Sciencemadness Discussion Board

Reducing aliphatic nitro compounds to amines

Melgar - 17-5-2011 at 10:58

I know there are plenty of ways to reduce nitro compounds to amines, I just need to know one good one. Reducing it with iron doesn't seem to work. Zinc and HCl does seem to work, but not so well, and presumably separating out the amine is a pain.

The compound is 1-phenyl,1-hydroxyl,2-nitro-propane, ie, the nitroalcohol that would be reduced to PPA.

I'm now split between Al/Ga reduction (very similar to Al/Hg) and catalytic hydrogenation. Al/Ga seems easy enough, and the aluminum is converted to the aluminate upon basification, so theoretically that could work. I'm just not sure if it would reduce the hydroxyl group too; I don't want that, but I don't think it would because if it did, people would be using that as an easy route to amphetamine.

Catalytic hydrogenation seems to require a more complicated setup, but I do have some PdCl2 solution that could be made into Pd/C easy enough, from what I hear. I'm just a bit reluctant to try it because I've never done catalytic reduction before. Plus, palladium is super expensive as of late.

Nickel catalysts seem to be the least likely to work. I've tried making Raney nickel and Urushibara nickel. I've heard Raney nickel + formic acid will do the job, but Raney nickel is kind of hard to make. I could barely melt nickel with an oxypropane torch. I did eventually, but I'm not sure how well it mixed with the aluminum. Urushibara nickel doesn't seem to have any good reviews here, so I'm reluctant to try it.

So apologies if this has been covered before, but I have used the search engine, and I'm still not sure what route to go, so I'm hoping someone who has done something like this can point me in the right direction. Thanks. :)

[Edited on 5/18/11 by Melgar]

postart - 17-5-2011 at 13:43

What is 1-phenyl,1-hydroxyl,2-amino-propane is there a case #, can't find such a chemical when searching. Are you speaking of alanine?

Sedit - 17-5-2011 at 16:39

Could you elaborate on the process used for the Dissolving metal reduction?

Melgar - 17-5-2011 at 18:46

The compound is phenylpropanolamine, but instead of the amino there is a nitro. And the goal is to turn that nitro into an amino to get phenylpropanolamine.

For the zinc reduction, there were 4 moles of zinc per one mole of reactant added into the mixture (not all at once though, it was scooped in as it ran out), then stirring was turned on and HCl dripped into the mixture, very slowly.

For Al/Ga reduction, a galinstan thermometer was broken open and the contents were mixed with about 20 g of molten aluminum. The chunk of metal was broken into smaller chunks which were added to an aqueous alcohol solution of the nitroalcohol bit by bit. It tended to bubble a lot when the temperature was above gallium's melting point, which is about 30 C. The bubbles were hydrogen.

For both zinc and Al/Ga, after basification, there was an amino smell eventually left, but there was also this nasty sweet smell that was a lot stronger but eventually went away. Not sure what that is, but it's gotta be lost yield.

azo - 17-5-2011 at 22:20

Hi melgar tin and hydrochloric acid is a very good way of reducing nitro groups, it is used in reducing aromatic nitro compounds in industry for ex. nitro benzene to aniline and can be used on aliphatic nitro compounds as well.
i have used this before with great success .
I also have to ask you how you derived your nitroalcohol was is it from propiophenone or was it from the henry reaction using benzaldehyde and nitroethane , I suspect the later,If you have derived it from the henry reaction what base and solvent was used as this would have an affect on what isomers of the nitro alcohol you would get .
If you used sodium hydroxide you would get 65% R,R and 35% R,S isomers but if you used triethylamine as the catylist you would then get 80% R,S and 20% RR isomers.
So if you intending on making amphetamine you would not use sodium hydroxide because you would get 65 % levro and only 35% mix of dextro and levro.but if you used triethylamine you would get 80% mix of levro and dextro and 20% of levro.
But of course this would all change if the end goal was 4 MAR

BEST OF LUCK GETTING HELP WITH 4 MAR ? ONLY SOME PEOPLE ON THIS SITE GET HELP WITH THIS SUBJECT
THEN THEY FALL OVER EACH OTHER TO HELP.
OR IT GETS RAILROADED BY MODERATORS AND END UP IN THE JUNK OR BEGININGS.



REGARDS AZO
:mad:


Nicodem - 18-5-2011 at 06:15

Open referenceless threads in the Beginnings section only! Why do I have to keep repeating this over and over again?

