[FROM TEE DANIEL SIEFF RESEARCH INSTITUTE]
THE HALOGENATION OF ARYLOXYACETIC ACIDS AND THEIR HOMOLOGS L. HASKELBERG Received December 16, 1946
Halogenated aryloxyacetic acids recently have attracted considerable interest as plant hormones and selective weed-killers (1, 9). The preparation usually has been carried out by condensation of chloro- or bromo-acetic acid with the appropriate halogenated phenol or naphthol, but an alternative route is open in the halogenation of phenoxy- and naphthoxy-acetic acids or their functional derivatives. The present paper deals with the latter reaction, which frequently has the advantage that it is less violent and more easily controlled than the halogenation of free phenols; one can obtain well-defined products of desired halogen content by varying the temperature of reaction. Furthermore, the blocking of the free phenolic hydroxyl before the halogenation sometimes permits the introduction of halogen in positions other than those occupied in the free phenol. Similar observations have been recorded for certain substitution reactions in the 1-naphthol series (2,3,4).l Several instances of halogenation of phenyloxyacetic acid are known. Ethyl phenoxyacetate has been brominated in the 4-position by Auwers and Hayman ( 5 ) , the free acid chlorinated by means of sulfuryl chloride by Peratoner (6) and with phosphorus pentachloride by Michael (7), and the phenyl ester brominated by Vandervelde (8). The present results show that phenoxyacctic acid is chlorinated and brominated first in the 4- and then in the 2-position; monohalogenation proceeds at room temperature, dihalogenation at 60-80'. The sodium salt, the ethyl ester, and the amide all give the 4-chloro compound a t room temperature and the 2,4dichloro derivative at 60-80°. An excess of chlorine at 80" gives finally 2,4,6trichlorophenoxyacetic acid. (Pentachlorophenoxyacetic acid could only be obtained from pentachlorophenol.) a- and /3-Phenoxypropionicacid are equally well para-chlorinated at low temperature, and c~-(2,4-dichlorophenoxy)-propionic and -butyric acid are obtained at 30'. As expected, diphenoxyacetic acid gives bis-(2,4-dichlorophenoxy)acetic acid, which has also been synthesized from 2,4-dichlorophenol and dichloroacetic acid. 1-Naphthoxyacetic acid gives at room temperature the 4-ChlOrO derivative, identical with the condensation product of 4-chloro-1-naphthol and bromoacetic acid and different from the product formed from 2-chloro-1-naphthol and bromoacetic acid. Further chlorination of 1-naphthoxyacetic acid a t 60' gives the 2,4-dichloro derivative, the constitution of which was established by condensa1 In unpublished experiments from our Institute, it has been observed that 1,5-dimethoxynaphthalene is brominated in carbon tetrachloridesolution at 4 and 8, while 5-methoxy3-naphthol in the same solvent gives the 2,Sderivative; and in benzene gives also the 2, 6dibromo isomer. 426
HALOGENbTION OF ARYLOXYACETIC ACIDS
427
tion of 2,4-dichloro-l-naphthol with ethyl bromoacetate and subsequent hydrolysis. Bromination proceeds analogously. 2-Naphthoxyacetic acid is monochlorinated best at 40°, dichlorinated at 60". The two halogen atoms enter presumably the 1- and 6-positions, respectively. A third series of halogenations was carried out with the cresoxyacetic acids. 