Sciencemadness Discussion Board

Reductions of Nitro groups with Zn and acid

stoichiometric_steve - 27-8-2008 at 00:55

Referring to the well-known procedures of Bandil and Barium, in response to some questions at the CTH thread:

In my experience, in Bariums (and Bandils) writeups it appears that everything is done in a flash. Trust me, it usually is not. Reductions with Zn/acid are a pain to deal with unless you steam distill your product out of the mix. It IS possible to extract the basified rxn mix with toluene, but you need a huge sep funnel and quite a bit of patience.

I do wish you good luck in getting NH4COOH to work with Zn. It didn't work for me, and i'd rather use HCOOH, CH3COOH or HCl.

starman - 27-8-2008 at 06:21

Well I did want to try ammonia formate,went to considerable trouble to synthesise.(we can't buy anything here)I haven't been able to produce formic acid more concentrated than around 50%(by density via oxalic).So practically limited to formate salt of some description,but I do possess good quantitites of reasonable purity zinc dust.
I know jack about CTH or reductions in general,The Zn/formate procedure I looked at didn't have A/B in the work up.So basically I would rather listen while you guys talk and ask a question or two here and there for my education.

stoichiometric_steve - 27-8-2008 at 06:25

Quote:
Originally posted by starmanThe Zn/formate procedure I looked at didn't have A/B in the work up.


If there also was no steam distillation, then it is pretty hard to get pure product from this procedure.

Nicodem - 27-8-2008 at 09:17

Quote:
Originally posted by starman
Well I did want to try ammonia formate,went to considerable trouble to synthesise.(we can't buy anything here)I haven't been able to produce formic acid more concentrated than around 50%(by density via oxalic).So practically limited to formate salt of some description,but I do possess good quantitites of reasonable purity zinc dust.

You went trough the trouble of preparing formic acid just to waste it in a reduction of a nitro compound with Zn powder? I hope you are aware that even HCl with Zn works. In some cases even acetic acid. And you don't even need Zn - even tin, iron or amalgamated aluminium works.
Quote:
I know jack about CTH or reductions in general,The Zn/formate procedure I looked at didn't have A/B in the work up.

The Zn/HCOOH and Zn/HCOONH4 are not CTH reductions and have nothing to do with CTH reductions using formates as hydrogen donors. The zinc powder is consumed during the reaction, acting as the reducent, while HCOONH4 is just a weak acid necessary as a proton donor (not hydrogen donor as in CTH based reductions).

Fe - HCl reduction

tapira1 - 27-8-2008 at 15:29

Iron filings and a strong acid is able to reduce nitro groups such as nitrobenzene to amines like aniline.

Klute - 27-8-2008 at 16:53

aromatic nitro groups are much easier to reduce than aliphatic, and give cleaner products (less side reactions).

I suppsoe in theory Sn, Fe, etc could reduce aliphatic nitro groups, but I don't recall seeing any preparative procedures, except perhasp for the lower chains: nitromethane, nitroethane, etc.

merlic79 - 27-8-2008 at 17:22

Couldn't one just use Sodium Dithionite in a basic H20 MeOH media to reduce to an aniline? It is readily available at the Home Depot as a rust cleaner in 1 pound containers for $6. However, it does contain a bit of bisulfite in it though.

smuv - 27-8-2008 at 18:31

Zn/HCl Reduction of Nitrostyrenes to phenylethylamines

Fe/HCl Reduction of Nitrostyrenes and nitroethanes
Synthetic Communications®, 35: 913-922, 2005

[Edited on 27-8-2008 by smuv]

Klute - 27-8-2008 at 20:03

My bad :)
The Zn reduction I knew about, but the Fe reduction gives the oximes (which are then hydrolyzed to ketones) IIRC. I suppose Sn gives similar results?

stoichiometric_steve - 28-8-2008 at 00:06

Quote:
Originally posted by smuv
Fe/HCl Reduction of Nitrostyrenes and nitroethanes
Synthetic Communications®, 35: 913-922, 2005


Please note that this procedure doesnt really work as advertised. It says that it gives a 60% yield of mescaline from the nitrostyrene, while it has been stated elsewhere that reduction of nitrostyrenes with acid and metal give predominantly the dimeric product. an addition of powdered Silica Gel is needed to make this reaction work with nitrostyrenes (as opposed to nitropropenes, which give ketones and oximes).

