Author Topic: hopeful new nitrostyrene/nitropropene catalyst?  (Read 4906 times)

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  • Guest
hopeful new nitrostyrene/nitropropene catalyst?
« on: October 03, 2003, 04:18:00 AM »
To date I have experienced ammonium acetate and aqueous methylamine as knovenagel condensation catalysts in the creation of nitrostyrenes and nitropropenes.

For some reason, with both these catalysts, it has been difficult to get the yields that other more experienced researchers have achieved. In addition, the product has often been quite contaminated with darker colored by-products (maybe quite a bit is being lost in the purification).

So I got to thinking that it would be great if I could find a catalyst that gave a cleaner product at a decent yield.

It seems like I may have found one - at least it works well in the one experiment performed so far:

10g of Benzaldehyde was put in a 250ml flask with 8ml of nitroethane. To this was added 1.5ml of ethanolamine. A reflux condenser was attached and the mixture was stirred and heated to 60C for 3 hours.

40ml of IPA was added to the reaction mixture whilst stirring. Seed crystals of P2NP were added and the mixture allowed to cool, first at 15C room temp, then in the fridge, then in the freezer overnight.

The mother liquor was poured off, and the crystalline mass was washed twice with ethanol from the freezer.

The crystals were dryed to constant weight.

Yield 10g - 65%

I reckon the yield would be better if the reaction were allowed to run longer, done with more nitroethane, and performed by more experienced individuals.

Normally this reaction goes dark orange (impurities) with ammonium acetate and the yield is poor with aqueous methylamine (Barium's method). The fact that the mixture only went light orange, and that the mother liquor after crystallisation in the freezer was a very light yellow color indicates to me that there are fewer impurities than when using ammonium acetate for this reaction.

I think we need to try this method on some other substrates and it may turn out to be a valuable alternative. I like the fact that the catalyst is high-boiling and seems quite clean.


  • Guest
On the topic of knovenagel condensation catalysts
« Reply #1 on: October 03, 2003, 04:51:00 AM »

or some reason, with both these catalysts, it has been difficult to get the yields that other more experienced researchers have achieved. In addition, the product has often been quite contaminated with darker colored by-products (maybe quite a bit is being lost in the purification).

Dear starlight!
I agree with you on the ammoniumacetate catalyst contamination issue. I also always get a very ugly darkred mixture from this one. But the methylamine, i can't understand you say is not high yielding? It is not difficult to work with at all, so it's no excuse that you are not a "experienced researcher"(heaven knows i'm not). Which benzaldehydes have you tried it on?

In my experience the following compounds, behaves like this, when subjected to knovenagel condensation with methylamine as catalyst:

Benzaldehyde + nitroethane: Rather low; usually about 70%. Quite hard to crystallize. Seed crystals are good to have for this one.

2,5-dimethoxybenzaldehyde + nitromethane: Yields are through the roof on this one. 90'ish % is not uncommong and is extremely easy to crystallise.

2,5-dimethoxybenzaldehyde + nitroethane: Quite high yields. 80'ish % usually and easy to crystallize after separation with water/DCM. Very pure reaction also!

2,4,5-dimethoxybenzaldehyde + nitroethane: On the lower side, yield wise. Max yield has been 75%, but the end product is sparkling pure.

Hest has argued several times, that the catalyst really doesn't matter(and i am not the person to oppose him; he's just to damn clever  :) ). I think that he is quite right with that statement. I do however think that there's quite a difference between ammoniumacetate and the alkylamines. It seems that the activation energy(or something like that) is lower for the alkylamines, which means lower reaction temperatures and thus lower amount of side products. But, primary and secondary alkylamines, should work equally well, regardless of the alkyl chain(true, "gazzilionyl"-amine, might not be good, but the somewhat lower ones).

But given, that the reaction works by forming the imine first, it is probably wise to chose a compound that is eager to form this. Ammonia sucks for making the imine with P2P for instance, whereas methylamine, ethylamine and hydroxylamine is way better at this. Maybe this could be an explanation for the better reactivity of the alkylamines compared to ammoniumacetate? So rather than experimenting with the length of the alkyl chain, i think it would be more interesting to look at some other factors:

1 - oxime's perhaps:
I think it could be fun to try out hydroxylamine as a catalyst and se if that would work. I don't know enough theoreticall stuff to predict if the knovenagel condensation will work with the oxime, but it just might.

2 - Water free environment:
As the reaction eliminates water, one might improve the yeilds by using anhydrous methylamine(bp is mid 40 celc AFAIK), and suck up the formed water with either molecular sieves or run the reaction in toluene and use a dean stark trap. Maybe we can push the reaction all the way to the right with these aids; don't know but it could be fun to try out a sleepless sunday!