Melgar - 18-5-2011 at 07:05

Quote: Originally posted by azo  
Hi melgar tin and hydrochloric acid is a very good way of reducing nitro groups, it is used in reducing aromatic nitro compounds in industry for ex. nitro benzene to aniline and can be used on aliphatic nitro compounds as well.
i have used this before with great success .
I also have to ask you how you derived your nitroalcohol was is it from propiophenone or was it from the henry reaction using benzaldehyde and nitroethane , I suspect the later,If you have derived it from the henry reaction what base and solvent was used as this would have an affect on what isomers of the nitro alcohol you would get .
If you used sodium hydroxide you would get 65% R,R and 35% R,S isomers but if you used triethylamine as the catylist you would then get 80% R,S and 20% RR isomers.
So if you intending on making amphetamine you would not use sodium hydroxide because you would get 65 % levro and only 35% mix of dextro and levro.but if you used triethylamine you would get 80% mix of levro and dextro and 20% of levro.
But of course this would all change if the end goal was 4 MAR

BEST OF LUCK GETTING HELP WITH 4 MAR ? ONLY SOME PEOPLE ON THIS SITE GET HELP WITH THIS SUBJECT
THEN THEY FALL OVER EACH OTHER TO HELP.
OR IT GETS RAILROADED BY MODERATORS AND END UP IN THE JUNK OR BEGININGS.



REGARDS AZO
:mad:



Both NaOH and DMAE freebase have been used in the Henry reaction. DMAE freebase is easier to acquire, but I'm not sure if you'd want that mixture of stereoisomers for 4mar.

I guess now that this thread is in the beginnings section, I'll get approximately 0 more replies, but hey, I might get lucky! I should have just added a reference or two at the beginning but I was on dial-up at the time and couldn't spend the requisite 1.5 hours searching for references. :-/

I suppose tin/HCl would work, just someone would have to cough up the $30/lb that tin seems to cost. Though I guess one atom of tin can reduce twice? Once to get SnCl2, and again to get SnCl4? There may be some tin solder floating around that would work for this though. Thanks for the tip.

As far as 4-mar synthesis, there's a pretty good writeup here:
http://www.erowid.org/archive/rhodium/chemistry/para-fluoro-...
I've heard this work fairly well, but can't verify it.

postart - 18-5-2011 at 13:30

Do you have a synthesis or write up on how this PPA but with a nitrogroup was created by chance? Anyways I would think that zinc/HCl would be far more economical than buying elemental gallium, right.

azo - 18-5-2011 at 18:50

Nicodem i can understand why its frustrating when there is no references provided,and i understand why they are needed to allow members to understand and be able to make an inform reply, but in a very small amount of the time there is no references on the subject as my post on cyclisation of amino alcohols with potasium cyanate.If you can find any references on that rxn you are better than me at searching.

regards azo:D

[Edited on 19-5-2011 by azo]

Melgar - 19-5-2011 at 17:22

Gallium is just used to expose the aluminum to the environment; you just need a very small amount of it, and often it can be reused.

The link I posted is what I've been trying to follow, but HCl was substituted for formic acid. That's also been proven to work, for example here:

http://www.erowid.org/archive/rhodium/chemistry/norpseudoeph...

The nitroalcohol was created via the Henry reaction between benzaldehyde and nitroethane.

azo - 19-5-2011 at 19:18

The isomers by the said method claim to make a mix of R,R AND S,S isomers
there for only the S,S isomer after resolustion can be reduced to amphetamine which then makes the yeild of 80% only 40% piss poor.

I have posted these references because they are controdicting what the rodium method states.

REGARDS AZO

Attachment: IPTFOUR79NP.pdf (344kB)
This file has been downloaded 1715 times

Sedit - 19-5-2011 at 20:45

Assuming he was after amphetamine he could use an organic base catalysed Henery reaction to yeild the nitrostyrene and reduce that to Amphetamine using aluminum amalgum.

I highly doubt that is the goal here.

Melgar - 20-5-2011 at 02:28

Yeah, the goal is 4mar, as opposed to amphetamine. Does this mean sodium hydroxide is an appropriate base? Or is a tertiary amine better?

azo - 20-5-2011 at 03:46

Well that would depend on whether the cyclisation is done with cyanate salts or cynagen bromide.
From memory the cyangen bromide with norephedrine would yeild cis 4mar ,but with cyanate salts the trans 4 mar is made.
And if you use norpsuedoephedrine with cynagen bromide it would yeild trans 4 mar.
If you are intending using cyanate salts you would need the erythro isomers for 4 mar.;)
I have posted this link. it shows the four isomers of ephedrine which is the same as norephedrine only they have a methyl group on the nitrogen.;)



regards azo


Attachment: Pseudoephedrine - Wikipedia, the free encyclopedia.mht (672kB)
This file has been downloaded 71252 times

Methyl.Magic - 20-5-2011 at 04:02

Quote: Originally posted by azo  

From memory the cyangen bromide with norephedrine would yeild cis 4mar ,but with cyanate salts the trans 4 mar is made.
And if you use norpsuedoephedrine with cynagen bromide it would yeild trans 4 mar.
If you are intending using cyanate salts you would need the erythro isomers for 4 mar.;)



very interesting !

