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Author: Subject: Synthesis of cyclohexylamine (via FR971429)
Scr0t
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[*] posted on 16-5-2012 at 01:07
Synthesis of cyclohexylamine (via FR971429)


I attempted the synthesis of Cyclohexylamine from the French patent 971429 as suggested by Nicodem in the isopropylamine thread which uses a Zn-Ni couple to effect the reductive amination of Cyclohexanone.

In a 500ml RBF 9g NiCl2·6H2O was dissolved in 160g 20% NH3, 30g Cyclohexanone was added with Mag. stirring followed by 50ml 95% EtOH to aid dissolution.

20g of Zn powder was added with vigorous stirring, Temp. rose to 25°C (ambient Temp. 19°C) with evolution of H2.

15mins after the 1st addition a 2nd 20g portion of Zn was added, Temp. rose to 32°C after 30mins and a 3rd 20g portion was then added.

When Temp. reached 49°C a cool water bath was briefly used to moderate the reaction, aimed to keep Temp. <50°C.

The reaction was allowed to stir keeping Temp. 30-40°C with heating as it began to subside. H2 evolution had nearly stopped after a total reaction time of 5.5hrs.

The mixture was filtered and solids washed with H2O. The filtrate and combined washings (~400ml) were refluxed to allow recovery of NH3, white solids were deposited.

The remaining solution was acidified with HCl and boiled down to ~200ml removing the EtOH and a small amount of Cyclohexanol.

It was then basified with NaOH that salted out the alkaloids, this was distilled to collect the Cyclohexylamine azeotrope bp 96.4°C 44.2% /w. The clear distillate was treated with a few grams NaOH, separated, dried over solid NaOH and distilled through a short column at atmospheric pressure (133-137°C) yielding 22.0g of a clear colorless liquid, yield 73% Cyclohexylamine.

Notes:
The salted-out alkaloids contain an appreciable amount of dissolved NH3.

Extraction can be done more simply by salting out directly from the filtered reaction medium and separating. Use of DCM in an attempt to extract the remaining aqueous portion gave me an emulsion.

Adding the 2nd and 3rd portions of Zn powder at longer intervals (e.g. the 2nd portion at 30mins and the 3rd after 2hrs) gave a slow reaction (Temp. did not exceed 25°C) which resulted in a lower yield. Unreacted Cyclohexanone was detectable during workup.



FR971429.png - 108kB
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[*] posted on 16-5-2012 at 02:30


Nice work.
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[*] posted on 18-5-2012 at 14:39


I thought it interesting so I thought I'd report on it.

I performed another run on this reaction and I simply changed the addition time of the Zn portions so that they were separated by a 10min interval.

The reaction proceeded faster as expected but abruptly ended at only 1-1.5hrs (based on visible H2 evolution) and not t 5.5hrs that I reported earlier. Reaction Temp. did not exceed 43°C this time but then ambient Temp. was 12°C and so did not require external cooling.

Solids obtained after NH3 recovery were pale green this time (probably Nickel hydroxide).
Yield was 84% Cyclohexylmine
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[*] posted on 19-5-2012 at 01:36


Thank you for the contribution. I split it from the thread where you originally posted it, because it was out of place in that demented discussion in the Cyclohexylamine thread. The mentioned thread where the patent was cited is Isopropylamine and Diisopropylamine from Acetone. The other recent thread on the synthesis of cyclohexylamine is the wet aminative reduction thread. The synthesis of cyclohexylamine according to FR971429 was otherwise also reported by Antoncho at The Hive forum, with a similar yield, but on the crude non-distilled product, if I remember correctly.



