Author Topic: High-yielding nitrostyrene catalyst  (Read 9163 times)

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Barium

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High-yielding nitrostyrene catalyst
« on: March 20, 2003, 12:40:00 PM »
I have been searching and searching and trying and trying for years to find a cheap  condensation/dehydration catalyst which doesn't require refluxing GAA or nitromethane to get good yields. Finally I have found it. Methylamine.


A general method for nitrostyrenes is as follows:

100 mmol of a aromatic aldehyde
105 mmol nitromethane or nitroethane
15-20 mmol methylamine as a 10-20% aqueous solution
Enough MeOH, EtOH or IPA to make the mixture stirable. Usually about 25 ml

To a 250 ml rb-flask equipped with a magnetic stirbar is added the aromatic aldehyde, nitromethane and the alcohol. Sirring is started and the aqueous methylamine solution is added in one portion. The reaction flask is placed in a water bath and heated to 40-50°C. The reaction progress can be monitored by TLC to see when the aldehyde is consumed. In most cases 45 minutes in the water bath is enough.
When the reaction is over 25 mmol GAA is added to the reaction mixture and the flask is placed in the freezer until the crystallisation is complete [1]. The solids are then broken up with a spatula, transferred to a filter funnel and washed with water to remove most of the methylamine acetate. The nitrostyrene is then recrystallised from MeOH, EtOH or IPA.



1-phenyl-2-nitroethene, 92%
1-phenyl-2-nitropropene, 93%
1-(4-ethoxyphenyl)-2-nitroethene, 88%
1-(4-ethoxyphenyl)-2-nitropropene, 90%
1-(2-methoxyphenyl)-2-nitroethene, 94%
1-(2-methoxyphenyl)-2-nitropropene, 89%
1-(4-methoxyphenyl)-2-nitroethene, 92%
1-(4-methoxyphenyl)-2-nitropropene, 88%
1-(2,4-dimethoxyphenyl)-2-nitroethene, 97%
1-(2,4-dimethoxyphenyl)-2-nitropropene, 74%
1-(2,5-dimethoxyphenyl)-2-nitroethene, 97%
1-(2,5-dimethoxyphenyl)-2-nitropropene, 89%
1-(2,4,5-trimethoxyphenyl)-2-nitroethene, 89%
1-(2,4,5-trimethoxyphenyl)-2-nitropropene, 94%
1-(2,4,6-trimethoxyphenyl)-2-nitroethene, 95%
1-(2,4,6-trimethoxyphenyl)-2-nitropropene, 96%
1-(3,4,5-trimethoxyphenyl)-2-nitroethene, 92%
1-(3,4,5-trimethoxyphenyl)-2-nitropropene, 93%


3-(2-nitrovinyl)-1H-indole, 79%
3-(2-nitropropenyl)-1H-indole, 72%
5-methoxy-3-(2-nitrovinyl)-1H-indole, 83%
5-methoxy-3-(2-nitropropenyl)-1H-indole, 91%

[1] In case of 1-(2,5-dimethoxyphenyl)-2-nitroethene crystallisation occurs during the reaction. After 20 minutes at 50°C the reaction mixture becomes a bright neon-orange solid cake.


pHarmacist

  • Guest
wow! Thanks a lot Barium!
« Reply #1 on: March 20, 2003, 02:11:00 PM »
Thank you sooo much for telling us about methylamine's use! Personally I'm going to have a lot of benefit from this in Henry's condensation. You've just opened my eyes! Are you actually talking about isolated yields, that YOU got?

If Barium does it, it will work!


Sunlight

  • Guest
Take a look
« Reply #2 on: March 20, 2003, 07:11:00 PM »
To this Rhodium's link:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenethylamines.dibah.html



They used four methods to prepare nitrostyrenes, methanolic methylamine 16-20 %, aqueous ethylamine 70 %, ethanol KOH and ammonium acetate acetic acid. Results show that using methods first or second, an apparent 90 % + yield of nitrostyrenes from piperonal and veratraldehyde are really 50-60 % due nitrostyrene is contaminated with high molecular mass products.
Anyway in Michael Valentine' Psychedelic Chemistry methanolic methylamine is proposed to get the 3,4,5 nitro, with an unespecefied yield. It's not a very good book.
And for example, 3,4,5 trimethoxy benzaldehyde condensation with cyclohexylamine in methanol yield a strange product that it is not the styrene. TLC aids almost nothing in this case because this product is not soluble in methanol.
Have you performed any analytical procecure to determine the purity of the products you got with this attractive method ?

