Author Topic: Vanillin  (Read 5966 times)

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Antoncho

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Syringaldehyde from p-cresol in two steps
« Reply #20 on: March 02, 2002, 07:35:00 AM »
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

  • Guest
Re: Vanillin
« Reply #21 on: March 02, 2002, 10:27:00 AM »
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

  • Guest
Re: Vanillin
« Reply #22 on: March 03, 2002, 10:25:00 AM »
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

  • Guest
EUREKA !!!
« Reply #23 on: March 22, 2002, 12:47:00 PM »
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 results :(  




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

  • Guest
Wow
« Reply #24 on: March 22, 2002, 10:00:00 PM »
That's quite an insight, Antoncho - I'm impressed!

uemura

  • Guest
Eureka
« Reply #25 on: March 23, 2002, 08:37:00 AM »

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  :( ).

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

  • Guest
DMF
« Reply #26 on: March 23, 2002, 11:36:00 AM »
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

  • Guest
mmmm...
« Reply #27 on: March 23, 2002, 04:19:00 PM »
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

  • Guest
Eureka indeed. Preparing your own methoxide ...
« Reply #28 on: March 23, 2002, 09:16:00 PM »
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

  • Guest
Hmmm, CO2????
« Reply #29 on: March 23, 2002, 10:18:00 PM »
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

  • Guest
Vaninlin
« Reply #30 on: March 25, 2002, 11:41:00 AM »
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

  • Guest
ArBr --NaOMe/Cu(I)--> ArOMe
« Reply #31 on: December 19, 2003, 05:33:00 PM »
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)

(https://www.thevespiary.org/rhodium/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.


Rhodium

  • Guest
Methoxylation of Aryl bromides cat. by Cu(II)-CO2
« Reply #32 on: April 27, 2004, 06:58:00 PM »
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)

(https://www.thevespiary.org/rhodium/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




demorol

  • Guest
Methoxylation of various aryl bromides
« Reply #33 on: June 02, 2004, 09:33:00 PM »
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. 8)

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

  • Guest
Re: P.S.: Does anyone know what ...
« Reply #34 on: June 02, 2004, 10:53:00 PM »

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

  • Guest
5-bromosalicylaldehyde
« Reply #35 on: June 03, 2004, 11:24:00 PM »

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




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



8)




Daphuk_up

  • Guest
forgive SWIDs Newbness, but
« Reply #36 on: September 21, 2004, 07:10:00 AM »
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.


Rhodium

  • Guest
5-bromosalicylaldehyde
« Reply #37 on: October 13, 2004, 09:15:00 AM »
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.



Rhodium

  • Guest
A rather odd synthetic route to salicylaldehydes
« Reply #38 on: October 15, 2004, 09:44:00 PM »
ortho-Hydroxybenzaldehydes from Phenyl-2-nitropropenes
S.L. Kelkar, C.P. Phadke, S. Marina

Ind. J. Chem. 23B, 458-459 (1984)

(https://www.thevespiary.org/rhodium/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.