Hydrogen Bromide → 4-(4-Chlorophenoxy)phenol

Participants

Reaction Steps

The 4-(4-chlorophenoxy)phenol precurser was prepared as follows. A 1 L 3-necked flask equipped with a mechanical stirrer, a Dean-Stark trap carrying a reflux condenser, and a heating mantle, was charged with 4-methoxyphenol (35.9 g, 0.29 mol), 85 percent KOH (19.1 g, 0.29 mol) and p-xylene (350 mL), and the mixture was heated at reflux for 1 hour, thus removing the water of reaction azeotropically. The mixture was cooled, and 1-chloro-4-iodobenzene (69 g, 0.29 mol), copper powder (2.9 g, 46 mmol), and cuprous chloride (2.9 g, 29 mmol) were added and the mixture was heated at reflux for 20 hours. The reaction was monitored periodically by HPLC. Workup consisted of diluting the cooled mixture with Et2O (200 mL), filtration through a medium-fritted funnel, and concentration of the filtrate to leave a deep dark oily residue. This crude material, consisting primarily of 4-(4-chlorophenoxy)anisole, was treated with glacial acetic acid (275 mL) and 48 percent HBr (105 mL), and the mixture was heated at reflux for 24 hours. Workup consisted of partitioning the mixture between H2O (1.2 L) and CH2Cl2 (0.5 L), washing the organic phase with H2O (0.5 L), and concentration to leave a deep dark oil residue. This residue was taken up in ethanol (0.5 L) and treated with activated carbon (Norit; 50 g). Filtration through celite, and concentration of the filtrate gave the crude 4-(4-chlorophenoxy)phenol as a thick, red oil. Further purification of the product was achieved by chromatography on a column packed with flash-grade silica gel (6"×2" i.d.), eluting with CH2Cl2, to give after concentration a pinkish solid, which was subsequently recrystallized from hexane-EtOAc to give 31.4 g (49% yield) of the pure product as off-white prisms m.p. 85-86° C.

Provenance & Evidence