Author Topic: Vanillin  (Read 6174 times)

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Natrix

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Vanillin
« on: February 28, 2002, 07:56:00 PM »
Vanillin from 4-hydroxybenzaldehyde:

http://valhalla.chem.udel.edu/vanillin.html


ChemicalSolution

  • Guest
Re: Vanillin
« Reply #1 on: February 28, 2002, 09:01:00 PM »
SWIM is all about new synthetic methods.. But, gosh.. after all of that..  You've gotta believe that methylenation of catechol followed by chloromethylation would be an easier route to piperonal.

xoxo Julia

Rhodium

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Re: Vanillin
« Reply #2 on: February 28, 2002, 10:57:00 PM »
Yes, definitely, but if piperonal wasn't a target, but instead 3,4,5-trimethoxybenzaldehyde - then this synthesis would be great.

uemura

  • Guest
Re: Vanillin
« Reply #3 on: March 01, 2002, 07:26:00 AM »

Combine 1.13 mL of a 4.0M sodium methoxide solution, 44 uL ethyl acetate, and 22 mg copper bromide in a 25-mL round-bottom flask with a stir bar. Stir this solution for 5 min. at room temperature to prepare the copper catalyst. Then, add 0.150 g (or all of the product from A above, whichever is less), and heat to reflux for 1 h.



A question from Uemura.
1) What is the purpose of the EtOAc? To be a co-solvent the amount is to less. Has it a catalytic function?
2) In the above preparation the stirr 1 hrs only. In the synthesis on Rhod's site (for syringaldehyde) they stir 14Hrs. Any idea on the factor 14?


Carpe Diem

Osmium

  • Guest
Re: Vanillin
« Reply #4 on: March 01, 2002, 12:21:00 PM »
> 1) What is the purpose of the EtOAc? To be a co-solvent
> the amount is to less. Has it a catalytic function?

Yes. Check the ref. given in the synth. of Rhodium's site for details.

> 2) In the above preparation the stirr 1 hrs only. In the
> synthesis on Rhod's site (for syringaldehyde) they stir
> 14Hrs. Any idea on the factor 14?

Solubility reasons according to the authors. Again see that ref. for more details.



I'm not fat just horizontally disproportionate.

uemura

  • Guest
Re: Vanillin
« Reply #5 on: March 01, 2002, 01:04:00 PM »
It's Tet Lett 34, 1007-1010 (1993) which Uemura can't access easily. It says:

5-bromovanilline (5mmol) is refluxed with EtOAc (3mmol) and CuBr (1mmol) in 5 M NaOMe/MeOH (10 ml) for 14 hours. Classical work-up (addition of water and acidification followed by extraction of the phenol) leads to pure syringaldehyde (95%). When starting from the more soluble 5-bromovanilline dimethyl acetal, reaction is achieved within 2 hours (yield 98%). Preparation of this acetal is probably not worth the extra work.

Beeing not that stupid, this desription seemed to bee easy.

However after 14 hrs reflux, Uemura got something which is a coffee cream solid which doesn't dissolve in anything!

Failure analysis still in progress.....

Osmium

  • Guest
Re: Vanillin
« Reply #6 on: March 01, 2002, 01:13:00 PM »
Did you properly exclude moisture? Can't hurt to work under an inert athmosphere either whenever dealing with phenolates and benzaldehydes.

I'm not fat just horizontally disproportionate.

Antoncho

  • Guest
Re: Vanillin
« Reply #7 on: March 01, 2002, 01:20:00 PM »
I have seen several patents on the issue - too bad didn't save any of em - and they absolutely all use DMF as a catalyst. Which makes me wonder as to the credibility of this proc. at all. BTW, the improved proc's gave yields not better than this one mentioned on Rh's. Which makes me wonder even more ::)

I'll try to dig some patent on the issue. Some of them were sexy (BTW, CuBr must bee hard to get - no? Does Cu(I) form hydrates - i.e., can it bee easily made at home?)

Antoncho

P.S. Uemura, i advise you to PM hest and ask him to join this thread - or discuss the issue privatly. SWIh has done that w/success.

uemura

  • Guest
Re: Vanillin
« Reply #8 on: March 01, 2002, 01:33:00 PM »
Antocho!

makes me wonder as to the credibility of this proc

Uemura feels this way as well. If you find the patents, this would be great.