GC_MS

  • Guest
Must
« Reply #3 on: March 20, 2003, 08:13:00 PM »
Must...find...benzaldehydes...Start...synthesis...aaaargh! Nice to hear you're still alive Ba  ;)


Barium

  • Guest
Tests
« Reply #4 on: March 21, 2003, 10:40:00 AM »
The following nitrostyrenes has been reduced to the corresponding nitroalkanes using the EtOAc/EtOH/NaBH4 method followed by reduction to the amines using the IPA/KCOOH/Pd-C system.

1-(4-ethoxyphenyl)-2-nitroethene, 89% nitroalkane*, 85% amine hydrochloride*, 97% by HPLC**.
1-(4-ethoxyphenyl)-2-nitropropene, 86% nitroalkane*, 85% amine hydrochloride*, 98% by HPLC**.
1-(2,5-dimethoxyphenyl)-2-nitroethene, 94% nitroalkane*, 82% amine hydrochloride*, 98% by HPLC**.
1-(2,4-dimethoxyphenyl)-2-nitropropene, 90% nitroalkane*, 91% amine hydrochloride*, 98% by HPLC**.
1-(2,4,6-trimethoxyphenyl)-2-nitropropene, 96% nitroalkane*, 94% amine hydrochloride*, 98% by HPLC**.

* Isolatetd yield
** Purity by HPLC, calculated as area %.


Sunlight

  • Guest
Good
« Reply #5 on: March 22, 2003, 02:47:00 AM »
Very good, congratulations !!! I hope I can try it soon with my own hands.

Chimimanie

  • Guest
Barium
« Reply #6 on: March 22, 2003, 10:06:00 AM »
Barium you are the best :)

Very good work, thank you man ;)

cattleprodder

  • Guest
Barium,
« Reply #7 on: March 24, 2003, 03:31:00 PM »

Bandil

  • Guest
skip this post
« Reply #8 on: March 24, 2003, 03:38:00 PM »

cattleprodder

  • Guest
Free acid for the school kids!
« Reply #9 on: March 24, 2003, 08:00:00 PM »

Bandil

  • Guest
To return to the topic
« Reply #10 on: March 24, 2003, 10:43:00 PM »
I don't know if this is a dumb question, but here goes:

The reaction is a condensation reaction, where water is from the two molecules, when reacting. In order to improve yeilds it has been proposed to remove the water via a dean stark trap during the reaction according to le chaleliers principle. 

This variant of the reaction is "swamp like" wet and yet provides high yeilds. Does anyone have an explanation of this? Could the yeilds go even higher if anhydrous methylamine dissolved in IPA was used?

Regards
Bandil


Megatherium

  • Guest
That is a rather interesting question.
« Reply #11 on: March 24, 2003, 11:19:00 PM »
That is a rather interesting question.

But if you use anhydrous MeNH2 in i-PrOH, what keeps the methylamine from reacting with the benzaldehyde to form an imine?

And, since the reaction temperature is 40 - 50 °C, anhydrous methylamine in an alcohol will jump out of the liquid phase and fill your room with a huge cloud of noxious gas  :) .

Bandil

  • Guest
Well, you have the methylamine in it's ...
« Reply #12 on: March 24, 2003, 11:27:00 PM »
Well, you have the methylamine in it's freebase form in the water aswell. Don't know the solubility in the different alcohols, but its quite high in water(959cc/100ml). Imagine it's high in alcohol aswell.

Regards
Bandil


Rhodium

  • Guest
Nitroalkene catalysis
« Reply #13 on: March 24, 2003, 11:38:00 PM »
But if you use anhydrous MeNH2 in i-PrOH, what keeps the methylamine from reacting with the benzaldehyde to form an imine?

That is the mechanism of the amine catalysis. The imine is more readily attacked by nitroalkanes than the aldehyde itself.

Megatherium

  • Guest
Hmm, cool. Then should the anhydrous...
« Reply #14 on: March 25, 2003, 12:07:00 AM »
Hmm, cool.  Then the anhydrous methylamine reaction should work fairly well  :)  (provided that the solubility doesn't cause any problems ... i-PrOH isn't as good as water in hydrogen bond formation).

However, the yields of this reaction itself are very good.  It probably won't bee worth the trouble preparing an isopropanolic methylamine solution.

