Masquerade (Stranger)
10-25-01 03:46
No 228509
      Cleavage of Alkoxy group to give Phenol     

The bond between a alkyl group and oxygen can be cleaved by Br- or I- nucleophiles (HBr or HI) to give phenol and alkyl halide.
Example: 3-MeObenzoic acid --HBr--> 3-Hydroxybenzoic acid in 90% yield.

This will be good to change methoxy groups in natural aldehydes, no? The 3-methoxy group in vanillin can be changed to give more aldehydes. Rhodiums page, a Americain Patent 3,855,306 gives synthesis of 5-bromovanillin for 3,4,5 aldehydes and Post 214369 (foxy2: "2 Bromination of 3,4-dimethoxybenzaldehyde", Chemistry Discourse) gives synthesis of 2,4,5 aldehydes. If SWIMs presentation works, chemist will not have to keep a methoxy, but can change it even when it was from nature.
SWIM would maybe like to do research, so he/she has a question... Is HBr in reaction in H2O, or is it gas going through solution? 
If SWIMs english is bad, he/she will put it through a english translator so maybe you understand more? sorry
(Old P2P Cook)
10-25-01 04:27
No 228515
      Re: Cleavage of Alkoxy group to give Phenol
(Rated as: good read)

You might want to look at these threads:

Post 58487 (psychokitty: "Has psychokitty won the OTC safrole contest?", Novel Discourse)
Post 71298 (startinout: "has startinout won the OTC safrole comp?", Novel Discourse)
Post 477628 (Rhodium: "Vanillin to Protocatechualdehyde (AlCl3/Py)", Methods Discourse)
Post 172095 (dreamer: "cleavage of methoxy group from vanillin", Chemistry Discourse)
10-25-01 04:49
No 228523
      Re: Cleavage of Alkoxy group to give Phenol     

Thank you very much, very good references. It will take SWIM much time to read and understand the first three, but post 172095 looks very good. The person called "Dreamer" had difficulty probably becuase he/she did not use a atmosphere.
The post was from 1998, where are these chemists?? There talks are more advanced than the talks at the hive now. Are there more chemists like this here now?? 
SWIM will do more reading and make a decision. Thank you very much terbium.
10-25-01 17:13
No 228690
      Re: Cleavage of Alkoxy group to give Phenol     

Sorry about the post above. When SWIM makes a reply, he/she has very little time to look over the english. It takes much time to write a post in good english. Here is what he means...
The discussions of the chemists from 1998 are more advanced than the discussions that are held now. Most discussions are about the same methods with people not knowing how to do them becuase they do not want to do there research on them. They are lazy and do not know chemistry good, but in 1998 it was much different, why? Was it a different posting board? Where can SWIM find this posting board??

Some of the more notable are the boron trihalide-dimethylsulfide complexes which are stable and can be safely handled at room temperature. 

This is very good, thank you again terbium.

(Chief Bee)
10-25-01 17:31
No 228693
      Re: Cleavage of Alkoxy group to give Phenol     

Back then when the board wasn't that well-known, only the most interested people found their way to the board. Now when it is more known, many completely clueless people are posting here, lowering the average quality of the posts (but I still think it is the same flow of good information now, it is just more of the uninformative ines inbetween).
(Distinctive Doe)
10-25-01 19:00
No 228721
      Re: Cleavage of Alkoxy group to give Phenol
(Rated as: excellent)

Some of these might bee helpful.

Selective demethylation of 3,4-dimethoxybenzaldehyde.     Prager, Rolf H.; Tan, Y. T.
Tetrahedron Lett.  (1967),   (38),  3661-4.

In development of a selective stepwise method of degradation of the acridone alkaloid melicopicine the effect of variation of demethylating agent, solvent, and temp. was studied on veratraldehyde (I) as a model compd.  Various amts. of the Lewis acids, AlCl3, BCl3, BBr3, and C5H5NHCl, were used and, with less than 1 equiv. of Lewis acid, the demethylation of the m-MeO group gave almost exclusively isovanillin (II).  With increase of acid to 1.5 moles, the monodemethylated product was mostly vanillin.  Lewis acids preferentially coordinated with the most electron-rich ethereal O and that coordination with the aldehyde occurred later with excess Lewis acid.  Demethylation of I with Ph2P- anion [from LiPPh2, NaPPh2, and LiAl(PPh2)4] was investigated in the expectation that nucleophilic attack would occur selectively at the MeO group in the position para to the CHO group.  The site of the attack was dependent on the solvent and the cationic species.  No satisfactory explanation for the results observed was offered and the demethylation of Me ethers with Ph2P- anion is not a simple SN2 process. 

