[CONTIIIBUTION F R ~
MTHE
CHEMICAL LABORATORY OF THE ACADEMY OF COMMERCE OF VIENNA]
THE PREPARATION OF TETRAHALOGENATED o-ANISIDINES MORITZ KO"'
AND
OSKAR KRASSO
Received February 6, 1946
Trihalogenated o-anisidines were employed in previous studies for the preparation of trihalogenated phenols (1). In this connection a series of tetrasubstituted o-anisidines, as well as the first example of a tetrahalogenated o-anisidine, ,5-dibromo-6-aminoa dichlorodibromo-o-anisidine, l-methoxy-2,4-dichloro-3 benzene (I),were prepared. This paper deals with the preparation of other tetrahalogenated o-anisidines. Tetrabromo-o-anisidine was prepared from phenol as follows: phenol was converted to the 2,4-dibromo derivative, and this by nitration to 2,4-dibromo-6nitrophenol. The silver salt of the latter, with methyl iodide, gave 2,4-dibromo6-nitroanisole (11) (2). By reduction this yielded the corresponding anisidine, l-methoxy-2,4-dibromo-6-aminobenzene (111) (2), which on bromination gave 2,3 ,4,5-tetrabromo-o-anisidine (IV).
OHCI NHzD(2:
0 CH3 NO.@
0 CH3 N H z O r
NCH3 N € I o
B
Br
c1 I
Br
I1
Br
Br
I11
IV
2,4-Dibromo-o-anisidine was converted to the acetyl derivative, which with fuming nitric acid and sulfuric acid gave the dinitrodibromoacetanisidide (V) ; this was deacetylated with concentrated sulfuric acid a t water-bath temperature ,5-dinitro-6to 2 ,4-dibromo-3 ,5-dinitro-o-anisidine (l-methoxy-2,4-dibromo-3 aminobenzene, (VI). Like 2,4-dichloroanisole (3), 2-bromo-4-chloroanisole can be nitrated with fuming nitric acid to 2-bromo-4-chloro-6-nitroanisole. The 2-bromo-4-chloroanisole was obtained by bromination of 4-chlorophenolwith one mole of bromine; the redistilled 2-bromo-4-chlorophenolwas methylated with alkali and dimethyl sulfate. On treatment of the anisole (VII) with fuming nitric acid, 2-bromo-4chloro-6-nitroanisole (VIII) was obtained, which on reduction gave 2-bromo-4IX) . This chloro-o-anisidine (1-methoxy-2-bromo-4-chloro-6-aminobenzene, product takes up two bromine atoms in glacial acetic acid, whereby 2,3,5tribromo-4-chloro-o-anisidine (1-methoxy-2,3 ,5-tribromo-4-chloro-6-aminobenzene, X) is formed. 2-Bromo-4-chlorophenol (XII) can also be prepared by bromination of 4-chlorophenol with two moles of bromine to 4-chloro-2 ,6-dibromophenol (XI), and partial debromination of this by 45-minute boiling with 1
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642
MORITZ KO"
AND OSKAR KRASSO
zinc dust in glacial acetic acid. Nitration of XI1 results in 2-bromo-4-chloro-6nitrophenol (XIII), which was prepared by Ling (4) by another method. The melting points of the tetrahalogenated o-anisidines lie fairly close together and are relatively low: I, m.p. 83'; X, m.p. 103'; IV, m.p. 112". The above described preparation of 2,4-dibromo-6-nitroanisole (11) through the silver salt of the nitrophenol had to be followed because the nitration of 2,4-dibromoanisole with fuming nitric acid caused difficulties. When, however, 2,4-dibromoanisole was treated with fuming nitric acid and sulfuric acid, a nitro compound was ob, that is, a tribromodinitroanisole. tained having the composition C7H3Br3N206 OCH,
:(Jo2
OCH,
0"'
Br
c1
VI1 OCHs
VI ocH3 NHJ(
c1
c1
c1
X
IX
VI11 B
Q B ;"
OH OH OH r p +o r + NOZ@
Br@13r2 OCH3
NO2
c1 XI
c1 XI1
c1
XI11
Br XIV
Demethylation of this gave the corresponding tribromodinitrophenol. The anisole is identical in melting point and other properties with the 2,4,6-tribromo3 ,Bdinitroanisole (XIV) prepared in the Vienna laboratory by Kohn and Strassmann ( 5 ) by nitration of 2,4 ,6-tribromoanisole, and the above tribromodinitrophenol has the melting point of their 2,4,6-tribromo-3,5-dinitrophenol. The investigation of the nitration of 2,4-dibromoanisole has thus led to the remarkable result, that during nitration a bromine atom was introduced. This can only be explained by the assumption that a portion of the 2,4-dibromoanisole was completely destroyed, and the liberated bromine served to brominate the remaining 2,4-dibromoanisole; the intermediate tribromoanisole was then converted to the dinitro derivative. Because of this complication, the yieldof dinitro product is poor. For the preparation of 2,3,4,6-tetrabromophenoland a series of other tetrahalogenated phenols we have always used the procedure of Benedikt ( 6 ) . The
TETRAHALOGENATED 0-ANISIDINES
643
phenol is transformed by the action of excess bromine into the corresponding keto bromide, with phenol itself XV, which on heating with sulfuric acid rearranges to tetrabromophenol, XVI.
