# Synthesis of 2,5-dimethoxybenzaldehyde from anise oil (small scale)



## William Dampier

*Step 1. Anisaldehyde from anethole via oxidative cleavage.



*
20 g anise oil was suspended in a mixture of 150 mL water and 30 mL conc. sulfuric acid; addition of 55 g sodium bichromate at such a rate that the temperature did not exceed 40 °C. The reaction mixture was extracted with 4 x 125 mL toluene and the solvent evaporated. The residual oil was vacuum distilled to yield 9.1 g anisaldehyde.


*Step 2. O-formyl-4-methoxyphenol.


*
6 mL anisaldehyde was dissolved in 75 mL dichloromethane (DCM). A mixture of 12g hydrogen peroxide 60% aq.soln and 10 mL conc. formic acid was added over 30 min. The reaction mixture was gently refluxed for 21 h.


*Step 3. 4-methoxyphenol.


*
Evaporating the solvent from reaction Step 2 and taking up the residue in 100 mL aqueous NaOH (20%) (25 mL MeOH as co-solvent) yielded 4.1 g 4-methoxyphenol as a white crystalline product after the usual work-up and purification steps.


*Step 4. Reimer-Tiemann formylation of 4-methoxyphenol to 2-hydroxy-5-methoxybenzaldehyde.


*
124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear, yellow oil that did not solidify upon standing at room temperature.


*Step 5. Methylation of 2-hydroxy-5-methoxybenzaldehyde.


*
The yellow oil from Step 4 was used without further purification. A 250 mL RB flask was charged with 100 mL acetone, 14 g anhydrous potassium carbonate and 10 g 2-hydroxy-5-methoxy-benzaldehyde. The mixture was brought at reflux temperature and 11 g dimethyl sulfate was added. The reaction was continued for 4 hours. The solvent is evaporated and the crude end product crystallized in cold water. Recrystallization from EtOH/water yielded 8.3 g 2,5-dimethoxybenzaldehyde.


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## MadHatter

Yes! I was looking for this. Much sought-after chemical, not an easy buy. Love to see the formation of the nitrostyrene on the way to 2C-H, it's supposed to be beautiful. Thank you!


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## MadHatter

Do you think the sodium dichromate can be substituted with potassium dc?


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## William Dampier

DocX said:


> Do you think the sodium dichromate can be substituted with potassium dc?



DocXYes, sure. Essentially the same oxidizers.


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## MadHatter

Thank you! And the hydrogen peroxide in step 2, is that 12 g of absolute peroxide, and then recalculated for the concentration it has in solution? Or is it for a given concentration? And what concentration is adviceable?


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## William Dampier

DocX said:


> Thank you! And the hydrogen peroxide in step 2, is that 12 g of absolute peroxide, and then recalculated for the concentration it has in solution? Or is it for a given concentration? And what concentration is adviceable?



DocXH2O2 and H2CO2 need for obtaining performic acid. We need 12 g of 60% hydrogen peroxide soln. for 10 ml 99% formic acid. A sufficient excess of acid is taken, so high accuracy is not obligatory here. Added to text, thank you!


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## ASheSChem

William Dampier said:


> 20 g anise oil



William Dampier
anise oil are essential oil of Illicium Verum ? (also named aniseed essential oil)


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## ASheSChem

William Dampier said:


> Evaporating the solvent from reaction Step 2 and taking up the residue in 100 mL aqueous NaOH (20%) (25 mL MeOH as co-solvent)* yielded 4.1 g* 4-methoxyphenol as a white crystalline product after the usual work-up and purification steps.



William Dampierthere is not 124.1 g ?


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## ASheSChem

DocX said:


> Do you think the sodium dichromate can be substituted with *potassium dc*?



DocXdo you speak about that ? CAS: 7778-50-9


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## MadHatter

ASheSChem said:


> do you speak about that ? CAS: 7778-50-9



ASheSChemYes, potassium dichromate. I have it available, but not sodium dichromate, that's why I was asking. Sometimes it is available from pyrotechnic supply vendors. 
Watch out though, it's poisonous as fuck. There's actually a really sad case report where a young man snorted a line of dichromate (it's a powder with a really nice orange colour) thinking it would get him high. He died in a pretty nasty way. 
Also, if you've seen "Erin Brochovich", potassium dichromate is what everyone's getting sick from. So responsible enviromental practices are called for when using this reagent.


