Natrix (Newbee)
02-28-02 19:56
No 274828
      Vanillin     

Vanillin from 4-hydroxybenzaldehyde:
http://valhalla.chem.udel.edu/vanillin.html
 
 
 
 
    ChemicalSolution
(Hive Bee)
02-28-02 21:01
No 274859
      Re: Vanillin     

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
(Chief Bee)
02-28-02 22:57
No 274929
      Re: Vanillin     

Yes, definitely, but if piperonal wasn't a target, but instead 3,4,5-trimethoxybenzaldehyde - then this synthesis would be great.
 
 
 
 
    uemura
(Hive Photographer)
03-01-02 07:26
No 275171
      Re: Vanillin     


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
(Stoni's sexual toy)
03-01-02 12:21
No 275256
      Re: Vanillin     

> 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
(Hive Photographer)
03-01-02 13:04
No 275262
      Re: Vanillin     

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
(Stoni's sexual toy)
03-01-02 13:13
No 275263
      Re: Vanillin     

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
(Official Hive Translator)
03-01-02 13:20
No 275265
      Re: Vanillin     

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 morecrazy

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
(Hive Photographer)
03-01-02 13:33
No 275268
      Re: Vanillin     

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
(Official Hive Translator)
03-01-02 13:34
No 275269
      Re: Vanillin
(Rated as: excellent)
    

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
(Hive Photographer)
03-01-02 13:45
No 275275
      Re: Vanillin     

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
(Official Hive Translator)
03-01-02 14:31
No 275279
      Re: Vanillin     

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 frown - 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
(Distinctive Doe)
03-01-02 14:47
No 275285
      5-Br-Vanillin Methoxylation (CuBr/EtOAc/NaOMe)
(Rated as: excellent)
    

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) (../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
(Hive Photographer)
03-01-02 16:05
No 275299
      Re: Vanillin     

foxy & Antocho!
What would the Hive and Uemura do without you! smile


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
(Stoni's sexual toy)
03-01-02 16:12
No 275303
      Re: Vanillin     

> 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
(Stoni's sexual toy)
03-01-02 16:14
No 275304
      Re: Vanillin
(Rated as: good read)
    


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
(Hive Bee)
03-01-02 16:30
No 275309
      Re: Vanillin     

Wath's wrong with [link] ../rhodium/chemistry /345-tmb.html [/link]
Ore am I missing the point here ?
 
 
 
 
    uemura
(Hive Photographer)
03-01-02 16:40
No 275310
      Re: Vanillin     

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
(Stoni's sexual toy)
03-01-02 17:04
No 275322
      Re: Vanillin     

> 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
(Chief Bee)
03-01-02 20:26
No 275400
      Re: Vanillin     

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.
 
 
 
 
    Antoncho
(Official Hive Translator)
03-02-02 07:35
No 275643
      Syringaldehyde from p-cresol in two steps
(Rated as: excellent)
    

Ooops - forgot to mention the pat# - it's Patent US4218567

There is also an absolutely hilarious synthesis of syringaldehyde from p-cresol in two steps in that patent. The 1st one is simultaneous dibromination and oxidation of the methyl group to carbonyl. The 2nd is double methoxylation. Here:




1) 3,5-dibromo-4-hydroxybenzaldehyde

A 2-l., 3-necked round-bottomed flask equipped with a condenser attached to a calcium sulfate drying tower, mechanical stirrer, thermometer, and dropping funnel was charged with a solution of 108.1 g. of p-cresol (99%) in 500 ml. of chlorobenzene (anhydrous). The solution was cooled to 10 C and treated during 30 minutes with a solution of 720 g. of bromine in 600 ml. of chlorobenzene at such a rate that the temperature was kept below 25 C. The mixture was stirred at room temperature for 30 minutes, heated under reflux for 4.5 hours, and then evaporated in vacuo (water aspirator) at 60 C to give a deep red oil which was dissolved in 1.0 l. of methanol. To the stirred, cooled (10 C) solution was added 500 ml. of 1 N hydrochloric acid at such a rate that the temperature was kept below 25 C. The mixture was left at 5 C overnight, diluted with 1.0 l. of cold (5 C) water and the product collected by filtration. The solid was washed with four 1-l. portions, a total of 4.0 l. of water, dissolved in 2.5 l. of warm (50 C) ethyl acetate, dried over magnesium sulfate, and evaporated to give 291 g. of an off-white solid. To the solid was added 600 ml. of methylene chloride and the heterogeneous mixture heated at reflux for 15 minutes, diluted with 600 ml. of hexane and left at 0 C overnight. The off-white solid was collected, washed with two 100 ml. portions, a total of 200 ml. of cold (5 C) hexane, and dried in vacuo at room temperature overnight to give 168.3 g. (60%) of 3,5-dibromo-4-hydroxybenzaldehyde as a colorless solid, mp 177 C-180 C. GLC analysis indicated a purity of 99.6%.