Do you know which isomer is the best one ?

DJF90 - 20-5-2011 at 04:19

Quote:
Do you know which isomer is the best one ?


I fear this thread is decending into cookery... Please keep it chemistry related?

azo - 20-5-2011 at 04:21

all 4 isomers of 4 mar are active cis and trans , so it wouldn't matter if you used both isomers of norephedrine .


regards azo

Sedit - 20-5-2011 at 05:20

Quote: Originally posted by Methyl.Magic  

very interesting !

Do you know which isomer is the best one ?


DJF90 makes a good point. Best is such a relative term when speaking about this compound. Are you looking for the best one to modulate Dopamine or are you looking for the best isomer to give yourself a serious and sometimes fatal heart condition?

This is where great care must be taken because even though there is evidence to suggest that the withdrawl of aminorex from the market may have been botched and bias research( placing the heart condition percentage up there with the common average), I would still take great caution before performing a bioassay and study enough on the heart valve effects to be fully sure what one is getting into.

Abstract
Quote:

4-Methylaminorex is a potential psychostimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. The racemic mixture of the cis-isomers has been encountered in illicit samples, but previous animal studies suggest that also the trans-isomers could have similar stimulant-like properties. We tested whether the stereoisomers possess rewarding properties and compared their potency using the conditioned place preference method in rats. Furthermore, the involvement of the brain dopaminergic system in the 4-methylaminorex reward was tested with the dopamine D1- and D2-receptor antagonists SCH 23390 and raclopride administered systemically, or with the neurotoxin 6-hydroxydopamine injected into the nucleus accumbens. All the four isomers induced place preference, with no apparent differences in their potency. SCH 23990 and raclopride attenuated 4-methylaminorex-induced increase in place preference, and 6-hydroxydopamine also tended to be efficacious. These findings indicate that all the four stereoisomers of 4-methylaminorex possess rewarding properties and thus abuse potential; the trans-isomers are at least as potent as the cis-isomers. Furthermore, the brain dopaminergic system appears to be involved in the 4-methylaminorex-reward.


Abstract link: http://ukpmc.ac.uk/abstract/MED/15982727/reload=0;jsessionid...

Melgar - 20-5-2011 at 06:22

I'm trying to make trans-4MAR, after all, it's more than meets the eye. ;)

Seriously though, should the base just be sodium hydroxide then?

azo - 21-5-2011 at 03:38

I could not have explained it better in my last couple of posts , the first thing you want to do is not rely on methods from rodiums site some of it is rubbish .

HENRY REACTION
triethylamine would give 80% norephedrine and 20% norpseudoephedrine ,norephedrine would yeild 4 mar but like i said in a previous post this would depend on what cyclisation method you use.


regards azo





Attachment: 4-MAR via alkali metal cyanates.mht (28kB)
This file has been downloaded 1082 times

Sedit - 21-5-2011 at 08:03

I was under the impression that performing the Henry reaction with Triethylamine as the base then one would yeild the nitrostyrene instead of the amino alcohol.

Melgar - 21-5-2011 at 11:51

As I understand it, primary amines yield nitrostyrenes because they form the imine intermediate with the aldehyde, whereas secondary and tertiary amines yield the nitroalcohol because they don't.

azo - 22-5-2011 at 16:40

melgar i think only tertiary amines can be used

here is a lot of info on nitroaldol reactions

Attachment: nitro3.pdf (521kB)
This file has been downloaded 2121 times

Sedit - 22-5-2011 at 16:48

Quote: Originally posted by azo  
melgar i think only tertiary amines can be used


At the very beggining of Chapter 3.1 PREPARATION OF NITRO ALCOHOLS it shows some of the bases that can be used. NaOR is one of the shown bases. It also shows the use of NaOH plus the phase transfer catalyst cetyltrimethylammonium chloride. Al2O3 seems interesting since I have never heard of its use in the condensation reaction.

postart - 24-5-2011 at 05:52

Is the starting compound P2NP? If so I thaught the Henry reaction would just reduce the nitro group leaving P2P not PPA, correct?

DJF90 - 24-5-2011 at 07:24

postart - The Henry reaction is a condensation (c.f. Aldol, but where the nucleophilic component is a nitroalkane). There is no reduction involved.

Nicodem - 24-5-2011 at 07:46

Quote: Originally posted by DJF90  
The Henry reaction is a condensation (c.f. Aldol, but where the nucleophilic component is a nitroalkane).

