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Author: Subject: 3,4,5-trimethoxy-beta-nitrostyrene synthesis
a123x
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[*] posted on 19-6-2005 at 14:46


I thought of another possible route to making 3,4,5-trimethoxybenzaldehyde, starting with anisaldehyde. Dinitrate the anisaldehyde to make 3,5-dinitroanisaldehyde. This is reduced with a reducing agent of choice to form the diamino compound. Diazotisation is then carried out in methanol. The methanol is then allowed to react with the diazonium salt to form methoxy groups. I did find reference to such a reaction being used to form methoxyninhydrin:

"Lennard and co-workers have synthesized many of the early substituted ninhydrin analogues, including 5-methoxyninhydrin (28).18 The synthesis began with commercially available dimethyl 4-nitrophthalate (23) (Scheme 6). Reduction of the nitro group to the amine 24, was followed by diazotization with nitrous acid in methanol to yield 4-methoxyphthalate (25). Reaction of this compound (25) with ethyl acetate and sodium hydride afforded the Claisen ester condensation product, which was treated with aqueous hydrochloric acid to yield the desired 1,3-diketone (26). Treatment with p-toluenesulfonyl azide in triethylamine delivered the 2-diazo intermediate (27) that was subsequently hydrolyzed with refluxing aqueous tert-butyl hypochlorite to yield 5-methoxyninhydrin (28). The reagent develops prints with a more intense fluorescence than ninhydrin-developed prints. Joullié and co-workers later developed an alternative route to 5-substituted ninhydrins. They used this method to synthesize 5-(methylthio)ninhydrin, which was shown to possess superior properties to those of 5-methoxyninhydrin.19"

Unfortunately that seems to be all the detail that I could find on the reaction. I myself am unaware of any reason why it can't be used to form 3,4,5-trimethoxybenzaldehyde starting with anisaldehyde but there may well be some reason why it won't work. I myself am quite curious as to whether it will work. Does anyone know of any reason it won't work or have more information on the specifics of carrying out the synthesis?
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[*] posted on 28-6-2005 at 00:48


while true that i've not looked i find it hard to belive that there are examples in the litterature where 2 amino groups are turned into diazonium salt and displaced by nuceophile stimulaneously. another problem is the nitration of anisaldehyde, formyl is slightly deactivating and putting not one but two nitros could be difficult, maybe start from p-phenol (followed by methylation) instead of methylether would solve this. But even if the diazotization and everything did work, the route is not a good one, I would rather di-brominate (preferably p-hydroxy-benzaldehyde) and do a copper catalyzed substitution with sodium methoxide for syringaldehyde to be methylated... If a vast array of compounds is looked for it is better to start from vanillin, so it depends what and how much compounds you want to make of course... Again, I haven't looked up your proposal, it might work, but i would be surprised and regardless it is too much work.

EDIT:

As you see this is much easier and well documented:

3,4-Dibromo-4-hydroxybenzaldehyde:

To a stirred, cooled (0°C) solution of 122.0 g (1.0 mol) 4-hydroxybenzaldehyde in 1.0 L of methanol was added during 30 min 325.0 g (2.2 mol) of bromine at such a rate that the temperature was kept below 20°C. The mixture was stirred at room temperature for 1.0 h, 800 mL of methanol was removed by distillation (water aspirator) at 50°C, and to the warm (45°C) solution was added 2.0 L of water during 20 min. The mixture was stirred at 0°C for 1.0 h and the product was collected by filtration. It was washed with water (5 x 1.0 L) and then with 500 mL of cold, 30% aqueous methanol, dried in vacuo at 70°C for 18 h to give 264.4 g (95.5%) of 6 as a colorless powder, mp 180-182°C. TLC (silica gel, 30:60:1 ethyl acetate: hexane: formic acid) showed only one spot under short wavelength UV light.

