Lego
(Stranger)
03-01-03 07:48
No 412790
      Betaine for O-methylation of Phenols
(Rated as: excellent)
 Bookmark   

Betaine - A methylation agent with clandestine potential

Monatshefte fuer Chemie (1966), 97(4), 1207-16

Abstract: Various phenols are transformed into the corresponding phenol methyl ethers (methoxy derivates) with betaine (trimethylglycine, trimethylammoniumacetate, carboxy-N,N,N-trimethylmethanaminium) in presence of CaO.

Keywords:methylation, methoxy, betaine


Experimental: The phenol (p.a., 0,05-0,1 mole) is mixed with an equimolar amount of betaine (p.a., anhydrous) and CaO (p.a., 50% molar) in a round-bottomed flask equipped with a destillation unit. The reaction mixture is slowly heated with an oilbath. Below 200 C the mixture becomes clear and an increasing gas evolution indicates beginning of the reaction. The formed ether passes over during the reaction.

The destillate is treated several times with 3N-NaOH and extracted with Et2O. The ether is washed with H2O, dried over Na2SO4 and evaporated.
Polysubstituted ethers with higher boling points are extracted several times with Et2O from the residue in the flask and treated as described.



Yields:
phenol yield (ether), % yield (phenoxy-aceticacid), % reaction time, h reaction temperature, C
phenol 71,3 26,3 3 180-235
o-cresol 69,1 30,1 5 175-200
m-cresol 61,7 36,6 5 200-230
p-cresol 59,0 27,1 5 185-235
2,3-xylenol 48,0 19,4 4 165-230
2,4-xylenol 64,9 33,3 5 155-190
2,5-xylenol 44,1 38,2 4 190-255
2,6-xylenol 62,6 34,0 4 170-205
3,4-xylenol 47,0 28,0 4 180-255
3,5-xylenol 58,9 32,3 4 170-225
mesitol 67,2 25,3 5 150-170
Na-phenolate 65,7 19,7
p-tert.-butylphenol 60,6 21,1 5 215-230
p-tert.-amylphenol 70,0 --- 5 220-240
p-phenylphenol 84,2 14,1 4 205-210
thymol 56,6 21,8 4 210-230
2,6-di-tert.-butyl-p-cresol 61,3 --- 3 240-260
a-naphtol 44,2 27,2 4 205-220
b-naphtol 70,1 28,2 4 165-210
o-chlorophenol 25,3 17,1 5 190-235
m-chlorophenol 67,0 24,0 4 200-220
p-chlorophenol 71,6 24,0 4 205-215
2,4-dichlorophenol 59,7 22,6 4 210-240
2,6-dichlorophenol 40,0 --- 4 210-240
2,4,5-trichlorophenol 43,0 --- 5 170-240
2,4,6-trichlorophenol 48,2 --- 6 170-190
p-chloro-m-cresol 61,0 22,5 4 175-185
4,6-dichloro-o-cresol 48,6 21,5 4 175-210
p-chloro-o-cresol 41,6 22,4 4 195-210


The byproducts of the reaction are the corresponding phenoxy-aceticacids and trimethylamine. (CAUTION: noxious gas, soluble in EtOH, H2O; should be trapped in an acid solution)


Betaine:Betaine hydrochloride and betaine dihydrogencitrate are OTC prescription-free medicaments (at least in the neighbour country of the authors) against liver diseases. 1 g betaine costs about ~1 US-$ as medicament.
1 kg of betaine hydrochloride cost about 50 US-$ from a well-known chem supplier. Betaine is for 4times cheaper than MeI, but twice as expensive as DMS ($/mole).

Preparation of betaine (anhydrous) from betaine hydrochlorid should be done analogous to the preparation of hydroxylamin from hydroxylammonium chloride/sulfate. Disolve in MeOH, treat with K2CO3, filter and evaporated MeOH. Last step might be skipped because heatin the reaction mixture as described above will get rid of MeOH.

Preparation via or from hydrochloride: Stoltzenberg, Z. Physiol. Chem. 92, 445 (1914). Quite useless, betaine hydrochloride is heated with H2SO4and then treated with a Ba-salt to precipitate the BaSO4.


Outlook: Although the authors didn't perform any experiments with polyphenols (e.g. hydroquinone, 2,5-dihydroxybenzaldehyde, 3,4,5-trihydroxybenzaldeyhde), one could expect similar results as even sterical hindered phenols react in good yields.

Benzoic acid was converted to benzoic acid methyl ester in 50% yield without CaO. Aliphatic alcohols didn't react until octanole, 1-methoxyoctan was prepared after 10 h reflux in 5% yield.

No other bases are mentioned by the authors. Perhaps K2CO3 or NaOH work, too.




Advantages: Methylation with betaine is OTC, non-carcinogenic, requires no special equipment, proceeds fast, yields are moderate to high and work-up is easy.


The candle burns twice as bright but half as long
 
 
 
 
    pHarmacist
(Hive Addict)
03-02-03 13:11
No 413151
      Lego  Bookmark   

Thank you very much for this! I try to avoid to work with MeI as much as possible, it's a nasty substance that can give you alergy very easy. This novel methylation agent is truly promising. This was just what I needed for some private projects, thank you kind Lego! Cool nickname you've got; "Lego" hihi, I liked to play with Lego when I was a kid... First thing that I ever stole as a kid was a Lego-piece from some stupid kid. It was a missing piece for some construction that I worked on at the time.