Nicodem - 28-8-2008 at 00:56

Zinc with conc. HCl in a cosolvent like isopropanol reduces aliphatic nitro compounds. If kept at 0°C it reduces omega-nitrostyrenes to 2-phenylethylamines as well (however, it only works with terminal nitro alkenes). There are plenty examples posted in several forums confirming that this method works as published once mastered.

Sodium dithionite only reduces nitroaromatic compounds. It does not work on aliphatic nitro compounds as far as I know (but I'm not sure). Though, since it reduces conjugated double bonds, it might actually be useful in preparing nitroalkanes from conjugated nitroalkenes which can then be reduced by other methods. Such a two step procedure could be higher yielding than a direct reduction of nitroalkenes to amines. However, I never saw dithionite being used on nitroalkenes, just acrylates.

Iron powder might not work as advertised in that Synth. commun. paper on nitrostyrenes, but there are plenty of other published papers where Fe/AcOH, Fe/HCl(aq)/cosolvent or Fe/NH4Cl/EtOH/H2O and even FeSO4/NH3(aq) is used to reduce nitroalkanes (both terminal and secondary nitroalkanes as well as beta-nitroalcohols) to amines (just make a literature search and you will find plenty references). The same goes for Sn/HCl(aq)/cosolvent and SnCl2/HCl(aq)/cosolvent combinations (SnCl2/HCl(aq)/MeOH does not reduce nitrostyrenes to amines, but the reduction stops at 2-aryl-2-methoxyetanal oximes).

starman - 28-8-2008 at 03:58

Quote:

The Zn/HCOOH and Zn/HCOONH4 are not CTH reductions and have nothing to do with CTH reductions using formates as hydrogen donors. The zinc powder is consumed during the reaction, acting as the reducent, while HCOONH4 is just a weak acid necessary as a proton donor (not hydrogen donor as in CTH based reductions).

Thanks for clearing that up.Saved me asking what is obviously a silly question.

Quote:

You went trough the trouble of preparing formic acid just to waste it in a reduction of a nitro compound with Zn powder?

Ah well....it was a fun learning experience and have subsequently improved my azeotrope to circa 75%,hopefully anhydrous CuSO4 will dry to the mid 80's.

Thanks for the replies,I'll research the suggested references.

Barium - 29-8-2008 at 04:12

Quote:
Originally posted by stoichiometric_steve
In my experience, in Bariums (and Bandils) writeups it appears that everything is done in a flash. Trust me, it usually is not. Reductions with Zn/acid are a pain to deal with unless you steam distill your product out of the mix.


What do you mean? Am I omitting details or what?

[Edited on 29-8-2008 by Barium]

Barium - 29-8-2008 at 05:01

Quote:
Originally posted by stoichiometric_steve
Please note that this procedure doesnt really work as advertised. It says that it gives a 60% yield of mescaline from the nitrostyrene, while it has been stated elsewhere that reduction of nitrostyrenes with acid and metal give predominantly the dimeric product. an addition of powdered Silica Gel is needed to make this reaction work with nitrostyrenes (as opposed to nitropropenes, which give ketones and oximes).


Does it really? I can't find the number 60% mentioned with mescaline in that article. What I can find, is that they claim to have reduced 3,4,5-trimethoxy-beta-nitrostyrene to mescaline in a 72% yield, and 1-(3,4,5-trimethoxyphenyl)-2-nitroethane to mescaline in a 75% yield. I can believe the latter but I have a hard time believing the former.

Seeing you talking about dimeric products and silica gel makes me believe you are talking about the borohydride/EtOH/Dioxane reduction system to reduce nitroalkenes to nitroalkanes and not any metal/acid system.

stoichiometric_steve - 29-8-2008 at 05:58

Yeah, i was wrong about the figures. Whatever those indians claimed, i don't believe them.

