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Author: Subject: demethylation of methyl aryl ethers
polymerizer87
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[*] posted on 16-8-2012 at 12:53
demethylation of methyl aryl ethers


Methyl aryl ethers are deprotected in high yields using Pyridine.HCl in absence of a solvent under microwave irradiation

P.P Kulkarni et al. J. Chem Research (S) 1999



would 4-chloropyridine.HCl do the trick?
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chemrox
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[*] posted on 16-8-2012 at 17:43


why would you want to substitute a more costly reagent for a relatively cheap one? Even though it's not required it would be nice to post the article to make it easier for everyone to look at it and weigh in. I don't believe the 4-Cl-pyridine will be as good a reducing agent.



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polymerizer87
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[*] posted on 16-8-2012 at 18:06


I was scrummaging through the "dispose" bin and found ~60 grams.
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Ephesian
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[*] posted on 21-8-2012 at 02:55


http://pubs.rsc.org/en/content/articlelanding/1999/jc/a90127...

It allowed me to sign up for free to read the article, I believe this is the one he is referring to.
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kristofvagyok
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[*] posted on 23-8-2012 at 11:54


Quote: Originally posted by polymerizer87  
Methyl aryl ethers are deprotected in high yields using Pyridine.HCl in absence of a solvent under microwave irradiation

would 4-chloropyridine.HCl do the trick?

I have not red he article, but I belive that not the pyridine matters, the HCl is important.

There are several known "ether breaking reactions", mainly with lewis acids, AlCl3, BBr3 ect. and with "common things" like HBr and so like.

I belive that here the HCl will turn the ether into an alcohol (phenol) and a halide, under MW radiation the HCl part of the pyridine.HCl could be really-really active, so i could easily do what it should, even if choropyridine or normal pyridine is used as the base. Also, TEA.HCl would worth a try.




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Dr.Bob
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[*] posted on 23-8-2012 at 18:55


Yes, the HCl will actually be present as Cl- and Py-H+, and the Cl- attacks the methyl group via a SN2 displacement to form methyl chloride and the carboxylic acid anion, which is now effectively exists as the pyridine salt of the acid. Since MeCl is volatile, the reaction does go backwards to any real degree. TEA-HCl does not work well, as there are other reactions that can occur with it. Pyridine is used, as it is not nucleophilic, especially once protonated, and cannot form quat salts or other byproducts easily. The HBr salt of pyridine might work better as well. But these reactions are quite variable depending on substrate, moisture content, and purity of the components. I have seen some go in high yield and purity and others that were a complete mess (especially when I run them).
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[*] posted on 12-9-2012 at 12:42


Hmmm. Cleaving Aryl-Methyl ethers can be difficult.

Enough so, that some folks seeking to develop a convenient industrial process for demethylating Vanillin, gave up on it.

They were much more successful at cleaving Aryl-Ethyl ethers.

Whereas regular Vanillin resisted their efforts, Ethyl Vanillin was more compliant.
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[*] posted on 17-9-2012 at 07:30


Wasn't there a patent not long ago that described cleavage of aryl methyl ethers with thiourea and AlCl3?
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[*] posted on 17-9-2012 at 07:44


what about AlCl3 solvated by pyridine?or nitrobenzene don't see any reason that would'nt work.

[Edited on 17-9-2012 by jon]




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zed
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[*] posted on 21-9-2012 at 10:44


Pyridine can be a tough acquisition these days. Apparently, it can be reduced to Piperidine without too much difficulty.

Piperidine, as most of us know, is a precursor for PCP, and it is listed.
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kristofvagyok
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[*] posted on 21-9-2012 at 12:32


Quote: Originally posted by zed  
Pyridine can be a tough acquisition these days.
Pyridine is one of the most widely used organic bases, we've got several 100 liters of it... Anyone want to deal it for acetone? -just joke, we won't supply home labs;)

There are also several preps for pyridine and a lot "home synthesis", I think that if someone want to make it then it's not that hard....

Also back to the demethylation, any Lewis acid will do it, methoxy group works as an Lewis base and and stronger L. acid will do the hard part. Even ammonium-chloride could work with harder conditions.




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[*] posted on 21-9-2012 at 19:00
Part I: Anhydrous Pyridine.HCl Preparation


I thought this would be relevant to this particular thread considering I will be using this material for the demethylation of eugenol.

Taylor, M.D; Grant, L.R. "Preparation of Anhydrous Pyridine Hydrochloride" J. Chem. Educ. 1955, 32 (1), p 39

To a 500 mL, 2 neck round bottom flask fitted with a 100 mL addition funnel and gas outlet adapter was charged with 55 g NaCl and ~75 mL of Conc. HCl. To the addition funnel was added 50 mL of Conc. H2SO4. The gas outlet adapter was connected in series with rubber tubing to a wash bottle containing CaCl2 followed by a gas dispersion vessel (shown below).

