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Author: Subject: Failed nitro-aldol reaction. Possible cause and fix?
zed
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[*] posted on 18-3-2019 at 17:58


In my opinion, that paper ain't kosher. It is full of typos and obvious errors.

Back in prehistoric times, I attempted the NiCl2/NaBH4 reduction of Nitropropenylbenzenes. Though to be clear, I made those attempts on substrates, that if successfully reduced, would not yield psychoactive or illegal products.

In no case, did such reductions produce amines.

Though at least some type of reduction was probably achieved, as indicated by significant de-colorization of my reaction mixture.

Most likely, reduction stopped at the oxime stage.

Easy enough to find out. It doesn't require a room full of equipment.

Filter, distill off organic solvents, acidify with aqueous HCl, and steam distill.

P2P might accumulate in your distillate.

In my neck of the woods, that ain't legal, unless you have a permit, of course.



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[*] posted on 18-3-2019 at 19:11


Thanks for the explanation @TheMasterOfTheInternet.

Why don't you make a write up here about your work with NiCl2/NaBH4 to people here try to reproduce it and check the consistency of the results and the yields?

You must have noted that the most of people here doubts NiCl2/NaBH4 can reduce completely, or at least at a reasonable yields, alpha alkyl nitrostyrenes to aryl alkylamines.

@C/J made a reference to an anonymous write up brought by @Clearly_not_atara in another thread about NaBH4/CuCl2 reduction I reproduce below. Why don't you do the same with NiCl2/NaBH4?

Amphetamine from P2NP and NaBH4-CuCl2

"With vigorous stirring, to 5ml of IPA / 1g of P2NP and 0.4 times volume of H2O in RBF was dumped 6 mol eq. of NaBH4.
Recrystallized P2NP was washed with sodium bisulfite solution, then with and water and it was then added in small portions to the mixture to minimize frothing. No external cooling applied. After all substrate was added and near-colourless solution is obtained, the solution left stirring for 30 minutes. Claisen adapter was fitted to the rbf with reflux setup and addition funnel. With one portion, 10%-mol equivalent (for the nitroalkene) of CuCl2.2H2O dissolved in IPA was added to the solution via the funnel. It was refluxed for 30 minutes. After which the remaining NaBH4 was destroyed by adding about 50% acetic acid untill the fizzing stopped and the solution was fairly acidic. With the claisen adapter still attaced, short path distillation setup was rigged and everything below 100'C was stripped. Then the solution was made basic dripping strong NaOH solution to the reaction flask and steam distilled. Additional very dilute NaOH solution was added through the addition funnel every now and then. The distillate was then made slightly acidic with H2SO4 and evaporated. Total yield after recrystallization: 80% mol wise from the P2NP due to very sloppy work"
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[*] posted on 19-3-2019 at 14:32


Quote: Originally posted by zed  
In my opinion, that paper ain't kosher. It is full of typos and obvious errors.

Back in prehistoric times, I attempted the NiCl2/NaBH4 reduction of Nitropropenylbenzenes. Though to be clear, I made those attempts on substrates, that if successfully reduced, would not yield psychoactive or illegal products.

In no case, did such reductions produce amines.

Though at least some type of reduction was probably achieved, as indicated by significant de-colorization of my reaction mixture.

Most likely, reduction stopped at the oxime stage.

Easy enough to find out. It doesn't require a room full of equipment.

Filter, distill off organic solvents, acidify with aqueous HCl, and steam distill.

P2P might accumulate in your distillate.

In my neck of the woods, that ain't legal, unless you have a permit, of course.

Note: As I recall I conducted this procedure as a hydrogenation. The premise being, that Nickel Boride formed from NaBH4/NiCl2, was acting as The hydrogenation catalyst. Ala Brown.



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[*] posted on 20-3-2019 at 09:58


Quote: Originally posted by zed  
Quote: Originally posted by zed  
In my opinion, that paper ain't kosher. It is full of typos and obvious errors.

Back in prehistoric times, I attempted the NiCl2/NaBH4 reduction of Nitropropenylbenzenes. Though to be clear, I made those attempts on substrates, that if successfully reduced, would not yield psychoactive or illegal products.

In no case, did such reductions produce amines.

Though at least some type of reduction was probably achieved, as indicated by significant de-colorization of my reaction mixture.

Most likely, reduction stopped at the oxime stage.

Easy enough to find out. It doesn't require a room full of equipment.

Filter, distill off organic solvents, acidify with aqueous HCl, and steam distill.

P2P might accumulate in your distillate.

