Sciencemadness Discussion Board - Failed nitro-aldol reaction. Possible cause and fix?

Last trial of making nitroethane was the classic Victor-Meyer substitution reaction of iodoethane and silver nitrite in diethyl ether. The yield of nitroethane was very poor even after prolonged reaction time and strong mechanical stirring (less than 10 mL distilling at 112-116 °C when starting with 90 g of AgNO2)

V Meyer (1874) did not use ether. The directions (Systematic Organic Chemistry or Lassar-Cohn's Laboratory Manual of Organic Chemistry) do not call for stirring because of the exothermic gas generating reaction. OTOH the only other author using EtX and nitrite is Ray and Neogi's comparison using mercurous nitrite, which works not as well as silver.

nimgoldman - 14-2-2019 at 11:49

Thanks for the help. I will try that. Fortunately, I have plenty of 96% and 99% ethanol at hand.

Yes I planned to use ethanol as the reaction solvent at first, but I really wanted to test my Dean-Stark trap and efficiency of a short reflux coil condenser.

Quote: Originally posted by S.C. Wack

Do you think making a slurry of EtX and AgNO2 is enough for the reaction to happen? I think a large excess of EtX must then be used to cover the nitrite salt as otherwise the AgNO2 will suck it up locally and most of it won't react. Some say both components have to be dissolved, at least partially, to react.

I though the EtX is dissolved in ether and dropped onto nitrite suspension in ether to slow down the exothermic reaction and stirring is for the reagents to come together.

Don't you think hot spots and thus rapid evaporation of reactants will more likely happened if EtX is just dropped over the nitrite?

What solvent did Victor Meyer used then, if any?

I would try that if the reagents weren't so expensive. It also takes time to prepare them correctly (just drying silver nitrite takes over a week, not to mention recycling the silver) so I like to try only tested methods... ChemPlayer showed the reaction works very well with ether though I was not able to reproduce the result. There are some high bioiling side products in the nitroethane.

S.C. Wack - 14-2-2019 at 17:27

With all the silver and iodine, if someone is going to give advice it should be sodium ethylsulfate or bromopropionic acid, and reading...SOC (1937) and LMOC (1895) were good books and in their way still are, so you should download them or perhaps read somewhere like archive.org. SOC as one of my scans is at my site and many other places. LMOC is from google books (where I downloaded it from) and it too has floated around.

The reaction is known in solvents, with other halides and nitrites, and people do try to pretend so and so process extends to nitrothane, but I have little faith in many things. I wonder why the literature as originally written makes everything but nitro(m)ethane and makes no claim that their new method might make them. I also wonder if the nitroethane compilation page in the Rhodium archive has ever actually helped anyone make nitroethane.

nimgoldman - 14-2-2019 at 19:07

Quote: Originally posted by S.C. Wack

The reaction is known in solvents, with other halides and nitrites, and people do try to pretend so and so process extends to nitrothane, but I have little faith in many things. I wonder why the literature as originally written makes everything but nitro(m)ethane and makes no claim that their new method might make them. I also wonder if the nitroethane compilation page in the Rhodium archive has ever actually helped anyone make nitroethane.

Well the reaction works. ChemPlayer has reproduced it with 57% yield,. Full Metal Alchemist had success with the sodium ethyl sulfate method, though purity and yield was not determined.

Sure I will study more. I tried three methods from Rhodium's page but none produced any reasonable yield of nitroethane (few drops actually). The only method that worked was the ethyl iodide + silver nitrite in ether which I originally found on PrepChem.com.

I would try the 2-bromopropionic method, but so far I invested so much time into learning the chemistry of silver and reagent preparations, that I don't want to give up the promising and already somewhat working method.

chemplayer... - 15-2-2019 at 18:48

Can't remember where we read it but apparently the ether solvent for the Victor-Meyer reaction is essential for a good yield. The reaction is also exothermic so you do really need to do this in a closed flask with magnetic stirring and an efficient cooled reflux condenser.

The first time we experimented with it on a very small scale (not shown on the video) we added the silver nitrite to the ethyl iodide ether solution, and put this in a sealed flask in the freezer. About 5 minutes later... BANG!

S.C. Wack - 16-2-2019 at 21:15

BTW the chloropropionic acid works too but the bromo is easier to make without alanine so I think of that first.

The only method that worked was the ethyl iodide + silver nitrite in ether which I originally found on PrepChem.com.

Quote: Originally posted by chemplayer...

Can't remember where we read it but apparently the ether solvent for the Victor-Meyer reaction is essential for a good yield.

Trumpism spreads to chemistry...the only nitroethane page at prepchem is copy/paste from SOC, where there is no ether, also none in reports of 71-90% yields of nitromethane...PS the LMOC version is true to Meyer's larger scale description and is a translation; SOC is an adaptation that may have been performed as written by someone else.

Good luck producing anything resembling an essential for good yield quote from a real chemist taking real care (not something made up and posted on Rhodium, ending in "The yield is about 83% of theory" BS) or any comparison of with and without ether by the same hands, anyone. Sounds like an idea for a video

[Edited on 17-2-2019 by S.C. Wack]

zed - 17-2-2019 at 14:14

Ummm. Stick the tip of a glass stirring rod into the solution. Remove and allow to air dry.

Crystalline haze should form on rod.

Use rod to stir the cooled solution. It should crystallize.

If it doesn't, you screwed up somewhere.

Not to worry. The path to success, is well-paved with failure.

nimgoldman - 19-2-2019 at 14:17

Okay I will try seeding the solution with a crystal. Good idea!

Quote: Originally posted by S.C. Wack

I am sorry. I used multiple sources and they got mixed up. I checked and realized indeed the SOC have not mentioned ether. Indeed I will try that approach too, not using an solvent.

I tried and compared several methods now and making notes about results from each. It's funny that I often discover the actual working method after trying everything else and the one working is the very last one... kind of like Murphy's Law.

I will try the sodium ethyl sulfate approach and then possibly the bromo-propionic acid approach. I can source propionic acid from a chem supplier, but this route requies making bromine and I have to wait till having more spare time to prepare it.

Sonce I am not an academic and not used to browsing journals and articles, I can only work with what I found on via internet searches... I do my best even though I know I will never be a "real chemist" unfortunately, I just do what I love...

strychnineissweet - 22-2-2019 at 06:32

I have performed this reaction every which way you can concieve of, what you are doing is probably the worst yielding and most complicated.

Do the reaction neat. Do not use a solvent. Mix your 40mL benzaldehyde with 40mL nitroethane in a flask. Carefully add 7mL of your amine (I used piperidine because it's what I had on hand). DO NOT reflux the mixture!!!!! This is where you are polymerizing everything and ruining your reaction. Heat it in the flask just until it starts to bubble, and remove from heat and submerge in cool water for a few moments. Place back on heat until it barely starts to bubble, and return to the cool water. Perform this action a total of three times. Be sure you are swirling the mixture in the flask throughout the procedure. After the third hot/cold cycle, place reaction flask into a freezer and leave it there for about an hour. You will have long, needly beautiful crystals. Most of your reaction mixture will solidify, you will only have a little bit of liquid left. Filter the crystals and recrystallize with IPA.