The Fe/HCl reduction (yielding ketones) works best at 100°C and 7:2:1 Fe:HCl:Nitroalkene, solvent water, vigorous stirring, and a dash of FeCl3.

Quote:
Originally posted by Barium
What do you mean? Am I omitting details or what?


I'm not sure what's wrong with some of your procedures, it could just as well be my fault. But as for your "really wet redfuctive amination", i know of several people (who have the right kind of experience) having been unable to reproduce your claimed yields. The best i got myself was 10%.

Quote:
Originally posted by Barium
Seeing you talking about dimeric products and silica gel makes me believe you are talking about the borohydride/EtOH/Dioxane reduction system


Nope, i do know my shit. The dimerization is also a problem here - Especially when making indoles the way these fellas did: Beer et al., J. Chem. Soc.; 1948, 1605-1609

BTW Barium, you probably never noticed how useful your water/toluene/PTC system is for reduction of secondary nitroalkenes. Your writeups and posts left me with the impression that all you wanted is to avoid PTCs, despite the fact that there is no double bond reduction as simple as this. I applied it to large scale batches and it is the best method - easy workup, reaction runs on its own, great yields, easily recycled solvent.

Barium - 29-8-2008 at 07:24

Quote:
Originally posted by stoichiometric_steve
The Fe/HCl reduction (yielding ketones) works best at 100°C and 7:2:1 Fe:HCl:Nitroalkene, solvent water, vigorous stirring, and a dash of FeCl3.


I'd use Fe/HCl and aqueous acetone or MEK at reflux, or even Fe/HCl in aqueous acetic acid at about 90 deg C. But that old patent works quite well too.


Quote:
Originally posted by stoichiometric_steve
I'm not sure what's wrong with some of your procedures, it could just as well be my fault. But as for your "really wet redfuctive amination", i know of several people (who have the right kind of experience) having been unable to reproduce your claimed yields. The best i got myself was 10%.


I report the yields I get. Why others have problems reproducing them can be due to a whole lot of reasons. It can be something as trivial as too low stirring speed (especially in PTC-reactions), as well as wrong catalyst (like trying to use platinum instead of palladium) or the correct catalyst but wrong support material (e.g. alumina instead of carbon).


Quote:
Originally posted by stoichiometric_steve
BTW Barium, you probably never noticed how useful your water/toluene/PTC system is for reduction of secondary nitroalkenes. Your writeups and posts left me with the impression that all you wanted is to avoid PTCs, despite the fact that there is no double bond reduction as simple as this. I applied it to large scale batches and it is the best method - easy workup, reaction runs on its own, great yields, easily recycled solvent.


I've modified that system a bit since the Hive went down. But yes, I know it is a clean method.

stoichiometric_steve - 20-10-2008 at 09:55

Quote:
Originally posted by Barium
I've modified that system a bit since the Hive went down. But yes, I know it is a clean method.


Please elaborate.

Isomeric_Fred - 28-10-2008 at 00:42

Quote:
Originally posted by Barium
Quote:
Originally posted by stoichiometric_steve
I'm not sure what's wrong with some of your procedures, it could just as well be my fault. But as for your "really wet redfuctive amination", i know of several people (who have the right kind of experience) having been unable to reproduce your claimed yields. The best i got myself was 10%.


I report the yields I get. Why others have problems reproducing them can be due to a whole lot of reasons. It can be something as trivial as too low stirring speed (especially in PTC-reactions), as well as wrong catalyst (like trying to use platinum instead of palladium) or the correct catalyst but wrong support material (e.g. alumina instead of carbon).


I feel like a broken record, but really most of ur procedures dont work, especially when followed to the letter. Perhaps you omitted some important side notes which you deem basic or something and we just dont figure it out? All I know is that the numerous times ive used your procedure ive failed to get any meaningful yields. Except for some stuff like what stoichiometric steve said bout nabh4 reduction of nitroalkenes...