Accept No Imitations, There Can Only Bee One; www.the-hive.ws
 
 
 
 
    LiquidGaia
(Newbee)
03-03-03 15:02
No 413444
      wow, found this for $2.3/kg if u're ordering...  Bookmark   

wow, found this for $2.3/kg if u're ordering bulk.....
woooow.

could this be applied to ho-vanillin?


everything posted above is completely 100% fictional.
 
 
 
 
    Rhodium
(Chief Bee)
03-03-03 15:12
No 413448
      Betaine  Bookmark   

That's nothing special, most stuff costs only a handful of dollars per kilo if bought in bulk. Piperonal is only $15/kg or less from most asian exporters, for example...

This betaine methylation most likely will be applicable to 5-Hydroxyvanillin.
 
 
 
 
    LiquidGaia
(Newbee)
03-03-03 15:25
No 413454
      thanks rhodium, my dream is not over.  Bookmark   

this proceedure looks very tempting, i will try it soon.



everything posted above is completely 100% fictional.
 
 
 
 
    Greensnake
(Hive Bee)
03-04-03 09:59
No 413731
      >This betaine methylation most likely will...  Bookmark   

>This betaine methylation most likely will be applicable to 5-Hydroxyvanillin.

Severe heating with CaO may be destructive for aldehydes (Cannizzaro reaction?)
 
 
 
 
    Antoncho
(Official Hive Translator)
03-05-03 03:32
No 414020
      Hate to say that, but...  Bookmark   

...betaine is probably not a very good methylator. Whilst you can see that the yields with reactive phenols are ...well, somewhat acceptable - with the more sensitive OR deactivated OR sterically hindered things they plainly suckfrown

I bet that good old NaMeSO4 will give better results on ANY of the above mentioned substrates.

And, just in my HO, don't even think of methylating 5-OH-vanillin w/it, even if it wasn't deactivated by a formyl group, it'd get ruined under such drastic conditions momentarily (again, IMHO - but one HO that fits in with GreenSnake's not-so-HO as well as with common sense).


Antoncho
 
 
 
 
    starlight
(Hive Bee)
03-05-03 07:08
No 414051
      if aldehydes are a problem  Bookmark   

do you think that the nitrostyrene would fare better or worse in this reaction?
 
 
 
 
    Aurelius
(Hive Addict)
03-05-03 12:51
No 414097
      Polymerization  Bookmark   

the Vanillin, ruined?  how?  Polymerization? 

What about starting with polyphenols (no other substitutions) such as pyrogallol, resorcinol, etc.  Times like this make me wish I had some betaine.
 
 
 
 
    Rhodium
(Chief Bee)
03-05-03 16:55
No 414129
      I think most reactions performed on ...  Bookmark   

I think most reactions performed on nitroalkenes (other than reductions or additions to the double bond) are doomed.
 
 
 
 
    Lego
(Stranger)
03-06-03 09:51
No 414333
      How to get betaine  Bookmark   


Times like this make me wish I had some betaine.



Where's the problem? Go to the next pharmacy, ask for betaine, pay (it's fucking cheap) and get it the next day.


The candle that burns twice as bright burns half as long
 
 
 
 
    Aurelius
(Hive Addict)
03-06-03 13:34
No 414392
      might just do that-  Bookmark   

i might just do that, but i've got a lot of other obligations rights now.
 
 
 
 
    ylid
(Newbee)
04-23-03 06:05
No 428952
      Conditions too harsh for allylbenzenes?  Bookmark   

Does anyone have any comments on the viability of this method for allylbenzenes such as 5-hydroxy-eugenol? Would they be likely to char/polymerize? Would the side chain isomerize?

BTW it seems that you can pick up betaine as an additive for fishing bait ($15/500g), although I doubt that it is anhydrous.

Who do you believe, me or your own eyes?
 
 
 
 
    mr_grieves
(Stranger)
04-26-03 19:37
No 429686
      anyone think it would work with hydroquinone.  Bookmark   

anyone think it would work with hydroquinone.  This along with the chloroform/NaOH formylation found here ../rhodium/chemistry /formylations.html
would give a great route to 2,5 dimethoxybenzaldehyde
 
 
 
 
    Lego
(Stranger)
04-27-03 10:42
No 429779
      Methylation will work, formylation not  Bookmark   

The methylation of hydroquinone with betaine might work but remember hyroquinone is sensitive to oxidation especially in basic media. If this method is applied to hydroquinone Lego suggests the use of a inert gas like N2, He or Ar and the use of two equivalents of CaO or another appropriate base.

The methylation product of hydroquinone 1,4-dimethoxybenzene can not be formylated with with CHCl3 and NaOH, only phenols can be formylated by Reimer-Tiemann conditions. Therefore one has to methylate 2,5-dihydroxybenzaldehyde or methylate hydroquinone to p-methoxyphenol, formylate and then methylate the second OH-group.

The candle that burns twice as bright burns half as long