Hope it wasn't to much babble!



  • Guest
poor results
« Reply #2 on: October 03, 2003, 06:20:00 AM »
hi bandil,

my guesses at previous yields using aqueous methylamine are:

BA + NE -- <50%
2,4,5 TMBA + NE -- 50%

these are yields after slow recrystallization - i.e. pure product.

2,5 DMBA and NM has given seemingly very high yields for me that become much lower after purification - product seems quite contaminated with something that is deep red in alcoholic solution. Very slow recrystallization of 2,5DMNS gives me crystals that are orange tending towards red. Faster recrystallization gives neon-orange crystals.

The 2,4,5 product is nice canary yellow crystals, but there is a dark orange contaminant in the alcohol from which it is recrystallized. Maybe I am heating too much (45C). The benzaldehyde does not have a very high solubility in IPA.

I am making aqueous methylamine using NaOH and MeNH2.HCl solutions(exact molar proportions). I doubt that NaCl could screw up the yields could it?

Things that I like about ethanolamine are:

- it is cheap and I have some.
- it is not suspicious
- i can use it straight out of the bottle
- it has a high bp. so it stays in the reaction with heating
- it seems to work for me on the first reaction

I will have to try more with the substituted BAs and report back.

As to your idea of the water free environment I have seen posts that say methanolic methylamine can create high mp polymeric byproducts in this reaction. Never tried it in practice though.

By the way, the BP of methylamine is -6.3C


  • Guest
Both chemfinder and acros, says that ...
« Reply #3 on: October 03, 2003, 07:01:00 AM »
Both chemfinder and acros, says that methylamine boils at 40 degrees...

Yes, IPA is very good for recrystallizing those compounds!

I usually heat to 60 degrees to ensure complete conversion. I do however think that all the water in your system(with you using aqueous solutions of both sodium hydroxide and methylamine), could be a problem. There's simply to much water in the system, which is on the product side(right side). Try lessening the amount of water somehow; i really think that can make a difference!

- Eliminate much of the water from you system
- Heat a little more
- 1½ reaction time
- Extract with DCM/chloroform in the end and wash with water and brine. Gives a very pure product!

Good luck!



  • Guest
The catalogs list the aq. solution...
« Reply #4 on: October 03, 2003, 07:21:00 AM »
40% aqueous methylamine (the stuff Acros sells) boils at 40°C, but the neat freebase boils below zero.


  • Guest
not the water, maybe longer and hotter
« Reply #5 on: October 03, 2003, 07:27:00 AM »
Water should not be the problem as I make up a 20% methylamine solution from concentrated NaOH and MeNH2.HCl solutions.

Maybe I am running the reactions too cool and too short. I have been doing 45mins at 40-45C. Thanks for these tips, they may help a bunch.

May try the chloroform/DCM thing - but I try not to use much chlorinated solvents as they are more difficult to dispose of for me (less environmentally friendly).


  • Guest
« Reply #6 on: October 03, 2003, 08:53:00 AM »
Follow the reaction on TLC, then you know when to stop.
I', working a bit with some nitrostyrenprojet, mabee I should try to make it with diff. catalyst like
and EDDA.
Think 2,4,6 TMBA will bee the aldehyde.


  • Guest
Hest> Do you know if hydroxylamine could be
« Reply #7 on: October 03, 2003, 10:24:00 AM »
Hest> Do you know if hydroxylamine could be used as catalyst, or will the oxime not react at all, or form something totally different?


  • Guest
don't think so
« Reply #8 on: October 03, 2003, 10:46:00 AM »
The mechanism goes by the formation of an imine due to the reaction of the aldehyde and the amine (or ammonia).

R-CHO + R'-NH2 --> R-C=NH-R' + H2O

I don't think it will work with oximes, they are not amines.

Hydroxylamine acetate maybe?


  • Guest
aromatic oximes too stable
« Reply #9 on: October 03, 2003, 01:00:00 PM »
The oxime which will form with benzaldehydes is probably too stable to easily react further with any nitroalkane.