Br
xv
XVI
Br XVII
It therefore seemed desirable to ascertain whether the keto bromide might be avoided, by treating the trihalogeno phenol (XVII) directly in sulfuric acid solution with bromine. Experiment showed that tetrabromophenol could be obtained in this way, but that the bromination proceeded very slowly. EXPERIMENTAL
Tetrabromo-o-anbidinefrom phenol. Phenol was converted in the usual way to 2,4dibromophenol, which was distilled. A solution of 25 g. of 2,4-dibromophenol in 100 cc. of glacial acetic acid was treated with 10 cc. of colorless conc'd nitric acid. It was warmed gently, and as the color darkened, cooled, whereupon crystallization took place. It was diluted strongly with water, and the nitro compound purified from a small volume of alcohol; m.p. 115". The phenol was converted to the potassium salt, and from an aqueous solution of this the silver salt was precipitated with excess silver nitrate. It was heated on the water-bath until the precipitate coagulated; this was filtered, washed with methanol, and refluxed with methanol and methyl iodide until completely converted to silver iodide. Methanol and methyl iodide were distilled off, the residue extracted with boiling alcohol, and filtered from silver iodide. Dilution of the filtrate with water precipitated the crude anisole, which was filtered after several hours, and extracted with 3% NaOH; it was recrystallized from alcohol, m.p. 80". I,4-23ibromo-o-anisidine(111). 2,4-Dibromo-6-nitroanisole(10 g.) was added in small portions to a warm solution of 30 g. of stannous chloride in 30 cc. of 37% HCI. It was refluxed until the anisole dissolved completely (a little more stannous chloride sometimes necessary). It was cooled and poured cautiously into 33% NaOH, solid NaOH added until considerable excess was present, and the anisidine distilled with steam. Tetrubromo-o-anisidine(IV). To a solution of 5 g. of 2,4-dibromo-o-anisidne in 50 cc. of glacial acetic acid was added with good stirring 2 molar equivalents of bromine diluted with an equal volume of acetic acid. The crude bromination product which separated immediately was allowed to stand 20 minutes with frequent stirring, filtered, and washed with acetic acid. It crystallized from alcohol in thin woolly needles of m.p. 112'. Anal. Calc'd for C,HsBrrNO: C, 19.11; H, 1.14; N,3.19;Br, 72.9; OCHs, 7.06. Found: C, 19.30; H. 1.19; N,3.36; Br, 73.13; OCH8, 7.42. 2,4-Dibromo-3,6-dinitro-o-anisidine (VZ) . Dibromo-o-anisidine (10 9.) was refluxed for 1.5 hours with 40 g. of acetic anhydride, poured into water, and vacuum dried. Dried and finely powdered 2,4-dibromoacetanisidide(5 g.) was added in small portions to a mixture of 60 cc. of fuming nitric acid and 40 cc. of conc'd sulfuric acid. After complete solution, i t was poured onto ice, filtered, washed well with water, and crystallized from alcohol; yellow, woolly needles, charring above 212'.
644
MORITZ KOHN AND OSKAR KRASSO
A n a l . Calc'd for CsHTBrZNaOe: N, 10.14. Found: N, 9.98. Ten grams of the pure dry acetyl compound (V) was treated with 50 g. of conc'd H2S04 and digested on the water-bath for 15 minutes. The substance yielded a dark solution which was cooled and poured into ice-water; the product was washed well with water and crystallized from alcohol; long yellow prisms, m.p. 173". A n a l . Calc'd for C,HIBraNaOs: C, 22.64; H, 1.35. Found: C, 22.81;H , 1.42. Preparation of 8,S, 6-tribromo-4-chloro-o-anisidine(X) f r o m ,&chlorophenol. The 4-chlorophenol was brominated in- CClr in the usual way, and distilled at atmospheric pressure; b.p. 230-235". Methylation with alkali and dimethyl sulfate gave 2-bromo-4chloroanisole (VII), a colorless oil of b.p. 244-250'. Eleven grams of VI1 was treated cautiously with 10 cc. of fuming nitric acid, poured onto ice, and the product triturated with water. It was extracted with 3% NaOH to remove phenolic material, and crystallized from alcohol; m.p. 58". A n a l . Calc'd for C,HbBrCINOs: OCHs, 11.65. Found: OCHa, 12.21. For reduction to the anisidine (IX), 18 g. of the nitroanisole (VIII) was refluxed with a solution of 55 g. of stannous chloride in 55 cc. of fuming hydrochloric acid. After treatment with excess conc'd alkali, the anisidine was steam distilled, extracted into ether, and vacuum distilled; a yellow oil of b.p. 151-154"/14 mm. Ten grams of I X was refluxed with 30-40 g. of acetic anhydride for 1.5 hours, poured into water, and after an hour filtered and washed with water; from alcohol, leaflets of m.p. 108". A n a l . Calc'd for CpH9BrC1NOt:C, 38.85; H, 3.24; OCHs, 11.15. Found: C, 38.91;H, 3.28;OCHs, 11.11. 