stoichiometric_steve
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general high-yielding one-pot procedure for the reduction of conjugated aliphatic nitro groups.
5-10x vol. amount of EtOH (may be denaturated, water content irrelevant) compared to nitroalkene substrate weight along with a bit of H2O is used for
dissolving 1.5-2 mol eq. of NaBH4 in a suitable reaction vessel (may be an open beaker) cooled by ice or water - reactivity of NaBH4 increases upon
addition of water to EtOH.
nitroalkene substrate (as clean as possible) is added in portions to control reaction (very small portions if no alpha-methyl group is present to
prevent polymerization).
after all substrate has been added and near-colourless solution is obtained, let stir for 1h.
residual NaBH4 (won't be much due to reactivity towards EtOH) and nitronate salts are liberated with slow addition of 50% (or even more dilute) acetic
acid - some foaming and caking may occur, add more acetic acid or water to dissolve it.
isolation of the nitroalkane intermediate is not necessary and not recommended.
a 10 mol eq. amount of Zn powder is activated by stirring with 2M HCl, letting fizz for a couple of moments (since it's a rather big excess, don't
worry about it being eaten up) FILTERED from the HCl and washed thoroughly with water and added to the intermediate in a RBF equipped with a reflux
condenser.
1 mol eq. of Potassium Formate is added along with 2-6 mol eq. of Formic acid, an exothermic reaction instantly occurs which is easily controlled.
vigorous stirring is vital.
let react until reaction temperature has subsided.
then add a gulp of more or less concentrated HCl and set up for reflux with stirring to break down amides which may have formed. let react for 30
mins. the liquid is colourless.
distill off liquid until salts fall out.
filter off water-insolubles and rinse filter cake with water until there is only Zn left (don't worry about precipitate in the vacuum flask).
since there will hardly be any side products, cleaning of the water phase with a nonpolar is usually not necessary (use toluene if desired).
common side products of this route are the result of impure nitroalkene! this will considerably lower yields by condensation of resulting carbonyl
compounds with amines.
NaOH or KOH is added as solid or solution (if solid is used, let cool down after addition) until pH=13 and the suspension extracted 3x with toluene
(which will not form an emulsion at all - don't worry about small amounts of residual precipitate particles in the toluene layer, the will leave in
the drying step).
stir with a suitable drying agent and filter off, rinse filter cake 3x with the nonpolar solvent used (disconnect vaccum and make a slurry in the
buchner, then continue filtration).
carefully add concentrated sulfuric acid in single drops with vigorous stirring (no splashing please) to the nonpolar phase. filter off precipitate
and wash with toluene. repeat until no more precipitate forms in the toluene. dry precipitate.
overall yield: very well above 70%, calculated from the sulfate salt of the amine (90% is likely if done carefully).
this is your x-mas gift for this year. did someone say O T C?
[Edited on 16-12-2005 by stoichiometric_steve]
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enima
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why are you adding additional formic acid to the potassium formate? why not just add 5 molar potassium formate? (not criticism, just curiousity).
[Edited on 16-12-2005 by enima]
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stoichiometric_steve
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| Quote: | Originally posted by enima
why are you adding additional formic acid to the potassium formate? why not just add 5 molar potassium formate? (not criticism, just curiousity).
[Edited on 16-12-2005 by enima] |
as pointed out by bandil:
KCOOH -> K2CO3
K2CO3 + HCOOH -> KCOOH
whereas
HCOOH + Zn -> Zn(2+) + 2H + CO2(g)
so: KCOOH is used in a pseudo-catalytic amount, since it is a better hydride donor than formic acid itself and by adding plain formic acid, KCOOH is
recycled, also preventing carbonate clogging of the condenser.
oh, i forgot: formic acid is cheaper than KCOOH. main reason 
[Edited on 16-12-2005 by stoichiometric_steve]
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CherrieBaby
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I have uploaded this: here:
Location: http://www7.rapidupload.com/d.php?file=dl&filepath=8769
Location 2: http://rapidshare.de/files/8566503/Synthetic.rar.html
filesize: 82 kbyte.
Title: Fe-HCl: An Efficient Reagent for Deprotection of Oximes as well as Selective Oxidative Hydrolysis of Nitroalkenes and Nitroalkanes to
Ketones
Ref: Synth. Commun. 35, #7, pp913-922 (2005)
With this, the nitrostyrene [Ar-CH=CH(NO2)], is reduced to nitroalkane [Ar-CH2-CH2(NO2)] but the nitropropene [Ar-CH=C(NO2)-CH3] gives the ketone
[Ar-CH2-CO-CH3]. I think this HCl-Fe method looks convenient from the point of view of HCl and Iron being such easy reagents to get hold of. They also
do the rxn. in methanol solvent (another easy to get reagent). Yields for the amine are only good, not excellent - but their ketone yields are better.