Syringaldehyde:

A 165-g (0.59 mol) batch of 6 in 156 mL of methanol and 312 mL of anhydrous DMF was reacted during 4.0 h with 4.78 moles of freshly prepared sodium methoxide in the presence of 9.45 g (0.047 mol) of cuprous chloride under the conditions described previously for the conversion of 5 to give 153.3 g (88% yield) of 7, mp 105-108°C

Ref: Synthetic Communications 20;17;1990;2659-2666

3,4,5-trimethoxybenzaldehyde

10g 3,5-dimethoxy-4-hydroxy-benzaldehyde, 13.5g K2CO3 and 8.3g dimethylsulfate is dissolved in 80mL dry DMF, the solution is stirred for 2h and then poured into 800mL ice/water, the product is filtered off and xtalised from cyclohexane.

Ref: Hest's mesc writeup

[Edited on 28-6-2005 by Sandmeyer]




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[*] posted on 29-6-2005 at 08:28


Quote:
Originally posted by Sandmeyer

Again, I haven't looked up your proposal, it might work, but i would be surprised and regardless it is too much work.



I'd be surprised if it would work. The carbonyl functional group will not survive this oxidation.

[Edited on 29-6-2005 by Sergei_Eisenstein]
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[*] posted on 29-6-2005 at 11:38


Quote:
Originally posted by Sandmeyer

3,4,5-trimethoxybenzaldehyde

10g 3,5-dimethoxy-4-hydroxy-benzaldehyde, 13.5g K2CO3 and 8.3g dimethylsulfate is dissolved in 80mL dry DMF, the solution is stirred for 2h and then poured into 800mL ice/water, the product is filtered off and xtalised from cyclohexane.

[Edited on 28-6-2005 by Sandmeyer]


I have a question, not about this specific synthesis, but about methylations with dimethylsulfate in general (in DMF as well as in water): After pouring the mixture into ice water, is the dimethylsulfate entirely gone or might there be some residues (dimethylsulfate decomposes very slowly in water)?
And does it decompose into H2SO4 and Methanol, or into Methylsulfuric acid?
And how dangerous is methylsulfuric acid?

[Edited on 29-6-2005 by garage chemist]
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[*] posted on 29-6-2005 at 13:54


Quote:
Originally posted by garage chemist

Quote:
And does it decompose into H2SO4 and Methanol, or into Methylsulfuric acid?
And how dangerous is methylsulfuric acid?


It decomposes into the anion MeSO4 (-) of methylsulfuric acid, material safty data sheet of potassium salt can be found here: https://fscimage.fishersci.com/msds/95639.htm

Should the post-reaction excess be destroyed with NaOH, then yes, MeOH would be produced as well...

[Edited on 29-6-2005 by Sandmeyer]




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[*] posted on 30-6-2005 at 04:32
cyclohexylamine


If you are going to condense 3,4,5-trimethoxybenzaldehyde with nitromethane i definately suggest to use cyclohexylamine as a catalyst, providing consistent good yields.

To a solution of 150 mL of acetic acid and 40 mL nitromethane there was added 20,21 gram (103 mmol) 3,4,5-trimethoxybenzaldehyde and 20 mL cyclohexylamine. The addition of the cyclohexylamine caused the RBF to fill up with smoke.

The solution was heated to 95°C and after 90 minutes of heating the orange solution was allowed to cool down.

When the solution had cooled down to to 60°C it was decanted into a beaker for quicker cooling this left a lot of smoke in the RBF, after adding some H2O to the RBF the smoke cleared up and caused formation of some residue yellow crystals.

With good stirring the now 20°C decanted solution was diluted slowly using 325 mL H2O, this caused the formation of a thick yellow crystalline mass.

The crystals from the beaker and the RBF were combined, filtered and washed thouroughly with 3 times with 65 mL H2O. The filtered crystals weighed 23,44 gram after sucking them dry for 20 minutes.

The entire mass recrystalized in 192 mL MeOH (8 mL/g) with 3 ml ethyl acetate to dissolve the impurities that did not go into solution.