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## ASheSChem

Thanks for all the details


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## Marvin "Popcorn" Sutton

ASheSChem said:


> anise oil are essential oil of Illicium Verum ? (also named aniseed essential oil)



ASheSChemIt is *Anethole*


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## ASheSChem

Marvin Popcorn Sutton said:


> It is *Anethole*



Marvin Popcorn Suttonessential oil are
Phenols methyl-ethers: trans-anethole (92%)
Monoterpenes: limonene (5%)

this is ok ? or we need to find pure anethole ?


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## ASheSChem

oups its was the coposition of badiane; star anis

essential oil of green anis (aniseed) are
Phenol methyl ethers: trans-anethole (95%), chavicol methyl ether.
Monoterpenols: anisole.


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## MadHatter

So its not the essential oil of star anise? I'd love to try this synth with star anises as starting material, the oil extracted with ethnaol in a soxhlet apparatus. Would that be possible?


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## MadHatter

I wish I had the ability to edit my posts. Can't see any option for that. 

Anyway, found this:

_*"Anethole is the main constituent of anise oil (anise oil from Pimpinella anisum (green anise) contains 80–90% anethole, anise oil obtained from Illicium verum (star anise) 75–90%)"*_ (_E. Guenther, The Essential Oils, D. Van Nostrand Company, New York, 1950, (a) vol. 4, pp. 563–570 and pp. 634–645, (b) vol. 5, pp. 361–379)_


From this publication: http://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/anethole.pma.precursor.pdf 
which incidentally also outlines the synthesis of PMA (para-methoxyamphetamine) from the same source. 

So possibly a quick steam distillation of commercially bought star anise oil should render a somewhat pure anethole. Or in my case, from the oil collected through soxhlet extraction straight from the source.


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## ASheSChem

William Dampier said:


> *Step 4. Reimer-Tiemann formylation of 4-methoxyphenol to 2-hydroxy-5-methoxybenzaldehyde.
> 
> 
> 
> *
> 124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear, yellow oil that did not solidify upon standing at room temperature.
> 
> 
> *Step 5. Methylation of 2-hydroxy-5-methoxybenzaldehyde.
> 
> 
> 
> *
> 124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear, yellow oil that did not solidify upon standing at room temperature.



William Dampier@William Dampier step 4 and 5 are the same text; i think not normal 



William Dampier said:


> in step 3 you says yielded 4.1 g


maybe an error too ?


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## woohoo

Can last stage be completed with methyl iodide?
Or what can i use instead of dimethyl sulfate?
How dimethylsulfate is can be made in home lab?


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## summer_child

Last step should be " The yellow oil from was used without further purification. A 250 mL RB flask was charged with 100 mL acetone, 14 g anhydrous potassium carbonate and 10 g 2-hydroxy-5-methoxybenzaldehyde; the mixture was brought at reflux temperature and 11 g dimethyl sulfate was added. The reaction was continued for 4 hours. The solvent is evaporated and the crude end product crystallized in cold water. Recrystallization from EtOH/water yielded 8.3 g 2,5-dimethoxybenzaldehyde (GC/MS: 98%+ 2,5-dimethoxybenzaldehyde)".


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## summer_child

woohoo said:


> Can last stage be completed with methyl iodide?
> Or what can i use instead of dimethyl sulfate?
> How dimethylsulfate is can be made in home lab?



woohooYou would need a large excess of MeI. Dimethyloxalate could be a replacement as it is much safer than DMS and MeI and easily accessible to a home chemist.


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## MadHatter

That



summer_child said:


> You would need a large excess of MeI. Dimethyloxalate could be a replacement as it is much safer than DMS and MeI and easily accessible to a home chemist.



summer_childThat's a great tip! Dimethyl sulphate is also very very nasty and not really something I'd like to whip up in my home lab. Oxalate is much preferred. Doug made some in his lab, see youtube link. 
But how's the stochiometry? How much is needed to replace the sulphate?


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## summer_child

DocX said:


> That
> 
> That's a great tip! Dimethyl sulphate is also very very nasty and not really something I'd like to whip up in my home lab. Oxalate is much preferred. Doug made some in his lab, see youtube link.
> But how's the stochiometry? How much is needed to replace the sulphate?



