Phenol methylation with Betaine1

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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.

Experimental:

The phenol (0.05-0.1 mole) is mixed with an equimolar amount of betaine (anhydrous) and CaO (50 mole%) 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.

Phenol
Ether,
Yield
Phenoxyacetic
Acid, Yield
Reaction
Time
Reaction
Temp
phenol
71.3%
26.3%
3h
180-235°C
p-cresol
59.0%
27.1%
5h
185-235°C
2,3-xylenol
48.0%
19.4%
4h
165-230°C
2,4-xylenol
64.9%
33.3%
5h
155-190°C
2,5-xylenol
44.1%
38.2%
4h
190-255°C
2,6-xylenol
62.6%
34.0%
4h
170-205°C
3,4-xylenol
47.0%
28.0%
4h
180-255°C
3,5-xylenol
58.9%
32.3%
4h
170-225°C
mesitol
67.2%
25.3%
5h
150-170°C
Na-phenolate
65.7%
19.7%
?
?
p-tert-butylphenol
60.6%
21.1%
5h
215-230°C
p-tert-amylphenol
70.0%
---
5h
220-240°C
p-phenylphenol
84.2%
14.1%
4h
205-210°C
thymol
56.6%
21.8%
4h
210-230°C
2,6-di-tert-butyl-p-cresol
61.3%
---
3h
240-260°C
a-naphthol
44.2%
27.2%
4h
205-220°C
b-naphtol
70.1%
28.2%
4h
165-210°C
o-chlorophenol
25.3%
17.1%
5h
190-235°C
m-chlorophenol
67.0%
24.0%
4h
200-220°C
p-chlorophenol
71.6%
24.0%
4h
205-215°C
2,4-dichlorophenol
59.7%
22.6%
4h
210-240°C
2,6-dichlorophenol
40.0%
---
4h
210-240°C
2,4,5-trichlorophenol
43.0%
---
5h
170-240°C
2,4,6-trichlorophenol
48.2%
---
6h
170-190°C
p-chloro-m-cresol
61.0%
22.5%
4h
175-185°C
4,6-dichloro-o-cresol
48.6%
21.5%
4h
175-210°C
p-chloro-o-cresol
41.6%
22.4%
4h
195-210°C

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 medication.

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. Dissolve 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 hydrochloride2

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.

References

[1] Monatshefte für Chemie (1966), 97(4), 1207-16.
[2] Stoltzenberg, Z. Physiol. Chem. 92, 445 (1914).