The color you are to avoid is orange. The reaction should be piss yellow. Any orange is indicitave of polymerization, and means you have heated too much. If you start to see any orange develop, or the yellow starts to get darker, STOP. Place into freezer and harvest what is in the reaction - you can attempt to rework the remaining liquid, but chances are you won't get anything out of it.

I have performed this reaction easily 30 times - if I can be of any assistance I will do anything I can to answer questions and be helpful.

nimgoldman - 23-2-2019 at 11:06

Evaporating the mixture is not an option as it haven't evaporated at all even after heating - then it all eventually vaporized in dark smoke when heated up too much. I think it's mostly benzaldehyde so the b.p. is too high and air-drying runs the risk of benzoic acid formation.

I am not sure why, but the product eventually crystallized out of solution anyway. I just moved the beaker several times between fume hood and a freezer, doing few test-tube experiments, and it suddenly crystallized.

I filtered the product and washed with cold MeOH. It indeed looks like phenyl-2-nitropropene:

One of my test tube experiment was successful in precipitating phenyl-2-nitropropene (probably). I simply added some methanol to decrease solubility of the said compound:

Therefore I added methanol to the filtrate and got a second crop of crystals:

I will recrystallize everything from MeOH since I have serious doubts about purity. The yield about 1/4th of the expected, but I am glad the method even works!

I have performed this reaction every which way you can concieve of, what you are doing is probably the worst yielding and most complicated.

Well this is the method I've seen many people do so I assumed it should work. I also wanted to test my Dean-Stark trap, among other reasons. I was not concerned about yield at that point, I just wanted to see if it even works, focusing on improvements later.

My favourite method uses absolute ethanol as a solvent and water scavenger.

Do not use a solvent.

How could this work? The product is solid so how is it that your reaction mixture does not solidify, preventing stirring?

I understand that the solvent is there for the reagents to react completely, keeping everything in solution, and to allow removal of water.

How is your product dehydrated in the reaction? The nitroaldol reaction intermediate has to be dehydtrated. The reaction is condensation reaction, producing water, which I guess should be removed from the mixture to yield the desired produce phenyl-2-nitropropene. In the toluene-Dean-Stark-approach, the dehydration is achieved by distilling off the water (because of lower b.p. than toluene). Another methods use absolute ethanol to "soak up" the water as it has high water affinity.

Thanks for your help offer!

I am planning reducing the product using Urushibara nickel (since it is not very toxic compared to mercury and not dangerous like LAH) - I will then try to confirm the resulting product (the corresponding amine) using TLC and reagents from DanceSafe to confirm the product.

[Edited on 23-2-2019 by nimgoldman]

Tsjerk - 23-2-2019 at 12:52

That is P2NP! Those needles are indistinguishable.

[Edited on 23-2-2019 by Tsjerk]

nimgoldman - 24-2-2019 at 11:42

Quote: Originally posted by Tsjerk

That is P2NP! Those needles are indistinguishable.

Yes I am happy for the success. It means the benzaldehyde extraction from kernels of Prunus spp. and the nitroethane synthesis were both successful.

morganbw - 24-2-2019 at 15:01

Perhaps not failed after all.
Be safe.

Chemi Pharma - 26-2-2019 at 09:21

I am planning reducing the product using Urushibara nickel (since it is not very toxic compared to mercury and not dangerous like LAH) - I will then try to confirm the resulting product (the corresponding amine) using TLC and reagents from DanceSafe to confirm the product.

[Edited on 23-2-2019 by nimgoldman]

Really? Urushibara nickel? Why don't you try something less outdated, easier and high yielding like nickel boride? Here's your recipe:

Attachment: amphetamine synthesis from phenylnitropropene - NaBH4 + NICL2.doc.doc (189kB)
This file has been downloaded 576 times

[Edited on 26-2-2019 by Chemi Pharma]

Tsjerk - 26-2-2019 at 10:54

Really? Urushibara nickel? Why don't you try something less outdated, easier and high yielding like nickel boride? Here's your recipe:

[Edited on 26-2-2019 by Chemi Pharma]

I wanted to suggest the same, but was sort of hoping for someone to get the Urushibara nickel to work... Just for scientific sake. But I wouldn't be the one to try to get the Urushibara nickel thing to work.

[Edited on 26-2-2019 by Tsjerk]

strychnineissweet - 26-2-2019 at 15:06

Evaporating the mixture is not an option as it haven't evaporated at all even after heating - then it all eventually vaporized in dark smoke when heated up too much. I think it's mostly benzaldehyde so the b.p. is too high and air-drying runs the risk of benzoic acid formation.

I am not sure why, but the product eventually crystallized out of solution anyway. I just moved the beaker several times between fume hood and a freezer, doing few test-tube experiments, and it suddenly crystallized.

I filtered the product and washed with cold MeOH. It indeed looks like phenyl-2-nitropropene:

https://imgur.com/9wiK16y

One of my test tube experiment was successful in precipitating phenyl-2-nitropropene (probably). I simply added some methanol to decrease solubility of the said compound:

https://imgur.com/FDnpxTm

Therefore I added methanol to the filtrate and got a second crop of crystals:

https://imgur.com/eMeqEa2

I will recrystallize everything from MeOH since I have serious doubts about purity. The yield about 1/4th of the expected, but I am glad the method even works!

I have performed this reaction every which way you can concieve of, what you are doing is probably the worst yielding and most complicated.

Do not use a solvent.

I'm not sure what you mean by how is it dehydrated.....the dehydration isn't solvent dependent. The majority of your reaction mixture will solidify, but only upon final cooling. You will be left with some orange-red liquid, but the lions share will solidify. This is the best yielding reaction method that I personally have found.

I don't have any thoughts as to Urushibara Nickel, but I can say that the NaBH4 + NiCl2 doesn't work. I lost many hours and lots of starting material trying to get it to - don't waste your time with that one. Your best bet really honestly is using Hg/Al. You can deal with the waste Hg by treating it with sulfur and turning it into cinnabar - a naturally occurring ore. Hg/Al is also going to be your best yielding, just shy of LAH.

Also, do future-you a favor and save a seed crystal of your nitropropene to help your future reactions crystallize. That is beyond all other methods the best and easiest way to induce crystallization.

Your product is most certainly P2NP, you should be happy with those crystals - they look good. I always used IPA to recrystallize, but I don't see why MeOH wouldn't work just as well. Any other questions I can answer please ask - I love helping other chemists work through places I've been before!

zed - 26-2-2019 at 15:36

Hunh?

You intend to reduce the product to an amine?

Not legal, where I live.

But, not to worry.

Generally speaking, that reduction always fails.

LiAlH4 works. Electrolytic Reduction sort of works, if you have the right gear; though most set-ups fail. And, I have read papers, possibly legitimate papers, suggesting some success with high pressure hydrogenation.