In my neck of the woods, that ain't legal, unless you have a permit, of course.

Note: As I recall I conducted this procedure as a hydrogenation. The premise being, that Nickel Boride formed from NaBH4/NiCl2, was acting as The hydrogenation catalyst. Ala Brown.





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[*] posted on 21-3-2019 at 06:18


I am bringing another paper attached that reinforces the theory that CU+2 salts combined with NaBH4 can reduce P2NP to amphetamine in one pot.

The paper talks about the reduction of oximes to amines with CuSO4/NaBH4 couple.

If some members here thinks the reduction of P2NP with CUSO4 (or CUCl2)/NaBH4 couple could stop, at the beginning, at the oxime stage, this paper proves that the oxime can be reduced, in the sequence, to the amine, just increasing the molar amount of the reagents.

Think about. Read the paper I brought talking about reduction of nitro compounds by CuSO4/NaBH4 couple: http://www.sciencemadness.org/talk/files.php?pid=603937&... Then read the anonymous write up brought by @Clearly_not_Atara I reproduced here: http://www.sciencemadness.org/talk/viewthread.php?tid=144546... And finally, read the paper I'm attaching now.

I think it worth I try experimenting the anonymous write up brought by @Clearly_not_atara, even substituting CuCl2 by the OTC CuSO4, and substituting IPA by ETOH, to increase NaBH4 solubility and the yields, like @TheMasterofTheInternet said.

Somebody would to try and post the results here?

Attachment: oximes to amines with NaBH4 + CuSO4 in methanol.pdf (690kB)
This file has been downloaded 128 times

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[*] posted on 21-3-2019 at 10:13


Chemi Pharma, just do it so you are convinced of it working exactly as stated.

The oxime reduction using Cu(II) salts isn't doing it, just look at the amount of produced dimeric and monomeric substance in there.
The Ni(II) method is valuable in turn instead for oximes, but despite your own claim of success, never seen that being reproduced by someone else on nitropropenes(just that one example on a nitrostyrene. with lower yield though).
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[*] posted on 21-3-2019 at 11:54


Quote: Originally posted by karlos³  
Chemi Pharma, just do it so you are convinced of it working exactly as stated.

The oxime reduction using Cu(II) salts isn't doing it, just look at the amount of produced dimeric and monomeric substance in there.
The Ni(II) method is valuable in turn instead for oximes, but despite your own claim of success, never seen that being reproduced by someone else on nitropropenes(just that one example on a nitrostyrene. with lower yield though).


Just not me claims about the viability of Raney Nickel or NiCl2/NaBH4 to reduce nitropropenes. @TheMasterofTheInternet say the same, see here:


http://www.sciencemadness.org/talk/viewthread.php?tid=144546...


A time ago @Bottle claimed sucess too with Ra-Ni/NaBH4 to reduce 2,5 dimethoxy nitrostyrene with good yield. See here:


http://www.sciencemadness.org/talk/viewthread.php?tid=80555&...


Besides too many papers I have brought here written by a lot of researchers about NiCl2/NaBH4 reductions kind. See here:


http://www.sciencemadness.org/talk/viewthread.php?tid=80555&...


I really think It's impossible these sciencemadness members and all these researchers worldwide were lying and have published only bullshits. Something is wrong with their published experiments, or about the equivalence of the substrate/reagent or with the work up. The theory seems nice to me, although neighter me, nor @Nimgoldman have got the theorical results in practice. May be impurities in the substrate or impure reagents we had used, I don't know.

I will try the CuCl2/NaBH4 write up for sure, but I was waiting somebody here bring more new ideas, to clarify my mind, before start the lab practice.
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[*] posted on 21-3-2019 at 12:52


Yeah I know about your papers, just quoting what several people told me in private mostly.

If you want to, I have here an experiment from someone named not_karlos where also some mistakes were made but which turned out quite nice.
This was done by that person:

2,51g 2,5-Dimethoxynitrostyrene(12mmol) was added to
3,5g NaBH4(93mmol) in 32/16ml of IPA/H2O, 20min after the reaction(no cooling applied), a solution of
0,2g CuCl2*2H2O(1,2mmol) in 6ml 1:1 IPA/H2O was added at once, then refluxed for 40min
After reaching r.t, a 25% solution of NaOH (20 ml) was added, the phases separated and
aqueous phase extracted again with IPA(2x30 ml).
The extractions combined, dried with Na2SO4, filtered, acidified.
The IPA was distilled off then, but the residue was still dirty.
So it was extracted with 3x15ml DCM, then basified and the freebase extracted with 3x30ml DCM,
the extracts acidified using diluted HCl, the aq. portion separated and
evaporated, boiled in dry acetone then filtered, washed with acetone to give
-1,84g of white HCl salt(8,4mmol or 70%)
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[*] posted on 21-3-2019 at 13:04


Thanks @Karlos. Very instrutive!

