Synthesis of 4-Methoxyphenol

From p-Anisaldehyde [1]

In a 500 mL flask were placed 5.0 g (36.7 mmol) of p-anisaldehyde and 184 mL of methylene chloride (0.2M). This mixture was vigorously stirred with a magnetic stir bar. To the homogeneous solution was added 9.37 mL of 30% aqueous hydrogen peroxide (92.0 mmol., 2.5 equivalents) and 5.54 mL of formic acid (147 mmol., 4.0 equivalents). The flask was then fitted with a reflux condenser and heated to reflux for 20.5 hours with stirring.

After cooling, 119 mL of 1.5N sodium hydroxide (179 mmol., 4.86 equivalents) was added to the flask. The mixture was stirred for 15 minutes. The organic layer was separated and concentrated to a residue using a rotary evaporator. The residue was combined with the aqueous solution and 79.3 mL of methanol was added. The solution was stirred for 30 minutes. The methanol was removed using a rotary evaporator.

The neutral materials were removed from the aqueous residue by extracting with two 100 mL portions of methylene chloride. The solution was adjusted to a pH of 1 to 2 with concentrated hydrochloric acid. The 4-methoxyphenol was extracted with three 100 mL portions of methylene chloride.

The organic solution containing the neutrals as well as the one containing the product were separately dried over anhydrous magnesium sulfate and filtered into tared round-bottom flasks. The methylene chloride was removed using a rotary evaporator. A total of 0.052 g of neutrals was recovered. A total of 4.13 g of the crude 4-methoxyphenol was obtained (33.3 mmol., 90.7% yield).

The 4-methoxyphenol was purified utilizing bulb-to-bulb distillation. A mass of 3.88 g of 4-methoxyphenol as a white crystalline solid was obtained (31.3 mmol., 85.1 % yield). The purity was determined by GC (99.7%) as well as HPLC (99.3%).

From Hydroquinone [2]

4-Methoxyphenol was produced according to the process of this invention by charging 660 grams of hydroquinone (6 moles), 4800 grams of benzene, and 300 grams of water into a three necked flask fitted with a reflux condenser, stirrer, and two addition funnels. Then 480 grams of 50 percent aqueous sodium hydroxide (6 moles), and 756 grams dimethyl sulfate (6 moles; an equimolar quantity) were gradually added simultaneously at reflux (70°-75°C) during a period of about one hour keeping the alkali slightly ahead of the dimethyl sulfate.

The addition was made under a nitrogen atmosphere to minimize air oxidation of the hydroquinone but this is not essential to the success of the reaction. The mixture was refluxed for another one-half hour and then acidified to litmus with about 12 grams of acetic acid. The top oil layer was separated from the aqueous phase, washed with about 600 grams of a five percent sodium sulfate solution and distilled. After recovering the benzene, there was obtained a 122 gram head fraction distilling from 109-140°C/20mmHg, followed by 525g 4-Methoxyphenol at 141°C/20mmHg. From the head fraction, a mixt. of 1,4-dimethoxybenzene and 4-methoxyphenol, was obtained 53 g. 4-methoxyphenol by extn. with aq. NaOH followed by acidification. A total of 578.5g (78%) 4-methoxyphenol was recovered. From the non-alkali-sol. portion of the head fraction was obtained 64g (7.7%) 1,4- dimethoxybenzene. The combined aq layers were extd. with methyl isobutyl ketone. Evapn. of the solvent gave 52 g. of 96% pure hydroquinone.

From p-Anisaldehyde using H2O2 and a Selenium catalyst [5]

p-anisaldehyde (50 mmol) is dissolved in CH2Cl2 (100mL) and 2-NO2C6H4SeSeC6H4NO2-2 (2 mmol) and 30% H2O2 (13mL, 128 mmol) are added. The mixture is stirred magnetically at room temperature (water bath) for 30 minutes. Insoluble catalyst is removed by filtration and washed with CH2Cl2 (20mL) and water (20mL). It can be reused after drying. To the filtrate and washings, water (100mL) is added, and the layers are separated after shaking. The organic layer is washed subsequently with 10% NaHSO3 solution (100mL), 10% Na2CO3 solution (100mL), water (100mL) and dried over Na2SO4. 4-methoxyphenol is obtained by alkaline hydrolysis of the residue. Yield: 93%.

Other methods for 4-methoxyphenol preparation

The oxidation of 4-methoxybenzaldehyde using the system hydrogen peroxide-boric acid-sulfuric acid gave 4-methoxyphenol in 97% yield [3], and using m-chloroperoxybenzoic acid in 92% yield [4].

[1] US Patent 5,840,997
[2] US Patent 3,274,260
[3] Synth. Commun. 29, pp. 3781-3791 (1999)
[4] J. Chem. Soc., Perkin Trans. 1, pp. 1354-1363 (1974)
[5] Synthesis, 1989, No. 3, pp 167