website. I would like to know what kinds of pressures this catalyst requires andhow much of it is needed per mole of imine reduced.

[Edited on 3-12-2004 by Mendeleev]



.....maybe missing but not lost....



Attachment: pat02828343.pdf (353kB)
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Baphomet - 25-4-2009 at 01:01

Quote:
Ammonium formate widd dissociate, giving off ammonia that will react with calcium chloride. Maybe replace the CaCl2 with NaOH crystals.


Correcto! The slush smells like formic acid. I had previously considered that such a reaction could take place, and did not think it so, but you are right.

I'll try NaOH.. thanks for the suggestion.

[Edited on 25-4-2009 by Baphomet]

jon - 9-11-2009 at 15:42

A good compound to remove water from the reaction as it is formed from the reaction (MgSO4 ex.)


wrong mgso4 complexes amines have fun with that expiriment!

Organikum - 10-11-2012 at 03:47

Quote: Originally posted by jon  
A good compound to remove water from the reaction as it is formed from the reaction (MgSO4 ex.)

wrong mgso4 complexes amines have fun with that expiriment!


Strangely Merck does not mention this, says MgSO4 is suitable for virtually about everything. I personally also don't think it is so strong acidic that it complexes with amines, but what do I know. But maybe carbonates are better if much slower. Molecular sieves gave ME the impression that they make amines stick to it, but thats subjective.



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Sydenhams chorea - 10-11-2012 at 15:40

As mentioned before, much depends on the stability of the imine. In this experiment I obtained 35% yield of 1-dimethylamino-1,2-diphenylethane from the reduction of the enamine of desoxybenzoin and dimethylamine using activated aluminium. The ketone and amine were stirred for 2 hours without removal of water, as the presence of some water is needed for the subsequent reduction. Perhaps more time should be given to allow for the formation of the enamine.