4-Methylphenoxyacetic acid is chlorinated and brominated in the 2-position, the methyl having a weaker o-directing influence than the (etherified) hydroxyl group. The chlorinated product has been prepared before by Synerholm and Zimmermann (9) from 2-chloro-4-methylpheno1,and the structure of the bromo compound follows from its non-identity with the 3-bromo-4-methylphenoxyacetic acid, obtained from 3-bromo-4-methylphenol and ethyl bromoacetate (with subsequent hydrolysis). The direction of the halogenation is, therefore, identical with that prevailing in the halogenation of p-cresol. 2-Methylphenoxyacetic acid has been converted into a mono-, a di-, and a tri-chloro derivative; judging from the well-known behavior of o-cresol, one would expect the positions 4, 6, and 3 (or 5 ) to be the most likely sites of substitution. The first attack, in any event, does not involve position 4, since the monochloro derivative obtained by us (m.p. 131') is different from the 4-chIoro-2methylphenoxyacetic acid (m.p. 119-120') prepared by Synerholm and Zimmermann (9) from the respective 4-chloro-2-methylpheno1.2 The halogenation seems, therefore, to deviate from the course it takes in the case of the free o-cresol. EXPERIMENTAL
As an example, the preparation of 4-chlorophenozyacetic acid is described. A. A solution of 15.2 g. of phenoxyacetic acid (10)in 60 cc. of glacial acetic acid containing a trace of iodine was chlorinated with 7.1 g. of gaseous chlorine a t room temperature. The product that separated was crystallized from water; m.p. 156"; yield 76% (6,7, 11). B. A solution of 15.2 g. of phenoxyacetic acid and 8 g. of sodium hydroxide in 150 cc. of water was cooled and treated with 7.1 g. of chlorine. The crystals were filtered and recrystallized from water; m.p. 156"; yield, 50% (12). The other halogenation experiments are summarized in Table I. I,4-Dichlorophenozyacetic acid from 2 , .&dichlorophenol(,%), 1.6). Ethyl 9,d-dichlorophenozyacetate. To a solution of 4.6 g. of sodium and 33 g. of 2,4-dichlorophenol in 100 cc. of butyl alcohol, 51 g. of ethyl chloroacetate was added a t 25". The mixture was heated for 2 hours on the water-bath, cooled, and diluted with water. The oil which separated was dried and fractionated; it boiled a t 128'/0.2 mm; yield 45 g., 90% ra; 1.5282. C, 48.1;H,4.0. Anal. Calc'd for CKJ~~OCIZOI: Found: C, 47.9; H, 4.2. Hydrolysis. Ten grams of the ester was heated for 3 hours a t 100"with a solution of 2 g. of sodium hydroxide in 20 cc. of water. Upon cooling, the sodium salt separated; it crystallized from alcohol in needles of m.p. 215". The acid formed white crystals; it boiled a t 160°/0.4 mm. and had m.p. 141'; yield 8 g. Anal. Calc'd for CsHsClzOa: C, 43.9;H, 2.6. Found: C, 43.7; H, 2.6. 2 Dr. Synerholm has kindly put a t our disposal a sample of his product, which depresses the melting point of the above-described monochloro-2-methylphenoxyacetic acid. His preparations of 2,4,6-trichlorophenoxyaceticacid, of 2-chloro4-methylphenoxyacetia acid, and of 2-bromo-4-methylphenoxyaceticacid have been found identical with the corresponding products prepared as described above. (Note added February 13, 1947).
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Pentachlorophenozyucetic acid. Ethyl pentachlorophenoxyacetate. To a solution of 1.2 g. of sodium in 50 cc. of absolute alcohol, 13.3 g. of pentachlorophenol (23) and 8.4 g. of ethyl bromoacetate were added in succession. The mixture was heated on the water-bath for one hour. The precipitate which appeared upon cooling, was collected, washed with water and recrystallized first from alcohol, then from petroleum ether. The ester formed needles of m.p. 110-11lo; yield 14 g., 80%. Anal. Calc'd for C I O H # ~ I ~C, O ~34.1; : H, 2.0. Found: C, 34.5; H, 2.5. Hydrolysis with 10% alcoholic potassium hydroxide solution gave the free acid which crystallized nicely from toluene. It melted at 195-196." Anal. Calc'd for C8HIC1601:Neutr. equiv., 324. Found: Neutr. equiv., 322.5. bis-(2,Q-Dich2orophenozy)uceticacid. To a solution of 12.5 g. of sodium in 150 cc. of butyl alcohol, 41 g. of 2,4-dichlorophenol and 33 g. of dichloroacetic acid were added in succession. The mixture was heated for three hours on the water-bath. The acid proved very soluble in alcohol and acetone, but crystallized well from benzene; yield 52%. It melted at 152" and did not depress the m.p. of the dichlorophenoxyacetic acid, prepared by chlorination of phenoxyacetic acid. Q-Chloro-1-naphthozyaceticacid. The solutions made from 7 g. of bromoacetic acid and 4.3 g. of sodium bicarbonate in 10 cc. of water, and from 9 g. of 4-chloro-1-naphthol (24) and 2 g. of sodium hydroxide in 10 cc. of water, respectively, were mixed and the mixture waa heated a t 100" for four hours. The solid which separated was brought into solution by addition of 250 cc. of water, and the solution was treated with charcoal, filtered, and acidified with 5% hydrochloric acid. The acid was recrystallized from benzene, it melted a t 169" and proved identical with the acid prepared from 1-naphthoxyacetic acid and chlorine. The yield was 64ajoo. 2-Chloro-I-naphthozyaceticacid. A solution of 0.6 g. of sodium, 4.5 g. of 2-chloro-lnaphthol (24a), and 4.1 g. of sodium bromoacetate in 20 cc. of alcohol was heated for four hours on the water-bath. The alcohol was evaporated and the residue dissolved in water and, after extraction with ether, acidified with 5% hydrochloric acid. After recrystallization from benzene, the acid had m.p. 134"; yield, 74%. Anal. Calc'd for Cl2H&IO$: Neutr. equiv., 236. Found: Neutr. equiv., 234.5; 235. I , .4-Dichloro-l -nuphthoxyacetic acid. To a solution of 2.3 g. of sodium in 75 cc. of alcohol, 21.5 g. of 2,4-dichloro-l-naphthol (25) in 75 cc. of alcohol and 16.8 g. of ethyl bromoacetate were added in succession. After one hour on the steam-bath, the mixture was cooled and the solid filtered and recrystallized from petroleum ether. The ethyl ester had m.p. 71'; b.p. 165"/0.05 mm; yield 90%. Anal. Calc'd for C14H12C120s: C , 56.0; H, 4.0; C1, 23.7. Found: C, 56.3; H, 4.4; C1, 23.9. Hydrolysis gave the free acid, m.p. 178", in 80% yield. It was identical with the product obtained by dichlorination of 1-naphthoxyacetic acid. 2,4-Dibromo-l-naphthol (26) could not be condensed with ethyl bromoacetate, msodium alkoxide and even acetate convert i t into an indigo-blue substance (27). 6-Bromo-I-naphthozyaceticacid. To a cold solution of 2.3 g. of sodium in 75 cc. of absolute alcohol, 22.3 g. of 6-bromo-2-naphthol (28) and 16.8 g. of ethyl bromoacetate were added in succession. After one hour on the water-bath, the difficultly soluble potassium salt of the desired acid was precipitated by addition of a concentrated aqueous solution of 14 g. of potassium hydroxide. The solution of the salt in boiling water was acidified. The acid had m.p. 210"; yield %%. Anal. Calc'd for CllHPBrO*:Neutr. equiv., 281. Found: Neutr. equiv., 280. 1,6-Dibromo-8-naphthozyacetic acid. To a solution of 1.2 g. of sodium in 50 cc. of alcohol, 16.1 g. of 1,6dibromo-2-napthol (28) and 8.4 g. of ethyl bromoacetate were added in succession. The crude ester obtained was hydrolyzed with alcoholic potassium hydroxide
432
L. HASKELBERG
