Feb., 1944
ARSONICACIDSAND AWENOSOCOMPOUNDS CONTAINING THE Azo LINKAGE
a-Amino-pdichloroarsinoacetanilide Hydrochloride.Reduction of the corresponding arsonic acid" in hydrochloric acid gave this dichlarosrsine. It could not be successfully hydrolyzed to the arsenoso derivative. Anal. Calcd. f& C&AsCltN~O.HCl: As, 22.6; N, 8.45. Found: As, 22.3; N, 8.45. &'-Ancmollo-p.csrbamylbenurnilldc.-By means of the Sc otten-Baumann reaction p-toluyl chloride was condensed with atoxyl to give N-p-toluylarsanilic acid. This compound was oxidized with potassium permanganate in neutral solution, in the presence of magnesium sulfate. From the reaction mixture terephthalic acid was isolated in quantitative yield. According to German Patent 191,54818 terephthalyl chloride condenses with arsanilic acid to give p-arsonoterephthalanilic acid. I n several experiments, using various experimental conditions, we obtained a mixture of this compound and N,N'-terephthaloyldiarsanilic acid. It was found that the two compounds could be separated by the differential solubilities of their magnesium salts, as described for the separation of a similar mixture in the biphenyl series,18 but the yield was poor. The desired compound was finally obtained by the following synthesis. p-Cyanobenzoic acid (14.7 g.) and 7.9 g. of pyridine were dissolved in 1 liter of absolute ether and the mixture treated with 11.9 g. of thionyl chloride according to the directions of -6 and Libermann.17 While the resulting p-cyanobenzoyl chloride could not be readily separated from pyridine hydrochloride, this was found unnecessary. After removing the solvent the residue was triturated with 43 g. of arsanilic acid and then warmed on the water-bath for one hour. An excess of 10% hydrochloric acid was added and the mixture stirred for one hour to dissolve any unchanged arsanilic acid. The (14) Jambs and Heidelbager, TmS JOURNAL, 41 1809 (1919). (16) German Patent 191,648; Chum. Zcnfr., 79, I, 779 (1908). (16) Doak, Eagle and Steinman, T m s JOURNAL, S4, 1064 (1942). (17) C a d and Libermann, Compl. rmd.. 199, 1422 (1934).
197
resulting N-(pcyanobenzoyl)-arsanilic acid was purified through its magnesium salt. Oxidation with 30% hydrogen peroxide gave N-(p-carbamylbenzoyl)-ar~icacid, which was reduced to the desired arsenoso derivative. p.(p.Carbamylphenylsonyl)-benzenearsonic Acid.The sheller-Bart reaction, applied to $-amino-$'nitrodiphenyl sulfide,I* gave p-(pnitropheny1thio)-benzenearsodc acid which was reduced catalytically to p-(pPminophenylthio)-benzenearsonic acid. The Sandmeyer reaction applied to this amine gave p(pcyanopheny1thio)-bemenearsonic acid. This nitrile was then oxidized with an excess of 30% hydrogen peroxide in alkaline solution. p-( p-Carbamylphenylsulfonyl)-bemenearsonic acid precipitated when tlie alkaline solution was acidified. Unfortunately all attempt-. to reduce this compound to the corresponding arsenoso derivative resulted in partial hydrolysis of the amide group. The table lists the arsonic acids and arsenoso compounds which are new compounds or are known compounds prepared by a new procedure. Under "description," the letters in parentheses refer to the solvent used for crystallizing: W = water, A = ethyl alcohol, M = methanol and AA = acetic acid. Melting points were taken by the procedure described in paper VI. All analytical results are the average of two or more determinations.
Acknowledgment.-The authors wish to acknowledge the assistance given by Leon D. Freedman throughout the course of the work.
summary A number of arsonic acids and arsenoso compounds containing amide groups have been prepared. (18) R a i z h . Clemence. Severnc and Moetsch, THISJOURNAL, 61, 2768 (isas).