2) 3,5-dimethoxy-4-hydroxybenzaldehyde

Into a 2-l., 3-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer, and a condenser was added 700 ml. of methanol. 68.0 G. of clean sodium was then added in small pieces and under nitrogen. After the reaction was complete, the methanol was removed in vacuo at 45 C-50 C and to the residue was added 312 ml. of dimethylformamide and 156 ml. of methanol. 5.85 G. of cuprous chloride was added followed, after 5 minutes, by 165 g. of 3,5-dibromo-4-hydroxybenzaldehyde, an exotherm resulted (25 C to 50 C during 5 minutes). The mixture was heated under reflux for 4 hours, the solvents were evaporated in vacuo (0.1 torr) at 55 C, and the residue was treated with 440 ml. of 15% brine. The mixture was stirred at room temperature for 30 minutes, again cooled to 0 C, and filtered over 100 g. of celite. The filter cake was washed with three 250 ml. portions, a total of 750 ml. of cold (5 C) water (that is, until neutral) followed, after discarding the aqueous washings, by three 500 ml. portions, a total of 1.5 l. of hot (60 C) ethyl acetate. The ethyl acetate washings were added to a separatory funnel, excess water (about 10 ml.) was removed, and the ethyl acetate dried over magnesium sulfate and evaporated to give 95.0 g. (88.5%) of 3,5-dimethoxy-4-hydroxybenzaldehyde as a yellow solid, mp 107 C-109 C. GLC indicated a purity of 99.7%



Of course, PhCl ain't a particularly available solvt - so i  wonder if CCl4 or TCE can bee substituted instead? Boiling points lower, but maybee longer rxn time will compensate for that.

Simple dibromination of cresol is also possible under milder conditions - compare:




3,5-dibromo-4-hydroxytoluene

To a cooled (0 C) solution of 108 g. of p-cresol in 500 ml. of methanol was added 336 g. of bromine at such a rate that the internal temperature was kept below 10 C. The mixture was stirred at room temperature for 2 hours, and then evaporated in vacuo. The residue was dissolved in a mixture of toluene in hexane (1:1) and left at -20 C for 18 hours. The product was collected by filtration to give 252 g. of 3,5-dibromo-4-hydroxy-toluene, mp 46 C-47 C.




I wish there was a way to dibrominate benzaldehyde, but it's probably impossible, anyone knows anything on the issue?

Antoncho
 
 
 
 
    uemura
(Hive Photographer)
03-02-02 10:27
No 275702
      Re: Vanillin     

It's this article Uemura refered to:

Aalten et al.' The copper catalysed reaction of sodium methoxide with aryl bromides, a mechanistic study leading to a facile synthesis of anisol derivates', Tetrahedron, Vol 45, pp5565-5578, 1989. Post 477850 (Rhodium: "ArBr --NaOMe/Cu(I)--> ArOMe", Chemistry Discourse)

Experimental Section (general):
The reagent combinations (in Table 1)(*) are used. To  a three necked reaction flask (250ml) equipped with a cooler (with a nitrogen in/out) and a thermometer were added the arylbromide, sodium methoxide and the other solvents or additives at ambient temperature. The reaction flask was brought to reaction temperature and the copper catalyst was added whereafter the third neck was equipped with a serum cap.

(*) 50 different combination with bromobenzene.