If the guys say Hg/Al works, to reduce Nitropropenyl benzenes to amines, it might be worth a try.

Past experience, on legal substrates, has shown me that NaBH4/NiCl2, CoCl2/NaBH4, and Pt/H2, are not effective at achieving the complete reduction of Nitropropenyl benzenes to amines.

Also, a most effective method of producing Nitropropenyl benzenes, is just mixing yer ingredients with a minimal amount of absolute ethanol, and letting the mixture sit for a week to 10 days at 100-120 F (absent air and light). Then let the mixture cool, and leave it undisturbed while it solidifies into a solid block of large crystals. Rinse and use.

[Edited on 26-2-2019 by zed]

karlos³ - 27-2-2019 at 01:04

Use NaBH4/CuCl2, it happens to become the new standard among a group of clandestine chemists, putting the Al/Hg to rest for now.

Chemi Pharma - 27-2-2019 at 03:29

I Agree with almost everything you wrote. You seems have a lot of experience in this process. I did many and many experiences in this way years ago in the University lab, just with scientific purposes of course, just to know if I was able to produce amphetamine salts.

At those times the studies with borohydrides and transition metal couples were at the beggining and was hard to find reliable references and experimental sections inside the researchs I barely get found at the web.

However I got found some articles talking about nickel boride and it's reductive power. I have experimented the P2NP reduction with NABH4 and NICl2 the same way the recipe I brought attached in my last comment and I got amphetamine. The smell of the amine is unmistakable but the yield sucks and I had some troubles with the work up.

First of all, every time I stripped of the methanol and add an acid, I got a red dark resin that ruins down all the reaction. Cause this I change the method from A-->B-->A to B-->A-->B. Researching a lot I discovered this dark red resin is some kind of nickel organic complex. Other thing to know it's not to use HCl in the work up followed or by Dicloromethane, cause amphetamine chloridrate is somewhat soluble in DCM. Use dilute sulfuric acid and work with the amphetamine sulphate.

I want to know from you about your negative experience reducing P2NP with NABH4 and NiCl2. Could we change some words about this? I'm quite interested in your personal experience.

Use NaBH4/CuCl2, it happens to become the new standard among a group of clandestine chemists, putting the Al/Hg to rest for now.

Karlos, could you give me more information about this method using copper boride instead nickel boride? I have read an article I donloaded here in the Forum talking about substituted nitrostyrene reduction to dopamine, but it's too much generical. Do you have any papers talking about NABH4/CuCl2 or CUSO4? I'm very interested on it.

Chemi Pharma - 27-2-2019 at 04:47

Hi fellows,

Talking about P2NP reduction, I want to know your oppinion about a method that employs HCl and Zn in isopropyl alcohol at 0-5ºC. I have a very good paper where the researchers did a very good job reducing nitrostyrenes with high yield. P2NP is just an alfa methyl nitrostyrene. I think this method worth a try to reduce P2NP and I'm intending to try this in my lab soon.

And before somebody say I'm talking about an illegal substance, here where I live only methamphetamine and derivatives are forbidden. Amphetamine salts can be legally prescribed by doctors in manipulated formulas, to treat morbid obesity and ADHD.

Read the attached article and give your comments, ok?

Attachment: Nitrostyrenes to amines with Zn & HCl II.pdf (265kB)
This file has been downloaded 1376 times

[Edited on 27-2-2019 by Chemi Pharma]

Corrosive Joeseph - 27-2-2019 at 07:29

The reduction of 1-phenyl-2-nitropropene in one step has been the bane of many a researcher for over 100 years now.

Al-Hg works, and quite well from what what I read........... But some people seem to have no luck with it and others just downright despise it.......... One outstanding quality is how cheap it is.

Ritter's Urushibara (with aluminum foil) was unrepeatable and subsequent experimenters reported 0-30% yield.
Antibody hit 50% on the 3,4,5-trimethoxy variant - https://www.erowid.org/archive/rhodium/chemistry/tmp2np-red....

The French patent with aluminum grains and anhydrous nickel chloride made from members of the cabbage family (yes, I know) states a 65% return of 1-phenyl 2-aminopropane
https://patents.google.com/patent/US9149796B2/en

The Leminger (zinc and aqueous HCl acid) does not work [EDIT] - for the nitropropene
https://the-hive.archive.erowid.org/forum/showflat.pl?Cat=&a...
https://tinyurl.com/ydyr6mza

But Nicodem seemed to think it would with anhydrous conditions
https://the-hive.archive.erowid.org/forum/showflat.pl?Cat=&a...

This has been a subject of debate elsewhere on the internet and is currently untested.

It is very doubtful that NaBH4-CuSO4 will do the business, and there is no NaBH4-CuCl2 paper because this reaction was discovered by the amateur community, and it is actually here already. Hiding in plain sight.
https://www.sciencemadness.org/whisper/viewthread.php?tid=80...

In other news, the reduction of the 1-phenyl-2-nitropropene with iron and HCl and it's subsequent hydrolysis to the ketone in 77% yields using the method of Hass and Susie https://chemistry.mdma.ch/hiveboard/palladium/pdf/US2233823....
followed by reductive amination with zinc, nickel acetate and aqueous NH3 has finally been proven, hitting a whopping 84% with the last one. Based on Scr0t's cyclohexylamine synthesis. Also found here.

Gentlemen.......... start your engines............. :cool:

/CJ

[Edited on 28-2-2019 by Corrosive Joeseph]

Chemi Pharma - 27-2-2019 at 07:41

Thank you @/CJ, you are my favorite librarian and historian here on this Forum!

followed by reductive amination with zinc, nickel acetate and aqueous NH3 has finally been proven, hitting a whopping 84% with the last one. Based on Scr0t's cyclohexylamine synthesis. Also found here.

@/CJ, where's the reference? I think you forgot to add the link, I guess!

[Edited on 27-2-2019 by Chemi Pharma]

Corrosive Joeseph - 27-2-2019 at 08:35

Based on Scr0t's cyclohexylamine synthesis. Also found here.

https://www.sciencemadness.org/whisper/viewthread.php?tid=20...

/CJ

[Edited on 27-2-2019 by Corrosive Joeseph]

Tsjerk - 27-2-2019 at 13:40

Nice review CJ!

The Leminger (zinc and aqueous HCl acid) does not work
https://the-hive.archive.erowid.org/forum/showflat.pl?Cat=&a...
https://tinyurl.com/ydyr6mza

This one does work wonderfully on β-Nitrostyrenes though. In methanol/aqueous HCl at least.

strychnineissweet - 27-2-2019 at 13:44

Use NaBH4/CuCl2, it happens to become the new standard among a group of clandestine chemists, putting the Al/Hg to rest for now.

My experience with the NaBH4/NiCl2 is that it destroyed everything, and as a result I was unable to recover any product OR any nitropropene. I'll be the first to admit that I have no idea where it went, because it sure didn't bubble out as CO2. I attempted this reaction several times, and had the same result each time.