BALTIMORE, MARYLAND
RECEIVED OCTOBER 12, 1943
[CONTRIBUTION FROM VENEREAL DISEASERESEARCH AND POSTGRADUATE TRAINING CENTER,UNITEDSTATESPUBLIC HEALTH SERVICE, JOHNS HOPKINS HOSPITAL]
Arsonic Acids and Arsenoso Compounds Containing the Azo Linkage' BY G. 0. DOAK, H. G. STEINMAN AND HARRY EAGLE In this Laboratory it has been found that diazo The customary preparation of arsonic acids containing the azo linkage consists in the coupling of compounds couple with 0- and m-hydroxybenzenediazotized aminoarylarsonic acids with phenols and arsonic acids, the coupling occumng in para amines. We have also prepared such compounds position to the hydroxy group. Where the para by coupling diazo compounds with hydroxyaryl- position is blocked, e. g., p-hydroxybenzenearsonic arsonic acids and by the application of the acid, the arsonic acid group is partially replaced Scheller-Bart reaction* to aminoazo compounds. by the phenylazo group. In addition, however, While it has been stated that 0- and m-hydroxy- some coupling occurs in ortho position to the benzenearsonic acids' and m-arsanilic acid' couple hydroxy group. The resulting azoarsonic acid with diazo compounds, the only evidence for then reacts further with the diazo compound to such a reaction was color formation. B a d a s give the bis-(phenylazo)-phenol. The extent to obtained only arsenic acid and the corresponding which each of these three reactions occurs dephenylazophenol from p-hydroxybenzenearsonic pends not only upon the strength of the reactants acid and diazo compounds. Lawrence and as coupling agents but is also influenced by the Hamilton,@j however, have successfully coupled PH of the reaction mixture. The results of a series of experiments are given in Table I. aminonaphthalenearsonicacids. (1) Paper VI11 io the Seriea Eotitled "The Preparation of Phenyl-oxides." (2) Scheller, French Pateot 624,028, Chem. Zmtr., )(I, 11, 2229 (1927); Doak, TRISJOURNAL, 69, I67 (1940). (3) Jacobs and Heidelberga, :bid., 41, 1440 (1918) (4) Bertheim, B e . . 41, 1055 (1908). (6) Denda, ibid., 44, a449 (1911). (8) Penonnl cornmumication from Dr. Hamilton.
Experimental Part
A. The Coupling of Diazo Compounds with Hydroxyarylarsonic Acids.-The following description illustrates the general procedure that was followed.
G. 0 . DOAK,H. G . STEINMAN AND HARRYEAGLE
1Y8
TABLE I THECOUPLINQ OF DIAZO COMPOUNDS WITH HYDROXYARYLARSONIC ACIDSIN RELATIONTO PH Arsonic acid
-
Diazo compound from
PH
(5.8-6.6"
P-HOCIH,-
Aniline
4-HOCloHe-1P-HOCsH4-
Aniline Sulfanilamide
% Yield of products
Phenylazophenol
4 7.3-7.4b [8.E~9.5~ 7.1-7 .4b
36.9 39.4 9.4
34.4
5.4-6.5"
Phenylazoarylarsonic acid
0.5 5.9 0 20.0 0 0
bis-(Phenylazo) phenol
4.6
12.2 27.8
33.8
7. 1-7.Sh No coupling 7.4-7.5' 0 95 0 7.0-7.1' 0 38 0 8.9-9.ld 0 88 0 Aniline 8.9-9. Id o-HOCaH484' Aniline 7.6-7. gb 2,4- (H0)zCsHsI 5.6' I 8.5-9.5' * Sodium bicarbonate buffer. 5 In sodium carbonate solution. I n sodium hydroxide solution. a Phosphate buffer. e Analysis indicated that a mixture of phenylazophenols was obtained, which could not be readily separated. This compound was 3,5-bis-(phenylazo)-2,4-dihydroxybenzenearsonicacid, obtained with an excess of the diazo solution. We were unable to obtain a phenylazo-2,4-dihydroxybenzenearsonic acid free from the bis compound. 0 A mixture was obtained from which only 2,4-bis-(phenylazo)-resorcinolcould be obtained in a pure state. p-HOCsHc VZ-HOCGHI-