Antocho!

another word to the CuBr preparation. If you have around CuSO4, NaBr (KBr) and NaSO3, the easiest way is to get Cu(I)Br is
1) dissolve all three chems seperately in enough dH2O.
2) mix CuSO4 and KBr solution. Make sure no precipitae forms, if so add water.
3) add thru a dropping funnel the NaSO3 solution under stirring. Stir for 20mins or so
4) Vac. filtrate the precipitated white CuBr. Wash with lots of water and immed. put into desic under vac.


Carpe Diem
 
 
 
 
    uemura
(Hive Photographer)
03-03-02 10:25
No 276145
      Re: Vanillin     

Some further observations, please comment!

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

Not having DMF, but formamide, Uemura tried formamide instead of DMF. And, he got indeed a clear blue solution of the CuBR in the MeOH/Formamide mix.

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,

This one Uemura can confirm. But now, the authors continue...

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...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).

This one Uemura cannot confirm. In any concentrations and relations of MeOCH3 and EtOAc there was never a clear colorless solution.

DMSO instead of formamide didn't work either. Voluminous brown precipiate formed. What other apriotic solvent could be used without interfering with the rxn? Would MeCN or Acetone a choice?

Carpe Diem
 
 
 
 
    Antoncho
(Official Hive Translator)
03-22-02 12:47
No 286379
      EUREKA !!!
(Rated as: good idea!)
    

Today, while walking home, i suddenly had an insight, which completely xplained everything.

Watch this:




2 NaOMe + 2 H2O ---> 2 MeOH + 2 NaOH (well, this part is clear)

2NaOH + 2 CuBr ---> 2 NaBr + 2 CuOH (yep, that'll happen since both of them are ionized, and CuOH is insoluble)

2 CuOH ---> Cu2O + H2O (CuOH is very unstable and turns to oxide, regenerating one molecule of water)


The following things complete the picture:

a) it can bee rather certainly assumed that cuprous oxide isn't capable of complexing w/NaOMe and thus can't serve as a catalyst.

b) Cu2O is a brown (NOT yellow!) powder - quite consistent with what Uemura observed , as well as Vitsh, who in a recent xperiment used KOMe made via K carbonate and got identical results.

c) As one molecule of either water or NaOH kills 2 mol's of catalyst, to destroy 100 mg of CuBr it will take:
100mg/(63,5+75)*18/2 = 6,5 mg H2O or 14,4 mg of NaOH.

d) Note that Hest and all the previous non-Hive experimenters made NaOMe in situ by dissolving sodium in methanol, which provided a OH-less solution; while Uemura and Vitsh used pre-made methoxide, which obviously contained a minor hydroxide impurity.
That fact also implies that by using a similar proc. in DMF one will probably get similar resultsfrown




So, dear bees, how do we handle this problem?
Similarly to many bees, SWIM and his many comrades don't have access to clean sodium - so he just can't reconcile with this.

The 1st thing that comes to mind is using a significantly larger amt of thoroughly dried CuBr.

But, maybee, there are more elegant ways to get rid of OH-s in a NaOMe solution?

Hope, someone will have a better idea.

Antoncho
 
 
 
 
    Rhodium
(Chief Bee)
03-22-02 22:00
No 286529
      Wow     

That's quite an insight, Antoncho - I'm impressed!
 
 
 
 
    uemura
(Hive Photographer)
03-23-02 08:37
No 286756
      Eureka     


Eureka



The understanding of a failure gives most times more insight than the successful repetition of an experiment.

Very good Antocho!

Uemura didn't continue to report his results due to the lack of good reasons for the failures. Some further notes:

1) In one of the patent foxy provided, a small sentence said any significant amount of moisture will inhibit the copper catalysator . Based on Antoncho's consideration, the word significant should bee dropped.

2) The repetition of the bromovanilline copper methoxylation using Formamid wasn't successful either. It started with the clean blue solution and ended with a yellow brown suspension from which mostly unreacted bromovanillin was recovered. BTW 5-bromovannillin is not yellow! If it's pure its almost white and has a mp. of 164-165. (Methoxylation used as a purification procedure for bromovanillin frown).

3) Another -again unsucessful - verification was tried using bromobenzene, hoping it would react better than the bromovanillin. In the Aalten paper (Post 275285 (foxy2: "5-Br-Vanillin Methoxylation (CuBr/EtOAc/NaOMe)", Chemistry Discourse)) they used in some of the parameter sets also solid MeONa. But again, bromobenzene was recovered to the full extent (minus workup losses).