Back to the thread at hand, someone i know tried Zn/HCl on 2,5-dimethoxynitrostyrene, and got a low yield. He followed the procedure found on rhodium - http://www.erowid.org/archive/rhodium/chemistry/leminger.htm...

Nicodem - 28-10-2008 at 05:02

Often, the yields of reactions repeated from other's written procedures are positively proportionally related to the theory understanding and knowledge of the experimentalist (among other factors). This does not necessarily impute a telepathic connection between the experimentalist and the mass of molecules in the flask, but rather all kind of other physical interactions all aimed at improving the reaction yield. I guess that is why a chemists need to study a lot before he is good at what he does - otherwise just about any idiot could do this job.

Barium - 28-10-2008 at 05:17

Quote:
Originally posted by Isomeric_Fred
Perhaps you omitted some important side notes which you deem basic or something and we just dont figure it out?


What can I say? Therein lies the difference between the cook and the chemist.

Isomeric_Fred - 29-10-2008 at 04:23

Quote:
Originally posted by Barium
Quote:
Originally posted by Isomeric_Fred
Perhaps you omitted some important side notes which you deem basic or something and we just dont figure it out?


What can I say? Therein lies the difference between the cook and the chemist.


Wrote a very long and angry reply to your condescending answer to my above polite question, but as I hate seeing good board fall into flame-wars, decided to delete it and wish you the best of luck in all your endeavours!

Have fun :D

[Edited on 29-10-2008 by Isomeric_Fred]

stoichiometric_steve - 29-10-2008 at 04:35

Quote:
Originally posted by Barium
What can I say? Therein lies the difference between the cook and the chemist.


I must admit, i didn't expect such a snotty answer. Hats off to the uber chemist!

Barium - 29-10-2008 at 16:11

Steve/Fred

There is actually, believe it or not, a limit to my patience. I know of several members of the Hive who have successfully used my methods. Both well trained chemists and simple cooks. By simple I mean people who have no idea what is actually happening in the rection vessel and why and are not capable to modify a protocol to a new substrate or exchange one solvent for another. Yet Steve decided to solemly declare the CTH-reduction system completely flawed and later, more or less openly call me a liar, when in truth he didn't even have the basic understanding how it worked. No Steve, the potassium formate does not have to be dissolved in the IPA layer. Read the patent!

I have over the years gained some expertise in hydrogenations and can more or less perform them blindfolded, but I have a terrible track record for Zn/formic acid and other dissolving metal reductions. A friend of mine can't understand how the fuck I can fail with those reactions when he rarely gets a bad yield with them. Do I claim those methods bogus? No, why should I?

I gave a couple of examples of reasons why one person can get results another person can't reproduce.

Quote:
I report the yields I get. Why others have problems reproducing them can be due to a whole lot of reasons. It can be something as trivial as too low stirring speed (especially in PTC-reactions), as well as wrong catalyst (like trying to use platinum instead of palladium) or the correct catalyst but wrong support material (e.g. alumina instead of carbon).



I have recieved complaints from several persons about the "really wet reductive alkylation" and without exception none of them had used the same substrates as I had. Yet they expected the same yields I reported. That is simple cook mentality and understanding of the procedures. I am not, nor have I ever been, interested in spoonfeeding information to people. If that makes me snotty and condescending, then so be it.

starman - 30-10-2008 at 03:14

I woukd of thought it important to remember that Barium's write ups are for the most part,minor modifications of publshed procedures.Reputable laboratories,well credentialed chemists under peer review scrutiny,working with the best of equipment and materials.Even these guys get into pretty heated debate in the literature as to the reproducibilty of a particular yeild or result.Sometimes with barely veiled accusations of massaging the data.I think it fair to state there is a great deal of art in the science of chemistry.
Back on thread..... If the acid merely acts as a proton donor,is there a particular explaination why Zn/HCL will only reduce a terminal nitro whereas Zn/HCOOH will reduce both intermediate and terminal nitros?

stoichiometric_steve - 30-10-2008 at 11:50

Quote:
Originally posted by starman If the acid merely acts as a proton donor,is there a particular explaination why Zn/HCL will only reduce a terminal nitro whereas Zn/HCOOH will reduce both intermediate and terminal nitros?