mIToluidine -4niline
4-Hydroxy-3-phenylazobenzenearsonic Acid.-The diazo solution, prepared from 0.93 g. (0.01 mole) of aniline and 0.03 mole of hydrochloric acid was added slowly to a solution of sodium p-hydroxyphenylarsonate (2.94 g. of the trihydrate, 0.01 mole) and 2.52 g. of sodium bicarbonate in 50 ml. of water, maintaining the temperature a t 10". The initial and final PH values were 7.4 and 7.3 (glass electrode). The reaction mixture was stirred for one hour, filtered and the residue washed with 100 ml. of warm lOYo sodium carbonate solution. The insoluble fraction (0.37 g.) was recrystallized from alcohol. Analysis and melting point (131")identified this substance as 2,4-bis-(phenylazo)-phenol. The combined filtrate and washings were acidified to congo red and cooled in the icebox for twentyfour hours. The mixture was filtered, the precipitate washed with 10 ml. of cold water and dried. Arsenic acid was determined in the filtrate as magnesium pyroarsenate. The dry precipitate was extracted with ether and the ether insoluble fraction (0.174 9.) recrystallized several times from water. This substance was identical with the 4hydroxy-3-phenylazobenzenearsonic acid later prepared by the Scheller-Bart reaction. The ether soluble fraction gave p-phenylazophenol (0.78 9.) and 2,4-bis-(phenylazo)phenol (0.15 9.) on fractional crystallization from alcohol. In subsequent reactions it was found advantageous to partially neutralize the diazo solution before coupling. 4-Hydroxy-3-phenylazo-1-naphthdenearsonic Acid.4-Hydroxy-1-naphthalenearsonicacid has been previously described.? The yield has been increased considerably by the following modification. 4-Amino-1-naphthyl benzoate hydrochloride was treated with ammonia to give the free base. It was also obtained by reducing 4nitro-I-naphthyl benzoate in alcohol, employing Raney catalyst. 4-Amino-I-naphthyl benzoate crystallized from aqueous alcohol in plates, m. p. 107.2-107.6". The yield was 95yo by either procedure. Anal. Calcd. for C17HlaNOI: N, 5.32. Found: N, 5.40. The Scheller-Bart reaction applied to this amine gave 4-arsono-1-naphthyt benzoate in 19% yield. It crystallized from aqueous alcohol in plates; m. p. 199.8-200'. Anal. Calcd. for C1,HI&Ob: As, 20.1. Found: As, 19.8. 4-Hydroxy-1-naphthalenearsonic acid
was prepared from this ester by hydrolyzing in methanol solution with dry hydrogen chloride in the cold. The solution was diluted with water, the methyl benzoate extracted with ether and the arsonic acid recrystallized from water. The yield was 57%. 17) Doak, Steinman and Eagle. THIS JOURNAL, 64, 1064 (1942).
Anal. Calcd. for CIOH&SO(: As, 28.0. Found: As, 28.0. The above arsonic acid (9 g.) was coupled with benzenediazonium chloride a t PH 7.1-7.4. After standing for two hours at IO" the mixture was acidified to congo red. The precipitate which formed was dried and extracted with benzene. The benzene insoluble fraction was then extracted with boiling 10% sodium bicarbonate solution. This solution when cooled deposited a small amount of solid which was added to the bicarbonate iusoluble fraction. When the bicarbonate solution was acidified to congo red 4-hydroxy-3-phenylazo-I-naphthalenearsonic acid precipitated (2.51 g.). I t was recrystallized from aqueous alcohol. The benzene soluble fraction (4.0 g . ) , after recrystallizing first from benzene and finally from amyl alcohol, was identified as 2,4-bis-(phenylazo)-l-naphtholby analysis and melting point (190-19lo). The bicarbonate insoluble fraction (2.87 g.), after recrystallizing several times from amyl alcohol was similarly identified as 4-phenylazo-lnaphthol, m. p. 206". J-Amino~-hydroxy-l-naphthalenearsonic Acid.