CHEMICAL STRUCTURE AND ANTIMICROBIAL ACTIVITY OF BIS-PHENOLS 719 Of the 2,2'-methylenebis (dichlorophenols), only 2,2'-methylenebis (4,6- dichlorophenol) and a substance claimed to be 2,2'-methylenebis (4,5-di- chlorophenol)* have been described previously (3,4). In the preceding papers (2, 5) we listed two compounds, 2,2'-methylenehis (5,6-dichloro- phenol), No. 9, and 2,2'-methylenehis (4-bromo-5,6-dichlorophenol), No. 5. It has now been determined that these compounds are actually 4,4'- methyleneNs (2,3-dichlorophenol) and 4,4'-methylenehis (6-bromo-2,3- dichlorophenol), respectively. The starting material had been 6-bromo- 2,3-dichlorophenol and not, as we had assumed, 4-bromo-2,3-dichloro- phenol. Bromination of 2,3-dichlorophenol leads to either compound, de- pending upon the solvent used. EXPERIMENTAL I. Chemical 2,3-Dichlorophenol and 3,4-dichlorophenol were purchased from Aldrich Chemical Co., Milwaukee, Wis. Of the various bromodichlorophenols (Table III) needed as starting materials, only the 4-bromo-2,3-dichloro- phenol could be prepared by direct bromination of the dichlorophenol. Otherwise, this procedure results in mixtures of isomers which could not be separated. Bromination of 2,3-dichlorophenol led to 4-bromo-2,3-di- chlorophenol when acetic acid was used as solvent in the presence of methanol, 6-bromo-2,3-dichlorophenol•' was predominantly formed. The other bromodichlorophenols were obtained from the corresponding bromo- dichloroanilines (Table III) through the diazonium salts as described by Tiessens (6). Specific details for the preparation of the bromodichloroanilines and bromodichlorophenols are as follows: 6-Bromo-3,¾-dich/oroani/ine. To a stirred slurry of 612 g. of 3,4-di- chloroacetanilide and of 24:6 g. of anhydrous sodium acetate in 1500 mi. of acetic acid was added a solution of 480 g. of bromine in 600 mi. of acetic acid during six hours. The next day, the batch was heated at 50 ø for a * The latter compound (4) was reportedly obtained by the condensation of 3,4-dichloro- phenol with formaldehyde in the presence of 80% sulfuric acid. Recrystallization of the crude product yielded a substance melting at 194-196 ø. Further purification raised the m.p. to 201 ø. Following the cited procedure we isolated a his-phenol with a m.p. of 199-201 ø. It is our belief that this Ns-phenol is actually the asymmetrical 3,4,4',5'-tetrachloro-2,2'-methylene- diphenol and does not have the structure of 2,2',-methylenebis(4,5-dichlorophenol) assigned to it in Geigy Co.'s patents. The basis for this conclusion is presented under preparation of Compound No. VI in the Experimental part of this article. J' Its structure was proved by the following sequence of reactions: Condensation with formaldehyde gave 4,4'-methylenehis (6-bromo-2,3-dichlorophenol) which, on debromination, yielded 4,4'-methylenehis (2,3-dichlorophenol). When this compound was chlorinated, 4,4'- methylenehis (2,3,6-trichlorophenol) was obtained. It melted at 162-164 ø. The m.p. of a mixture with pure 4,4'-methylenehis (2,3,6-trichlorophenol), m.p. 166-167 ø (1), was 163-165 ø showing no depression.

720 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS period of five hours. After cooling, the solid was filtered, washed with water and crystallized from a mixture of 1000 mi. of isopropanol and 200 mi. of dimethylformamide. To the first flitrate a small amount of water was added, and the precipitate formed was crystallized from the isopro- panol-dimethylformamide mother liquor. A total of 331 g. of 6-bromo-3,4- dichloroacetanilide, m.p. of 172-173 ø, was obtained. It was slowly heated to 120 ø with a mixture of 330 g. of a 50% (by weight) aqueous sodium hydroxide solution and 1000 g. of ethylene glycol and kept at this tempera- ture for five hours. The batch was poured into a large amount of cold water, the precipitate filtered, washed with water and, while moist, crystal- lized from 450 mi. of isopropanol. First and second crops amounted to 258 g., m.p. 90.5-92 ø. Recrystallization from 450 mi. of petroleum naphtha (b.p. 120-135ø), with the aid of Filtrol ©*, yielded 210 g. of pure 6-bromo-3,4-dichloro aniline, m.p. 91-93 o. 4-Bromo-2,5-dichloroaniline. It was prepared from 2,5-dichloroaniline by the following steps: 2,5-dichloroaniline • 2,5-dichlorobromobenzene 4-bromo-2,5-dichloronitrobenzene --• 4-bromo-2,5-dichloroaniline (8). ¾-Bromo-3,5-dichloroaniline. Its preparation from 3,5-dichloroacet- anilide was conducted as described for that of 6-bromo-3,4-dichloroaniline. ¾-Bromo-2,3-dichlorophenol. In order to demonstrate that the bromina- tion of 2,3-dichlorophenol in acetic acid solution results in the 4-bromo- derivative, a small amount of the bromination product was chlorinated in acetic acid. Crystallizations of the crude product from heptane and aqueous alcohol yielded a pure bromotrichlorophenol, m.p. 83-84 ø. Bromo-2,3,6-trichlorophenol, obtained by bromination of 2,3,6-trichloro- phenol (9), had the same m.p. and a mixture of both substances showed no depression. ¾-Bromo-3,5-dichlorophenol. To 420 mi. of 96% sulfuric acid was added 42 g. of sodium nitrite with agitation and cooling, and then 144 g. of 4- bromo-3,5-dichloroaniline during 90 minutes at 25-30 ø. After addition of 410 mi. of 96% sulfuric acid, the mixture was slowly heated to 80-85 ø, held at this temperature for three hours, and overnight at room temperature. The diazonium salt solution was then dropped into a heated mixture of 1200 g. of cryst. cupric sulfate and 1200 mi. of water while steam passed through. Following a nine hour steam distillation, the distillates were extracted with isopropyl ether, the extract concentrated to dryness (101 g.) and the residue crystallized from 350 mi. of heptane, Filtrol being used fordecolorization. Yield: 80.5 g. In a similar manner, ¾-bromo-2,5-dichlorophenol (8) and 6-bromo-3,¾- dich/orophenol (10)-]- were obtained from the corresponding bromodi- chloroanilines. * Filtrol Corp., I,os Angeles, Calif. • The compound was mentioned in the reference by name only. Its structure was estab- lished by chlorinating it to 6-bromo-2,3,4-trichlomphenol. The latter substance was identical with the one obtained by bromination of 2,3,4-trichlorophenol (8).