Conclusions: This copper catalysed methoxylation is VERY picky! It's water sensitive like a Grignard. Using bromovannilin as a starting substance for the 345- TMBenzaldehyde, the hydroxyvanillin route should be more accessable.


Carpe Diem
 
 
 
 
    hest
(Hive Bee)
03-23-02 11:36
No 286802
      DMF     

Add alot of NaOMe to the dmf (like 500mol%) ad your bromobenzene and Cu(I)X then heat it to app.100°C for 2-3 houers, you now have methoxybenzene in a yeald over 80%
Th Cu(I)X has to bee fairly pure (but don't bee hysterical, Personal I use big bach of Cu(I)Br from the 1980's)
It wil give you a thick pasta, imposible to stir the first 10-15min, but thats ok, just heat it up.
 
 
 
 
    Antoncho
(Official Hive Translator)
03-23-02 16:19
No 286860
      mmmm...     

Hest:

How much Cu(I)?

And, i am sorry, but, i don't quite get what you mean by 500%mol NaOMe?

Otherwise, you mean that using pre-made NaOMe works fine in DMF? Very pleasant to know!

Antoncho
 
 
 
 
    yellium
(Hive Addict)
03-23-02 21:16
No 286949
      Eureka indeed.
Preparing your own methoxide ...
    

Eureka indeed.
Preparing your own methoxide probably isn't the only thing. It probably also means `use dried MeOH', instead of that bottle of methanol which has been standing there for ages..

(BTDT; preparing a 5M methoxide solution sucks, especially when you find out that you only get brown shit.. The workup procedure sucked too.)
 
 
 
 
    foxy2
(Distinctive Doe)
03-23-02 22:18
No 286983
      Hmmm, CO2????
(Rated as: good read)
    

Environmentally friendly methoxylation of non-activated aromatic bromides    
Ji, Ya-fei; Zong, Zhi-min; Wei, Xian-yong; Li, Qian-rong
Zhongguo Kuangye Daxue Xuebao  (2001), 30(2),  206-208. Journal written in Chinese. CAN 135:290399 AN 2001:306061

Abstract
Syringaldehyde and vanillin were prepd. by using 3,5-dibromo-4-hydroxybenzaldehyde and 3-bromo-4-hydroxybenzaldehyde as starting materials, sodium methoxide as methoxylation agent, methanol as solvent, and cuprous chloride assocd. with DMF or carbon dioxide as catalysts.  The yield of syringaldehyde and vanillin is more than 90%, providing a mild and efficient method for methoxylation of non-activated arom. bromides.  The cuprous chloride/carbon dioxide catalyzed system releases heat smoothly and retrieves purified methanol directly.  So it is helpful in environment protection.
 
 
 
 
    hest
(Hive Bee)
03-25-02 11:41
No 287596
      Vaninlin     

With 500mol% I mean 5 mole NaOME to one aromatic bromine, When I make NaOME, I usual make a 1-2mole solution (40g Na into 1,2 L com. methanol, some of it ewaporate) then I ewaporate the rest of the methanol on the ro.vap. I now have a white powder, not so hygroscopic, that I can weigh.
I use com, not dry DMF as the solvent, and usual 2-4mol%
Cu(I)X as the catalyst (sometims I', to lazy to use the balance)
 
 
 
 
    Rhodium
(Chief Bee)
12-19-03 17:33
No 477850
      ArBr --NaOMe/Cu(I)--> ArOMe
(Rated as: excellent)
    

The copper catalysed reaction of sodium methoxide with aryl bromides, a mechanistic study leading to a facile synthesis of anisol derivates 
Aalten et al.
Tetrahedron 45, 5565-5578 (1989) (../rhodium/djvu /arylbromide.methoxylation.djvu)

Abstract
The copper catalysed reaction of unactivated aryl bromides with sodium methoxide has been investigated by studying a number of parameters (copper catalyst, cosolvent, concentration and relative ratio of the reactants, additives and aryl bromide substituents) which influence this reaction. The ipso-substitution reaction was found to proceed via an intimate electron transfer mechanism involving a cuprate-like intermediate, Na[Cu(OMe)2]. A convenient synthesis of methyl aryl ethers from aryl bromides and concentrated sodium methoxide solutions in dimethylformamide and methanol is presented. Also an attempt to extend this reaction to the use of chlorine derivatives was made.

