BROMO-4-HYDROXYTOLUENE

Submitted by H. E. Ungnade and E. F. Orwoll Checked by C. F. H. Allen and Alan Bell. 

In a 2-1. beaker is placed 75 g. (0.4 mole) of 3-bromo-4-amino-toluene (Note 1), and to it is added the hot diluted acid obtained by adding 72 cc. of concentrated sulfuric acid to 200 cc. of water. The clear solution is stirred and cooled to about 15°, after which 180 g. of ice is added the amine sulfate usually separates. As soon as the temperature has dropped below +5°, a solution of 32.2 g. (0.47 mole) of sodium nitrite in 88 cc. of water is added from a dropping funnel, the stem of which extends below the surface of the liquid. The temperature of the solution is kept below +5° during the addition, which requires about fifteen minutes. The solution is stirred for five minutes after the addition of all the sodium nitrite, and 300 g. of cold water, 3 g. of urea, and 300 g. of cracked ice are then added successively. The solution is kept in an ice bath until used. 

Claisen flask fitted with a dropping funnel and a thermometer dipping into the liquid is attached to a condenser set for downward distillation. In the flask are placed 150 g. of anhydrous sodium sulfate, 200 g. (108 cc.) of concentrated sulfuric acid, and 100 cc. of water. The flask is heated over a wire gauze, and while the internal temperature is maintained at 130-135°, the diazo-nium solution, in 25-cc. portions, is added at the same rate as the distillate is collected (Note 2). When this operation has 

The distillate is extracted with two 150-cc. portions of ether, and the combined extracts are washed successively with 100 cc. of water and 150 cc. of 10 per cent sodium bicarbonate solution. The phenol is then extracted from the ether layer by use of one 200-cc. and two 50-cc. portions of 10 per cent sodium hydroxide solution. The combined alkaline solutions are acidified, with cooling, by addition of 100 cc. of concentrated hydrochloric acid. The phenol is extracted with one 200-cc. and two 100-cc. portions of ether, and the combined extracts are washed with 100 cc. of water and dried over 50 g. of anhydrous sodium sulfate. The mixture is filtered, and the ether is removed from the filtrate by distillation on a water bath. The residue, 65-72 g. of a brown oil (Note 3), is then distilled from a Claisen flask with modified side arm (Org. Syn. 22, 11) b.p. 102-104°/20 mm. The yield is 60-69 g. (80-92 per cent of the theoretical amount) (Note 4). 

The 3-bromo-4-aminotoluene may be purchased, or prepared according to Org. Syn. Coll. Vol. 1, 1941, 111. The material used melted at 12-13°. 

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Bromo-2-ethoxyethane, 23, 32 3-BROMO-4-HYDROXYTOLUENE, 23, 11 a-BROMOISOCAPROIC ACID, 21, 74 a-B ROMOISOVALERIC ACID, 20, 106... 

Bromo-4-hydroxytoluene, 23,11 a-BROMOISOCAPROlC ACID, 21, 74 a-BROMOISOVALERIC ACID, 20, 106 Bromomesitylene, 21, 77 a-BROMO-/S-MEl HOXY- -BDTYRIC ACID, 20,101... 

Problem 19.28 Prepare (a) 2-bromo-4-hydroxytoluene from toluene, (b) 2-hydroxy-5-methylbenzaIdehyde from p-toluidine, (c) m-methoxyaniline from benzenesulfonic acid. M... 

A number of inhibitors of this enzyme are known. They include epoxides that are hydrolyzed by the enzymes, such as trichloropropene oxide, metal ions such as Hg2+, Zn2+, and Cd2+ and 2-bromo-4 -acetophenone, a potent inhibitor that binds to imidazole nitrogen atoms. Microsomal epoxide hydrolase can be induced by compounds such asphenobarbital, Arochlor 1254,2(3)-t-butyl-4-hydroxyanisole (BHA), and 3,5-di-f-butyl-hydroxytoluene (BHT). Many microsomal epoxide hydrolase inducers are inducers also of CYP and produce a general proliferation of the endoplasmic reticulum. Induction does, however, involve an increase in the mRNA specific for the hydrolase. 

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