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Author: Subject: crap yields of phenol-alkyl ether
Kalle anka
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[*] posted on 9-8-2005 at 13:57
crap yields of phenol-alkyl ether


Man.. total disaster today when trying to O-alkylate a phenolic compound..

I started out with 10,641 grams of vanillin in 150 ml dry acetone. I added 14 grams of right-then fused Na2CO3 and 21 grams dry methyl iodide. The mixture was set at reflux for five and a half hours and then a simple distillation apparatus was set up. I distilled off 30ml of acetone and added cold salt saturated water to turbidity.. 5.253 grams of MeI were recovered.
Acetone was decanted from solid residues, which were again washed with 2x50ml acetone. the pooled acetone was evaporated to yield solids which were dissolved in 200ml water and basified with NaOH and extracted with 3x75ml DCM. The organic layer was stripped of solvent to get some 200mg (that's 0,2 g) of some wax which was discarded...

WTF!! I acidified the water in which i had dissolved the solids after the methylation and extracted with 3x100ml DCM just to see that i so-to-say "recovered" the phenolic compound that i had started out with..

Figured that maybe the product of this reaction wasn't soluble in acetone (???) and extracted the solids (carbonates and iodides) with 3x50ml DCM.. yield was ~50mg of some crap that was discarded together with rest of the materials i had used in an outrageous fury :P

Anyway.. that was just experimental so no hard feelings, but anyway, can anybody figure why the phenol, in this case vanillin, was not O-alkylated? I am sure my materials were of an adequate (relative to this type of reaction) dryness and i used 5,5 hours of constant reflux but in the end: nothing..

I am thinking of trying to alkylate the firstmentioned phenol in ethyl alcohol with MeI.. Can the disaster be related to the use of sodium instead of potassium carbonate?? thought this wouldn't make a difference..

I only have 94% ethyl alcohol and sodium hydroxide and it takes weeks to get dimethyl formamide which i could use instead..

Does anybody know if vanillin or such phenolic compounds could be methylated in ethyl alcohol that is not dry, with MeI??
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Tacho
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[*] posted on 10-8-2005 at 09:04


Kalle,

I'm surprised. In my humble bag of chemical tricks, alkylation of phenols in DMF with MeI is a well established one. I have made dimethoxy benzene and diethoxy benzene from hydroquinone. I've made a few other phenol ethers and if I remember right, I've alkylated vanillin as well.

I always heard that acetone would be a fine substitute for DMF. I don't have MeI right now to do a test, but, as soon as possible, I'll try it in hydroquinone with acetone as solvent, to see what happens, or better yet, I'll try it on vanillin.

Edit. BTW, I always add a bit of water to the DMF to prevent acetal formation, and use NaOH as a base. Alkilated vanillin is very likely steam distillable, simplifying its extraction and purification. All compounds I'v alkylated so far turn out to be insoluble in water and steam distillable. Sometimes they are not directly steam distillable from the DMF solution, you must add water, filter the precipitate and then distill, as a purification step.

[Edited on 10-8-2005 by Tacho]
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flyingbanana
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[*] posted on 11-8-2005 at 20:57
trimethyl phosphate


i didn't want to start a new thread for this one, since it's sort of related. i've been having trouble using trimethyl phosphate for o-methylation of both phenols and phenolic aldehydes - bad yields or nothing at all. the only procedure i can find is from rhodium, that melt-phase method. i've tried different things - NaOH as base, K2CO3 as base, water as solvent, acetone as solvent...i give up! anyone have experience using this methylating agent and have a proper procedure they can share?
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[*] posted on 14-8-2005 at 04:26


I have a procedure for 3,4-dimethoxybenzaldehyde (veratraldehyde) from vanillin using DMS.

The important thing is to form the phenolate using KOH before methylation, Na2CO3 will NOT work!

1 mol of the phenol (vanillin in this case) is mixed with 1,25mol KOH in the form of a 10% KOH solution. Then it is methylated with
1mol DMS at under 40°C first and then at the boiling point (after alll DMS has been added).

Then cool it down and filter the solid product (the crude veratraldehyde) and recrystallise it.
Mp of Veratraldehyde: 46°C.

DMS can directly be substituted with an equimolar amount of MeI.

Moral of the story: Work in aqueous solution and with KOH!

[Edited on 14-8-2005 by garage chemist]
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[*] posted on 19-8-2005 at 10:33


Some general remarks.

Kalle, give it at least more time, 5 h is not enough especially not in acetone, besides what is your original reference?

