Sciencemadness Discussion Board

The synthesis of primairy amines -> NH2OH.HCl + ketone

KiWiki - 3-4-2019 at 10:00

I have made a monoaromatic ketone and I wonder how to make a primairy amine. I decided to give hydroxylamine.HCl a chance and further reduction with Fe/HCl or maybe Zn/HCl might work but I'm not sure if the latter is able to reduce the corresponding hydroxylamine with dissolving metal reductions ?

There are 2 procedures, the DIRECT and INDIRECT method. If you had the chance, which one should you choose and why?

Procedure 1
12.5 g of hydroxylamine hydrochloride is dissolved in 20 ml of water and the solution is placed in a 100 ml conical flask.
7 g of powdered sodium hydroxide dissolved in 20 ml of water, is added to previously prepared hydroxylamine hydrochloride solution. During the addition of sodium hydroxide the solution of hydroxylamine hydrochloride is cooled in ice-water.
It is important that the sodium hydroxide must be accurately weighed out, for an excess will dissolve the acetone oxime.
A thermometer is placed in the mixed solution, and when the temperature drops to 5-10° C 9.5 g (or 12 ml) of dry acetone are added with stirring in small quantities so that, the temperature does not rise above 15° C. The acetone oxime usually starts to crystallize when about half the acetone has been added. When the addition is complete, the mixture is allowed to stand in ice-water for additional 15 minutes.
The solution is filtered and the crude acetone oxime is collected, yielding 12-13 g of crystalline product. The acetone oxime so obtained contains the small amount of sodium chloride, but is otherwise almost pure for the most synthesis purposes. Crude acetone oxime is purified by crystallization from petroleum ether (with boiling point 60-80° C) or cyclohexane. The acetone oxime is freely soluble in water and in most organic liquids.
Ref Practical organic chemistry, by F. G. Mann, 8, 1960


Procedure 2
In a 2-gallon (8-l.) wide-mouthed bottle (Note 1) packed in ice-salt mixture are placed 630 g. (8.7 moles) of commercial (95 per cent) sodium nitrite and 5 kg. of chopped ice, and the mixture is well stirred. A cold (0–5°) solution of sodium bisulfite, made by saturating with sulfur dioxide a solution of 495 g. (4.7 moles) of anhydrous sodium carbonate in 1500 cc. of water, is now added slowly with hand stirring. When all is in, a sufficiently large quantity of the ice will have melted to allow a mechanical stirrer to be fitted. A stream of sulfur dioxide is now passed in, with continual stirring, the temperature being kept at 0–2°, until an acid reaction to Congo red paper is obtained and the dark color, which appears just before the reaction is complete, has faded. During the addition of the sulfur dioxide, 500 g. more of ice may be added.

The mixture is now transferred to a 12-l. flask, 495 g. (625 cc., 8.5 moles) of acetone is added, and the solution is heated on the steam bath to 70°. Heating is then discontinued, the flask wrapped in burlap in order to retard loss of heat, and the mixture allowed to stand overnight. The acid is then neutralized with a concentrated (50 per cent) solution of sodium hydroxide (about 720 g. of alkali is required), until a distinctly alkaline reaction to litmus is just obtained.

The resulting acetoxime is now distilled in a current of steam (Note 2), and the distillation is continued until a 5-cc. sample, shaken with 2 cc. of ether, yields no appreciable residue on evaporating the ether.
Ref. Org. Synth. 1923, 3, 61Org. Synth. 1923, 3, 61

[Edited on 4-4-2019 by KiWiki]

chemplayer... - 18-4-2019 at 01:01

We tried both (you can find both in our Bitchute video archive https://www.bitchute.com/channel/chemplayer/) and to be clear, if you have access to hydroxylamine hydrochloride then this is by far the easiest way to proceed. You can literally do the reaction and have your oxime intermediate crystals sitting on the bench in 30 minutes:

https://www.bitchute.com/video/tSWTVkuxUVR0/
https://www.bitchute.com/video/IOLOcSFtgYuq/

Do note however that reduction of the oxime to the amine we found to be not so easy, with lots of potential reducing agents not working or possibly only partially reducing to a substituted hydroxylamine.

qt314 - 22-4-2019 at 21:16

Ketoximes may be prepared with ease using hydroxylammonium salt and sodium acetate as base in refluxing methanol. Usually 1 hour reaction time is sufficient for most ketones.
See - https://www.erowid.org/archive/rhodium/chemistry/mdaoxime.ht...

Benzylic oximes will be reduced by fe, zn and hcl. They are easier to reduce then aliphatic oximes. However, forcing conditions are required (long rxn times, reflux, excess of reagents).

In my experience the best route to primary amines from ketones is the reductive amination with ammonium formate and pd/c (tetrahedron 28, p5669). 5-10 eq. of ammonium formate, 10weight% pd/c, in 9:1 meoh:h2o.
Ammonium acetate may be used as supplementary amine source, reducing required ammonium formate (3 eq. ammonium formate, 3-6 eq. ammonium acetate).

This reaction never failed for me.

KiWiki - 30-4-2019 at 06:11

Quote: Originally posted by chemplayer...  
We tried both (you can find both in our Bitchute video archive https://www.bitchute.com/channel/chemplayer/) and to be clear, if you have access to hydroxylamine hydrochloride then this is by far the easiest way to proceed. You can literally do the reaction and have your oxime intermediate crystals sitting on the bench in 30 minutes:

https://www.bitchute.com/video/tSWTVkuxUVR0/
https://www.bitchute.com/video/IOLOcSFtgYuq/

Do note however that reduction of the oxime to the amine we found to be not so easy, with lots of potential reducing agents not working or possibly only partially reducing to a substituted hydroxylamine.


Thanks a lot!
I did read it somewhere but I forgot the source and couldn't find it back in my own huge library.

From an expert I did read the following; SET reduction with Zn/HCl works if the acid is strong enough and the activation energy is high enough to go over the hydroxylamine intermediate to obtain the corresponding amine.

The reductive amination of the imine is way too smelly with THF, very exothermic and have to be very dry when working with excess sodium triacetoxyborohydride.

karlos³ - 30-4-2019 at 11:52

Please take note that the very long forgotten Nickel/Zinc reduction, which uses a Ni(II) salt in conc. ammonia solution, a bit of EtOH, and repeated additions of zinc powder to the solution produces excellent results!
It is a long forgotten method that resembles an Urushibara catalyst, but was invented at 1940 in france, before urushibara himself got the idea.
It is prepared in-situ and is even easier to use.

I have myself tried it out on phenylacetoxime and got a nice yield of the corresponding amine.

Search for the posts of Scr0t for the synthesis of cyclohexylamine, I worked exactly after his writeup, twice with the free ketone(70,5 and 84%!).
Then you find the many other sources and references for this reaction, and you will be happy, I can assure you this :)

[Edited on 30-4-2019 by karlos³]

stoichiometric_steve - 30-4-2019 at 13:15

Quote: Originally posted by karlos³  
I worked exactly after his writeup


Meaning you dissolved the Ketoxime in 30% aq. NH3?

TGSpecialist1 - 1-5-2019 at 18:07

Zinc metal with ammonium salt in alcohol

Potassium formate with palladium on carbon.

Sodium metal in ethanol.

[Edited on 2-5-2019 by TGSpecialist1]