UncleFester

  • Guest
old wine in a new bottle
« Reply #15 on: March 26, 2003, 02:35:00 AM »
In some of the original work done on the Knoevenagel condensation (see JACS vol. 56, pages 1556-8 (1934)), the catalyst they used for their studies was methylamine. I sited this work in SOMM 5 years ago, and noted the use of methylamine.
When I go to Org Syn, the amines preferred are higher boiling amines so they can boil the mixture without driving out the catalyst, and run a Dean Stark trap to get out the water.
I laud your work on this subject, but it seems that higher boiling amines are preferred by people doing the reactions.
The most easily available higher amine is ethylenediamine, used as a component for nickel stripping solutions. I could pick up drums or pails without so much as a howdy-do, and the Russians claim it is great for making phenylacetone from benzaldehyde. I don't want to rain on the parade, but it is really old news.

Rhodium

  • Guest
What catalyst for which benzaldehyde?
« Reply #16 on: March 26, 2003, 03:24:00 AM »
But there is something I have never understood, and that is why there is no obvious pattern to which catalyst gives the best yields with what substrate - Ethylenediamine works wonders with most things, but fails miserably with fluorine-substituted benzaldehydes, 3,4,5-trimethoxybenzaldehyde and piperonal. The latter two gives great yields with cyclohexylamine though, but not the fluorine ones, they "need" ammonium acetate...

Why this randomness?

lugh

  • Guest
Knoevenagel Catalysts
« Reply #17 on: March 26, 2003, 04:04:00 AM »
From the Organic Reactions article by Jones  :)

Selection of Experimental Conditions

The most generally used catalyst is still pyridine with or without added piperidine, while for the production of arylidenemalonic acids alcoholic ammonia is preferred. Piperidine or other secondary amines are suitable for the condensations which involve malonic esters, malononitrile, beta-diketones, beta-ketonic esters, and methyl groups activated by attachment to a heterocyclic or nitro aromatic system. A study of condensations between ketones and ethyl cyanoacetate led to the suggestion that ammonium acetate is the best catalyst for condensations with hindered ketones, and primary amines, especially benzylamine, for unhindered ketones and aldehydes. A startling increase in yield in condensations involving ketones carrying other functional groups (notably ester groups) was obtained by the use of piperidine containing a little benzylamine. The cyclopentanone condensed with ethyl cyanoacetate to give the unsaturated compound in 55% yield with piperidine as catalyst. With added benzylamine the yield was 89%. Secondary amines are on the whole less successful in condensations involving aliphatic nitro compounds, where the catalyst of choice is a primary amine or ammonium acetate in boiling benzene. In a comparative study the latter was found superior. The Schiff bases can be used without catalysts.

The most significant modification of the Knoevenagel reaction has been the introduction by Cope of ammonium and amine acetates as catalysts. They are used with a solvent mixture of acetic acid (minor component) and some water-immiscible solvent such as benzene, chloroform, or toluene (major component).  By boiling the reaction mixture and using a Dean-Stark water separator the reaction can be accelerated and the progress of the reaction observed. Raja has studied the yields obtained with a variety of second solvents and has found the most effective to be benzene and toluene, followed by chloroform and hexane. The Cope modification has proved most valuable for condensations involving cyanoacetic esters, but it has been used successfully for reactions with malononitrile, malonic esters, cyanoacetamide, acetoacetic esters, alkyl- and aryl-sulfonylacetic esters, and aliphatic nitro compounds. Variations in the acid component include the use of benzoic and caproic acids to minimize the loss of amine salt by amide formation during prolonged reactions. Increase in yield by reduction in acetamide formation has also been achieved by adding the ammonium acetate catalyst at intervals during lengthy reactions. In some cases, however, this has been reported to be without effect. The suggestion that amine salts are active catalysts has led to the use of amino acids. An extensive range of amino acids has been tested and four selected as superior. All give yields of the same order as piperidinium acetate under Cope conditions in the condensation between acetone and ethyl cyanoacetate. The four selected (para-aminophenol, alpha-aminophenyl-acetic acid, beta-alanine, and epsilon-aminocaproic acid) were used with acetic acid and benzene; it was found that with increasing amounts of p-aminophenol the acetic acid became unnecessary. A number of successful conden-sations have been performed with weakly basic resins such as Amberlite IR-4B and Dowex 3, preferably in the acetate or benzoate form. The resins have the advantage of easy removal by filtration after completion of the reaction. The use of triethanolamine to obtain high yields of beta, gamma-unsaturated acid in the malonic acid condensation has been mentioned. No general rules regarding temperature of reaction can be given,. although it has been reported that a number of aromatic aldehydes failed to condense with malonic acid at -10° to -6°. The proportion of catalyst used varies considerably from a large excess (as with pyridine in the Verley-Doebner modification of the cinnamic acid synthesis) to a few drops, as commonly with piperidine. A number of studies of individual reactions with the intention of discovering the optimum amount of catalyst have not led to any general rule. In some cases 0.1 to 0.2 mole of catalyst to each mole of aldehyde has been used; in others a 1: 1 ratio; in others a large excess of catalyst. The usual proportion of ammonium acetate or amine acetate in the Cope modification is 0.2 mole to each mole of active methylene component. Variations in concentration of the acetic acid alter the yield in the condensation between ethyl pyruvate and ethyl cyanoacetate, the maximum yield being attained with a concentration of 0.075-0.1 M.  In the condensation of furfural with acetylacetone in water using glycine as catalyst the yield of condensation product rose with increasing concentration of catalyst, but this may have been due in part to a salting-out effect. A considerable increase in yield and in rate of reaction was achieved by application of high pressures (15,000 atmospheres) to the condensation between cyclopentanone and ethyl cyanoacetate. Using cyclohexanone the condensation could be achieved without the piperidine catalyst.