Now: The MeOH and the MeONa are lab grade quality. Bromovanillin was bone-dry and had a mp of 160-162. The EtOAc was also specified quality from a fresh opened bottle. The CuBr has been prepared by reducing a CuSO4/NaBr aequous solution with NaSO3 as described in 'Organo Copper Reactions...' CuBr just 1 week old, dried for 6Hrs under 2Torr vacuum. 

Indeed, no inert atmosphere, but high speedy reflux, condensor equipped with Bunsen valve. bromovanilline, NaOMe and MeOH heated up to almost reflux, then CuBr added.

Uemura has another reference around, where bromobenzene is converted into anisol, with and without DMF AND NO ETOAC. DMF gives higher yields in shorter time (100% in 6Hrs, 5N MeOCH3, DMF and 82% in 6Hrs, 5N MeOCH3, no DMF). Major factor is the molar concentration of the OCH3- ion. Should be at least 5N, which BTW isn't simple at rt.

Any further ideas? Anybee have been successful with this one???

Carpe Diem

Antoncho

  • Guest
Re: Vanillin
« Reply #9 on: March 01, 2002, 01:34:00 PM »
Here's one.

No ethylacetate, much (relatively) DMF, CuCl as catalyst (will CuCl prepared as described on Rh's bee good for this?)




EXAMPLE 4

Preparation of 3,5-dimethoxy-4-hydroxybenzaldehyde

Into a 5-l., 3-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer, and condenser was added 1.0 l. of methanol. 85.2 G. of clean sodium was then added in small pieces and under nitrogen. After the reaction was complete, the methanol was removed at 45.degree.-50.degree. and 450 ml. of dimethylformamide added to the residue. To the rapidly stirred slurry of sodium methoxide in dimethylformamide was added 10.7 g. of cuprous chloride to give a deep blue mixture which was stirred at 25.degree. for 15 minutes. 214.4 G. of 3-methoxy-4-hydroxy-5-bromobenzaldehyde was added during 3 minutes, whereupon a slight exotherm ensued. The temperature of the reaction was increased to 97.degree. during 15 minutes and the mixture was stirred at this temperature for 1.75 hours. The reaction was cooled to 60.degree. and the dimethylformamide distilled off under high vacuum. 1.0 l. of 15% brine was added to the residue, the mixture was stirred at 50.degree. for 30 minutes, cooled to 0.degree. and treated with 300 ml. of cold (0.degree.) concentrated hydrochloric acid at such a rate that the temperature was kept below 15.degree.. The mixture was stirred at room temperature for 1 hour, again cooled to 0.degree. and filtered over 100 g. of celite. The filter cake was washed with four 400 ml. portions, a total of 1.6 l. of cold (5.degree.) water, followed, after discarding the aqueous wash, by five 500 ml. portions, a total of 2.5 l. of hot (60.degree.) ethyl acetate. The ethyl acetate washings were added to a separatory funnel, excess water (about 15 ml.) was ran off, and the ethyl acetate dried over magnesium sulfate and evaporated in vacuo to give 154.0 g. (91%) of 3,5-dimethoxy-4-hydroxybenzaldehyde as yellow crystals, mp 109.degree.-111.degree., purity of 99.72%.




Antoncho

P.S. Obviously, i edited my prev post after you posted. Here again:

Uemura, i advise you to PM hest and ask him to join this thread - or discuss the issue privatly. SWIh has done that w/success.

uemura

  • Guest
Re: Vanillin
« Reply #10 on: March 01, 2002, 01:45:00 PM »
It goes quick and fast. Thanks Antocho.
In your ref, they reflux 1.75hours. Not 14hrs!!! Uemura's paper says CuCl works, but CuBr is better. Even Cu metal or Cu(II) salts work, since the 5N MeONa soltution reduced the Cu(II) to Cu(I). PMed hest, let's see what he thinks.
The EtOAC usage is also referenced in the article (see

http://valhalla.chem.udel.edu/vanillin.html

) refered to earlier.
Carpe Diem

Antoncho

  • Guest
Re: Vanillin
« Reply #11 on: March 01, 2002, 02:31:00 PM »
Darn it, i swear i seen a patent when the rxn is performed w/catalytic amt of DMF in EtOAc - and as a catalyst they use basic Cu carbonate! But - fuckin' mystiquely - i can't find it on USPat. although i literally shuffled the place upside down.