  • Guest
Imine formation the key?
« Reply #10 on: October 03, 2003, 06:06:00 PM »
are you sure about the imine thing as a first reaction step, I wonder about the mechanism of the reaction then?
I think the purpose of an amine in the Knoevenagel reaction is simply to react as a base. It will deprotonate the CH-acidic compound, nitroethane here, thus forming the nitronate of nitroethane, which in turn will react with the carbonylic compound, here benzaldehyde or one of its derivatives. Imine formation, IMHO, will be counterproductive in this reaction and maybe lead to unwanted side-products.
The initial reaction step should look like this:
The nuclophile (nitronate) [CH3CHNO2]- will then simply add to the electrophile (benzaldehyde) and the nitroalcoholate forms. This intermediate will then in turn be protonated on the oxygen of the alcoholate and deprotonated on the beta-carbon. An OH-substituted nitroenolate forms, which splits off the OH in an E1-elimination, resulting in the nitropropene derivative.
The nitronate from the initial step should add much faster to the aldehyde than the amine, thus avoiding imine formation.


  • Guest
Yes I agree with you
« Reply #11 on: October 04, 2003, 02:57:00 AM »
But which reaction occurs first if the reactans are added at the same time? Imine formation or deprotonation? Nitrostyrenes are also obtanined if the aromatic aldehyde and amine are allowed to react alone to form the imine first followed by addtion of the nitroalkane. This is a known good metod to get nitrostyrenes from 1-nitropropane and 1-nitrobutane wich otherwise aren't very eager to form nitrostyrenes.


  • Guest
Good point,
« Reply #12 on: October 04, 2003, 03:57:00 AM »
Barium! But I still wonder about the mechanism then...
Perhaps someone should give it a try and do it also the other way round, i.e. mix the base with the nitroethane and add this mixture to the aldehyde solution? Yields could be compared and the appropriate method be chosen then..
Btw., I think with the nitrobutane and nitropropane (longer carbon chain) some kind of steric hinderance comes more into play.
Besides, nitroalkanes are very CH-acidic compounds, they really like to donate the alpha-proton to a base, so there shouldn't be much of imine formation, even at the same time.


  • Guest
Both pathways are actually happening
« Reply #13 on: October 04, 2003, 09:53:00 AM »
Both pathways are actually happening, I have a reference with kinetic data which argue for that in the case of all amines except tertiary, the latter only causing deprotonation of the nitroalkane.


  • Guest
I can try your suggested order of adding the...
« Reply #14 on: October 05, 2003, 01:59:00 AM »
I can try your suggested order of adding the reactants. I have never thought of checking what happens if it is done in that order.


  • Guest
That's research ...
« Reply #15 on: October 05, 2003, 04:31:00 PM »
...I like your way of thinking, Barium! And thanks for your offer, you almost make me embarassed, but I gladly accept it  :)
I would really like to do this myself, but I have no lab to work in at the moment - and this will be the status for the next months, unfortunately  :(
But then there will be a lot of experiments to perform:

- testing primary, secondary, tertiary amines
- amine mixed with aldehyde and nitroethane added
- amine mixed with nitroethane and added to aldehyde
- all mixed together at once

Some precious precursors will surely be wasted due to bad yields and it's a heap of work for one man!
But I'd say, for the first, "only" 3 experiments need to be performed, all under the same reaction conditions:
- aldehyde + primary amine, letting the imine form, then adding the nitroethane
- all "ingredients" mixed together
- aldehyde, mixture of primary amine + nitroethane, letting the nitronate form, then adding mixture to aldehyde
What do you think, Barium?

A word of caution at last (I'm sure you know yourself and I don't want to offend you, but it doesn't hurt to be cautious) the nitronates or the aci-nitro forms of nitroalkanes can be dangerously explosive if pure and undiluted.


  • Guest
« Reply #16 on: October 06, 2003, 01:38:00 PM »
First shot
1g(5,1mmol) 2,4,6-tmba was disolved int 50mL IPA. Then 0,8g(11mmol) nitroethane was added and some cat. The reaction was left on a warm (50°C) stirplate. Reaction 1 was stopped after 1 houer due to formation of red polymere, the two next's after 3 houers. When the reraction was stopped there was no more aldehyde on TLC. The mixture was then chromatographed with drycollumchromatography (hexane:ethylaccetate in 10% step's)

Reacton 1 cat Am.Formiate yeald 1g(77%)
Reaction 2 cat Cyclohexylammine 0,73g(56%)
Reaction 3 cat 1,3-diaminopropane 0,42g(32%)

strange. I now have reacton 2 and 3 running at 25°C for 12 houers. 12 h. later still lots of aldehyde back and some white precipitate in the flask.
(Note, my eksp. with Nitroethane as solvent is greath, both with Am.Formiate and Cyclohexylamine, but It would bee nice not to waste all that nitroethane)