There is no explanation because this is not true, assuming that you are talking about saturated nitroalkanes. Zn/HCl does also reduce secondary nitroalkEnes, but you get oximes and ketones instead of amines.

I've just successfully reduced a primary and a secondary nitroalkAne with Zn/HCl in IPA, and the yield was great (about 80% for each amine).

edit: This may be something some people are overlooking: A nitro group needs 6 electrons for complete reduction to the amine, hence you need 3 eq. Zn(0) and 6 eq. H+ per nitro group.

[Edited on 30-10-2008 by stoichiometric_steve]

xwinorb - 31-10-2008 at 14:58

To Isomeric_Fred :

I never got less than 55 % with the modified Leminger method. I never tried exactly the procedure as in the Rhodium page ( Leminger paper ). Can tell you it works very well for the 2,5-DMBA, my latest was 75 %. If interested see my previous posts.

It DOES NOT works so well for 3,4,5-TMBA though, yields much lower. I would suggest acidic Al-Hg for this one.

I usually use batch sizes 20 g or so of the 2,5-DMBA, in a 2 l BF.

xw.

stoichiometric_steve - 1-11-2008 at 04:20

Something else that seems to be critical for a nice yield: keep the reaction hot and don't add the HCl too slowly, otherwise the Nitroso intermediate will tautomerize to the Oxime and hydrolyze to the parent Carbonyl compound.

stoichiometric_steve - 23-9-2020 at 13:58

Quote: Originally posted by Barium  
I know of several members of the Hive who have successfully used my methods. Both well trained chemists and simple cooks.


If you ever come back to read this:

Fuck you, Thomas Lillius

njl - 23-9-2020 at 17:51

Yet another rollercoaster of a thread. Steve, what prep are you referring to in that 11/1/08 reply? I've been try a few variations on the SM thread linked in the rhodium archive where HCl is added to the substrate in methanol, with zinc being added afterwards and the reaction being cooled.

stoichiometric_steve - 24-9-2020 at 01:30

Referring to the reduction of secondary nitro compounds with Zn/HCl.

You meant the Leminger variant, which is preferable for primary nitrostyrenes.


njl - 24-9-2020 at 02:18

Right. Honestly the procedure calling for zinc held in suspension with the substrate and addition of the acid over time was much more convenient when I tried it on nitrostyrenes and I did end up getting reasonable yields despite screwing up isolation. What about the kinetics makes the order of addition more favorable for different substrates?

OrganicGuy - 20-12-2020 at 05:07

Quote: Originally posted by stoichiometric_steve  
Yeah, i was wrong about the figures. Whatever those indians claimed, i don't believe them.

The Fe/HCl reduction (yielding ketones) works best at 100°C and 7:2:1 Fe:HCl:Nitroalkene, solvent water, vigorous stirring, and a dash of FeCl3.

Quote:
Originally posted by Barium
What do you mean? Am I omitting details or what?


I'm not sure what's wrong with some of your procedures, it could just as well be my fault. But as for your "really wet redfuctive amination", i know of several people (who have the right kind of experience) having been unable to reproduce your claimed yields. The best i got myself was 10%.

Quote:
Originally posted by Barium
Seeing you talking about dimeric products and silica gel makes me believe you are talking about the borohydride/EtOH/Dioxane reduction system


Nope, i do know my shit. The dimerization is also a problem here - Especially when making indoles the way these fellas did: Beer et al., J. Chem. Soc.; 1948, 1605-1609

BTW Barium, you probably never noticed how useful your water/toluene/PTC system is for reduction of secondary nitroalkenes. Your writeups and posts left me with the impression that all you wanted is to avoid PTCs, despite the fact that there is no double bond reduction as simple as this. I applied it to large scale batches and it is the best method - easy workup, reaction runs on its own, great yields, easily recycled solvent.