Very, very  :(  - i remember i was quite pleased w/that patent. Anyone else recalls smth like this?

Antoncho

P.S. Here, in case you got some ethyl formate:




(from

Patent US4495353


Methoxylation of 2-Bromophenol to yield Guaiacol

2-Bromophenol (17.3 g, 0.1 mole) was dissolved in a solution of sodium methoxide (32 g, 0.6 mole) in methanol (98 ml) and this mixture was flushed with nitrogen. It should be noted that the extra equivalents of the sodium methoxide base were added in order to neutralize the phenol. Methyl formate (3.6 g, 0.06 mole) was then added, followed by cuprous bromide (2.9 g, 0.02 mole).

A vigorous reaction occurred on the addition of the cuprous bromide, and TLC showed the reaction to be virtually complete after 30 minutes.

After 13/4 hours the reaction mixture was worked up, and the product was isolated as a quantitative yield of a red oil. This was identified as guaiacol by comparison of the infra-red spectrum with an authentic specimen as recorded in the Aldrich catalogue. Bulb-to-bulb distillation of a sample yielded a colorless solid, m.p. 28.degree. C. (lit. 28.degree. C.).




They use the proc on all sorts of compd's - unfortunately, not on aldehydic ones.

foxy2

  • Guest
5-Br-Vanillin Methoxylation (CuBr/EtOAc/NaOMe)
« Reply #12 on: March 01, 2002, 02:47:00 PM »
Uemura, here you go:

Esters are effective co-catalysts in copper-catalyzed methanolysis of aryl bromides
Patrice Capdevielle, and Michel Maumy

Tetrahedron Letters 34(6), 1007-1010 (1993)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/arylhalide.methanolysis.cu-etoac.pdf)

Abstract
Anisole is also quasi-quantitatively obtained from bromobenzene in presence of ethylacetate (10 mmole C6H5Br, 4 mmol EtOAc, 1.4 mmol CuBr in 6 ml 5M MeONa/MeOH, 98% conversion after lh reflux, 100% after 2h, yield of isolated anisole > 95% without detected phenetole).

Copper-catalyzed reaction of sodium methoxide with aryl bromides in methanol is generally a method of value for the preparation of methyl aryl ethers(1) : However, this process is often sluggish or even ineffective in the case of unactivated (devoid of electron withdrawing substituents Z) aryl bromides such as bromobenzene, and various studies have been undertaken to resolve this problem. Several publications and patents claimed that amide co-solvents such as N,N-dimethylformamide (DMF) were very useful,(2a-d) allowing satisfacting solubility and stability of cuprous salts catalysts, which are less soluble and readily disproportionate in methanol alone. Remaining disadvantage was the high cost of such solvents face to methanol, and R. J. Bryant reported that formamides could be replaced by alkyl formates,(3) in relatively small proportions toward methanol solvent. Methoxylation of bromobenzene so proceeds in 56% yield and 2-bromophenol is quantitatively converted into guaiacol.
More recently, H. L. Aalten et al. revisited this chemistry, concluding inter alia that amide co-solvents (DMF) were quite effective to obtain a quantitative bromobenzene + anisole substitution, but methyl formate was curiously found to have no effect on reaction rate in methanol.(4)

Another example, of industrial interest, is the transformation of 5-bromovanilline into syringaldehyde : substrate (5 mmol) is refluxed with EtOAc (3 mmol) and CuBr (1 mmol) in 5 M MeONa / MeOH (10 ml) for 14 h; classical work-up leads to pure syringaldehyde (95%). When starting from more soluble 5-bromovanilline dimethyl acetal, reaction is achieved within two hours (yield 98%).