  • Guest
Interesting results..
« Reply #17 on: October 06, 2003, 04:59:00 PM »
..but, I'm sorry to say, these experiments won't tell us the whole story, because it's difficult to compare them. The reason is that these experiments must all be conducted under the same reaction conditions like time, temperature, order and time of addition, equimolarity of catalyst and reactants etc.
But it is good to see you are trying to work on a scientific base, trying to find the optimal catalyst for this kind of reaction. Please keep on with the good work, Hest!
But I've been digging in my literature this weekend and
I've stumbled upon one thing in your tests, you will see later what I mean.
It's primarily the very  question of discussing the pathways of the reaction, Rhodium is right when he says both ways of reaction, the one via imine formation and the one via an aldol-like condensation will happen at the same time, both leading to the same product. As already said, I've done some reading the last days because I was curious about this subject. One book of mine states in a single sentence (which I have overlooked to this very day):
"The simoultaneousness of acid- and base-catalysed reaction steps explains why ammonium salts are so particulary effective as catalysts (in the Knoevenagel condensation), because these are able to accomplish both functions".
[Translated from:
Uhl/Kyriatsoulis: "Namen - und Schlagwortreaktionen in der Organischen Chemie, Vieweg, 1984; italics mine]
In other words, ammonium salts are more effective than other catalysts because these are able to catalyse the imine pathway as well as the aldol pathway of reaction!

So it appears to me that the stronger bases like 1,3-diaminopropane (pKa1=10.94, pKa2=9.03) and cyclohexylamine (pKa=10.66), both are primary amines, give less yields than the not so strong ammonium acetate (pKa=4.75 for acetic acid, ammonia pKa=9.25) in your experiments because the ammonium acetate catalysed both pathways.
(Note, I'm not talking about hardness of bases, just about base strength!
Isn't this a nice and simple explanation for your results  ;)  ?
The question is now, is it more preferable to work with ammonium salts as catalysts because these will assist both reaction pathways? I think the answer is yes, when I look at your yields.
But here comes the next question then, is it more preferable to work with the salt of a primary amine, or a secondary or tertiary amine?
I remember the famous EDDA is very often used in Knoevenagel condensations because it's weakly basic, showing an almost neutral pH in water, but if I remember right EDDA wasn't much superior to plain ammonium acetate in our special kind of Knoevenagel condensations.
Another question, can all reactants, including catalyst, simply be dumped together in a reaction flask or will some order of addition or pre-reaction of catalyst with one reactant (aldehyde or nitrocompound) have a great impact on the yield?

Questions, always questions... :)


  • Guest
« Reply #18 on: January 05, 2004, 06:27:00 PM »
This originally was found by Vitus:

Microwave assisted Knovenagel condensation using NaC1 and NH4OAc-AcOH
system as catalysts under solvent-free conditions

Indian Journal of Chemistry, Sect. B, 2000, 39B(6), 403-405

Though they didnt try it on nitroalkanes, the yealds and the ease of the procedure is tempting. ;D

Experimental Section
General procedure. A mixture of aromatic alde-
hydes 1 (0.01 mole), active methylene compounds 2
(0.01 mole) and NaC1 (0.001 mole, 0.0585g) or a
mixture of NH4OAc (0.001 mole, 0.0770g) and
HOAc (0.002 mole, 0.12g) was taken in an open py-
rex tube and subjected to microwave irradiation in a
domestic microwave oven (BPL, BMO 700T) at an
output of about 210-280 watts
for the specified time
as mentioned in Table I.

The completion of the reaction was checked by TLC
using hexane-ethyl acetate (9:1; v/v) as solvent system.
The reaction mixture was then cooled to room temperature
and treated with 1% aqueous ethanol. The product thus
obtained was filtered, dried and crystallised from ethanol.
The same yields of arylidene compounds were obtained by
reacting one mole of aldehydes and active methylene compounds.


  • Guest
Microwave Henry
« Reply #19 on: January 06, 2004, 04:54:00 AM »
I had some experience with solventless MW assisted condensation reactions some time ago. They are so incredibly easy once you get some practice, they don’t need expensive solvents and the isolation is usually just a recrystallization of the raw product from an alcohol. It can be and it is done in any household MW oven, but you need an alumina bath (Al2O3) that absorb MW and heats the reactants in the beaker to a melting point where the MW effect pushes the reaction forward. Alumina is easy to get, then you just put some half a kg in a wide (glass) beaker and in the alumina you put the small beaker with the homogenized reactant mixture. It usually takes less than an hour from reactants to pure product while the MW irradiation is only of few minutes.