Selective demethylation of 3,4-dimethoxy-substituted aromatic aldehydes and ketones.     Brossi, Arnold; Gurien, Harvey; Rachlin, Albert I.; Teitel, Sidney.
J. Org. Chem.  (1967),  32(4),  1269-70.

I, II, and III are treated with H2SO4 under N to give resp., IV, V, and VI. 

Some patents

United States Patent 3367972 Selective Dealkylation of Aromatic ethers

United States Patent 5,786,516 Process for the preparation of isovanillin (dealkylation)

Find these here

You need a TIFF viewer installed in your browser to look at the older ones.

Do Your Part To Win The War
10-26-01 06:43
No 228897
      Re: Cleavage of Alkoxy group to give Phenol
(Rated as: excellent)

Foxy the method you presented was good, but only good for 2-carbon alkyl groupes. The synthesis is only good for ethylvanillin or higher alkyl groups. SWIM found this...

Synthesis of Veratic Aldehyde from Vanillin
Heat 1,000 grams U.S.P. vanillin (7 moles) and 260 grams of water in a 5 liter reaction flask and heat to 70@C., to form a liquid mixture. Commence simultaneous addition of 1,030 cc. each of dimethyl sulfate and aqueous sodium hydroxide (34.9 percent by weight). The temperature rises to about 107@C. during the additions. Time of addition is about 100 minutes. Extract the resulting veratic aldehyde oil with ethylene dichloride, wash the extract with water until free of alkali, and remove the solvent by distillation. About 1,070 grams (98 percent) of crystalline veratic aldehyde is obtained.

Converting Veratic Aldehyde to Isovanillin (3-hydroxy-4-methoxy-benzaldehyde)
Add 1000 grams of the thus-obtained veratic aldehyde over a 15 minute period to 5500 grams of 66@ Be.sulfuric acid at 83@C. The temperature rises to 92@C. Hold at 92@C. +- 1@ for 120 minutes. Cool the acid solution to 15@C. and pour into 32 liters of water at 16@C. The temperature rises to 60@C. Extract the diluted acid with ethylene dichloride and wash the extract with 3.5 M sodium hydroxide. Distill the solvent from the washed extract to recover about 272 grams of unreacted veratic aldehyde. Lower the pH of the aqueous sodium hydroxide wash to 8.3 with 50 percent sulfuric acid. Wash the precipitate, filter and dry. 515 g. of isovanillin is obtained, a yield of 71 percent calculated on the veratic aldehyde which reacted.

Converting Isovanillin to 3-EtO-4-MeO-benzaldehyde
Introduce 1000 grams of isovanillin, prepared according to the above procedure, into a mechanically agitated autoclave along with 645 grams ethyl chloride, 400 grams sodium hyroxide, and 11,500 grams of water. Heat the mixture with agitation for 30 minutes at 150@C. and 96 p.s.i.g. maximum pressure. Cool the reaction mixture, adjust to a pH of 3.7 with 50 percent sulfuric acid and extract with ethylene dichloride. Wash the extract with aqueous sodium hydroxide and remove the solvent by distillation. There is obtained about 850 grams of 3-ethoxy-4-methoxy-benzaldehyde, a 77 percent yield.