Hence, the positive influence of esters on the course of these aromatic copper-catalyzed substitutions is well established. and the necessity of high methoxide concentration is checked and explained by the following findings:
Whereas copper(I) bromide (or chloride) catalyst, once added to methoxide solution, gives rise to unsoluble yellow copper(I) methoxide, which decomposes under refluxing to C0 and C2, presence of an ester in concentrated (3 to 5 M) methoxide solutions prevents precipitation of copper(I) methoxide, but provides a colorless mixture in which added aryl bromides are readily transformed into methyl aryl ethers. Use of smaller amounts of copper (0.5 mmol CuBr in 15 ml 4M MeONa / MeOH) even leads to colorless clear solutions (copper complex and NaBr are entirely soluble under MeOH refluxing). Lower methoxide concentrations (up to 2.5 M) render esters co-catalysts uneffective, as copper(I)methoxide remains unsoluble; further addition of methoxide to the mixture leads again to clear solutions.

High efficiency of ethyl acetate is not due to any baso-catalyzed condensation into ethyl acetoacetate, since the latter has a negative effect on the reaction: it slows the rate down to c.a. 75% of the blank’s one when added to the 2-bromophenol / CuBr/MeONa system. The observed stabilization and increased solubility of Cu(1) catalyst in presence of esters MeO-CO-R - even unenolixable - can then be attributed to their adduct with methoxide ion, obtained at high concentrations of the latter, and written as follow:

(proposed mechanism here)

Tetrahedral intermediate 1 is well known to be formed in very small amounts during baso-catalyzed methanolysis of esters;(5a,b) it is obviously here a potent ligand for added copper(I), tentatively drawn as complex 2, allowing in turn the substitution ArBr + ArOMe to proceed with a great etBciency. Such a stabilization of primary catalyst, and also probably of various Cu(II) or Cu(III) intermediate species previously proposed to occur in the aromatic substitutioneitself, implies ester to be substantially transformed (CuOMe no more precipitates from 5M MeONa solution).

This work was partly performed with financial support from Rhane-Poulenc Chimie, and industrial applications are patented.(9)

References
(1)Bacon, R. G. R. ; Rennison, S. C.  J. Chem. Soc.(C) 1969,312 - 315.
(2a)Baldwin, D.; Gates, P. S. (Fisons Ltd.):

Patent DE2627874

, 1977 (C.A. 1977,86,171074).
(2b)Manchand, P. S.; Townsend, J. M. (Hoffmann-La Roche Inc.):

Patent US4218567

, 1980 (CA. 1981,94,15391).
(2c)Rao, D. V.; Stuber, F. A. Synthesis 1983,308.
(2d)Borgaonkar, H. V. ; Chandalia, S. B.  J. Chem. Tech. Biotechnol. 1984,34A, 446 - 452.
(3)Bryant, R. J.(SterwinA.G.):

Patent GB2089672

, 1982 (C. A. .1982,97,215738).
(4)Aalten, A.L., et. al.; Tetrahedron 1989, 45, 5565-5578.

Post 477850

(Rhodium: "ArBr --NaOMe/Cu(I)--> ArOMe", Chemistry Discourse)

(5a)Bender, M. L. Chem. Rev. 1960,60,53 - 113.
(5b)McClelland, R. A.; Patel, G.  J. Am. Chem. Soc. 1981,103,6912 - 6915.
(6)Bowman, W. R.; Heaney, H.; Smith, P. H. G. Terrahedron Lerrers 1984.25, 5821-5824.
(9)Capdevielle, P.; Maumy, M.; Nobel, D. (Rhane-Poulenc Chimie):

Patent FR2669922

1992.

uemura

  • Guest
Re: Vanillin
« Reply #13 on: March 01, 2002, 04:05:00 PM »
foxy & Antocho!
What would the Hive and Uemura do without you!  :)


Anisole is also quasi-quantitatively obtained from bromobenzene in presence of ethylacetate (10 mmole C6H5Br, 4 mmol EtOAc, 1.4 mmol CuBr in 6 ml 5M MeONa/MeOH, 98% conversion after lh reflux, 100% after 2h, yield of isolated anisole > 95% without detected phenetole).




Again, much less reflux time than 14 hours. Also more indepth infos (*)! Also no DMF! This is good honey.