[Edited on 1-21-2011 by Polverone]




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[*] posted on 30-6-2005 at 08:28


Quote:
Originally posted by samsung

...there was added 20,21 gram (103 mmol) 3,4,5-trimethoxybenzaldehyde and 20 mL cyclohexylamine...
[Edited on 30-6-2005 by samsung]


have you tried EDDA 10 mol % in GAA?




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[*] posted on 30-6-2005 at 12:29
Easier still..A truly facile route to 5-iodovanillin


1) Vanillin (1g), ethanol (20 mL), and sodium iodide (1.2g) were added to a conical
flask furnished with a magnetic stir-bar and the solution was placed in an ice bath for approximately 5-10 minutes with vigorous stirring.

2) 12 mL of sodium hypochlorite solution -household bleach- was drawn into a syringe and then added dropwise to the stirred reaction mixture over a period of 10 minutes. As the sodium hypochlorite is added the solution will turn from a pale yellow solution to a light auburn color.

3) Once the addition of the sodium hypochlorite solution was complete, the mixture was allowed to
warm to room temperature and stirring continued for 10 minutes.

4) 50 mL of sodium thiosulfate solution (10% aqueous) was added, then the solution was acidified with a 10% hydrochloric acid solution. Acidifying the solution to a pH level of approximately 4 should be adequate. The aryl iodide may precipitate at this point.

5) Once acidified, the solution was stripped of EtOH with the aid of a vacuum and gentle heat.

6) The remaining aqueous solution was placed in an ice bath for 10 minutes to allow the precipitate to form, then the ppt was collected by vacuum filtration, washed well with ice-cold water, then washed again with a few [!] mls of cold ethanol.

7) The crude product was placed into a vial and, with gentle heating, just enough IPA added to dissolve the solid. While continuing to heat, hot water was added slowly until the mixture became cloudy, then IPA was again added, just enough to return a clear solution. The vial was placed in an ice bath for approximately 10-15 minutes to ensure complete crystallization.

8) The crystals were collected by vacuum filtration and air drawn through for several
minutes to facilitate drying.

Yield 1.5g 5-iodovanillin (~80% of theoretical)
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[*] posted on 30-6-2005 at 15:49


Quote:
Originally posted by Sandmeyer

have you tried EDDA 10 mol % in GAA?


No, how are the yields? and what is the polymer to nitrostyrene ratio?




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[*] posted on 5-7-2005 at 06:47


Is it possible to methylate syringaldehyde with methyl iodide instead of dimethyl sulfate? I want to get an idea of the methylating power of MeI, as e.g. trimethyl phosphate is not strong enough to methylate syringaldehyde to trimethoxybenzaldehyde. Is methyl iodide strong enough?
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[*] posted on 5-7-2005 at 07:35


From:US4453004

EXAMPLE 4

In an apparatus similar to Example 1, 15.2 g (0.083 mol) of syringaldehyde and 15.0 g (0.11 mol) of potassium carbonate were heated to 105 DEG C. under nitrogen and 15 ml (0.12 mol) of trimethyl phosphate were added over 10 minutes. The mixture was maintained at about 80 DEG C. for 3 hours then cooled to 45 DEG C. and quenched with 50 ml of H2 O. The tan solid which precipitated was collected, washed with 3.times.50 ml of water and dried to give 15 g (92%) of 3,4,5-trimethoxybenzaldehyde.

Of course MeI wil also work.......;)
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[*] posted on 5-7-2005 at 13:21


The reaction proceeds above the melting point of the compound to be alkylated. Syringaldehyde melts around 110-113°C, methyl iodide boils at 41-43°C, also the patent says that "In the process of the invention it is usually advantageous to choose an alkylating agent which has a boiling point several degrees higher than the melting point of the phenol being alkylated to control pressure surges during the course of the reaction."