An example of the MW assisted Henry reaction with nitromethane/nitroethane where the yield for the methoxybenzaldehides were from 80 to 90% with the NH4AcO catalyst:
Varma R. J., Dahiya R., Kumar S.; Microwave-assisted Henry reaction: Solventless Synthesis of conjugated Nitroalkanes. Tetrahedron Letters 38 (1997), 5131-5134.
(already referenced by

Post 231951 (missing)

(Aurelius: "microwave", Chemistry Discourse)

Post 108383 (missing)

(dormouse: "More microwave ref's  -Rhodium", Novel Discourse)
without exciting an appropriate response)

An related paper with similar reactants like the ones in the paper posted by dioulasso is:
Synthetic communications 29 (1999), 2731-2739.

Piperidine is also a very powerful catalyst in the MW assisted Knoevenagel condensation (though I think primary amine are better for the Henry reaction). An example with the methoxybenzaldehides:
Coumarins - Fast Synthesis by the Knoevenagel Condensation under Microwave Irradiation


  • Guest
Zinc Chloride as Knoevenagel Catalyst
« Reply #20 on: January 07, 2004, 06:04:00 PM »
Zinc Chloride as a New Catalyst for Knoevenagel Condensation
P. Shantan Rao & R. V. Venkataratnam

Tetrahedron Letters 32, 5821 (1991)

( (Article retrieved by dioulasso)

The knoevenagel condensation of carbonyl substrates with acidic methylene reagents proceeds smoothly in presence of zinc chloride, without the need for solvent, to produce products of good purity in high yield.


  • Guest
Microwave-assisted Henry reaction
« Reply #21 on: April 06, 2004, 12:07:00 PM »
If somebee wants to play chemistry with his microwave owen, here is the PDF of the paper I referenced two posts above.

Microwave-assisted Henry reaction: Solventless Synthesis of conjugated Nitroalkanes.
Tetrahedron Letters 38 (1997), 5131-5134.
Varma R. J., Dahiya R., Kumar S.

Abstract: In a solventless system and under microwave irradiation, nitroalkanes react with arylaldehydes in the presence of a catalytic amount of ammonium acetate to afford, in one step, conjugated nitroalkenes without the isolation of intermediary beta-nitro alcohols.


  • Guest
« Reply #22 on: April 07, 2004, 01:02:00 AM »
Dont forget that these article's usual run the reactons in the 1mmol scale. Things become more trickey when you run a 10g batch. Esp. the polymeristions become a problem. But it works usual greath, the tric is to stop at the right time (as usual I know)


  • Guest
EDDA again
« Reply #23 on: April 17, 2004, 08:21:00 AM »
Ethylenediamine diacetate is almost always a great Knoevenagel/Henry catalyst - besides that the condensation takes up to 36 hours. This time can be decreased by adding silica gel (it adsorbs water, ~30% of its own weight; per mol nitrostyrene 1 mol water is formed, so ~59g should work well for 1 mol) and keep rxn slightly above room temp. (~50°C). Everything will turn orange within hours...


  • Guest
boosting yields
« Reply #24 on: May 31, 2004, 09:42:00 AM »
Even better yields (70%+ for P2NP) can be obtained if the nitropropene mother liquor and silica gel are put under vac - even if having already filtered off the first precipitation of crystals, applying vacuum to the mother liquor & drying agent will result in more fine needles appearing in the liquid...  8)

Greetz A


  • Guest
nitroalkene reactions / literature review
« Reply #25 on: September 16, 2004, 08:40:00 PM »
Conjugated Nitroalkenes: Versatile Intermediates in Organic Synthesis

(Anthony G.M. Barrett, Gregory G. Graboski; Chem.Rev. 1986, 86 (751-762))


The nitro group is a powerful electron-withdrawing substituent, and this property dominates the chemistry of all molecules containing this functional group. For example, nitroalkenes, being markedly electron deficient, are powerful dienophiles in the Diels-Alder reaction. Alternatively, these electrophilic alkenes readily undergo addition reactions with many different nucleophiles. The nitro group is particularly versatile in synthesis since it may be transformed into a legion of diverse functionality. It can be readily replaced by hydrogen in a denitration process or converted to a carbonyl substituent in the classical Nef reaction. Additionally primary nitro groups can be dehydrated to produce nitrile oxides or oxidized to produce carboxylic acids. Finally, the nitro substituent can be reduced to produce oximes, ketones, hydroxylamines, or amines. Clearly nitro compounds and nitroalkenes in particular are versatile compounds in synthetic organic chemistry.
This article covers a review of the literature on the synthesis and reactions of nitroalkenes in the time interval 1980-1985. (...)

EDIT: Oops - I just realized that this article is already archieved at Rhodiums site. Sorry!
I have changed the link above... (hope the file I uploaded will be autodeleted, as it is not in use anymore?)  :-[