One more experiment to do soon. I'm curious too see if the yield with nitrostyrenes will be the same with nitropropenes.;)
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[*] posted on 21-3-2019 at 23:24


One needs to add the nitrostyrene at a much colder temperature, this will give a better yield.
A friend recently got from the unsubstituted nitropropene a yield of 88% of amine sulfate!
This surely can be done with both nitrostyrenes and -propenes(or longer).
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[*] posted on 22-3-2019 at 09:28


Quote: Originally posted by Chemi Pharma  
nor @Nimgoldman have got the theorical results in practice. May be impurities in the substrate or impure reagents we had used, I don't know.


This is absolutely possible. I think maybe the reaction worked partly, most of the products being isomerised, polymerised or incompletely reduced compounds (AFAIK). I might not have driven the reaction to completion as other noted.

I have ordered some mercury to perform the traditional Al/Hg, then I will try other, less toxic pathways: Ur-Ni (maybe Urushibara style aluminium might work better), Ra-Ni, NiCl/NaBH4, CuCl/NaBH4, Leuckart and maybe even Gallium-activated aluminium (Al/Ga) - which seems really interesting "non-toxic" process.

Obivously some people have success with methods other claim not working. It's probably in driving the reaction to endpoint correctly and in the workup stage.
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[*] posted on 26-3-2019 at 12:53


If I might help you a little from experience on this, I know a few people who attempted this already and had success, also probably have some experience myself?
The Al/Hg was the gold standard for years, it needs some experience but then it works consistent.
You need to use Al grains, a friend swears on the I think it was 0,6mm size? I use grains in 0,6-2mm size and they finally made amalgamation reactions absolutely consistent yielding.
The U-Ni was gotten to work by a friend, but he had low yield.
With selfmade raney he tried it as well, but he also got lower yields.
You need to reduce the nitropropene to the alkane before, then both methods will be very high yielding.
The NaBH4/CuCl2 is what we consider the new gold standard by the way.
Leuckart will get you around 50-60% yield at most, use base hydrolysis afterwards.
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[*] posted on 1-4-2019 at 22:14


Quote: Originally posted by karlos³  
You need to reduce the nitropropene to the alkane before, then both methods will be very high yielding.


By alkane did you mean ketone, i.e. Ph-2-propanone?

Sure I will try different reduction methods but now I will start with the old "gold standard" so I have some reference method to compare the others with.
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[*] posted on 1-4-2019 at 23:13


He means the saturated Phenylnitro-alkane.............. After you do that, a large number of reduction systems are open to you to take it to the amine......... I have more to add to this thread but I am drowning in papers and reports.
I will bee back after I glue my brain together.


/CJ




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[*] posted on 30-4-2020 at 03:47


Quote: Originally posted by karlos³  
Yeah I know about your papers, just quoting what several people told me in private mostly.

If you want to, I have here an experiment from someone named not_karlos where also some mistakes were made but which turned out quite nice.
This was done by that person:

2,51g 2,5-Dimethoxynitrostyrene(12mmol) was added to
3,5g NaBH4(93mmol) in 32/16ml of IPA/H2O, 20min after the reaction(no cooling applied), a solution of
0,2g CuCl2*2H2O(1,2mmol) in 6ml 1:1 IPA/H2O was added at once, then refluxed for 40min
After reaching r.t, a 25% solution of NaOH (20 ml) was added, the phases separated and
aqueous phase extracted again with IPA(2x30 ml).
The extractions combined, dried with Na2SO4, filtered, acidified.
The IPA was distilled off then, but the residue was still dirty.
So it was extracted with 3x15ml DCM, then basified and the freebase extracted with 3x30ml DCM,
the extracts acidified using diluted HCl, the aq. portion separated and
evaporated, boiled in dry acetone then filtered, washed with acetone to give
-1,84g of white HCl salt(8,4mmol or 70%)


Well @Karlos, I tried this but it didn't worked at all. Nor a milligram of amphetamine. I were hopeful cause at the end I've got a respectable amount of white solid precipitate, after acetone cleaning, but after drying the solid, it has liquefied and I did Marquis test into the residue and no color I've got at all. Just an efervecence, like when I did this reaction with NiCl2 instead CuCl2. I wonder the white solid precipitate is NaCl, resulted of basic NaOH/DCM neutralization. As I know amphetamine hydrochloride is not deliquescent and Marquis test were definitive to accuse no amphetamine at all. So, I give up.