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[*] posted on 24-5-2012 at 09:57


I applied the same or similar procedures described above to a few simple ketones and the results have been comparatively poor.
MEK yielded only 29% sec-Butylamine after purification and similar results were obtained for the primary amines corresponding to MIBK and Acetone.
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[*] posted on 24-5-2012 at 21:22


I find it strange that acetone gives a significantly lower yield than cyclohexanone. Have you tried substituting the ammonia for a batch of the cyclohexylamine, with the aim being to make dicyclohexylamine. I guess theres always the leukart reduction, and it probably works out about the same economy wise (Zn might even be more expensive than formic acid?, definately so on a mol for mol basis.)
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[*] posted on 3-6-2012 at 12:32


No I haven't tried making Dicyclohexylamine. I did try changing the NH3 to Acetone ratio to favor more production of Disopropylamine although none could be isolated either due it not being present or too small for me to isolate even though I scaled up the reaction by a factor of four.

The patent gives examples of two oximes that were reduced in 80%+ yields but does not give any experimental details. I will probably improvise something in the near future and apply it to MEK.
I expect the presence of NH3 would still be required as a convenient base for this reaction to proceed, I have read that K2CO3 is used in cases where NH3 causes problems e.g. forming insoluble complexes with the reaction products.
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[*] posted on 23-6-2012 at 18:37


That is very interesting.

I am looking to prepare 3-phenylpropylamine from cinnamaldehyde oxime, and this looks like a solid preparatory method. According to the patent, the Ni-Zn couple will reduce both oximes and double bonds.

What are the reaction specifics between the zinc and the ammonia-H2O? Is the zinc oxidized to a zincate anion (ammonium zincate?) by the alkaline solution?

Quote: Originally posted by Scr0t  

I expect the presence of NH3 would still be required as a convenient base for this reaction to proceed, I have read that K2CO3 is used in cases where NH3 causes problems e.g. forming insoluble complexes with the reaction products.


It might be worthwhile to supplement weaker ammonia solution with another base, like Na2CO3.

[Edited on 24-6-2012 by manimal]
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[*] posted on 26-6-2012 at 12:44


Quote:
What are the reaction specifics between the zinc and the ammonia-H2O? Is the zinc oxidized to a zincate anion (ammonium zincate?) by the alkaline solution?

I don't know.
However most of the Zn is oxidized to a water insoluble dark-grey powder that I suspect is oxide/hydroxide contaminated with metallic Ni and a relatively small amount of a Zn ammine complex is probably formed which precipitates as the oxide/hydroxide after boiling off the NH3.

Ni is also present as the ammine complex as evident by a violet color which often persists after the reaction is complete.
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[*] posted on 17-10-2012 at 03:39


how about desulfonation of cyclamate, has anyone ever tried that route? i can't find any info, except about intestinal bacteria being able to accomplish this.
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[*] posted on 6-8-2013 at 10:41


Sorry for digging up this old thread, but I just had to ask something I didn't notice before.

Did you use magnetic stirring through the whole procedure? Was there any problems with metallic nickel sticking to the magnet, or is the nickel actually not in metallic form during the procedure?

When forming Urushibara nickel from Zn/NiCl2 you have to use mechanical stirring, so if you can use magnetic stirring with this "variation", it suddenly seems much more convenient!
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[*] posted on 11-8-2013 at 11:22


Yes Mag. stirring was used throughout and it worked fine for this scale of the reaction.
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[*] posted on 26-9-2019 at 09:26


Necroposting!

Thanks to Scr0t and Corrosive Joeseph, I tried this reaction on several substrates, mostly with great success.
I tried it on the following substrates, mostly just once: acetophenone(55% yield), P2P(70,5% and 84% yield), isonitrosopropiophenone(76% yield) and P2P oxime(71% yield).

I really like this reduction/reductive amination method, it is neat and cheap and good yielding.

Edit: attached a picture of the wonderful blue color of nickel acetate dissolved in ammonia :)
The tiny supernatant is composed of 50g of acetophenone, about to be aminated.

blue ni-zn nh4oh.jpg - 110kB

[Edited on 26-9-2019 by karlos³]
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[*] posted on 18-5-2020 at 19:41


Cool. :cool:

[Edited on 19-5-2020 by ChemistryGhost]




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