I also attempted Zn/HCl reduction, which if I recall correctly only reduces the nitropropene to a nitropropane, not the amine. This reaction was quite vigorous, but ultimately didn't produce any amine product for me. The only reduction condition that I have ever had success, and very high yielding success with is with Al/Hg. I was getting >90% yield every time, and the workup and purification was just so simple and straightforward that I never put much stock in other methods beyond the ones that I tried. Most of my true experimentation was with the nitropropene synthesis, as I has such good luck with the reduction to amine right away that it never really warranted much prodding.

Chemi Pharma - 27-2-2019 at 19:59

Here's an article I just have found about NaBH4/CuSO4 couple reductions:

Attachment: Reduction Of Aliphatic Nitro Compounds To Amines Using NaBH4_CuSO4.PDF (132kB)
This file has been downloaded 833 times

karlos³ - 27-2-2019 at 20:08

Yes of course, but it is not copper boride which act as the reducing agent there, just the copper nanoparticles are what is doing the job here.
Take a look here: http://www.sciencemadness.org/talk/viewthread.php?tid=84596

It is very doubtful that NaBH4-CuSO4 will do the business, and there is no NaBH4-CuCl2 paper because this reaction was discovered by the amateur community, and it is actually here already. Hiding in plain sight.
https://www.sciencemadness.org/whisper/viewthread.php?tid=80...

Joe(also my favorite librarian

) is wrong with this claim but he couldn't know it.
Well, still partially right, since while this reduction was adapted by the clandestine community with some changes, there really is a reference existing.
The changes made are practical, a bit less of borohydride(6x at least), and, logically also a different workup depending on the product is done, which makes that route even more convienient, easier to carry out, with less work involved too.
It could be that it is somewhat based on the NaBH4/CuSO4 paper out there, but I don't know it for sure.

The differences I am talking about are in detail, 6 instead of 7,5 equivalents of borohydride, usually.
For valuable substrates, I would still use up to 7,5 molar equivalents of borohydride, as that will be in almost any case be the cheaper reagent here.
In case an amine able to get steam distilled is the product, then we do this different workup instead: acidic quench with aq. acetic acid after the reaction, distill the alcoholic solvent off, freebase it and steam distill the product off.
In case the amine is not, like a subst. phenethylamine, we still distill the alcoholic solvent off, and then after basification, extract the amine with portions of for example DCM, from which the product is recovered by the usual means.
Do not, I repeat, do not use the workup method cited in the paper!
They do it this crude only because they purify their result only later on sufficiently enough.

Thank you @/CJ, you are my favorite librarian and historian here on this Forum!

@/CJ, where's the reference? I think you forgot to add the link, I guess!

[Edited on 27-2-2019 by Chemi Pharma]

Comes from patent FR 971429 from the 40ies.
Barely noticed while a very valuable gem, we have in that paper not only reductive aminations, but reductions of some other very interesting substrates.
Like, Nitrosoketones to amino alcohols, double bonds, oximes, ketones, nitriles and lastly, nitro groups too... and all in high yields.
(no, it can not yet reduce nitroalkenes, does not work under the conditions this bimetallic reagent system is used in...)

I can really vouch for his claim, the 84%, that was really neat in every aspect!
It also was the substrate doing best in that synthesis for the chemist in question, at least among that half dozen of different starting materials he tried(reducing different functional groups mostly, not only aminating ketones).
The same substrate in a second experiment yielded still above seventy percent, due to being carried out using less vigorous conditions with reduced reagent quantities(to the theoretical needed amount, but on a really small scale), and was just done as concept of proof.
When doing it exactly like Scr0t's second experiment, one can possibly aminate whatever ketone one wants to with good yield, as his second experiment is optimised, it runs much better and smoother this way.

(Joe, you are an awful person! Making a grown man blush like a little girl!

)

nimgoldman - 27-2-2019 at 20:23

Thanks for all the input and references!

I know Al/Hg works, but I am quite opposed to working with highly toxic materials. My original project is actually getting to amphetamine all the way from bitter almond kernels (or bitter apricot kernels) using only easy to obtain materials. This is just a hobby project.

The reason for choosing Urushibara nickel was 1) the fact I found some tricks to improve it's activity based on NurdRage and ChemPlayer's videos, 2) that I have NiCl on hand, which is readily available, unlike HgCl which I was unable to get without causing unwanted attention, 3) becasue I read in some chemistry texts, that aliphatic nitro groups can be reduced to amino groups using zinc and acetic acid ... but I might not work after all and I have to get back to the drawing board and books (still having lot to learn unfortunately).

What seems more plausible now is making the ketone (phenylacetone) followed by the Leuckart reaction.

In the worst case, I was thinking about making water soluble Hg salt from cinnabar (which is easily obtained), but this would spawn another huge project.

Even getting to phenyl-2-nitropropene took several months of preparations (mostly going through hardships of making nitroethane and almost every non-working method there is), it seems one step away from finishing the project, but maybe the hardest part is actually there.

[Edited on 28-2-2019 by nimgoldman]

Corrosive Joeseph - 27-2-2019 at 20:34

(Joe, you are an awful person! Making a grown man blush like a little girl!

)

Followed by..........

Quote: Originally posted by Tsjerk

Nice review CJ!

The Leminger (zinc and aqueous HCl acid) does not work
https://the-hive.archive.erowid.org/forum/showflat.pl?Cat=&a...
https://tinyurl.com/ydyr6mza

This one does work wonderfully on β-Nitrostyrenes though. In methanol/aqueous HCl at least.

Thank you, Tsjerk.

Yes, it works well with beta-substituted hydrogens, but seemingly not so good with beta-substituted methyl groups........ Which confusingly (for some people, at least), become the alpha substituents upon reduction.
Of course, the atoms don't move, this is just the nomenclature, because styrene carbons are counted from the phenyl ring (because they are styrenes), and amine carbons are counted from the amino group, obviously........ because they are amines.

The zinc and HCl reduction of phenylnitrostyrenes, especially phenylnitropropenes has never been properly explored in my opinion.
Characterization has always been poor and if people don't hit the active amine, many seem to call failure, and this has been repeated on the boards ad nauseum. Nobody seems to want to poke about in that slop.

Molecules with ring methoxys and substituents seem to do well, and the original researchers hit the oximes a number of times in ~50% and 'good yields', respectively.
2,3-dimethoxynitrostyrene - https://sci-hub.se/10.1007/BF00899898
1-anisyl-2-nitropropene and 2-nitro-l-piperonylpropene - https://chemistry.mdma.ch/hiveboard/rhodium/pdf/pseudonitros...

In my link quoted by Tsjerk, GC_MS reports a yield of 80:20, ketone:amine, on 4-methoxyphenyl-2-nitropropene, probably using GC-MS analytical equiptment............ One would hope, with a username like that.