I haven't been annoying for a long time, so I will grab the opportunity.
The Henry reaction is not a condensation, it is an addition (nucleophilic).
The Knoevenagel reaction is the one that is a condensation (and starts with a nucleophilic addition followed by an elimination).

DJF90 - 24-5-2011 at 08:31

Can you therefore explain why an aldol condensation is not called a Knoevenagel reaction..?

I can see the why the Aldol is called a condensation if you consider the product is the enone (which is actually the Knoevenagel product), but the actual product of an Aldol is the hydroxy-carbonyl compound (hence derivation of the name, Aldehydic alcohol. Seems as if people have been too loose with their definitions and caused too much confusion.

Not meaning to be a pedantic ass, just wondering if theres some kind of explanation (other than looseness of definitions).

[Edited on 24-5-2011 by DJF90]

Nicodem - 25-5-2011 at 13:09

Quote: Originally posted by DJF90  
Can you therefore explain why an aldol condensation is not called a Knoevenagel reaction..?

You can call a condensation of a ketone/aldehyde with an aldehyde to give an enone as a Knoevenagel reaction whenever the reaction goes trough the enolate addition on the iminium ion (meaning that it is catalyzed by amines, piperidine being the one most commonly used).
For example, benzaldehyde and some methyl alkyl ketones will condense under Knoevenagel reaction conditions with secondary amine catalysis to give the corresponding enone. It is however not proper to call a base catalyzed condensation of these same reactants as a Knoevenagel reaction even when it gives the same enone as the product, because this reaction is based on an aldol reaction followed by E1cB.
In the case of nitroalkane's condensations with benzaldehydes, the reaction is clearly a Knoevenagel under amine catalysis, but there is also an aldol-like version of this same transformation (using NaOH or KOH followed by acidification). This version can not be called a Knoevenagel, because it is mechanistically and methodologically different (nucleophilic addition of nitronate on the carbonyl, which is essentially a Henry reaction, followed by acid catalyzed elimination).

Quote:
I can see the why the Aldol is called a condensation if you consider the product is the enone (which is actually the Knoevenagel product), but the actual product of an Aldol is the hydroxy-carbonyl compound (hence derivation of the name, Aldehydic alcohol. Seems as if people have been too loose with their definitions and caused too much confusion.

Whenever you have two different reactions that starting from the same reactants give the same product, there is such confusion. A Knoevenagel condensation and an aldol + E1cB reaction can both give the same product, but their mechanism and methodology is different. There are many such cases where confusion is common. For example, the Ullmann condensation, Buchwald-Hartwig cross coupling, the nucleophilic aromatic substitution and the aromatic elimination-addition reaction ("benzyne reaction") also give the same product from the same combination of reactants, but they are several different types of reactions with very different mechanisms, methodologies and scope&limitations.

DJF90 - 26-5-2011 at 12:45

Thanks for the clarity, makes much more sense after breifly revising the mechanisms involved.

palladium8 - 20-12-2014 at 22:03

Quote: Originally posted by Melgar  
Gallium is just used to expose the aluminum to the environment; you just need a very small amount of it, and often it can be reused.

The link I posted is what I've been trying to follow, but HCl was substituted for formic acid. That's also been proven to work, for example here:

http://www.erowid.org/archive/rhodium/chemistry/norpseudoeph...

The nitroalcohol was created via the Henry reaction between benzaldehyde and nitroethane.


This is not totally accurate. Gallium removes the oxide later from aluminum by alloying with it. The Ga and Al would have to be melt together with a high percentage of Ga. The electron transfer/"reduction" occurs on the surface of amalgamated Al. Salts of Hg in solution can catalytically expose the surface of Al for reaction. I wonder if Ga salts can do this. It wouldn't make sense if it couldn't. That would be much more cost efficient than elemental Ga if avoidance if Hg is in mind.

CuReUS - 21-12-2014 at 04:43

generally metal reductions are slow ,need a lot of metal,are messy and most of the metal stays unreacted .catalytic hydrogenation is a better idea
Quote: Originally posted by Melgar  

For the zinc reduction, there were 4 moles of zinc per one mole of reactant added into the mixture (not all at once though, it was scooped in as it ran out), then stirring was turned on and HCl dripped into the mixture, very slowly.


IIRC,small amounts of Zn should be added to the mixture of nitro+HCl after regular intervals ,not the other way round :)

raney nickel is very good for reducing nitro groups(heating the nitro compound with raney nickel at 60'C will give the amine)

but as you are starting with para-flourobenzaldehyde(because you want to make 4-MAR) then raney cannot be used because raney nickel will remove all halogen groups from the benzene ring ,even flourine :o

Urushibara nickel should be immediately used after it has been made,otherwise it loses its reducing power