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!
Regards
Bandil
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
http://www.angelfire.com/scary/beedioulasso/k1.djvu (http://www.angelfire.com/scary/beedioulasso/k1.djvu)
http://www.angelfire.com/scary/beedioulasso/k2.djvu (http://www.angelfire.com/scary/beedioulasso/k2.djvu)
http://www.angelfire.com/scary/beedioulasso/k3.djvu (http://www.angelfire.com/scary/beedioulasso/k3.djvu)
Though they didnt try it on nitroalkanes, the yealds and the ease of the procedure is tempting. ;D
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000462374-file_z4uo.jpg)
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.
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) and 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
http://www.ch.ic.ac.uk/ectoc/echet98/pub/087/index.html (http://www.ch.ic.ac.uk/ectoc/echet98/pub/087/index.html)
Zinc Chloride as a New Catalyst for Knoevenagel Condensation
P. Shantan Rao & R. V. Venkataratnam
Tetrahedron Letters 32, 5821 (1991) (https://www.thevespiary.org/rhodium/Rhodium/djvu/knoevenagel.zncl2.djvu)
(https://www.thevespiary.org/rhodium/Rhodium/djvu/knoevenagel.zncl2.djvu) (Article retrieved by dioulasso)
Abstract
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.
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.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/pdf.gif)
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.
Conjugated Nitroalkenes: Versatile Intermediates in Organic Synthesis
(Anthony G.M. Barrett, Gregory G. Graboski; Chem.Rev. 1986, 86 (751-762))
Introduction
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. (...)
https://www.thevespiary.org/rhodium/Rhodium/pdf/conjugated.nitroalkenes.review.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/conjugated.nitroalkenes.review.pdf)
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?) :-[
indole_amine