Btw, your workup is nonsence, you don't need to do extractions with DCM, nor to strip off reaction-solvent, simply add a lot of water to the post-reaction mix, put the flask in freezer, a small crystal will form - then BOOM snowstorm, filter the crystals and wash them under suction with 5% NaOH, 5% HCl followed by water. That's the beauty of synthesizing substituted benzaldehydes.

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

Use the above method, just adjust the stochiometry to vanillin and use NaOH as base and add MeI after other reagents, let it react for ~ 15 h. When using alkylbromides as alkylating agents, put 0.5 - 1 g KI as catalyst (iodine is much faster and softer nucleophile than phenolate).

[Edited on 19-8-2005 by Sandmeyer]




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Kalle anka
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[*] posted on 20-8-2005 at 08:14


I did another run in 94% EtOH with NaOH to form the phenolate. But we didn't have any more vanillin so i used the isomer 2-hydroxy-5methoxybenzaldehyde. First i let the mixture with MeI at RT over night. interestingly, as i added the MeI, in a few minutes the solution turned dark at RT.. Next morning i let it at reflux 4h and finally vacuumed off the ethanol, the mixture cooled and a red oilish mixture remained. i rubbed a droplet of this on a glass plate and added these crystals to the mixture which solidified.

I used the carbonate in acetone method which shulgin describes lot of times in pihkal.. it seems that it just did't work with vanillin and na2co3..

I'll try and see yields when i have access to more vanillin..
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Sandmeyer
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[*] posted on 21-8-2005 at 01:38


NMP can be found as OTC grafitti remover, it works at least as good as DMF for Sn2 reactions and since it does not need to be distilled off, its boiling point dosen't posess a problem. Yes, Shulgin use acetone throughout the Pihkal. I have allways wondered why he does this. DMF is better and gives quantitatative yields with an easy workup. Unless you force yourself to switch to NMP or simillar you will get crappy results.

[Edited on 21-8-2005 by Sandmeyer]




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Sergei_Eisenstein
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[*] posted on 21-8-2005 at 05:46


In my experience, acetone works either very well or very poor. My yields are either 80-99% or 20-40%, but they never seem to fall inbetween...

When methylating with DMS in acetone, I generally apply the following rule: 0.50 mol substrate, 0.55 mol DMS, 0.60 mol K2CO3, 400-500 ml acetone. Heat to reflux overnight (i.e. "18 hours";), vacuum-filter and wash the cake with 200 ml acetone. Evaporate the filtrate's solvent in vacuo. The residue is taken up into an appropriate solvent and washed with dil aq NaOH (or KOH). The solvent is evaporated (I usually go for DCM or ether) and the residue recrystallized (solid) or distilled (oil). Note that the product is often pure enough for further syntheses though. So far, I have had very bad results with 2,5-dihydroxytoluene and o-vanillin.

DMF/DMS indeed is a good combination too. I make use of it when I have to methylate smaller batches (100-200 mmol). I tried out NMP once for allylation of vanillin but dropped the flask :( But DMF is very easy. Just dump the reaction mixture in water (10 ml/mmol), allow full precipitation, filter and recrystallize.

Also, when alkylating vanillin, it is remarkable how much the odour intensity of veratraldehyde is decreased compared to vanillin! Vanillin has a nice odour in diluted form, but becomes a bit harsh when concentrated and exposed to it for longer times. Ethyl vanillin doesn't seem to have this problem. It does have a similar smell - even more intens than vanillin - but it doesn't seem to have this "burning sensation". Veratraldehyde has a much less intense odour and is reminiscent of vanillin, but with a sweet touch. Veratraldoxime seems to have lost most of veratraldehyde's odour.
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Sandmeyer
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[*] posted on 22-8-2005 at 09:54


This is how syringaldehyde was alkylated under autogenous pressure.

NOTE:

The flask used for this reaction was of exactly this type: http://www.livingstone.com.au/ITMimages/DB1000S.jpg

I have tried this reaction under ordinary 1 atm heating and got only 60%-70% yields, needless to say pressure rox!