DocX


Sciencemadness Discussion Board - Solventless methylation with dimethyloxalate - Powered by XMB 1.9.11



I was thinking it could also be possible to start from phenol, formylate using Reimer-Tiemann and then use the Elbs persulfate oxidation to get 2,5 dihydroxybenzaldehyde , and finally methylate with DMO to the dimethoxybenzaldehyde. No need for anise oil and dichromates .
Not sure what order would give the greater yield formylation then oxidation or the other way around. But starting from phenol all the way to 2C-B i would expect something like 2.5% yield.


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## MadHatter

Well, the issue is OTC, as always. Anethole is really OTC, achievable in good concentrations from online sources or available through relatively simple extraction methods from anise. I used a soxhlet with good results. 
Dichromate is not really OTC though, but neither is phenol. You CAN however come across potassium dichromate from pyrotechnic supply stores. It's used in several star compositions. But if oxidation is the goal, could it be replaced with KMnO4?


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## summer_child

DocX said:


> Well, the issue is OTC, as always. Anethole is really OTC, achievable in good concentrations from online sources or available through relatively simple extraction methods from anise. I used a soxhlet with good results.
> Dichromate is not really OTC though, but neither is phenol. You CAN however come across potassium dichromate from pyrotechnic supply stores. It's used in several star compositions. But if oxidation is the goal, could it be replaced with KMnO4?



DocXPhenol can be easily made from salicylic acid.


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## MadHatter

summer_child said:


> Phenol can be easily made from salicylic acid.



summer_childYes, but it requires relatively high temperatures and is yet another synthesis that needs to be done. Also, you need the salicylic acid. And yes, you can extract that from pain medication or skin products, but there's _another_ thing you need to do ...


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## summer_child

I have some salicylic acid on hand. I might give it a try , really curious what the yield of the dimethoxybenzaldehyde would be.


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## MadHatter

Really exciting! I'd LOVE to see a write-up on that! I have some phenol lying around (in need of purification though, too bad it's a smelly process ...) so if you're successful I might just try too. 

BTW, do you think the dichromate can be replaced with permanganate as an oxidising agent?


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## summer_child

DocX said:


> Really exciting! I'd LOVE to see a write-up on that! I have some phenol lying around (in need of purification though, too bad it's a smelly process ...) so if you're successful I might just try too.
> 
> BTW, do you think the dichromate can be replaced with permanganate as an oxidising agent?



DocX


https://www.researchgate.net/publication/331953336_TLC_and_GC-MS_Analyses_of_Essential_Oil_Isolated_from_Macedonian_Foeniculi_fructus


Seem so , but it required some quaternary ammonium salt. Not sure if it's crucial to the reaction.


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## ASheSChem

i have found this on ebay, this is the same anisaldehyde (in this synthesis)?

Anisaldehyde
4-Anisaldehyde 
99% food grade
Synonym: p-Anisaldehyde, 4-Methoxybenzaldehyde, p-Methoxybenzaldehyde, Aubépine
CAS Number 123-11-5
EC Number 204-602-6
MDL number MFCD00003385


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## MadHatter

That would be it. Link? Shipping from?


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## ASheSChem

DocX said:


> That would be it. Link? Shipping from?



DocX








100 g anisaldehyde 99% FG | eBay


Les meilleures offres pour 100 g anisaldehyde 99% FG sont sur eBay ✓ Comparez les prix et les spécificités des produits neufs et d'occasion ✓ Pleins d'articles en livraison gratuite!



www.befr.ebay.be


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## HIGGS BOSSON

ASheSChem said:


> i have found this on ebay, this is the same anisaldehyde (in this synthesis)?
> 
> Anisaldehyde
> 4-Anisaldehyde
> 99% food grade
> Synonym: p-Anisaldehyde, 4-Methoxybenzaldehyde, p-Methoxybenzaldehyde, Aubépine
> CAS Number 123-11-5
> EC Number 204-602-6
> MDL number MFCD00003385



ASheSChemDifferent benzaldehydes
Anisaldehyde - 4-Methoxybenzaldehyde. From it, you can obtain 4-methoxy-amphetamine (PMA)
For 2c-b, DOB, N-bomes you need 2,5-dimethoxybenzaldehyde


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## ASheSChem

thanks


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## summer_child

ASheSChem said:


> i have found this on ebay, this is the same anisaldehyde (in this synthesis)?
> 
> Anisaldehyde
> 4-Anisaldehyde
> 99% food grade
> Synonym: p-Anisaldehyde, 4-Methoxybenzaldehyde, p-Methoxybenzaldehyde, Aubépine
> CAS Number 123-11-5
> EC Number 204-602-6
> MDL number MFCD00003385



ASheSChemYes it is


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## MadHatter

HIGGS BOSSON said:


> Different benzaldehydes
> Anisaldehyde - 4-Methoxybenzaldehyde. From it, you can obtain 4-methoxy-amphetamine (PMA)
> For 2c-b, DOB, N-bomes you need 2,5-dimethoxybenzaldehyde



HIGGS BOSSONYes, but to produce 2,5-dmbenzaldehyde through the reaction you posted this could be the starting material, no?


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## ASheSChem

summer_child said:


> Yes it is



summer_child


HIGGS BOSSON said:


> Different benzaldehydes
> Anisaldehyde - 4-Methoxybenzaldehyde. From it, you can obtain 4-methoxy-amphetamine (PMA)
> For 2c-b, DOB, N-bomes you need 2,5-dimethoxybenzaldehyde



think the expert have reason


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## MadHatter

ASheSChem said:


> 100 g anisaldehyde 99% FG | eBay
> 
> 
> Les meilleures offres pour 100 g anisaldehyde 99% FG sont sur eBay ✓ Comparez les prix et les spécificités des produits neufs et d'occasion ✓ Pleins d'articles en livraison gratuite!
> 
> 
> 
> www.befr.ebay.be



ASheSChemHey man, this ships from Ukraine. You sure you'll get it with the current situation?


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## summer_child

ASheSChem said:


> think the expert have reason



ASheSChemIt is the same precursor that is made by the first reaction.


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## MadHatter

ASheSChem said:


> 100 g anisaldehyde 99% FG | eBay
> 
> 
> Les meilleures offres pour 100 g anisaldehyde 99% FG sont sur eBay ✓ Comparez les prix et les spécificités des produits neufs et d'occasion ✓ Pleins d'articles en livraison gratuite!
> 
> 
> 
> www.befr.ebay.be



ASheSChemActually, I have bought reagents from this seller. Very trustworthy. But that was before the war. I actually want to buy Phtalic Anhydride from him, which is very reasonably prized and a good precursor to anthranilic acid. But I've been reluctant to, since well, you know what. So if you buy, please report back! I'd love to hear if the package comes through.


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## ASheSChem

William Dampier said:


> Step 4. Reimer-Tiemann formylation of *4-methoxyphenol* to 2-hydroxy-5-methoxybenzaldehyde.



William Dampier this ? https://www.befr.ebay.be/itm/184667...f1I1vBmUd8cUqBE9RnYLPZNk4uq3|tkp:BFBMnoS5uKNg

if yes... a lot of step are skip ^^


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## HIGGS BOSSON

DocX said:


> Yes, but to produce 2,5-dmbenzaldehyde through the reaction you posted this could be the starting material, no?



DocXIt's impossible. If the pair position is already occupied by the methoxy group, it cannot be shifted to the position along the benzene ring in 2 or 5.


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## summer_child

HIGGS BOSSON said:


> It's impossible. If the pair position is already occupied by the methoxy group, it cannot be shifted to the position along the benzene ring in 2 or 5.



HIGGS BOSSONYou can just as the synthesis suggest , Bayer-Villiger oxidation of the aldehyde will give 4-methoxyphenol, and formylation yields 2-hydroxy-5-methoxybenzaldehyde.


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## Joker_333

William Dampier said:


> *Step 1. Anisaldehyde from anethole via oxidative cleavage.
> View attachment 1403*
> 20 g anise oil was suspended in a mixture of 150 mL water and 30 mL conc. sulfuric acid; addition of 55 g sodium bichromate at such a rate that the temperature did not exceed 40 °C. The reaction mixture was extracted with 4 x 125 mL toluene and the solvent evaporated. The residual oil was vacuum distilled to yield 9.1 g anisaldehyde.
> 
> 
> *Step 2. O-formyl-4-methoxyphenol.
> View attachment 1404*
> 6 mL anisaldehyde was dissolved in 75 mL dichloromethane (DCM). A mixture of 12g hydrogen peroxide 60% aq.soln and 10 mL conc. formic acid was added over 30 min. The reaction mixture was gently refluxed for 21 h.
> 
> 
> *Step 3. 4-methoxyphenol.
> View attachment 1405*
> Evaporating the solvent from reaction Step 2 and taking up the residue in 100 mL aqueous NaOH (20%) (25 mL MeOH as co-solvent) yielded 4.1 g 4-methoxyphenol as a white crystalline product after the usual work-up and purification steps.
> 
> 
> *Step 4. Reimer-Tiemann formylation of 4-methoxyphenol to 2-hydroxy-5-methoxybenzaldehyde.
> View attachment 1407*
> 124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear, yellow oil that did not solidify upon standing at room temperature.
> 
> 
> *Step 5. Methylation of 2-hydroxy-5-methoxybenzaldehyde.
> View attachment 1408*
> The yellow oil from Step 4 was used without further purification. A 250 mL RB flask was charged with 100 mL acetone, 14 g anhydrous potassium carbonate and 10 g 2-hydroxy-5-methoxy-benzaldehyde. The mixture was brought at reflux temperature and 11 g dimethyl sulfate was added. The reaction was continued for 4 hours. The solvent is evaporated and the crude end product crystallized in cold water. Recrystallization from EtOH/water yielded 8.3 g 2,5-dimethoxybenzaldehyde.
> View attachment 1410



William DampierHi frend in step 4, At this stage you did not convert the salt with dilute acid, your writing is incomplete and the yield you reported is high, is this yield real???

200g of hydroquinone monomethyl ether were dissolved in a solution of 190 g of sodium hydroxide in 550 ml of water and the resulting solution was heated to 50°C on a water bath. To the solution maintained at 50-60°C, there were added dropwise 420 g of chloroform and a solution of 560 g of sodium hydroxide in 500 ml of water from two separate dropping funnels and, thereafter, the reaction mixture was heated for 1 hour at a temperature of 50-60°C and atmospheric pressure. After cooling, the precipitated sodium salt of 2-hydroxy-5-methoxybenzaldehyde was recovered by filtration and washed with 100 ml of ethanol.The sodium salt thus obtained was dissolved in 800 ml of water, slightly acidified with dilute sulphuric acid (1200 mL of 3N dilute sulphuric acid were added at room temperature and atmospheric pressure) and then extracted with 200 ml of toluene. The extract was dried with calcium chloride, distilled to eliminate toluene and then distilled under reduced pressure to obtain 132 g of 2-hydroxy-5 methoxybenzaldehyde having a boiling point of 110°C/5mmHg.


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## MadHatter

Joker_333 said:


> Hi frend in step 4, At this stage you did not convert the salt with dilute acid, your writing is incomplete and the yield you reported is high, is this yield real???
> 
> 200g of hydroquinone monomethyl ether were dissolved in a solution of 190 g of sodium hydroxide in 550 ml of water and the resulting solution was heated to 50°C on a water bath. To the solution maintained at 50-60°C, there were added dropwise 420 g of chloroform and a solution of 560 g of sodium hydroxide in 500 ml of water from two separate dropping funnels and, thereafter, the reaction mixture was heated for 1 hour at a temperature of 50-60°C and atmospheric pressure. After cooling, the precipitated sodium salt of 2-hydroxy-5-methoxybenzaldehyde was recovered by filtration and washed with 100 ml of ethanol.The sodium salt thus obtained was dissolved in 800 ml of water, slightly acidified with dilute sulphuric acid (1200 mL of 3N dilute sulphuric acid were added at room temperature and atmospheric pressure) and then extracted with 200 ml of toluene. The extract was dried with calcium chloride, distilled to eliminate toluene and then distilled under reduced pressure to obtain 132 g of 2-hydroxy-5 methoxybenzaldehyde having a boiling point of 110°C/5mmHg.



Joker_333So this is another write-up using hydroquinine as starting material? Could you please provide osurce for this? Is it a synth that you performed yourself or is it just a quote?


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## summer_child

DocX said:


> So this is another write-up using hydroquinine as starting material? Could you please provide osurce for this? Is it a synth that you performed yourself or is it just a quote?



DocXIt's taken from here https://www.thevespiary.org/rhodium/Rhodium/chemistry/25-dimethoxybenzaldehyde.html


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## Joker_333

source is erowid 



DocX said:


> So this is another write-up using hydroquinine as starting material? Could you please provide osurce for this? Is it a synth that you performed yourself or is it just a quote?



DocX


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