In PIKHAL, Shulgin uses Fe/HCl to go from nitropropene to ketone: PIKHAL #98, #109, #110, #131, #173; but he does it in glacial acetic acid, and uses
'electrolytic iron'. It looks like they just use ordinary iron here.
I find the terminology for this confusing. They call it oxidative hydrolysis but the alkene bond is getting REDUCED in either variant of the rxn.
I haven't used it yet, so I'm not willing to compare it with the above procedure. However, this is only suitable for nitrostyrenes to nitroalkanes.
With a nitropropene, it has to go to the ketone and then with a reductive amination to the amine. I guess the above method would be better most of the
time (yield-wise).
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Sandmeyer
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Does the addition of formate salt give better yields than plain formic acid?
I've heard that the Zn/HCOOH method does not work for 2C (nitroethanes), have you tried it?
EDIT: typo
[Edited on 5-2-2006 by Sandmeyer]
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niobium
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swin thinks but does not know for sure this works well for ethenes. formate salts are much better donors then formic acid
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stoichiometric_steve
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| Quote: | Originally posted by Sandmeyer
Does the addition of formate salt give better yields than plain formic acid?
I've heard that the Zn/HCOOH method does not work for 2C (nitroethanes), have you tried it?
EDIT: typo
[Edited on 5-2-2006 by Sandmeyer] |
up to now, it is certainly quite unclear which factor influences yields to what extent.
one critical factor seems to be the solution after NaBH4 reduction, adding dilute acetic acid will result in incredibly large volumes, while adding
glacial acetic acid works just fine and does not at all induce a nef reaction. according to experimental experience, a clear solution after NaBH4
reduction is a must for good yields, since it ensures that all nitroalkane is in solution.
another one is the ratio of formic vs. formate. adding a great deal of formate all at once and adding formic in drops over the course of the reaction
seems not to be the way for good yields.
dropping a formic/formate mix 50/50 by weight in all at once (for small scale of course!) seemed appropriate (75% on this one). buffering reasons?
since the oxime is a potential intermediate in this reduction, an excess of acid is probably not favorable.
using an excess of GAA to liberate the nitroalkane also didn't hurt (>80% with p2np).
trials using KCOOH and GAA (no formic) should be conducted. maybe GAA alone can do the job with Zn?
sure it's not a hydrogen donor but there's a bunch of water around which will donate.
sandmeyer: not sure about nitroethanes with this method, it's curious enough that phenylacetaldoximes don't get hydrolysed when reducing with Zn/HCl.
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stoichiometric_steve
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| Quote: | Fe-HCl: An Efficient Reagent for Deprotection of Oximes as well as Selective Oxidative Hydrolysis of Nitroalkenes and Nitroalkanes to Ketones
Ref: Synth. Commun. 35, #7, pp913-922 (2005) |
this procedure is either fake or shit. i have tried it with a number of substrates, including substituted and nonsubstituted phenyl-2-nitropropenes,
and none of them yielded an amount of the ketone which was worth isolating.
especially the methylenedioxy-bridge of mdp2np doesn't withstand the reflux conditions in HCl very well.
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pharmacological
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| Quote: | Originally posted by stoichiometric_steve
a 10 mol eq. amount of Zn powder is activated by stirring with 2M HCl, letting fizz for a couple of moments (since it's a rather big excess, don't
worry about it being eaten up) FILTERED from the HCl and washed thoroughly with water and added to the intermediate in a RBF equipped with a reflux
condenser.
[Edited on 16-12-2005 by stoichiometric_steve] |
I am a bit confused about what this statement means. WHAT exactly is in excess? Are you saying that not all of the Zn should be activated? The
confusion arises from the fact that you didn't specify an amount of HCl to use, only a concentration.
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stoichiometric_steve
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then, why does everybody else seem to understand it?
see, it is a general procedure and it requires you to have basic lab practice, which would enable you to estimate the "excess". in the case of Zn
activation, do you think 0,005ml of 2M HCl would suffice to activate 1 mol of Zn dust? how much would do it in your opinion? did you even think about
this? do you know what a MOLE is (not the animal)?
the confusion arises from the fact that you don't obviously know shizzy about organic synthesis and the related terminology. i'm sorry for you.