Obviously the methyl iodide would most likely reside somewhere else than the same phase with the phenol. Of course it might be possible with suitable tricks, like a pressure vessel or continuously recycling the distilled methyl iodide and injecting it below the surface of the phenol... but not likely as simple as with the higher boiling alkylation agents.
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[*] posted on 6-7-2005 at 01:55


I wasn't referring to the method of melting the phenol with TMP or DMS, rather to the method where the phenol is dissolved in DMF with K2CO3 and stirred with DMS at ROOM TEMP.
Would THIS also work with methyl iodide?

Thanks for the other info anyway, I didn't know that TMP is able to methylate syringaldehyde.

[Edited on 6-7-2005 by garage chemist]
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[*] posted on 6-7-2005 at 03:05


Of course it will work, but let it stirr overnight instead of 2h. If DMF is unavailable, acetone can be used:

3,4,5-Trimethoxybenzaldehyde (1)

A stirred mixture of 153.0 g (0.84 mol) of syringaldehyde (7) in 1.0 L of acetone, was treated with 127.0 g (1.02 mol) of dimethylsulfate, 118.0 g (1.11 mol) of anhyd. Na2CO3, and 3.0 g (0.053 mol) of KOH in 32 mL of water. The mixture was stirred under reflux for 18 h. cooled to room temperature and filtered. The filter cake was washed with acetone (3 x 200 mL) and the filtrate and washings were concentrated to ca. 200 mL. The stirred solution was diluted with 500 mL of water during 30 min, followed by 1.5 L of water during 15 min. Stirring was continued at room temperature for 15 min and then at 0°C for 30 min, and the product was collected by filtration. It was washed with water (4 x 2.0 L) and dried in vacuo at 25°C for 24 h to give 150.2 (91.5%) of 1 as colorless crystals, mp 73-75°C (Lit.9 74°C). TLC (4:1 ether-hexane) revealed only one spot, Rf 0.57.

[Edited on 6-7-2005 by Sandmeyer]
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[*] posted on 6-7-2005 at 04:10


what about substituting cyclohexylamine for butylamine(acetate) or methylamine(acetate), are those 2 worth a try being used as catalysts?
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[*] posted on 6-7-2005 at 21:27


Yes, methylamine works.
You could also do a Henry Reaction, base catalysed to an alcohol then dehydrate it with an acid. Works good for 3,4,5-TMNS with decent yields.

http://www.organic-chemistry.org/frames.htm?http://www.organ...

[Edited on 7-7-2005 by KidCurry]
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[*] posted on 8-7-2005 at 03:43


Quote:
Originally posted by KidCurry
Yes, methylamine works.
You could also do a Henry Reaction, base catalysed to an alcohol then dehydrate it with an acid. Works good for 3,4,5-TMNS with decent yields.

http://www.organic-chemistry.org/frames.htm?http://www.organ...

[Edited on 7-7-2005 by KidCurry]


To the solution of 5.5 g 3,4,5-TMBA in 25 ml of GAA was added 3.5 g of nitromethane and 0,5 g of ethylenediamine diacetate. Obtained mixture was heated with reflux for 1 h, diluted with 150 ml of water, obtained crystals were washed with water, minimal amount of cold IPA and hexane and dried. Yield – 5.6 g (84%). I mean, 1 mL of butylamine or cyclohexylamine instead EDDA will work too.

Ref: priv. communication.

Obviously, any reasonable primary amine works, and, as far as 345 goes GAA should be used as a solvent. If one can't afford ethylenediamine then ethanolamine might be an option, although I have no refs for this statement.

I have also seen examples from litterature when secondary amines are being used under MW irradiation (e-flask in a domestic MW-oven) giving also very good results in no-time, but for now I'm away from my refs.