In the gas dispersion vessel 200 mL of pre-chilled anhydrous diethyl ether and 69.5 g pyridine were added, mixed and set up for HCl (g) delivery.

After 25 mL of H2SO4 addition to NaCl an EXPLOSION of snow flake like crystals started to precipitate from the Ether/pyridine solution. Until no more precipitation occured, gassing was ceased. The ether was vacuum distilled off and collected (for re-use) and the remaining pyridine.hcl/ether was vacuum dessicated to dryness to collect 82.12 g Pyridine.HCl. ~85% yield

below are links to the articles ! enjoy

Attachment: prep pyr.hcl.pdf (639kB)
This file has been downloaded 727 times

IMG_0782.jpg - 51kB



Attachment: a901278h.pdf (88kB)
This file has been downloaded 902 times



[Edited on 22-9-2012 by Ephesian]

[Edited on 22-9-2012 by Ephesian]
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zed
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[*] posted on 23-9-2012 at 13:58


Pyridine is a fairly common solvent, but here in the U.S., Pyridine and its salts are on the DEA's Special Surveillance List.

As such, it may be somewhat difficult to acquire. What a commercial entity or university in Europe might easily procure, a private person in the U.S. might not.

Of course, we can sometimes purchase things in the U.S., that few other countries of the world would permit.
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Ephesian
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[*] posted on 23-9-2012 at 17:02


I wanted to try THF as a suitable solvent for this prep, and it worked wonderfully, actually it promoted salt formation much faster than anhydrous ether.

In the original procedure I vacuum distilled off the ether, a better method is put the beaker containing your pyridine salt in the freezer for about 10-20 minutes then decant off the solvent (for re-use). Then set up your flask under vacuum to pull of the remainder until bone dry.

After 5 times of re-using the solvent the pyridine.hcl salt started to turn yellow (I assume from the high concentration of HCl in solvent). One washing of chilled ether took the color away.

THF pyr.hcl.jpg - 421kB yellow pyr.hcl.jpg - 455kB
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[*] posted on 17-10-2012 at 06:26
Part II. Demethylation of eugenol




Microwave irradiation was carried out on eugenol (4-Allyl-2-methoxyphenol) using a home microwave oven (Whirlpool Gold, GH4155XPQ-0).

Here are the specifications of the microwave:

Whirlpool Gold
Model: GH4155XPQ-0
Input: 120 V, 60 Hz, 1800 W single phase
Output: 1000 W 3450 MHz

The article uses a 215 W commercial microwave oven, so I set the microwave on LOW (power 2) for 2 minute intervals. One interval I set to power 3, and POW the stopper blasted off in the microwave and fumes went everywhere.


Since our methoxy substituent is on the meta position from our allyl chain, I expected a yield of around 70-80% considering the article in Table 1 showed around that value for m-methoxy compounds.

The eugenol was vacuum distilled from store purchased 100% Clove oil, 113 mL (Now Essential Oils ©, I took the middle fraction that came off under vacuum and used for the following procedure:

4-allyl-2-methoxyphenol (20 g, 0.122 mol, MW: 164.20) and pyridine.HCl (70.376 g, 0.609 mol, MW: 115.56) was added to a 250 mL round bottom flask, sealed with a rubber stopper and heated under microwave irradiation for 2-3 minute time intervals on (power 2). During irradiation, the entire mass became liquid and turned a bright yellow. Upon cooling, the entire flask crystallized into one solid mass with no signs of eugenol (l). After carrying out the above procedure 6 times, the flask was let cool and sit overnight. I repeated the same procedure 3 more times the next morning, poured dH2O in flask to decompose the material and extracted with 2 x 100 mL portions of ether. The ether extracts were pooled and washed with 3x50 mL 10% HCl. Dried over K2CO3 Ether removed by rotovap to yield ~ 17 g of clear brown oil with virtually no smell of eugenol.


Wait…isn’t 4-allylcatechol a solid? Hmmm what are your thoughts?

Figure 1: Mass upon cooling
Figure 2: Final product

IMG_1021.jpg - 26kB IMG_1026.jpg - 50kB

[Edited on 17-10-2012 by Ephesian]
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Dr.Bob
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[*] posted on 18-10-2012 at 11:38


Pure 4-allylcatechol may be a solid, but your crude product is likely not 100% pure, thus an oil. I would suggest trying to crystallize or vacuum distill the product, depending on what the literature states as the method used before. But for a simple prep, that yield looks good, and sounds like a reasonable way to demethylate the phenol. You may also have to watch that you don't polymerize the allyl groups, as they might generate polypropylenecatechol. You may need to add a trace of some inhibitor, although the catechol may act as one anyway.

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