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pharmacological
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I will not even acknowledge what a mole is, because of course I know how much a mole is. And I do not AT ALL appreciate your attitude.
Personally, I would add an equimolar amount of HCl (or just a little excess, to be sure), which means that to activate said mole of Zn, i'd require
>500ml of 2M HCl soln.
I was just asking for clarification, and not in the least bit did not come off as rude. I don't know why you persist in insulting me like you do.
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Nicodem
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It seams the problem arises from the obvious fact that you don't know what "activate" means in the context of metal dissolving reductions. It does not
mean to dissolve the zinc like your statement above implies. If you would know what it means you would not ask such obsolete questions as about the
"amount of HCl to use". I suggest you to read some preparative organic chemistry books. Vogel's and Organikum are a good start.
And "excess of zinc" means the excess from the quantity needed to reduce the nitro group (3 mol equivalents). It has nothing to do with the activation
process in itself.
PS1: With your level of knowledge it seams a waste of asarone to try the TMA-2 synthesis. The 1-(2,4,5-trimethoxyphenyl)-2-nitropropene is highly
sensitive for polymerization and is not really a good choice for a beginner. If you live in EU, I should also warn you that TMA-2 was set illegal with
an EU directive. Needless to mention, in USA it fells into the famously irrational “Analogue act”.
PS2: As far as I know, this is not a drug forum! Not yet, at least.
[Edited on 26-5-2006 by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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pharmacological
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Very well. It seems i was just trying to ignore the fact that i am not prepared to undertake such a task. I will stay away from it, and just stick to
college for now. I hope to return to this forum with a vastly increased knowledge in organic chemistry.
Though I still think some of the statements made here were a bit harsh, I would still like to thank everyone who contributed to opening my eyes to the
fact that this is not for me.
I'm off to hit the books!
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stoichiometric_steve
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this may very well be for you, but not at this point in time.
at least i would certainly appreciate it if you joined us again in a year or so when you have gained the related knowledge.
in the meantime, read syntheses until your eyes burn out. i did and it helped a lot. apart from that, i still have silly failures.
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dextro
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| Quote: | Originally posted by stoichiometric_steve
reactivity of NaBH4 increases upon addition of water to EtOH.
nitroalkene substrate (as clean as possible) is added in portions |
swim has the some idea so he is very happy to see that there is another one ou there
my idea was to run the rxn in absolut EtOH, but if you mean some water will help, this will be o.k. but how much ?
second question: you add the p2np crystals direkt to the NaBH4 slurry? without dissolving them in a solvent ?
my idea was do dissolve them in THF and add this solution via addition funnel to the NaBH4/EtOH (But this result in a lot of solventmixture which must
distilled off later  )
thx for your post (and adcice ?)
dex
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dextro
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| Quote: | Originally posted by stoichiometric_steve
1 mol eq. of Potassium Formate is added along with 2-6 mol eq. of Formic acid |
o.k. this means with ~ 100 mmol nitroalkan:
1 mole zinc (10eq.)
100 mmol Potassium Formate (1eq.)
but then 2-6 eq. formic acid = 200-600mmol =7,5-22,5ml ??
this seams quite little for 65,37g zinc.
or did you mean 2-6 eq. (from the amount of Zn) which is then 75-225ml ?
thx
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stoichiometric_steve
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the first.
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jon
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potasium formate is a better hydride donor than formic acid i read some patents that the reduction catylysed by palladium of aromatic nitro groups
reduce more effectively in the prescence of the potassium salt. of course the problem of carbonates so the need to titurate with acids as the reaction
progresses, that also regenerates the reducing agent potasium formate.
but i like that zinc catlysed reaction that's slicker than horse shit.
[Edited on 29-10-2006 by jon]
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karlos³
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Thank you for that method, I look forward to use it on azidoketones to aminoalcohols instead!
Used it on nitroalkenes too but just had this realisation as I planned the reduction of an azidoketone, then *bam*, I remembered this one-pot
two-step.
Wonderful, now I don't have to carry out the separate reactions in two vessels, this confirms I can do the reduction to the alcohol and then azide to
amine likewise in the same pot
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karlos³
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You should have included the original reference, would be way easier to look at where you got this from.
This post makes it look like it was your own invention, but I am sure you haven't intended it do be like this.
That is the original reference: Indian Journal of Chemistry, Section B: Organic Chemistry (2001), 40B(1), 75-77
And here it was discussed at the hive: https://the-hive.archive.erowid.org/forum/showflat.pl?Number...
You have had one good idea by combining those two in one-pot though!
[Edited on 29-9-2020 by karlos³]
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