Another good review can bee found here.
''Selective Reduction of Conjugated NitroOlefins'
https://etd.ohiolink.edu/!etd.send_file?accession=osu1448465...

Keeping the reaction cold and having a high dilution (and the correct amount of acid) seems to help avoid the hydrolysis......... And there is also this.

"Nitroethenes and nitropropenes are electronically analogous to alpha,beta-unsaturated ketones(the classical Michael acceptor). The benzyllic carbon is electrophillic and is subject to attack by suitable nucleophiles, which in the case of nitrostyrene reductions could either be the fully reduced amine or the deprotonated nitroethane(electronically analogous to an enolate). Both nitroethenes and nitropropenes are good michael acceptors, and a deprotonated nitroethane is a good nucleophile, but a deprotonated nitropropane is usually so sterically hindered that it is not very reactive as a nucleophile, and dimerization is therefore much less of a problem in nitropropene reductions than it is in nitroethene reductions."

And as we all know, addition in a dissolving metal reduction happens in a 1,2 fashion, and not in a 1,4.
Analogous to an electro-chemical reduction..........

This means the nitro group is attacked preferably over the double bond, and reduction should happen 'from that end'.

The oxime of 1-phenyl-2-propanone has also been reduced to the amine in 76%, again using zinc, nickel(II)acetate and aqueous ammonia.
Another tried this system with the beta-methyl nitrostyrene and reported failure,
[EDIT] - No amine
but only one test was done, and it is possible his homemade Ni(II)acetate and low quantity of zinc contributed to this. Possibly something as simple as more acidic conditons are needed. Although, nitropropenes are much less prone to dimerization under basic conditions than nitrostyrenes.
But I do believe something else which is unproven at this point in time...........

So after all that, it would appear that iron, nickel(II)acetate, acetic acid and H20 should work even better to reduce the beta-methyl nitrostyrene to the saturated amino compound.
Because for nearly 100 years now, it has been known that addition of a nickel salt to an iron and acid reduction will cause the reaction to go to completion and to occur in less time. 2 hours instead of 8
http://www.orgsyn.org/demo.aspx?prep=CV1P0304

And exactly as has been shown to work with another a,b unsaturated compound, cinnamaldehyde............. In 1924
https://sci-hub.tw/10.1021/ja01675a014

They also noted in that paper, that the zinc reduction of the unsaturated compound produced a mix of products, and that iron and mildly acidic conditions gave good results,
keeping the double bond, which is the case of beta-methyl-nitrostyrene, amazingly quite similar, except the double bond seems to 'crack open and swing around, forming the unsaturated oxime. So, not surprising really, that both compounds do this.
And iron is less reactive than zinc.

/CJ

[Edited on 28-2-2019 by Corrosive Joeseph]

nimgoldman - 28-2-2019 at 01:53

Thanks for all the sources and articles. I have skimmed some of them and will try some of the approaches, then post the results in appropriate thread. The community is really helpful!

Fortunately, I have plenty of NaBH4 to experiment with so I can try using it either with NiCl or CuSO4 as advised. I might try the freshly prepared and activated Urushibara type-A catalyst for fun if I will have some phenyl-2-nitropropene (now beautifully recrystallized) left over.

Of course, the reduction has been done a billion plus one times in both pharmaceutical industry and clandestine laboratories, so I believe such reduction is a fairly well tried and tested process. It amazes me there is still a discussion actually, and so little well-written writeups.

The scientific literature I have calls either for LAH in THF or the Leuckart reaction, which I think is harder to work up as there are more organic impurities and side products.

Corrosive Joeseph - 28-2-2019 at 04:18

You are very welcome.
Notice that certain members are very interested in this, well, there is a reason for that.

The reduction of this conjugated nitro compound in one step has tortured chemists for over a century now. There is so little discussion because it is so difficult.

Some of the routes I have posted have only been developed in the last year or two. This is why there are not really any write-ups.

I don't know what Big Pharma do, surely hydrogenation and more than likely not in one step from P2NP.
The mafias of Europe have been using the low-yielding Leuckart for about 40 or 50 years in a 'hand-me down' recipe. Same again, the nitropropene has to bee taken to the ketone first.

There is so much disconnect between them and the community that nobody here (or anywhere) really knows a decent Leuckart procedure, and so far
the best Leuckart I have personally seen was 48%
And that was reported by another experimenter 6 weeks ago, not here. Before that, user 'logical' reported a yield in the 60's, but that was over two decades ago on the old Hive board.
Nothing much of note in between then.

The Al-Hg has been the gold standard in the community for about 20 years, when it was reported by Antoncho and those
tenacious bees over at the HyperLab, and was based on earlier pioneering work of Sunlight who discovered it would work on reducing 2,5-dimethoxynitrostyrene.
And nobody wants to use it.

The only major discovery since then was the work of stoichiometric_steve, posted here -
general high-yielding one-pot procedure for the reduction of conjugated aliphatic nitro groups - https://www.sciencemadness.org/whisper/viewthread.php?tid=49...

Based on the work of Bandil and Barium, https://chemistry.mdma.ch/hiveboard/methods/000460139.html
but you must NEVER believe a word posted by Barium, almost everything he wrote was utter fiction and many have wasted their chemicals following his write-ups and bullshit.

There are a couple of NaBH4 reduction write-ups, and reducion of the nitropropane can bee done with zinc or iron and most acids.

LAH is dangerous, explosive and hard to obtain, and apart from Alexander Shulgin and one scientific paper (Gilsdorf and Nord 1952),
you will not find much on that one either.

Apologies, maybe I dumped too much information on you in one go, but from what I read, NaBH4/NiCl2 and NaBH4/CuSO4 will not work, or at least, not very well or consistently.

'NaBH4/CuSO4 nitro reduction success!!' - https://sciencemadness.org/talk/viewthread.php?tid=6733
'new/old nitroalkene reduction method' - https://sciencemadness.org/talk/viewthread.php?tid=7190
'New nitroalkene reduction with NaBH4 / Cu(OAc)2' - https://chemistry.mdma.ch/hiveboard/novel/000246001.html

This is why this reduction is such an academic pursuit. It really is a genuine and legitimate scientific puzzle. Up until fairly recently, every route has what people regard as one major drawback or another.

/CJ

[Edited on 1-3-2019 by Corrosive Joeseph]

Chemi Pharma - 28-2-2019 at 05:59

The French patent with aluminum grains and anhydrous nickel chloride made from members of the cabbage family (yes, I know) states a 65% return of 1-phenyl 2-aminopropane
https://patents.google.com/patent/US9149796B2/en

@/CJ I enjoyed your explanations, references and historical data about the one pot reduction of P2NP to amphetamine. I understand now there are too much controversy! I read all the references you've posted and I want to know from you if the reference I quoted, from "Cabbage family" worth a try? is it reliable?

And just for curiosity. Why did you write "(yes, I know)" in parenthesis while writing about this reference?