Synthesis of Ethylvanillin from 3-EtO-4-MeO-benzaldehyde
Pump simultaneously a 0.24 mole/liter solution of 3-ethoxy-4-methoxy-benzaldehyde in 0.373 mole/liter sodium bisulfite and 1.25 mole/liter aqueous sodium hydroxide at equal rates into an oil jacketed tubular reactor so as to convert the bisulfite soultion to a sodium sulfite-sodium hydroxide solution. Maintain a jacket temperature of 275@C and a residence time of 3.8 minutes. Extract the resulting alkaline reaction mixture with ethylene dichloride, treat with sulfur dioxide, and filter to remove small amounts of 3-ethoxy-4-methoxy benzoic acid. Acidify the purified bisulfite solution with sulfuric acid, boil, and extract with ethylene dichloride. Remove the solvent by distillation, leaving about 820 grams of crude ethylvanillin per 1000 grams of 3-ethoxy-4-methoxy-benzaldehyde. Vacuum distill and crystallize from aqueous methanol to produce white crystalline pure ethylvanillin melting at 77-78@C.

Acide hydrolysis of veratic aldehyde into isovanillin is selective only at the 3 position. This is much of what SWIM was looking for. SWIM still likes to perform several reactions using HBr and lewis acid to cleave the alkoxy bond for some research. He/She will see what can do.

Thank you foxy. Finding this was becuase of your post. If you have ideas for synthesis of somethings, let SWIM know so maybe he/she can do research if you cannot. Thanks you again. 

Rhodium you are the owner of the board? You have a impressive chemistry page.
(Stoni's sexual toy)
10-26-01 12:47
No 228994
      Re: Cleavage of Alkoxy group to give Phenol     

Holy shit! There is the proof! I told you years ago H2SO4 will work to hydrolyse phenolic ethers and nobody bought it! So there! Even if there are better yielding procedures I'd prefer using OTC H2SO4 on a cheap precursor like eugenol in the first or second reaction step over such nasty stuff like BF3 or other Lewis acids any day of the week! Fuck it, 30% would make me happy in that reaction since it is so cheap.
10-26-01 16:47
No 229045
      Re: Cleavage of Alkoxy group to give Phenol     

My comment to all that is still the same:  H2SO4.
Fuck the yield, eugenol is cheap and most bees would prefer a lower yielding OTC procedure over anhydrous compounds which can only be had from chemical suppliers. When you consider the amount of chems needed I'm even sure that the H2SO4 procedure will be much cheaper, even if it produced only 30% or so yields.

You are the one who posted this, no? If you are interested there is alkaline hydrolysis to. You are interested in synthesis of safrole?? SWIM thinks this procedure is much useful for other things than safrole. It would not be effcient(?)  to use this for safrole when there is so much of it from other places.
Ethylvanillin would be good for synthesis of compound that Shulgin calls Meta-Escaline. A chemist could maybe bridge a methylenedioxy ring to make a ethylated version of MMDA. Not very interesting.

10-27-01 00:16
No 229141
      Re: Cleavage of Alkoxy group to give Phenol
(Rated as: excellent)

THIS is what SWIM was looking for...

Demethylation of Vanillin to form Protocatechuic Aldehyde
The demethylation is effected by heating the vanillin, in a suitable solvent or medium, with an ether-cleaving agent such as the hydrogen halides (hydrogen chloride, hydrogen bromide, hydrogen iodide), the organic primary ammonium halides (such as aniline hydrochloride, ethanolamine hydrochloride), the organic secondary ammonium halides (such as dimethylamine hydrobromide, N-ethylaniline hydrochloride), the organic tertiary ammonium halides (such as pyridine hydrochloride, the hydrochlorides of the picoline-lutidine fraction of coal tar distillate) and the halides of aluminum, zinc, iron, tin, antimony and boron (such as anhydrous AlCl3, AlBr3, ZnCl2, SnCl4, SbCl5, BF3).
Best results are obtained by the use of demethylating agents of hydrogen chloride, hydrogen bromide, aluminum chloride, aluminum bromide, aniline hydrochloride and pyridine hydrochloride.
The demethylation is effected by heating vanillin in a suitable medium or solvent with at least a reacting proportion of the ether-splitting reagent, at a temperature between 50@C. and 250@C., whereupon it is converted to protocatechuic aldehyde and the methyl halide, which distills off during the reaction. A wide group of media or solvents may be employed for effecting this demethylation of the vanillin, including water, acetic acid, benzene, nitrobenzene, methanol, ethanol, n-propanol and isopropanol. It is also feasible to effect this demethylation by fusing the vanillin, in the absence of solvent, with the ether-splitting reagent whenever said reagent is not volatile at the temperature of the demethylation (e.g. 50@-250@). Thus vanillin may be demethylated to protocatechuic aldehyde by heating in the absence of a solvent with aniline hydrochloride, pyridine hydrochloride, aluminum chloride, zinc chloride, at 50@-250@ C., until methyl halide evolution is complete.
The reaction product of demethylation step consists predominantly of protocatechuic aldehyde (85%-95%) with minor amounts of unreacted vanillin. The reaction product is freed of concomitant ether-cleaving reagent (e.g. by slurrying in water in which such ether-cleaving reagents are soluble, and filtering off the protocatechuic aldehyde) and is then employed in the second step of the process.

