Author Topic: Synthesis of 2-Fluorinated Hydroquinones  (Read 1223 times)

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Synthesis of 2-Fluorinated Hydroquinones
« on: August 13, 2003, 08:53:00 PM »
2-Fluorohydroquinone is a DOF (4-Fluoro-2,5-Dimethoxy-amphetamine) precursor, see

Synthesis of DOF

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/dof.html)


Fluorinated Hydroquinones
Andrew E. Feiring and William A. Sheppard
J. Org. Chem. 40(17), 2543 (1975)

Fluorohydroquinone (1) was prepared in 40% yield by oxidation of o-fluorophenol with potassium persulfate11 in aqueous alkali, followed by hydrolysis of the intermediate p-hydroxyphenyl potassium sulfate with dilute HCl. The compound, a white solid, mp 124-126°C, was isolated by silica gel chromatography and recrystallization from chloroform. In addition to 1 and ca. 35% recovered o-fluorophenol, a small amount of cis,cis-2,4-hexadienedioic acid (4) was obtained from the reaction, possibly due to oxidation of o-hydroquinone derived from displacement of fluoride in the starting phenol by OH.

In a similar fashion, oxidation of m-hydroxybenzotrifluoride with potassium persulfate afforded trifluoromethylhydroquinone (3) in 6% yield together with 40% recovered phenol. The extremely low yield of product may be due in part to steric hindrance to attack of the persulfate anion by the bulky trifluoromethyl group.



Experimental Section

Fluorohydroquinone (1)

o-Fluorophenol (11.3 g, 0.100 mol) was dissolved in 400 ml of 6% aqueous NaOH. Solid potassium persulfate (27 g, 0.10 mol) was added to this stirred solution in several portions over 10 min. The dark mixture was stirred overnight at room temperature, then concentrated to about a third of its original volume on the rotary evaporator. The solution was neutralized with concentrated HCl and extracted once with 200 ml of ether. The aqueous solution was acidified with 100 ml of concentrated HCl, boiled for 1 hr, then concentrated to ca. 50 ml on the rotary evaporator.

Addition of 200 ml of acetone precipitated the inorganic salts, which were removed by filtration. The filtrate was taken to dryness on the rotary evaporator and the dark residue, dissolved in acetone, was added to 15 g of silica gel. The solvent was removed and the material was added to a column of 100 g of silica gel packed in hexane. The column was eluted with 10% acetonitrile in chloroform, taking 75-ml fractions. Fractions 5-20 contained 5.3 g (41%) of product, showing a single spot on TLC. Further purification could be effected by dissolving the material in boiling chloroform (60 ml/g), concentrating the solution to about a third of its original volume, and cooling in an ice bath to give white plates: mp 122-123°C: The ether extract of the aqueous reaction solution was concentrated to an oil (4.0 g) which was identified as mostly unreacted o-fluorophenol by its 1H-NMR spectrum (6.6-7.3 ppm, complex multiplet). A small amount of white solid was noted in the oil. Crystallization of the material from 30 ml of acetone gave 0.2 g of white crystals, identified as cis,cis-2,4-hexadienedioic acid: mp 199°C. (lit.18 mp 194-195°C).

Trifluoromethylhydroquinone (3)

m-Hydroxybenzotrifluoride (16.2 g, 0.100 mol) was dissolved in 350 ml of H2O and 50 ml of 50% aqueous NaOH. Solid potassium persulfate (27 g, 0.10 mol) was added in portions over 10 min. The resulting mixture was stirred overnight at room temperature. The solution was concentrated to about a third of  its original volume on the rotary evaporator, neutralized with concentrated HCl, and extracted with 200 ml of ether. The aqueous solution was acidified with an additional 100ml of concentrated HCl and boiled for 1 hr. After cooling to room temperature, the solution was concentrated to ca. 50 ml on the rotary evaporator. Addition of 200 ml of acetone precipitated the inorganic salts, which were removed by filtration. The filtrate was concentrated to a black oil on the rotary evaporator. The residue was dissolved in 600 ml of ether, dried over MgSO4 and concentrated to a black oil (5.5 g). The material was dissolved in acetone and added to 15 g of silica gel. The solvent was removed and the material was added to a column of 100 g of silica gel packed in chloroform. The column was eluted with 10% acetonitrile in chloroform; 50-ml fractions were taken. Fractions 10-16, showing a single spot on TLC, were combined and concentrated to a red solid. Trituration with chloroform and drying on the vacuum pump gave 1.0 g of white crystals: mp 106-107°C (lit.10 mp 109°C); The ether extract of the original aqueous solution was dried (MgSO4) and concentrated on the rotary evaporator to a dark oil. Distillation of the oil gave 6.5 g of unreacted m-hydroxybenzotrifluoride, bp 67°C/6mmHg.

References

[10] W. B. Whalley, J. Chem. Soc., 3016 (1949). .
[11] W. Baker and N. C. Brown, J. Chem. Soc., 2303 (1948).
[18] "The Merck Index", 8th ed, Merck and Co., Inc., Rahway, N.J., 1968, p 704.