The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Rhodium
(Chief Bee)
04-27-04 18:58
No 503332
      Methoxylation of Aryl bromides cat. by Cu(II)-CO2
(Rated as: good read)
    

This article is a request from Vitus_Verdegast:

The copper–carbon dioxide system, a new mild and selective catalyst for the methoxylation of non-activated aromatic bromides
D. Nobel
J. Chem. Soc. Chem. Commun. (4), 419-420 (1993) (../rhodium/pdf /aromatic.methoxylation.cu-co2.pdf)
DOI:10.1039/C39930000419

Abstract
Copper when associated with carbon dioxide is a mild and selective catalyst for the methoxylation of numerous non-activated aromatic bromides.

Reactant:  NaOMe; carbon dioxide; 3-bromo-4-hydroxy-5-methoxy-benzaldehyde
Reagent:  Cu(OH)2CuCO3
Product:  4-hydroxy-3,5-dimethoxy-benzaldehyde; carbonic acid monomethyl ester sodium-salt
Yield:  99 percent
Solvent:  methanol
Time:  3 hour(s)
Temperature:  125°C
Other Conditions:  var. time; also without CO2, other aromatic bromides



The Hive - Clandestine Chemists Without Borders
 
 
 
 
    demorol
(Hive Bee)
06-02-04 21:33
No 511008
      Methoxylation of various aryl bromides     

This is a variation of methoxylation procedure found on Espacenet. Even though it is almost the same as other procedures for methoxylation I decided to post the procedure, because it deals with  preparation of 2-hydroxy-5-methoxybenzaldehyde. Now it's time to find a procedure to make that damn 5-bromosalicylaldehyde.cool

Process for the Preparation of Alkoxybenzaldehydes
Patent IE903608

Abstract
Process for the preparation of alkoxybenzaldehydes from halobenzaldehydes. The invention relates more particularly to the preparation of 3-alkoxy-4-hydroxybenzaldehydes from 3-halo-4-hydroxybenzaldehydes and of 5-alkoxy-2-hydroxybenzaldehydes from 5-halo-2-hydroxybenzaldehydes. More precisely, the invention consists of a process for the preparation of alkoxybenzaldehydes by reaction of halobenzaldehydes with an alkali metal or alkaline-earth metal alcoholate in the presence of copper or of a copper compound, characterised in that it is carried out in the presence of an effective quantity of an organic carbonate, of a mixed organometallic carbonate, of carbon dioxide or of a compound capable of forming carbon dioxide in the reaction mixture.

Example 1: Syringaldehyde
Into a 40 mL teflon-coated reactor equipped with a heating and stirring system are introduced 2.22g (9.62 mmol) of 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 25g of a methanolic solution containing 2g (37 mmol) of sodium methylate and 0.099g (1 mmol) of cuprous chloride.

Anhydrous carbon dioxide is bubbled into this suspension for 30 sec., followed by heating for 3 h at 125°C, accompanied by stirring and under autogenous pressure. Cooling takes place to ambient temperature, followed by dilution with distilled water, adjustment of pH of the reaction mixture to 4 with the aid of sulfuric acid and the filtration of the insoluble part. Determination takes place by liquid chromatography.

Degree of conversion of the benzaldehyde: 100%
Yield of syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde): 97.5%

Example 6: Vanillin
Into a 40 mL teflon-coated reactor equipped with a heating and stirring system are introduced 2.10g of 3-bromo-4-hydroxybenzaldehyde, 2.16g of sodium methylate, 0.110g of basic copper carbonate and 25 mL of methanol.

Anhydrous carbon dioxide is bubbled into this suspension for 30 sec., followed by heating for 5 h at 125°C, accompanied by stirring and under autogenous pressure. This is followed by cooling to ambient temperature, dilution with distilled water, adjusting the pH to 4 with sulfuric acid and filtration of the insoluble part. Determination takes place by liquid chromatography.