When the f*cking bromovanillin is so picky, why not first methylate it to the 5-bromo-3,4-dimethoxybenzaldehyd and then replace the bromo-  by the methoxygroup. The 5-bromo-3,4-dimethoxybenzaldehyd should be less sensitive to air and basic conditions as it has no longer the phenolic group attached??? It may also be much more soluable. Does that sound reasonable??

Uemura will first make another try with bromobenzene and see what will happen then.

Hope hest will add his comments to this thread.

(*) Uemuras mixture was some kind of copper-brown suspension, all 14 hours long?!

Keep you informed!

Uemura


Osmium

  • Guest
Re: Vanillin
« Reply #14 on: March 01, 2002, 04:12:00 PM »
> The 5-bromo-3,4-dimethoxybenzaldehyd should be less
> sensitive to air and basic conditions as it has no longer
> the phenolic group attached??? It may also be much more
> soluable. Does that sound reasonable??

Not necessarily. 4M NaOMe is a pretty concentrated solution, which is also quite polar. The methylated bromovanillin might not readily dissolve in there either.

> Uemuras mixture was some kind of copper-brown suspension,
> all 14 hours long?!

Because you added the ingredients in the wrong order. You added the ester AFTER you added the CuBr, right? Do it the other way round, then wait some time, THEN add the bromovanillin.


I'm not fat just horizontally disproportionate.

Osmium

  • Guest
Re: Vanillin
« Reply #15 on: March 01, 2002, 04:14:00 PM »

Whereas copper(I) bromide (or chloride) catalyst, once added to methoxide solution, gives rise to unsoluble yellow copper(I) methoxide, which decomposes under refluxing to Cu0 and Cu2+, presence of an ester in concentrated (3 to 5 M) methoxide solutions prevents precipitation of copper(I) methoxide, but provides a colorless mixture in which added aryl bromides are readily transformed into methyl aryl ethers. Use of smaller amounts of copper (0.5 mmol CuBr in 15 ml 4M MeONa / MeOH) even leads to colorless clear solutions (copper complex and NaBr are entirely soluble under MeOH refluxing). Lower methoxide concentrations (up to 2.5 M) render esters co-catalysts uneffective, as copper(1) methoxide remains unsoluble; further addition of methoxide to the mixture leads again to clear solutions.





I'm not fat just horizontally disproportionate.

hest

  • Guest
Re: Vanillin
« Reply #16 on: March 01, 2002, 04:30:00 PM »
Wath's wrong with [link]

https://www.thevespiary.org/rhodium/Rhodium/chemistry/345-tmb.html

[/link]
Ore am I missing the point here ?

uemura

  • Guest
Re: Vanillin
« Reply #17 on: March 01, 2002, 04:40:00 PM »
Os,

Because you added the ingredients in the wrong order. You added the ester AFTER you added the CuBr, right? Do it the other way round, then wait some time, THEN add the bromovanillin.




You added the ester AFTER you added the CuBr, right? NO.

Mmm..
Uemura's other paper (the one dealing with bromobenzene -> anisol, don't have it here, so I can't tell you the journal now) clearly says :

Put the NaOMe, the MeOH, the bromobenzene, EtOAc and (add, if used) the DMF in a 3-neck rbf and bring to reflux. Then add the CuBr and seal the third neck.

This is for sure!!!!! Obviously the order of the compunds to be used depend on the experimenters.

hest,
nothing is wrong with the reference you give. Just one 'minor' problem. Uemura has no access to DMF, therefore he went for the DMF free rxn!


Carpe Diem

Osmium

  • Guest
Re: Vanillin
« Reply #18 on: March 01, 2002, 05:04:00 PM »
> This is for sure!!!!! Obviously the order of the compunds
> to be used depend on the experimenters.

Then follow the procedure for the vanillin synth in the first post. That should definitely work, as they obviously tried it out before having their students perform it.


I'm not fat just horizontally disproportionate.

Rhodium

  • Guest
Re: Vanillin
« Reply #19 on: March 01, 2002, 08:26:00 PM »
Antoncho: What is the patent you are referring to in

Post 275269

(Antoncho: "Re: Vanillin", Chemistry Discourse)
? And yes, the CuCl prepared as described on my page will do just fine in the reaction, as will any Cu(I) compound, I believe.