solution and the acid isolated in 85% yield. After recrystallization from toluene, it melted a t 178". Anal. Calc'd for ClzHsBroOt: Neutr. equiv., 360. Found: Neutr. equiv., 360. 3-Bromo-~-methyZphenoxyacetic acid. To a solution of sodium ethoxide, prepared from 2.3 g. of sodium in 75 cc. of alcohol, 18.7g. of 3-bromo-4-methylphenol (29) (b.p. 218-219') and 16.7 g. of ethyl bromoacetate were added in succession at 0". Within one hour, the mixture was gradually brought up to boiling temperature and, after addition of 65 CC. of 10% sodium hydroxide solution, was kept for ten more minutes on the stem-bath. The solution of the sodium salt was treated with charcoal, filtered and acidified; yield 85%; m.p. 145". A n d Calc'd for CoHoBrOa:Neutr. equiv., 245. Found: Neutr. equiv., 243. This product gave a strong depression of the melting point, when mixed with the acid formed in the direct bromination of 4-methylphenoxyacetic acid. SUMMARY
Aryloxy-fatty acids and their esters and amides are easily chlorinated and brominated step by step. The following substances have been investigated : phenoxyacetic acid and its ethyl ester and amide ; a- and 8-phenoxypropionic acid; ethyl a-phenoxypropionate; a-phenoxybutyric acid; diphenoxyacetic acid; 1- and 2-naphthoxyacetic acid; (4-methy1phenoxy)aceticacid and (2-methy1phenoxy)aceticacid. Thirty-two halogenated derivatives have been synthesized either by this method or by the usual condensation of halogenated phenols with halogenofatty acids. REEIOVOTH, PALESTINE REFERENCES
(1) HITCHCOCK AND ZIMMERMANN,Contrib. Boyce Thompson Znst., 14, 21 (1945); Chem. Abstr., 39, 4918 (1946). (2) GATTERMA", EHRHARDT, AND MAISCH, Ber., 23, 1219 (1890). (3) FRIEDLANDER, Ber., aS, 1957 (1895). (4) DEICHLER AND WEIZMA",Ber., 36,649,553 (1903). CE. WEIZMAHN AND E. BERQ-, J . Chem. Soc., 567 (1936). (5) AUWERSAND HAYMAN, Ber., 27,2795 (1894). Gazz. chim. ital., 28,239 (1898). (6) PERATONER, J . Am. Chem. Soc., 9,216 (1887). (7) MICHAEL, (8) VANDERVELDE, Chem. Zentr., 1898, I, 988. AND ZIMMERMAN,Contrib. Boyce Thompson Znst., 14, 91 (1945). Chem. (9) SYNEREOLM Abstr., 40, 1473 (1946). (10) GIACOSA, J . prakt. chem., (2)19,396 (1879). (11) (a) MINTONAND STEPEEN,J . Chem. Soc., 121,1599 (1921). (b) HAYE$ AND BRANCEI,J . Am. Chem. Soc., 66,1555 (1943). (12) See KOELGCH AND FREDERICK, J . Am. Chem. SOC.,63,304 (1931). (13) FRITZSCBE, J . prakt. chem., (2) 20,267 (1879). (14) POKORXY, J . Am. Chem. SOC.,63,1768 (1941) (15) BISCEIOFF, Ber., 33, 1605 (1910) (m.p. 177"). Ber., 9s. 925 (1900). J . prakt. chem., ( 2 ) 21, 152 (1880). (b) BISCHOPF, (16) (a) SAARBACH, (17) CEAXRAVARTI AND DUTTA,Chem. Abstr., 34, 4735 (1940). (18) SPICA,Gazz. chim. ital., 16, 438 (1885). Ber., 34, 3192 (1901). (19) SPITZER, Ber., 14, 923 (1881). (20) GABRIEL,
HhLOGENATION OF ARYLOXYACETIC ACIDS
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(21) OQLIALORO AND CANNONE, Gaz. chim. ital., 18, 511 (1888). HEWITT,JOHNSON, AND POPE,J . Chem. SOC.,103,1629 (1913). MAMELI,Chem. Zentr., 1914, I, 139. (22) CHANDELON, Ber., 16, 1751 (1883); HOLLEMAN, Rec. trav. chim., 37, 97 (1918). (23) BARRAL AND JAMBON, Bull. SOC. chim., (3) 23,823 (1900). (24) (a) LESSER AM) GAD, Ber., 66,972 (1923). (b) AGFA,D. R. P. 240,038; Chem. Zentr., 1911, 11, 325. (25) CLEVE,Ber., 21, 891 (1888). ZINCXE,Ber., 21, 1035 (1888). J. Chem. Soc., 67, 395 (26) BIEDERMA",Ber., 6, 1119 (1873). MELDOLAAND HUQHEEI, (1890). (27) DAHMER,Ann., 333, 367 (1904). (28) Organic Syntheses, Vol. XX, p. 18. (29) D. R. P. 156,333; Chem. Zentr., 1904, 11, 1672.
