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.