Definitively, borohydride/transitions metal (metal borides) don't work to reduce the remaining nitro group. It's very effective to reduce nitropropenes to nitropropanes, but the Beta nitro propane group is a pain in the ass to be reduced.

I will try that one step reduction with the classic LiAlH4 method told by Strike at "Total Synthesis book" and with the old Al/Hg amalgam to see if I have any results. It's not possible my P2NP were impure. They were made with care and gave beauty yellow crystal needles.

@Stoichiometric_Steve gave a method dealing with Zn, formate and formic acid reduction: http://www.sciencemadness.org/talk/viewthread.php?tid=4965&a... to reduce the remaining nitro group of the nitropropane at a second step. May be I'll give a try too.
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[*] posted on 30-4-2020 at 04:01


Thats strange because many other people at our forum and at the hyperlab can confirm success.
Try it again, you must have done something very wrong, as the cause is clearly in you and not the procedure.
Copper nanoparticles(not borides) do reduce the nitro group very well.

By the way, Stoichiometric_Steve got the NaBH4/CuCl2 method to work too.
Actually, everyone who tried it has gotten it to work, you're the first person who failed.

Just read the respective threads at the hyperlab and at the vespiary and you will see that you're wrong with your claim that this reduction does not work.
It really does only not work for you.
Maybe you will get it to work as well if you do it properly?
After all, it is also confirmed in two research papers, besides the confirmed success of a few dozen hobby chemists.

[Edited on 30-4-2020 by karlos³]
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[*] posted on 30-4-2020 at 04:07


Quote: Originally posted by karlos³  
Thats strange because many other people at our forum and at the hyperlab can confirm success.
Try it again, you must have done something very wrong, as the cause is clearly in you and not the procedure.
Copper nanoparticles do reduce the nitro group very well.

By the way, Stoichiometric_Steve got the NaBH4/CuCl2 method to work too.
Actually, everyone who tried it has gotten it to work, you're the first person who failed.


@Karlos, are you sure the people who did that reaction did it with P2NP and not with Nitrostyrenes instead? I believe this reaction works with Nitrostyrenes, although I've never tried with, but, in my case, it didn't work with P2NP to give amphetamine, reducing the beta nitropropane nitro group after reducing the nitropropene to nitropropane. It seems the reduction have stopped at oxime stage.

[Edited on 30-4-2020 by Chemi Pharma]
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[*] posted on 30-4-2020 at 05:01


Yes, most on the unsubstituted P2NP. Two of them with 88% and 90% yield.
One of us even on 3-indolylnitropropene.
I did it myself on several nitropropenes, unsubstituted, 4-fluoro-, 3,4-methylendioxy-, 2,5-dimethoxy-, on all of those nitropropenes.
The last time I did it successfully on 2,5-dimethoxyphenylnitrobutene even.
There is no limit on which nitroalkenes it works.
P2NP gives the best yields, 80% of amine are easily reached.

I assume you haven't added the CuCl2 fast enough and dripped it in?
This is an usual source of failure, you need a large reaction vessel so that you're able to add it all at once in a vigorous reaction.
Only then the required concentration of copper nanoparticles will be reached to affect reduction of the nitro group to the amine.

[Edited on 30-4-2020 by karlos³]
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[*] posted on 30-4-2020 at 15:38


All the legit tips have been said already but I will add that saving a seed crystal is never a bad idea!

THIS document is ironically quite the nitro aldol treasure trove. Replete with experimental section from seized "recipes" as they call them.

Using ammonium carbonate in GAA instead of n-butylamine (or etheylenediamine; I've sub'd this in and as long as your halve the molar amount due to it having 2 amino groups it works like a charm as a catalyst) is quite the nice little tidbit insofar as OTC goes IMO.

Where I am neither benzaldehyde, nitroethane nor the resultant nitropropene are considered illegal so I'm actually tempted to try out their one-pot to 1-Phenyl-2-Propanone in 44% yield...... but alas P2P is for some strange reason illegal here:P



Attachment: M. B. Tolmie Masters Thesis - Australian Federal Police - Copy.pdf (1.9MB)
This file has been downloaded 57 times

[Edited on 30-4-2020 by Johnny Windchimes]
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