Bets results I had was with 5:2:1 if carbonyl iron powder, but with regular cheap 99% iron powder then I had best results with 12:2:1 eq of Iron/Hcl/p2np.
But best of all works 5:2:1 with zinc/acetic acid 98%/p2np. Reaction time only 30-40 min

Corrosive Joeseph - 20-12-2020 at 05:20

Quote: Originally posted by OrganicGuy  

Bets results...


Hey OG, you got any actual yields for that.....?



/CJ

RustyShackleford - 20-12-2020 at 05:35

Zn/HCl aint so bad to extract if you just add a large excess of hydroxide to re-dissolve the zinc.

stoichiometric_steve - 20-12-2020 at 10:59

Quote: Originally posted by OrganicGuy  

But best of all works 5:2:1 with zinc/acetic acid 98%/p2np. Reaction time only 30-40 min


I'd like to know the exact conditions for this procedure, would you be so kind to share them?

OrganicGuy - 2-1-2021 at 09:05

Quote: Originally posted by stoichiometric_steve  
Quote: Originally posted by OrganicGuy  

But best of all works 5:2:1 with zinc/acetic acid 98%/p2np. Reaction time only 30-40 min


I'd like to know the exact conditions for this procedure, would you be so kind to share them?

yes I can do it in a week when I'm home at my computer, but check this doc. I've seen you had a lot of good posts here & there, so you'll figure it out yourself by then ;)


Attachment: AUS amphetamine.pdf (1.9MB)
This file has been downloaded 203 times


stoichiometric_steve - 2-1-2021 at 22:44

You probably misread that document. There is no mention whatsoever of any yield that high.

OrganicGuy - 3-1-2021 at 07:48

Quote: Originally posted by stoichiometric_steve  
You probably misread that document. There is no mention whatsoever of any yield that high.

What yield?, I didn't mentioned how much yield I had, I only stated "the best yield I had was with..." and not how much
The percentage 98 and 99 is purity of iron and concentration of the acetic acid and has nothng to to with yields.

OrganicGuy - 3-1-2021 at 07:56

Quote: Originally posted by stoichiometric_steve  
You probably misread that document. There is no mention whatsoever of any yield that high.

During the yrs I have also understood that because a certain document says so and so, doesn't mean you will have the same yield. I have seen many fake indian documents claiming excellent yields, but when running it exactly the same conditions I got half. And I have seen documents where I had better yield than they got after some experimentation. A document or journal is not static information, experimentation is always recommended

stoichiometric_steve - 3-1-2021 at 13:50

I stand corrected, i misread. I thought the 98% stood for yield. But the actual yield of the procedure is absolute shit.

clearly_not_atara - 3-1-2021 at 14:40

Interesting that a key here seems to be a fast addition and high temp. It seems more often "difficult" reactions call for exactly the opposite. Maybe the reason this rxn is so famously unreliable is that people optimize for the wrong thing.

ChemichaelRXN - 3-1-2021 at 23:09

If the reaction works ok, you can extract it with chloroform 1.49g/ml instead of toluene 0.865g/ml, which may form emulsion easier than chloroform would.

OrganicGuy - 4-1-2021 at 06:56

Quote: Originally posted by stoichiometric_steve  
I stand corrected, i misread. I thought the 98% stood for yield. But the actual yield of the procedure is absolute shit.

If using the iron method, then the carbonyl and reduced/electrolytic iron powder gave yields better than regulare cheap iron powder (80-85%). For the zinc/GAA method, with electrolytic zinc powder I had 75-80% and with cheap zinc below 70%, however the short reaction time is preferable to me since I value family time. It also depends of course of the nitroalkene purity, AFAIK that's of highest concern when talking yields in these methods. Crap in crap out...

The most recent doc I had is this attached. It's indian though, but seems worth checking out. Good luck to you with the yield


Attachment: Fe_HCl_MeOH.pdf (435kB)
This file has been downloaded 134 times


stoichiometric_steve - 4-1-2021 at 22:59

Quote: Originally posted by OrganicGuy  
Good luck to you with the yield


No worries my little dude, i had awesome yields with electrolytic iron powder.

750ml H2O
200g Fe
1 mol Nitroalkene
2.5g FeCl3
650ml HCl conc.