The second step of the process is for bourbonal (ethylvanillin). This is like Rhodiums page, but gives a better reaction conditions and choices. Pyridine is a very disgusting reagent, and SWIM will not work with it.
(Official Hive Translator)
10-27-01 00:47
No 229154
      Re: Cleavage of Alkoxy group to give Phenol     

It would not be effcient(?)  to use this for safrole when there is so much of it from other places.

Dear Masquerade! It just happens so that i live in a place where the closest safrole one can get is in 5000 km rangeblush - as well as many, many other things without which a normal chemist wouldn't even consider working - not that i'm a real chemist, but you get what i mean...
And this IS the 1st procedure i've ever seen that uses none of these things.

So - first - i want to thank you very much for this procedure, thank you!
And second - i'm very interested in that alkaline hydrolysis procedure, PLEASE, post if you would.


My comment to all that is still the same:  H2SO4.
Fuck the yield, eugenol is cheap and ...

Naturally, H2SO4 hydrolysis won't bee suitable for eugenol because of its double bond, will it? Whereas it should bee pretty stable to alkali in inert atmosphere - please, correct me if i'm wrong.



10-27-01 19:23
No 229309
      Re: Cleavage of Alkoxy group to give Phenol     

It is absurde! Buy the sassafras oil, you make it to hard for yourself Antoncho. But, SWIM said to post it and he/she will...
The conditions of reaction are much more harsh(?) then acide hydrolysis...

The hydrolysis reaction is conducted at between about 200@ and 325@, preferable from 240-300@ and most preferable from 250-275@ C. The lower limit is determined by hydrolysis rate and the upper limit by loss of selectivity and decompostion of the products. Sufficient pressure is employed to prevent substantial volatilization of the water. About 5 to 50 p.s.i.g. above the steam pressure produced at the selected temperature suffices.
Any alkaline material or mixtures of alkaline materials which will provide an alkaline pH at the reaction temperature can be used in the hydrolysis, e.g., the alkali-metal hydroxides, preferably sodium or potassium hydroxide, the alkali-metal carbonates, preferable sodium bicarbonate, the alkali-metal sulfites, lime, calcium carbonate, trisodium phosphate, etc. A reducing agent, e.g., one to two moles of sodium sulfite or sodium bisulfite per mole of aldehyde in the reaction mixture, increases yields. The alkali-metal hydroxides, carbonates and bicarbonates, alone or in mixture with an alkali-metal sulfite or bisulfite, are the preferred hydrolyzing agents.
The reaction product can be isolated by lowering the pH of the reaction mixture to less than 9, preferably about 8.3, and extraction with solvent, e.g., ethylene dichloride.

In the following runs, 17.8 g. (0.1 mole) of 3-ethoxy-4-methoxy-benzaldehyde, 300 cc. of 0.5 M aqueous Na2SO3 and 100 cc. of 1.0 M NaOH were heated in an evacuated sealed nickel bomb in a 450@ C. salt bath under the conditions shown in Table III...


Heat-up        At Temp.         PeakTemp.      %Bourbonal
210 sec         60 sec         290-298C        81.3
210 sec         60 sec          290-298C        78.3
210 sec         18 sec          290-296C        80.6

The reaction is very short. Antoncho, the reaction is showing MUCH selectivity at the 4 postion, it is not knowed if cleavage will happen for eugenol. If you try, do the alkaline for eugenol. Evacuate and pressure with Ar gas first. The reaction conditions are good becuase...
1. It is aqueous, no burning.
2. It is short.
3. Concentrations of alkali are good.
4. It can be done easy.