The only major discovery since then was the work of stoichiometric_steve, posted here -
general high-yielding one-pot procedure for the reduction of conjugated aliphatic nitro groups - https://www.sciencemadness.org/whisper/viewthread.php?tid=49...

As a note, reading all the thread you've posted, signed by @Stoichiometric_Steve, now I'm felling relieved, cause now I know the problem in not me. This guy is really rude with a lot of other members here, since 2006, as we can see reading the humiliation he tryed to do against @pharmacological.

karlos³ - 28-2-2019 at 10:32

nimgoldman, don't use CuSO4, that sulfate is an inferior salt.
Better use the chloride, that is for some reason others can explain better almost functioning ideally(only the bromide, acetate, likewise maybe, are better to use here).

As for the nickel salts, I did the reduction of an oxime(l-phenacetylcarbinol) maybe 3-4 times already with the hydrates of both NiCl2(just once) and Ni(II)acetate(the remaining few times).
Yield was always improvable, but rather bad only that one time when I fumbled some reduction together myself(MeOH/DCM solvent combination), and got around ~28%, with the reduction being enriched with a little bit of the PTC agent triethylbenzylammonium chloride(0,25eq. mol of that PTC agent for one mol of borohydride).
On nitrostyrenes/-propenes Joe is right, it won't work satisfying if at all, I am sure.

Nothing else for LiAlH4 for the reduction of nitropropenes?
I think our member Halogen did it on simple P2NP with an acceptable yield, no?

@Chemi Pharma:
That is just the way stoichiometric_steve is...
If you find him already offensive, you would have had a hard time at the old hive I have to say

So better to just look over it, and if it offends you this much, then just shrug it off.
Because after all, he posts contain really worthwhile experimental data, with his findings being composed of very valuable details.

[Edited on 28-2-2019 by karlos³]

zed - 28-2-2019 at 18:13

Assuming that a procedure for the reduction of a nitrostyrene, will work to reduce a nitropropenylbenzene, is just wrong thinking. Logical thinking.... perhaps even clever thinking, but wrong thinking.

Generally, the first stage of a nitrostyrene reduction, produces an aldoxime. This aldoxime, is then further reduced, to an amine.

The first stage of reduction, of a nitropropenylbenzene, produces a ketoxime. Regretfully, those ketoximes are quite resistant to further reduction.

Furthermore, during most types of nitrostyrene or nitropropenylbenzene reductions, acetic conditions are probably preferable.

Otherwise, extensive polymerization may occur.

Thus the dark crud, instead of a usable product.

clearly_not_atara - 28-2-2019 at 23:01

CuSO4 is much less soluble in organic solvents than CuCl2. I assume the copper particles are much smaller when using CuCl2 than CuSO4, with Cu(OAc)2 somewhere in between. Following this trend CuBr2 may be even better since it is more covalent, but more expensive. (the correlation is more covalent -> more soluble -> better catalyst)

CuCl2 seems to work fine. I assume that you can convert the sulfate to the chloride with CaCl2 which is widely available as an air dehydrator (DampRid) or road deicer.

Corrosive Joeseph - 1-3-2019 at 01:16

if the reference I quoted, from "Cabbage family" worth a try? is it reliable?

And just for curiosity. Why did you write "(yes, I know)" in parenthesis while writing about this reference?

Is it reliable...........? I don't know.......... I would hope so, but my wishful thinking does not work on the same laws as chemistry.

If you look through the whole paper, you will read stuff like this

Example 5.2 Psychotria douarrei Plant

Calcining: The calcining is carried out according to the standard programme (300° C. for 2 hours, then 550° C. for 3 hours).

Preparation of the catalyst: 1 g of Psychotria douarrei ash is taken. A minimum of 12N HCl is added to the ash (approximately 20 mL); all of the solid passes into solution and rapidly becomes a pale green colour. After 2 hours at 60° C., the mixture is evaporated at 80° C., filtered and produces 1 g of a fine powder having a pale yellow colour, the colour of dehydrated nickel dichloride.

Results of ICP-MS (Table XIV):

TABLE XIV
Mg Al Ca Fe Cu Zn Cd Pb Mn Ni
Ash 87020 880 105945 260 4740 7040 20 300 260 185600
Crude catalyst 78240 1620 93719 1760 4560 5760 14 360 1160 270320

The patent is VERY long and has loads of other 'madness' in there about 'doped' nickel catalysts made from plants fed on huge amounts of metals.
(yes, I know)

Now do you get why I said that............?

And that's just TOO weird............. But I think I get what's happening here now. All the trace metals and minerals are exchanging charge, bouncing it about while it changes each time.

This actually reminds me of Organikum's (by now) famous post about metal impurities.
'Some remarks regarding older chemistry texts' - https://chemistry.mdma.ch/hiveboard/newbee/000478009.html

I don't know why, but the first thing that comes to mind is precipitation of Ni(0) from nickel chloride with zinc followed by addition of aluminum grains will do a similar thing. (Tri-metallic couple!)

But maybe it will work with regular NiCl2 and aluminum grains (and NOT the aluminum foil used by Ritter)............ Who knows.

Another thing to note is that in the procedure, the HCl acid is added in increments, leading me to think this helps with the reduction, reducing 'a little bit at a time', keeping the mix slightly acidic, but never too much, because if it was all added at once, the phenyl-2-nitropropene would just hydrolyse on it's way to the amine. That's the thinking anyways.

/CJ

[Edited on 1-3-2019 by Corrosive Joeseph]

karlos³ - 1-3-2019 at 03:27

Thank you for the explaination about the different salts affecting the microparticle size(and thus the ability of the reduction going to completion).
Considering how little of the copper salt is actually used here, it may be very valuable to switch to using CuBr2 for the reduction instead...
May have to try that soon, it is after all either cheap to acquire or easily and simply made if one has some HBr readily one hand.

Quote: Originally posted by clearly_not_atara

CuCl2 seems to work fine. I assume that you can convert the sulfate to the chloride with CaCl2 which is widely available as an air dehydrator (DampRid) or road deicer.

I had once, because I lacked the patience to wait on it getting delivered, prepared some CuCl2 out of hardware store copper tubing(HNO3 and H2SO4 to the sulfate), then worked via that to the chloride(no OTC CuSO4 here to be found or maybe I have lost all the skills once had in discovering OTC chemicals, so had to reside to this).

I found it very straight forward to convert the obtained CuSO4 solution to the carbonate directly, then react the filtered copper carbonate with HCl.
All in all from buying the tubing and having the CuCl2 ready took me only a half day if my memory serves me right.

But it may be easier when one already has a container of pure CuSO4 already on hand to do it with calcium chloride.

Chemi Pharma - 1-3-2019 at 04:15

Nurd Rage teaches in his you tube video how to produce CuCl2 in three ways. One of this is from CuSO4. See here: https://www.youtube.com/watch?v=V8mHiFYmlBc

nimgoldman - 15-3-2019 at 14:19

Apologies, maybe I dumped too much information on you in one go, but from what I read, NaBH4/NiCl2 and NaBH4/CuSO4 will not work, or at least, not very well or consistently.[Edited on 1-3-2019 by Corrosive Joeseph]

I just tried the NaBH4/NiCl2 procedure that Chemi Pharma proposed few posts back, but it didn't worked.

