Sciencemadness Discussion Board

How to reduce oximes to amines?

Cou - 25-6-2020 at 14:20

I would like to start playing with nitrogen organic compounds and find out for myself what the fishy smell is.

My organic chemistry textbook says amines are often prepared in the laboratory by reductive amination. To make isopropylamine, i would first make acetone oxime with hydroxylamine HCl (not hard, chemplayer has a video about that). but i'm not sure how to do the reduction from oxime to amine.

Vogel's practical organic chemistry uses ethanol and sodium metal to reduce oximes to amines. I never saw ethanol and sodium used as a reducing agent in modern organic chemistry classes. Is there a reason it isn't used anymore (replaced with hydride reducing agents), or does it work fine?

what about clemmensen reduction?

karlos³ - 25-6-2020 at 14:58

The best way I know of, and from those I tried, is a variation of the Al/Hg in presence of ammonia, using grains(or maybe shavings), but definitely not aluminium foil.
It is described in DE1014553B, and I've never seen this variation of the aluminium amalgam reduction anywhere else, ever.
Some have tried it though on other substrates, who are not as sensitive to heat to require a slow and less exothermic reaction, and it can also be done in just 2h while still giving very high yields... although the ammonia inevitably will evaporate off during that(but not so important and bad in the tiny amounts used).
But knowing you, I guess that is nothing you would like to work with, even if the amounts of mercury salts are so small.

So I have another, well working method for you, but it might be a more tricky in practice to push it to a really good yield.
This is using a nickel(II) salt in ammonia solution, some ethanol to get the substrate soluble, and then successively adding zinc powder portionswise, like every five minutes, to the well stirred solution.
This can apparently give high yields too, not as high as the former method, but still quite good if you got it to work.
Once I reduced an oxime with it, and got around 70% yield.
Put if your goal is a primary amine anyways, you can use that method already directly on the ketone, it is the only method I know of which is able to produce primary amines directly from ketones with ammonia, that is able to give those yields.
Usually, the imine-forming properties of ammonia will be the cause why those reductions always give low yields, but no rule without an exception.
And this is the exception.
See here:

Ethanol and sodium is not easy to run.
First, the ethanol of course has to be bone-dry.
And second, this reaction is run at best when the sodium is added at reflux... making it quite dangerous as well.

The clemmensen is a reduction of carbonyls to alkanes.
It will not reduce oximes as it is.
If you're talking about using zinc to reduce oximes, then use the second method I gave.
The active reagent in there is actually an urushibara catalyst, only that the description stems from 1940, 15 years before urushibara itself discovered it.

Another method, of which I am not very fond, is the use of nickel boride, using NaBH4 and NiCl2(or another nickel(II) salt), but in my experience its not as good as the two other methods I mentioned.

Those are probably most noteworthy for oximes, for the amateur chemist.
Everything else, well... some methods, like the one or other in the rhodium archive, remain doubtful as they couldn't get reproduced so far.
If you choose one of the three I mentioned, you will not be disappointed as you get to your amine for sure.

Cou - 25-6-2020 at 15:51

I used to be very scared of dangerous chemicals, like mercury salts, but my attitude has changed on that recently. This hobby is what stopped my suicidal thoughts, severe depression can be more deadly than minor exposure to chemicals. I am interested in that method.

Holy Cow, 5 grams of sodium cyanoborohydride costs $21.

[Edited on 25-6-2020 by Cou]

karlos³ - 25-6-2020 at 16:05

Alright, then use the following quotes, of Corrosive Joeseph who put in the effort to translate that certain patent:
Sorry that I don't format it properly right now.


Example 2:
An ice-cooled solution of 50 g of levorotatory phenylacetylcarbinol ([a]. D = -13.4°) in 670 cc of methanol is mixed with 37 g of hydroxylamine hydrochloride, then 10% KOH solution is carefully added with stirring until the solution has a pH of 6 to 7 and 54 cc of 25% ammonia, 7 cc of water and 30 g of HgCl activated aluminum turnings are added. The temperature gradually increases and is kept at 30°. It is stirred until the aluminum chips are consumed (about 60 hours). After the reaction has ended, the aluminum slurry is filtered off with suction, the filtrate is evaporated off with the addition of water, the methanol-free residue is subjected to a brief steam distillation in order to remove the by-produced, readily volatile benzylamine, and the residue is acidified to a pH of 5 to 6 with 25% sulfuric acid. The aqueous solution is evaporated to crystallization and, after cooling, the resulting sulfate of the base is filtered off with suction. After recrystallizing the sulfate twice from water, the specific rotation is [a] D = -31.5°.

Of course, those temperatures and the tight control of the temperature are only needed because that substrate is very sensitive towards those things.
You don't need this for anything else, in fact, I have already reduced acetophenone oxime in around two hours too, just by letting the reaction run its course.

I would still recommend the nickel-zinc method, as this way you don't need to form an oxime first, and still get comparably high yields.
This method is always very handy and useful in case you want to turn a ketone into a primary amine which can stand a little bit of somewhat hot conditions.
Maybe not of the first try, but surely with repeated use, you can get the yield up just right so you will get at least as much as it is possible with the amalgam reduction.

But I understand that nickel salts are more expensive, especially in the quantities needed, than with an amalgam which still remains to this day one of the most cheapest reduction methods for quite a few substrates, that is existing.

One thing to add about those amalgams: never use foil!
Always use grains of aluminium, for example I use 0,7-2mm grains, but you can use a bit smaller ones, just not very much.
Powder, never, avoid that absolutely!
Shavings, I don't recommend them either, too long and slow reaction.
The best is if you use those small grains, with them every reduction will run just the same, easily foreseeable and easy.
If you run two reductions just the same with those grains, both will turn out equally.... try that with foil, no way, they will not even resemble each other.

morganbw - 26-6-2020 at 05:11

If you search for the grains of Al, use the search term Aluminium Granules.

njl - 26-6-2020 at 09:10

The aluminum from baking tins is apparently adequate for Al/Hg reductions

karlos³ - 26-6-2020 at 09:20

Foil is adequate too for that reduction, but neither those baking trays nor foil will give one the same relative ease and highly controllable reaction, proceeding always similar as expected, as the one you get with those grains.

arkoma - 26-6-2020 at 17:13

Unexpected geysers are BAD thing with this stuff. mmmm, mercury salts.... surface area to weight ratio much less with granules, less fury post induction.

Eddie Current - 27-6-2020 at 14:32

Quote: Originally posted by njl  
The aluminum from baking tins is apparently adequate for Al/Hg reductions

All aluminum is adequate, but the reaction rate is determined by the available surface area of the aluminum. If thin foil or fine powder is utilised then the reaction can runaway, and if something like thick aluminum building sheeting is used then the reaction can take days to complete. The trick is in learning to pace the reaction properly, and also at a certain scale magnetic stirring will not be viable as the stir bar will become locked up in the resulting sludge. An overhead stirrer is required at this point.

I would suggest utilising thicker aluminum and overhead stirring and then practicing some small scale runs utilising solvent/Al/Hg only, without ROR and an amine source, in order to get a better understanding of the reaction dynamics.

UC235 - 27-6-2020 at 19:52

If you really want to smell it and not actually isolate it, just buy some roundup (make sure it's glyphosate isopropylamine salt) and add NaOH solution. It will be immediately apparent. The other suggestion I have is to look up the thread about methylamine production and find the bits I wrote about ammonium methylsulfate production from sulfamic acid. I did not isolate product but some methylamine or dimethylamine is definitely formed when it is fused. Absolutely vile smelling.

Cou - 27-6-2020 at 20:36

Overhead stirrer