Degree of conversion of the benzaldehyde: 100%
Yield of vanillin: 99%

Example 11: 2-hydroxy-5-methoxybenzaldehyde
Into a 40 mL teflon-coated reactor equipped with a heating and stirring system are introduced 4.1g (20 mmol) of 5-bromo-2-hydroxybenzaldehyde, 0.221g (1 mmol) of basic copper carbonate and 15 mL of methanol. 14.4g of a methanolic solution containing 4.32g (40 mmol) of sodium methylate are added with stirring.

Anhydrous carbon dioxide is bubbled into this suspension for 30 sec., followed by heating for 4 h at 125°C (under autogenous pressure), with stirring. The mixture is cooled to ambient temperature and diluted with distilled water, and the pH is adjusted to 4 with sulfuric acid. The insoluble part is filtered off. Determination takes place by liquid chromatography.

Degree of conversion of the benzaldehyde: 58%
Yield of 2-hydroxy-5-methoxybenzaldehyde: 79%


P.S.: Does anyone know what "autogenous pressure" is?
 
 
 
 
    SpicyBrown
(Hive Bee)
06-02-04 22:53
No 511030
      Re: P.S.: Does anyone know what ...     


P.S.: Does anyone know what "autogenous pressure" is?



au·tog·e·nous    also au·to·gen·ic
adj.

   1. Produced from within; self-generating.

I assume this definition applies here (ie, no pressure applied, but it's not left open to atmospheric).

-SpicyBrown

 
 
 
 
    lugh
(Moderator)
06-03-04 23:24
No 511284
      5-bromosalicylaldehyde
(Rated as: good read)
    


Now it's time to find a procedure to make that damn 5-bromosalicylaldehyde




This article, Ber 37 1129-37 (1904) should bee helpful wink



cool


Chemistry is our Covalent Bond
 
 
 
 
    Daphuk_up
(Hive Bee)
09-21-04 07:10
No 532445
      forgive SWIDs Newbness, but     

Since CO2 catalyzes this reaction anyway, the hydroxide in the NaOMe formed through the methanol/NaOH methodology could be easily eliminated by taking the NaOMe solution (formed from NaOMe precipitate and fresh anhydrous methanol) and bubbling CO2 through it for a bit before adding to the main reaction vessel.  How fast does NaOH(aq) dissociate into Na2CO3 in the presence of CO2?  Pretty fast, right?  Perhaps the easiest way would be to just use the potassium carbonate method of synthing alkali alkoxides in the first place.

Hmm, SWID supposes maybe that was the point of the CO2 catalyzed post in the first place.  Oh well, hopefully this will serve as validation of a conclusion SWID came to.

Drug Chemists are Ta to a good Sm.
 
 
 
 
    Rhodium
(Chief Bee)
10-13-04 09:15
No 535672
      5-bromosalicylaldehyde     

As requested in Post 535646 (demorol: "Possible new way to 2C-B", Novel Discourse) here follows a translation of the (rather poetically worded) procedure from Ber. 37, 1129-37 (1904) (posted in Post 511284 (lugh: "5-bromosalicylaldehyde", Chemistry Discourse))

The various preparations of [5-bromo-salicylaldehyde] in the literature all describe a rather low-yielding reaction, therefore the result of the following procedure was very satifying:

10 grams salicylaldehyde was dissolved in 20g glacial acetic acid and with cooling, 13.1g bromine (100 mol%) in a little GAA was added dropwise. Soon a plentiful crystallization of pure [5-bromo-salicylaldehyde] took place, and yet more could be precipitated by the addition of water. The melting point of this substance agreed with the reported value of 104-105°C.


The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Rhodium
(Chief Bee)
10-15-04 21:44
No 536041
      A rather odd synthetic route to salicylaldehydes
(Rated as: good read)
    

ortho-Hydroxybenzaldehydes from Phenyl-2-nitropropenes
S.L. Kelkar, C.P. Phadke, S. Marina
Ind. J. Chem. 23B, 458-459 (1984) (../rhodium/chemistry /nitrostyrene2salicylaldehyde.html)

Abstract
A short, convenient and general route to synthesise two important intermediates in coumarin synthesis, viz. 2-hydroxy-4,5-methylenedioxybenzaldehyde (4a) and 2-hydroxy-4,5-dimethoxybenzaldehyde (4b), is described.

The Hive - Clandestine Chemists Without Borders