I followed the procedure to the letter and everything worked perfectly, even the smell of amine was very distinctive and I already though I have the desired propanamine. Well, I didn't.

The product simply refused to precipitate. I tried pulling it in dry acetone, then crash it out with conc. sulfuric acid - no result. Then I tried HCl - no result. I tried pulling it in IPA and add sulfuric - no result. I tried adding hexane to lower solubility but it only pushed everying into separate aqueous layer.

I was desperate and even tried IPA + ether which produced some clouding that quickly disappeared. I managed to make white precipitate in one test tube, but that ether was impure and I had to distill it first.

Meanwhile I placed the product in the freezer and when I finally had my ether, I pulled the product in IPA and added ether... and no reaction again.

So I ended up kind of frustrated and maybe some day try the Leuckart reaction. I came all this way to the nitropropene only to realize the damn super toxic mercury seems to be the only way... well I don't want to use mercury since I am a home experimenter and not skilled in handling highly toxic substances unfortunately. I just wanted to make a writeup on making an interesting psychoactive compound on microscale using only easily available and as eco-friendly materials as possible...

nimgoldman - 16-3-2019 at 06:52

Okay I've read the following paper from 1994 suggesting several routes from phenyl-2-nitropropene to phenyl-2-aminopropane (amphetamine):

Quote:

DeRuiter, Jack, C. Randall Clark, and F. Taylor Noggle. "Gas chromatographic and mass spectral analysis of amphetamine products synthesized from 1-phenyl-2-nitropropene." Journal of chromatographic science 32.11 (1994): 511-519.

One method requires Pd/C catalyst and hydrogenation in a Parr apparatus, neither of which I have.

Another method uses LAH in THF, which is known to work but even though I can get both LAH and THF, the procedure requires dry THF and many precautions as there are fire and explosion hazards.

Finally two other methods work on phenyl-2-pronanone and look much more viable (the synthesis of the phenyl-2-pronanone intermetidate is included in the paper):

One method uses sodium cyanoborohydride and ammonium acetate in methanol, which I am able to perform. I still hesitate in using the precious cyanoborohydride as I save it for another reactions.

Second method uses the Leuckart amination (using formamide). The researchers didn't use a Kugelrorh for workup and the GC-MS spectra still looked very good.

I will post this in a new, more relevant thread, summarizing what others posted to the topic since all this went OT.

Corrosive Joeseph - 16-3-2019 at 07:44

Will you do me a favour and keep it here please. In my opinion, you have two real options.........

(1) Iron and acid to the ketone, steam it out, vacuum distill, zinc-nickel-NH3 to the primary amine.

(2) NaBH4-CuCl2 one-pot

You can thank me later.

/CJ

Attachment: deruiter1994.pdf (1.5MB)
This file has been downloaded 624 times

karlos³ - 16-3-2019 at 08:23

I agree very much on that, I used both routes that CJ described, and both result when done right, in more than 80% yield even!

Corrosive Joeseph - 16-3-2019 at 08:37

Second method uses the Leuckart amination (using formamide). The researchers didn't use a Kugelrorh for workup and the GC-MS spectra still looked very good.

These guys copied the errors straight from the MDA synthesis in M.V. Smith's 'Psychedelic Chemistry', which was in turn copied from Chemical Abstracts 52, 11965 (1958), let me know what happens when you stir your formyl-amphetamine with H2O2............ It should read H2O.

They don't give any yields either (facepalm)

/CJ

[Edited on 17-3-2019 by Corrosive Joeseph]

nimgoldman - 17-3-2019 at 07:45

Yes I am surprised I found the procedure in "Psychedelic Chemistry" from Smith. I have it printed but I never thought it is there... it is under "Mescaline and friends" chapter - I would never look for it there.

Will you do me a favour and keep it here please. In my opinion, you have two real options.........

(1) Iron and acid to the ketone, steam it out, vacuum distill, zinc-nickel-NH3 to the primary amine.

(2) NaBH4-CuCl2 one-pot

You can thank me later.
/CJ

Sure no problem.

(1) Can you please elaborate on "zinc-nickel-NH3 to the primary amine" ?

(2) I tried NaBH4-NiCl but that turned up as failure, but I might as well made some mistake in the workup.

I still have about 5 grams of very pure nitropropene, so I will decide on the reduction after I am sure the method actually works, at least for some people. I am suprised how many writeups and even methods published in academic journals turn out not actually working ... especially about a reaction that is extremely common in clandestine laboratories.

TheMasterOfTheInternet - 17-3-2019 at 15:01

NiCl2+NaBH4 and Ra-Ni+NaBH4 both have a slightly tricky workup and if the reaction time was too short I ended up with the solid colorless oxime (I think) instead of the amine. Also I think the reaction is extremly sensitive towards inpurities in the educt.
Decolorisation (hydrogenation of the double bond) is very fast in this reaction but reduction of the -NO2 to -NH2 is slow, so this might be also a reason why many failed it (looks like it's finished when it's not even the half way through the reduction).
After several failures got yield around 55% for the harder ones (which also won't work with most other methods) and reproducable 80-90%(!) for the more usual simpler educts. The most important trick is to avoid A/B extraction*. An Ra-Ni is better than NiCl2/NiB but it works aswell. I haven't tried copper chloride yet.

*For better workup:
I recommend first filtering the catalyst (can be reused several times btw.), wash catalyst with alcohol, add enough saturated potassium carbonate solution to salt out an amine/alcohol layer, seperate phases, distill the alcohol off, then directly water-jet-vacuum-distill the clear colorless product.

That's very much faster, cheaper, much safer and higher yielding than usual workup with B/A/B and especially simple A/B, which is a pain in the ass with such a huge amount of NaBH4 and nickel in the reaction mixture (NaBH4 and acids can cause explosive reactions, Ni will form unfilterable slime containing most of your product)

I also used a different procedure than ChemiPharma
On a-alkyl nitroarenes I added the educt first to an ethanolic NaBH4-solution (huge excess) slowly spatula by spatula, always waiting for discoloration before the next spoon is added, keeping then temperature below 20°C with ice/water cooling to avoid dimeric byproducts. THEN I slowly added the seperatly prepared catalyst in MeOH (NiB) or EtOH (Ra-Ni). Always got ~60-75% with NiB and easily 80-90% with Ra-Ni (I recommend W7- or T4 type as they're easy to make on your own and very active) on alpha-alkyl nitroarenes, but much less yield in the 35-65% range with nitroethenes, unless adding tons of silical gel and the catalyst before, then I got 55~70% aswell, but that's different topic

[Edited on 18-3-2019 by TheMasterOfTheInternet]

Chemi Pharma - 18-3-2019 at 06:06

Yeah man, I got frustrated like you when I tried this kind of reaction a lot of times at the University Lab. I feel I wasn't completely honesty with you guys about the study I've brought in my last threads. Alhough the smell of amine is preponderant, I had the same problems @nimgoldman had, following the recipe. At the end of the work up I got just a few crystals that were filtered and had gave positive result to amphetamine, giving a deep orange color with some efervecence with Marquis Reagent.