Catalysts Other Than Amines or Their Salts

Catalysts other than amines or their salts have been used frequently in condensation between aldehydes or ketones and active methylene compounds. Among the more common catalysts are caustic alkalies or sodium carbonate, the latter in what amounts to an extension of the aldol condensation; and, less often, quaternary ammonium hydroxides or strongly basic resins. An example of the use of quaternary ammonium hydroxide resins is the formation of the coumarin from ethyl acetoacetate and o-hydroxyacetophenone. Catalysis by sodium hydroxide is as common as the use of amines in the condensation of cyanoacetic acid with aldehydes. Sodium cyano-acetate, as synthesized in aqueous alkaline solution, can be used directly in the condensation. Condensations involving malonic esters have been performed with acetic anhydride or zinc chloride as catalyst, and a number of cases have been recorded for which the yields were higher with acetic anhydride than with piperidinium acetate. Potassium fluoride has been used extensively in recent years as a catalyst for condensations involving malonic esters and cyanoacetic esters. Most of the yields reported are lower than those obtained by using conventional Knoevenagel catalysts. Titanium tetrachloride has been used to catalyze the condensation of aldehydes with ethyl malonate, ethyl acetoacetate, and ethyl cyanoacetate.

Acta Chem Scand 3 (1949)
Bull Soc Chim France 797 (1956)
Ber 37 4502 (1904)
Chem Rev 32 373 (1943)
Compt Rend 246 3079 (1958)
Ind Eng Chem 44 2867 (1952)
JACS 56 1556 (1934)
JACS 59 2327 (1937)
JACS 63 3452 (1941)
JACS 80 4949 (1958)
J Ind Chem Soc 9 311 (1932)
J Ind Chem Soc 30 206, 665 (1953)
J Ind Chem Soc 34 537 (1957)
J Sci Res Inst 52 99 (1958)
J Sci Res Inst 52 105 (1958)
J Sci Res Inst 52 112 (1958)
J Sci Res Inst 52 151 (1958)
J Sci Res Inst 53 19 (1959)
JCS 844 (1927)
JCS 74 (1931)
JCS 876 (1937)
JCS 3155 (1951)
JOC 15 388 (1950)
JOC 18 3 (1953)
JOC 26 4874 (1961)
JOC 27 3505 (1962)
Proc Acad Sci, Agra Oudh 4 290 (1934/5)


UncleFester

  • Guest
don't add too much!
« Reply #18 on: March 26, 2003, 04:18:00 AM »
While we are on the topic, the original works also covered the effect of adding more than the prescribed dose of catalyst. It was not favorable, so it is not season to taste.

UncleFester

  • Guest
understanding this stuff
« Reply #19 on: March 26, 2003, 05:33:00 AM »
I've been studying this field for about 25 years now. Damnded if I can understand why one molecular structure wants to dive into a catalyst, while another turns up its nose. I just attempt to catalog and be a happy cooker.