What you want is SWIMs post after that, cleavage of vanillin to give protocatechuic aldehyde. That reaction will do what you want for eugenol. Methylenate and you get safrole. OR... do not do safrole and make protocatechuic aldehyde a vanillin. Methylenate and get piperonal. Much better, no?
Safrole is only good when you can get it easy and in big amounts like sassafras. If you don't have sassafras, then don't waste time with safrole get other route.
(Hive Bee)
02-02-02 00:36
No 263987
      Re: Cleavage of Alkoxy group to give Phenol
(Rated as: excellent)

Here's more on the same subject. Although the compound's aren't vanillin I thought they were close enough:

US5710343, the example:

3,4-Dihydroxy-5-nitrobenzaldehyde: A mixture of 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (20.0 g), zinc chloride (60.0 g) and hydrochloric acid (37%, 15mL) was stirred at 90C. for 17 h. The mixture was diluted with water (100 mL) and then cooled to 3C. After 1 h the product was filtered and washed with cold water. The product was dried in vacuo at 100C. to give 16.5 g (95.1%) of crude product. The crude product was mixed with toluene (275 mL) and activated carbon (2.0 g) and the resulting mixture was refluxed for 45 min. The hot solution was filtered and then cooled to 3C. After 1 h the product was filtered and washed with cold toluene. It was dried in vacuo at 50C. to give 12.6 g (72.6%) of pure 3,4-dihydroxy-5-nitrobenzaldehyde (mp. 146-8C.).

US4963590, example 94:

3,4-dihydroxy-5-methylsulfonylbenzaldehyde: A solution containing 0,5 g of 3,4-dimethoxy-5-methylsulfonylbenzaldehyde and 5 ml of 48% hydrobromic acid in 5 ml of acetic acid was refulxed for 8 h. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated in vacuo. Yield 0.3 g (68%), a viscous oil.

US4963590, example 111:

3,4-dihydroxy-5-nitrobenzaldehyde: A solution containing 8.0 kg of 5-nitrovanillin and 8.7 kg of acetic acid in 35 kg of conc. hydrobromic acid was refluxed for 20h. 0.6 kg of charcoal was added and the mixture was filtered. 32 kg of water was added with stirring and the solution was cooled to -10C. and stirring was continued for 2 h more. The crystalline product was filtered and washed with water. Yield 5.66 kg (80%), mp 135-137C.

It seems they typoed a melting point for the 5-nitro compound, they are different. Well, most probably none of our concern.
(Official Hive Translator)
02-02-02 07:35
No 264138
      Re: Cleavage of Alkoxy group to give Phenol     

Well i'm afraid that HBr method won't bee as good for vanillin, beecause - here's an exert from the 1st patent:

"...This method uses hydrobromic acid in stead of hydrochloric acid. A specific problem with this method is the formation of a ring brominated impurity (probably 2-bromo-3,4-dihydroxy-5-nitrobenzaldehyde) and of an unspecified brownish black impurity. "

I mean to say that non-nitrated or sulfonated vanillin will bee much much more prone to electrophyllic ring substitution. If it is _ring_ substitution, of course.

(Official Hive Translator)
02-02-02 07:51
No 264140
      Re: Cleavage of Alkoxy group to give Phenol     

smilesmile moo, i'm terribly sorry for being an asshole, but looks like _maybee_ the 1st method won't work either:

"...The method described here is specific for 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde and it is not applicable to 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, which is practically inert under the conditions used. "

However, that's for the nitro- stuff, who knows; and here are some good news:

"...This finding is surprising, because an ethoxy group is reported to have low reactivity compared to a methoxy group in common acid catalyzed dealkylation (K. F. Wedemeyer in Methoden der Organischen Chemie (Houben-Weyl, Vol 6/1c, p. 314, Georg Thieme Verlag, Stuttgart 1976). "

Someone, could you see what Houben-Weyl says about it? Uemura, maybee you? I know you have itwink

(Hive Bee)
02-02-02 15:41
No 264191
      Re: Cleavage of Alkoxy group to give Phenol     

moo, i'm terribly sorry for being an asshole, but looks like _maybee_ the 1st method won't work either:

It's ok, critique is always welcome. I thought it might be worth a try. After all, vanillin and ethyl vanillin are cheap and pyridine is to be avoided. I also found it interesting that a HBr method worked with a benzaldehyde because of a literature review that stated that HBr demethylations were incompatible with aldehydes...
02-27-02 17:16
No 274314
      Re: Cleavage of Alkoxy group to give Phenol     

Synthetic Communications, 2001, 31(6), 869-875
Katsuya Maeyama, Masato Kobayashi, Noriyuki Yonezawa

Alkyl carbon-oxygen bonds of alkyl aryl ethers bearing
suitable coordination sites were efficiently cleaved
by treatment with nickel(II) chloride and zinc in p-xylene
under neutral conditions.

"Whatever there is to learn has to be learned the hard way."
Castaneda's teacher Don Juan Matus
(Chief Bee)
02-28-02 00:15
No 274495
      Re: Cleavage of Alkoxy group to give Phenol     

I'm afraid that system would also reduce the aldehyde of vanillin, but it is still worth looking up, it may be applicable to eugenol.
(Her Majesty, Stoni's Kitty)
02-28-02 01:51
No 274536
      Re: Cleavage of Alkoxy group to give Phenol
(Rated as: good read)

Use of AlI3 is still probably the best option for those looking for an OTC route of eugenol or MVK ether-cleavage (Al, OTC; I2 from NaI or KI and oxone). 

Take from Synthesis 1983 p253-254 (entire review from pp.249-281):

Cleavage of Isopropyl Phenyl Ehter (24):
Pieces of dry aluminum foil (250 mg, 9.3 mmol) and iodine (1900 mg, 15 mmol) are refluxed in carbon disulfide (20 mL) till the color of iodine is discharged (~2 h).  This solution is then brought to room temperature and isopropyl phenyl ether (24; 680 mg, 5 mmol) in carbon disulfide (2.5 mL) is added dropwise with stirring.  The reaction mixture is then boiled over a water bath for 1.5 h, poured into ice-cold water (50 mL) with stirring, then extracted with ether (3 tms 15 mL), and washed with sodium thiosulfate solution (25 mL).  The ether extract is then washed with ~5% sodium hydroxide solution (4 tms 20 mL), the aqueous layer is neutralised with 5 normal hydrochloric acid (~25 mL), and extracted with ether (5 tms 20 mL).  After drying with anhydrous magnesium sulfate, the ether is evaporated to afford phenol; yield: 400 mg (89%); m.p. 39-41 C.

Acetonitrile can substitute for the solvent in this reaction.

The interesting thing is that the authors of the article use 3-methoxyallybenzene in one of their examples.  After reacting it with AlI3 (1:1) for three hours, they obtained 3-hydroxyallylbenzene in a yield of 74% with NO migration of the double bond.

At the time the Synthesis ether-cleavage review was published, the above experimental details were derived from, according to reference 22, "unpublished observations".  However, the same reaction scheme has been published (probably by the same author) in Tetrahedron Letters somewhere (possibly with a more advanced methodology).  The actual reference is listed at the end of the Synthesis article wherein the authors use AlI3 and a PTC for the cleavage of ethers.  Might be worth digging up.
(Chief Bee)
12-18-03 18:37
No 477643
      Aryl Ether Cleavage with Zn/NiCl2
(Rated as: good read)

As mentioned in Post 274314 (3base: "Re: Cleavage of Alkoxy group to give Phenol", Chemistry Discourse)

Nickel/Zinc-Mediated Alkyl Carbon-Oxygen Bond Cleavage of Alkyl Aryl Ethers
Katsuya Maeyama, Masato Kobayashi, and Noriyuki Yonezawa
Synthetic Communications, 31(6), 869875 (2001) (../rhodium/pdf /ether.cleavage.zn-nicl2.pdf)

Alkyl carbon-oxygen bonds of alkyl aryl ethers bearing suitable coordination sites were efficiently cleaved by treatment with nickel(II)chloride and zinc in p-xylene under neutral conditions.

The Hive - Clandestine Chemists Without Borders