Experimental:


A vigorously stirred suspension of 39.4 g (0.22 mol) syringaldehyde in 170 mL DMA was heated on an oil-bath adjusted to 150 ºC until all syringaldehyde dissolved. The resulting black solution was treated first with 9.2 g (0.23 mol) NaOH followed by ½ teaspoon of KI. The intensive stirring and heating continued until a grey suspension was obtained. At this point the flask was cooled below room temperature and charged with 14.7 mL (0.272 mol) allyl chloride. The tightly closed flask was put back in the oil-bath resting on hot-plate (this time adjusted to 140 ºC) and the mixture was stirred for 24 hours. The resulting black solution was allowed to cool [important], poured into 3 L ice-cold water and placed in freezer. Half an hour later the obtained crystals were vacuum filtered and washed, first with 200 mL 5% NaOH, then 200 mL 5% HCl and finally with 1,5 litre water. The solids were air-dried to constant weight, yield 98% of 3,5-dimethoxy-4-allyloxybenzaldehyde as beige, pleasant-smelling, bitter crystals, M.P 45 C (sharp), (litt: from 42 to 49 C depending on the ref).

Best to stick to the temperature I have tried, it has not exploded ever. Don't ever use acetone when usimg this prep or other solvent with bp under 140 C.

Propz to Nicodem for private communication suggesting me to cut the solvent amount by 50% as originally intended, also to Sergei for interesting discussions!

Hope this helped, have a nice night!

[Edited on 22-8-2005 by Sandmeyer]




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Sandmeyer
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[*] posted on 5-9-2005 at 13:37


Btw, Kalle, alcohol sucks, esp with MeI as in your case I suppose it is a wrong solvent, I was thinking for the sake of OTC-ness that allylation could have some sucsess potential in alcohol as carbocation of allylchloride can be rezonance-stabilised and reaction as well follow Sn1 pathway, indeed I found a ref:

J. Med. Chem.; 1981; 24(8); 933-941:

4-(Allyloxy)-3,5-dimethoxybenzaldehyde (49).

To 18.2 g (0.1 mol) of syringic aldehyde in 40 mL of MeOH was added a solution of 6 g (0.11 mol) of NaOMe in 35 mL of MeOH. A clear yellow solution was formed. Allyl bromide (15.4 g, 0.13 mol) was added, and the mixture was refluxed for 1.5 h. A clear solution was formed within about 15 min. The solvent was removed in vacuo and the residue recrystallized twice from hexane: yield 18 g (81%); mp 45-46 "C. Anal. (ClZH14O4) C, H.

I tried it and it didn't work, i think it might be bullshit, I couldn't get it to dissolve at all.

Btw, if you decide to make syringaldehyde from vanillin, generally, bee careful in the house with syringaldehyde, it stains things yellow, put some large plastic garbage bag under the scale. hands are stained too, but it's OK, also 4-allyloxylated derivate has some very mild anestetic effect on the tounge.




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[*] posted on 5-1-2009 at 11:17


Hi possums,

sorry if this has been posted before (I didn't find anything in the search).

D. Trachsel, Helv. Chim. Acta, 85, 3019-3026(2002) describes alkylation of syringaldehyde in DMSO with good yields.

A crude translation follows (but better check it yourself):

To a solution of 10.94g (60 mmol) syringaldehyde in 70 ml DMSO was added 50 mg KI and 13.4 g K2CO3. The solution was heated to 85°C under a blanket of argon. 61 mmol of alkylhalide was added, the suspension becoming subsequently easier to stir.
After 1 h the suspension was poured onto 300 ml ice/H2O with intense stirring. The organics were extracted with 3x100 ml DCM, the combined extracts washed with 2x50 ml 2M NaOH and dried over Na2SO4. The solvent was boiled off and traces of DMSO were removed under high vacuum.

1-bromo-2-fluoroethane: 83% (cryst. from MeOH)
1-bromo-2,2-difluoroethane: 95% (crude)
1-iodo-2,2,2-trifluoroethane (higher temp, longer reaction time): 50% (crude)
1-bromo-3-fluoropropane: 92% (crude)
iso-butylbromide: 92% (crude)
1-bromopropane: 93% (crude)
allylchloride: 87% (crude)
isopropybromide: 97% (crude)
methallylchloride: 96% (crude)

PS, Sandmeyer: The link to the picture of the used flask doesn't work anymore. :(
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[*] posted on 20-2-2009 at 09:54


I tried the Trachsel method with propyl bromide and it worked as described. I had to distill the resulting aldehyde though since the syringaldehyde was not clean.
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[*] posted on 21-2-2009 at 02:48


Allow the base and the phenolic compound to react for some time, add MeI afterwards. Adding MeI at the start will just destroy most of the MeI before it has a chance to react with the phenolate.

[Edited on 21-2-2009 by vulture]




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