I tried to ajust the work up, first doing an B/A/B work up, instead A/B/A, like I just have said in my last threads, cause the dark red resine formed while you put acid into the residue of the reaction (no matter if it was diluted HCL, ACOH or H2SO4, and I feel @TheMasterOfTheInternet is right when he say Nickel hates acid media) after strip off the solvent (MEOH), because always some NIB pass trough the filter paper, and you end up with a black sludge at the final of destilling MEOH.

Although I never tried or pay attencion to what @TheMasterOfTheInternet said in his last post, I think he is right talking about the tips and tricks you have to pay attencion while doing this kind of reaction, mainly about the reaction time and the need of mantain the reaction temperature near to 0ºC, to avoiding polimerizated byproducts.

I remember that after follow the recipe I brought, in the part relative with the P2NP reduction, I had extended the time of the reaction, although following the quantity of reagents and the order of adding it into the reaction flask.

First I did the methanolic NICl2 solution and put the indicated amount of NaBH4, turning the solution into a black color one. Next I added the P2NP at once and extended the time of stirring to half an hour. Then I added the last required quantity of NaBH4 in very little quantities at a time to avoid frothing, always mantaining the becker inside an ice bath. After all have been added, I still have stirred the reaction one more hour, to guarranty total reduction of the NO2 group.

Its like @TheMasterOfTheInternet have said. The double bond is quickly reduced by alcoholic solution of NaBH4, no matter if you use MeOH, EtOH or IPrOH. I'm trying yet to understand the role this three kind of alcohol does at the reaction, talking about the yields. On the other hand, the NO2 group is reduced to NH2 very slowly. First to oxime and then to amine and you have to use huge amounts of NaBH4 into alcoholic media with NIB (or may be CuCl2 - I will try it yet) to do that as a second step, besides stand up the time of reaction.

Another thing I repute interesting in what @TheMasterOfTheInternet have said is about to avoiding the use of A/B or B/A work up and about the losses, mainly using DCM in the work up. I don't know why, but I think he's right. DCM for some reason seems to screw up all the yield at the work up. May be EtOAc could be better.

The idea of vaccum distilling the reaction mixture after distilling off the solvent seems to mee a good idea, and I will try this in my personnal lab when I have a chance.

Good to see we are, all of us, evoluting here in this topic, switching experiences and knowledge, trying to solve a problem that became not solved for the last 100 years, like @C/J said. And remembering @C/J, let's try to keep in this thread all discussion about alkyl nitrostyrenes synthesis and reduction to aryl alkylamines, to facilitate the forum research in the future.

TheMasterOfTheInternet - 18-3-2019 at 15:23

I can easily tell you the difference between MeOH, EtOH and IPA, I've used them all for NaBH4 reductions.

NaBH4 has a high soloubility in MeOH but is very unstable in this solvent, so it's not useful for long reaction times or you have to add it continously or as late as possible or several times the amount of NaBH4 than you would need than in EtOH or IPA. But also reaction times seem to the fastest in MeOH

NaBH4 is quite stable in IPA, but has a very low soloubitly in it - you would need much more solvent OR you're getting a higher tendency towards dimeric byproducts, as if the NaBH4 isn't fully dissolved there's never such an high excess of it available than in EtOH or MeOH. IPA works but it's inferior to MeOH and EtOH, as it has longer reaction times and product is less clean. Also most salts are insolouble in this solvent so you can't produce NiB or CuB in-situ. I don't recommend this solvent for most NaBH4 reductions. Another benifit is that the workup is easier, as you can salt-out it much easier than MeOH and EtOH (no K2CO3 necessary, sodium chlorid solution is good enough).

EtOH is in the middle between them and usually the solvent I recommend for NaBH4 reductions. It don't has to be dry 99% EtOH, usual azeotropic 94-96% with a little MEK works well too. Nickel acetate has quite a low soloubilty in this solvent, that's why I don't prepare the NiB-catalyst in situ when using this solvent. Though NiCl2 dissolves quite good. It don't know which copper salts could be used.

And I don't think 0°C are necessary, it would only lower the reaction times and soloubility of NaBH4 - 10-20°C works perfectly well for alpha-alky-nitroarenes and gives best yields.
After complete discoloration much higher temperatures (refluxing) are no problem.

[Edited on 19-3-2019 by TheMasterOfTheInternet]

zed - 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.

Chemi Pharma - 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"

zed - 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.

morganbw - 20-3-2019 at 09:58

Quote: Originally posted by zed

Sometimes I smile while reading a post. I may return when sober and see if I still smile. I think I may.

Chemi Pharma - 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 1002 times

karlos³ - 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).

Chemi Pharma - 21-3-2019 at 11:54

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.

karlos³ - 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%)

Chemi Pharma - 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.

karlos³ - 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).

nimgoldman - 22-3-2019 at 09:28

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.

karlos³ - 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.

nimgoldman - 1-4-2019 at 22:14

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.

Corrosive Joeseph - 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

Chemi Pharma - 30-4-2020 at 03:47

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.

karlos³ - 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]

Chemi Pharma - 30-4-2020 at 04:07

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]

karlos³ - 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]

Johnny Windchimes - 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

Attachment: M. B. Tolmie Masters Thesis - Australian Federal Police - Copy.pdf (1.9MB)
This file has been downloaded 1191 times

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

OrganicGuy - 10-2-2021 at 08:00

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"

I also did the NiCl2*6H2O with NaBH4 reduction at least 5 times, not once did I have any success. I want to add I used very high grade regaent's which a buddy brought me from his work place (a legit pharma industry). I call that NiCl2 method total crap & bogus ... like many other Indian Journal papers I tried is also complete nonsens and I'm amazed that some Journals publish Indian chemistry since it's over and over lies and BS. The Varma & Kabalka papers are to 50% total BS, and the rest 50% the yield they claime is heavily exaggerated

The Cucl2 + NaBH4 method is superior, best of all p2np reduction I've ever done, but only up to 20 gr batches, the more you increase Mol per batch the lower theoretical yield you'll have (all people I know say the same., so I would be very suprized if someone have other news to tell) . The sodium bisulphite washings of the p2np is first time I see someone mention here (THUMBS UP), that superb, very important to have good yield for whatever you're using your p2np. That's the far best way to clean out all benzaldehyde contamination of the p2np, and whatever reaction you wanna do with your p2np the benzaldehyde is a bitch and will interfere and gives lower yield ketone, oxime, nitroalkane or amine. Always wash p2np with sodium bisulphite solution and recrystalize before doing any reaction

OrganicGuy - 7-3-2021 at 15:49