[Edited on 8-7-2005 by Sandmeyer]
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[*] posted on 8-7-2005 at 06:21


Quote:
Originally posted by joe_aldehyde
swim has too little 3,4,5-TMBA to go experimenting with the catalysts, but still he has methylamine, butylamine, ethanolamine.

i wonder if ethanolamine is any good in knoevenagel condensations.


Not only is it clear from my last post that butylamine has been tried and works, but it seems like replying is a total wate of time. If you wonder whether etanolamine works try it now that you have chemicals, or is it to complicated?

[Edited on 8-7-2005 by Sandmeyer]
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[*] posted on 8-7-2005 at 10:01


oh SAM...
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[*] posted on 20-7-2005 at 09:11


joe, the ethylenediamine can be found at photo suppliers. It is pretty cheap. The freebase is in liquid form.

To make acetate salt use 2x molar acetate per 1 mol ethylendiamine. DCM works as the solvent. Use an ice bath, keep the temp around 15C.
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[*] posted on 20-7-2005 at 10:58


Methyl iodide is specifically mentioned in Vogel. Methyl bromide can methylate pyrogallol and syringol, volatility is not an issue as the reaction is fast. An interesting alternative is diazomethane, though not on the aldehyde.

Of course this is on the phenols or acids, how well the original Williamson works on benzaldehydes, and what can be done to minimize Bad Things, I don't know.
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[*] posted on 24-7-2005 at 08:55


Quote:

An interesting alternative is diazomethane, though not on the aldehyde.


You mean it wouldn't work on the aldehyde?

Also, how well does diazomethane compare with other methylating agents? Say with dimethylsulfate? Would be nice if it would work as a substitute as diazomethane is - atleast for me - the most easily made methylating agent.
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[*] posted on 24-7-2005 at 10:44


I'm not even sure that it would work on pyrogallol, I have no refs.

This is something that I've always been meaning to look up further but never have. I was going to spend some hours at the library today anyways. I've never seen it used on phenols in a journal, I've only seen passing mentions without references to it being done on phenols, here and there. There is an example in OS on a cyclohexanol. Note the catalyst, which is a typical one for this. CH2N2 converts benzaldehydes to acetophenones, and interesting but in this case undesirable epoxides and 2-propanones.

Again, whether or not the aldehyde could be protected/hydrolyzed back to the aldehyde I don't know.

With gallic acid this would be very interesting if it could be made to work, as the resulting trimethoxy methyl ester could be reduced to the alcohol.
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[*] posted on 24-7-2005 at 12:46


I've seen references here and there where phenolic benzoic acids where permethylated with diazomethane, so it should work indeed. Also, the homologation reaction of benzaldehydes with diazomethane usually stops at acetophenone. P2P and corresponding oxiranes are only found in trace amounts. I thought piperonal to be one of the few exceptions, and it still is solvent dependant.
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[*] posted on 24-7-2005 at 21:51


Yes, phenylacetaldehyde is more interesting for some, not benzaldehyde itself. I too have read the Org. Reactions chapter, and have Mosettig's 1928-9 Ber. articles. The dissertation is a little harder to find from here.

There are many references on tannin methylation with diazomethane, but I still have nothing on pyrogallol, etc. I've only scratched the surface.

The plain hydroxybenzenes should be less acidic IIRC, especially with partial methylation. I'm not sure what the cutoff is, where you have to start using catalyst as in the OS article. It seems that with gallotannin, conversion is OK, the procedure simple, and partially methylated acid can be recovered and used again.

Most of the refs on tannin that I came across today were in obscure journals, Chinese patents, and/or not in English. It seems that the usual DMS/KMnO4 to the methylated benzoic acids doesn't suit everyone, but the CH2N2/alcoholic KOH is definitely less common. Various dry solvents have been used for the methylation. Tannin/diazomethane interests me, so here is the best of the few refs that I could find today, like it or not. This one uses acetone as solvent and of course is in German, only a small part of a larger, badly microfilmed article:

Attachment: ber_47_2485_1914.pdf (721kB)
This file has been downloaded 1005 times

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