CHEMICAL STRUCTURE AND ANTIMICROBIAL ACTIVITY OF BIS-PHENOLS 271 by Johary, et al. (4) and Tiessens (5). 6-Bromo-2,3,4-trichlorophenol (6) was obtained by bromination of 2,3,4-trichlorophenol in acetic acid solu- tion similar procedures yielded 6-bromo-2,4,5-trichlorophenol (6) from 2,4,5-trichlorophenol and 4-bromo-2,3,6-trichlorophenol (7) from 2,3,6- trichlorophenol. Bis-phenols were obtained by condensation of the monophenols with formaldehyde in the presence of ethylene dichloride and 20% oleum or 96% sulfuric acid. Reaction ortho or para to the hydroxyl group of the phenols proceeds rapidly whereas linkage in the meta position requires considerably more time. The 3,3'-methylenebis compounds with an un- substituted ortho or para position (Nos. 65, 66, 67 in Table I) were syn- thesized by blocking these positions in the trichlorophenols with bromine, condensing the bromotrichlorophenols with formaldehyde and removing the bromine from the 3,3'-methylenebis(bromotrichlorophenols) with zinc dust in potassium hydroxide solution (8). The crude bis-phenols were purified by repeated crystallization from various solvents. No efforts were made to obtain maximum yields. Specific details for the preparation of each of the isomers are as follows: 2,2'-Methylenehis (4,5,6-trichlorophenoO, No. 2 A mixture of 50 g. of 2,3,4-trichlorophenol, 125 ml. of ethylene dichloride and 20 g. of tech. oleum (20-23% SOa) was stirred and heated at 55-60 ø. Paraformaldehyde (4.1 g.) was added over a period of one hour, and the resultant mixture was refluxed for two hours. After cooling to room tem- perature, crushed ice and water were carefully added, and the solvent and unreacted trichlorophenol were removed by steam distillation. The crude product was filtered, washed with water and dried (42 g.). The substance was recrystallized from 900 ml. of ethylene dichloride using Filtrol © (Filtrol Corp., Los Angeles, Calif.) as a decolorizing agent white needles (31 g.) were obtained. 2,2'-Methylen ebis (3,4,5-lrichlorophenol), No. 3 A solution of 4 g. of 37% aqueous formaldehyde in 6 ml. of methanol was added dropwise to a stirred mixture of 20 g. of 3,4,5-trichlorophenol, 70 ml. of ethylene dichloride and 20 ml. of 96% sulfuric acid over a period of two hours. The batch was then heated to 60 ø for two hours. After dilution with water, the solvent and the unchanged trichlorophenol were removed by steam distillation. The remaining solid was filtered, washed with water and dried (17 g.). A slurry was made with 100 ml. of acetone to separate the desired substance from an acetone-insoluble by-product of higher molecular weight. The acetone slurry was filtered and the bis- phenol precipitated by dilution with water. The pure substance (7 g.) was obtained by recrystallization of the dried precipitate from a small amount of toluene with the aid of Filtrol.

272 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS 4,4'-Melhylen ebis (2,3,6-trichlorophen ol), No. 42 Condensation of 2,3,6-trichlorophenol (50 g.) with paraformaldehyde was performed in the same manner as described for compound No. 2, except that the mixture was refiuxed for 4 hours. Crystallization of the crude material (46 g.) from 150 mi. of ethylene dichloride with addition of Filtrol yielded 34 g. of white, fine needles. $,3'-Methylenebis(2,4,6-trichlorophenol), No. 40 ]'he procedure was similar to that used for the preparation of compound No. 2. Paraformaldehyde (5.6 g.) was added to a mixture of 70 g. of 2,4,6- trichlorophenol, 150 ml. of ethylene dichloride and 35 g. of oleum. The mixture was refiuxed for twenty hours and processed by steam distillation ,as described above. The crude bis-phenol (64 g.) was crystallized fi-om 250 ml. of toluene with addition of Filtrol. A low purity product which softened from 190 ø and melted at 198-200 ø was obtained (37.6 g.) it was therefore recrystallized from 145 ml. of acetic acid and then fi'om 120 ml. of ethylene dichloride which yielded 9.1 g. of white, crystalline powder. 3,3'-Melhylenebis( 2,s/ ,5-trichlorophenol) , No. 65 I71. 3,3'-Methylenebis(6-bromo-2,4,5-trichlorophenol). A mixture of 105 g. of 6-bromo-2,4,5-trichlorophenol, 200 ml. of ethylene dichloride, and 105 g. of oleum was stirred and heated to 75 ø. A slurry of 5.5 g. of para- formaldehyde in 50 ml. of ethylene dichloride was added over a period of one hour. Stirring and refluxing were continued for twenty-four hours. The batch was processed as before recovery of unchanged 6-bromo-2,4,5- trichlorophenol amounted to 33 g. The crude material was crystallized from 730 ml. of methanol plus 175 ml. of dioxane with the addition of Nuchar © (West Virgina Pulp and Paper Co., New York, N.Y.) The re- sulting 61 g. were recrystallized from 960 ml. of toluene plus 100 ml. of dioxane, Filtrol being used for decolorization. A light, tan-colored product (48 g.) was obtained with a m.p. of 275-278 ø. lB. 3,3'-Methylenebis(2,4,5-1ric/./orophenol). A solution of 48 g. of IA in 400 g. of potassium hydroxide and 2000 ml. of water was heated to 85 ø and 105 g. of zinc dust added with vigorous stirring during a period of two hours. Agitation and heating at 85--90 ø were continued for five hours. The mixture was filtered, and ice was added to the tiltrate, which was made acid to Congo Red paper with hydrochloric acid. The precipitate was filtered, washed with water and crystallized from 699 ml. of methanol and 150 ml. of water. The solution was held at - 10 ø overnight, after which the resulting product (16.1 g. m.p. 235-238 ø) was recrystallized from 600 ml. of petroleum naphtha (b.p. 120-135 ø) and 80 ml. of dioxane. Yield: 13 g. of white, crystalline powder.