8, S,6-Tribromo-4-chloro-o-anisidine ( X ) . The bromination of I X was carried out like that of 111. The crude product was washed with a little acetic acid, sulfurous acid, and water. After drying, i t was crystallized from ligroin (charcoal), giving thin needles of m.p. 103". Anal. Calc'd for C7HsBr&lNO: C, 21.32;H, 1.27;N, 3.55;Halogen, 69.80;OCHa, 7.87. Found: C, 21.61;H, 1.50;N,3.72; Halogen, 69.57;OCH1, 8.3. Preparation of 8-bromo-4-chlorophenol (XZZ) b y partial debromination of 8 ,d-dibrorno-.$chlorophenol ( X I ) . An aqueous suspension of 4-chlorophenol was treated with 2 molecular equivalents of bromine (as aqueous Br,-KBr solution) with frequent shaking. The crude product was washed with water, melted, cooled, and excess water removed. The 2,6dibromo-4-chlorophenol, with the same quantity of zinc dust and 5 parts of glacial acetic acid, was refluxed for45 minutes, poured into water, and extracted with ether. The product distilled at atmospheric pressure at 228-235". The nitration was carried out like that of melted at 125", in agreement 2,4-dibromophenol. The 2-bromo-4-chloro-6-nitrophenol with Ling (4). d,4,6-Tribromo-S, 6-dinitroanisole ( X I V ) f r o m nitrution of 8, ~-dibromounisole. The methylation of 2,4-dibromophenol was done in the usual way, and the product purified by distillation, b.p. 263-269". Finely powdered dibromoanisole (9 9.) was added in small portions to 50 cc. of fuming nitric acid.' Concentrated H&3Oc (150 cc.) waa added in portions, with cooling if necessary. When about half of the acid was added, separation of crystals began. After 20-30 minutes standing cold, i t was poured cautiously on ice, filtered, and washed with water as long as oil droplets separated from the washings. The solid product was crystallized from alcohol, m.p. 149", yield about 10% of the amount of dibromoanisole. Anal. Calc'd for CtHsBr8NsOs: C, 19.3; H, 0.69;N, 6.43;Br, 55.17. Found: C, 19.63,19.56;H, 0.87,0.97;N, 6.27,6.75,6.63;Br, 55.01. The tribromodinitroanisole was demethylated with hydrogen bromide in acetic acid t o give 2,4,6-tribromo-3,5-dinitrophenol, m.p. 195". Anal. Calc'd for C&IBrsN*Or: C, 17.1; H, 0.24;N,6.65;Br, 57.0. Found: C, 17.31;H, 0.79;N, 6.71,6.67,6.99;Br, 57.09. 2
The preliminary experiments were carried out with the assistance of Alma Segel.
TETRAHALOQENATED 0-ANISIDINES
645
Bromination of d,4,6-tribromophenol in sulfuric acid to 9,S,4,6-letrabromophenol.To a suspension of 20 g. of 2,4,6-tribromophenol in 100 cc. of conc'd HISOl was added 3.5 cc. of bromine, and the mixture was heated in the oil-bath to 120". After 18 hours, evolution of HBr had ceased. The sulfuric acid was poured off and the solidified cake washed with water and crystallized from glacial acetic acid; m.p. 111". The methyl ether of this had the b.p. 340" (7);crystallized from alcohol, the m.p. 104' (8). SUMX4RY
1. Starting from phenol, the preparations of tetrabromo-o-aniside and of 2,4-dibromo-3,5-dinitro-o-anisidineare described; from 4-chlorophenol, that of 4-chloro-2,3,5-tribromo-o-anisidine. 2. Intensive nitration of 2,4-dibromoanisole results in introduction of another bromine atom, with formation of 2,4,6-tribromo-3,5-dinitroanisole. 3. Bromination of 2,4,6-tribromophenol in sulfuric acid gives 2,3,4,6tetrabromophenol. REFERENCES
(1) KOHNAND KARLIN, Monatsh., 48, 599,613 (1927). KOENAND KRAMER, Monatsh., 49, 161 (1928). (2) KOERNER, Jahresber., 337 (1875). S T A ~ D EAnn., L . 217,63 (1883). (3) KOHNAND KRAYER,Monatsh., 49,156 (1928). (4) LING,J. Chem. Soc., 61,787 (1887). (5) KOHNAND STRASSMANN, Monatsh., 46,601 (1924). (6) BENEDIKT, Ann., 199, 132 (1879);Monatsh., 1, 361 (1880). (7) KOHNAND SU~SMAN, Monatsh., 46,578 (1925). (8) KOHNAND FINK,Monatsh., 44, 194 (1923).