-The preceding azoarsonic acid was converted to the monosodium salt and reduced catalytically, employing Raney nickel. The solution was filtered directly into dilute hydrochloric acid and the arsonic acid which precipitated purified by the method of Christiansen.* It was obtained as white needles which colored rapidly in the air and slowly when preserved in an atmosphere of hydrogen. It decomposed on heating. The yield was 52%. Anal. Calcd. for CIOH&NOI.H~O: As, 24.9. Found: As, 24.4. 3-Hydroxy-l,4,~-naphthisolxazie-6-arsonic Acid.This compound was prepared by the method of Newberry, Phillips and Stickingsg for the corresponding benzene analog, employing chloroacetyl chloride. It crystallized from water in clusters of needles. Anal. Calcd. for Cl&Il,,AsNOs: As, 23.2. Found: As, 22.7. The formation of the cyclic arsonic acid offers considerable evidence for the coupling of 4-hydroxy-1-naphthalenearsonic acid in the 3-position. 2-Hydroxy-5-phenylazobenzenearsonic Acid.-The crude product from the coupling of o-hydroxybenzenearsonic acid and benzenediazonium chloride was purified through the magnesium salt and finally by recrystallizing from water. It was reduced catalytically, employing
______
(8) Chrietianscn, ibid., 0,2402 (1920). (9) Newberry, Phillips and Stickiogs.J . Chrm. Sac., 3051 (lQ28).
Feb., 1944
ARSONICACIDSAND ARSENOSOCOMPOUNDS CONTAINING THE Azo LINKAGE
199
TABLE I1 ARSONIC ACIDS AND ARSENOSO COMPOUNDS CONTAINING THE Azo LINKAGE
-
-
Compound Description R Phenylazo, R’ Benzene-arsonic acid 4-Hydroxy-3-R-R’ Orange needles 2-Hydroxy-5-R-R’ Orange needles 5-Hydroxy-2-R-R’ Golden plates 4-Hydroxy-3-R-1-naphthalenearsonic Red needles acid 3,5-Bis-(R)-2,4-dihydroxy-R’ Orange powder P-R-R’ Orange plates Orange needles P-(9-Tolylazo)-R’ Orange needles p-(9-Arsono-R)-benzoic acid Red powder P- (3-Acetamido-4-hydroxy-R)-R’ Red powder 9-(3-Amino-4-hydroxy-R)-R’ hydrochloride
R = Phenylazo, R‘ fi-R’-R-benzene #-(P-R’-R)-phenold 9-R’-2-R-phenol 9-(p-R‘-R)-benzamide
-
M. p., OC.
Yield,
I
290 257.3 237.5 245
40,” 5.9’ 45 65 20
268 332.5-333.5 > 360 > 360 224.8-226,Z Dec.
84 24 41 68 75 70
Formula
Aa analyses,
N analyw,
Calcd. Found
Calcd. Found
%
%
CirHiiAsNSr CinCiiAsNtOi CirHiiAsN201 CisHiiAsNiOd
23.2 23.2 23.2 20.1
22.9 22.7 23.0 19.4
CieHisAsNrOb CizHiiAsNzOa CirHiaAsNzOr CiaHiiAsNnOr CicKirAsNzOr CizHuAsCINnO~
17.0 24.6 23.4 21.4 19.8 20.1
16.2 24.2 23.5 21.5 19.6 19.9
12.7 12.5 9.16 9.30 8.76 8.25 8.01 8.41 11.1 11.1 11.3 11 1
CirHoAsNsO CIZHDASNZOI CiiHBAsNzOz CiiHioAsNaOz Ci1HirAsNsOa~H~0
27.5 26.0 26.0 23.8 19.9
27.6 26.0 25.9 24.8 19.4
10.3 10.4 9 . 7 3 9.73 9.73 9.66 13.3 13.7 11.1 11.1
CiaHizAsNaOsSr2H~O 13.6
13.5
8.70 8.70 8.70
8.70 8.59 8.64 C
Arsenoao
Orange powder 214-214.5 Orange powder > 360 Orange powder 215 Orange powder Chars > 260 p-(p-R’-R)-(N-2-hydroxyethyl)-benz- Orange powder Chars > 275 amide 8-Amino-P-(p-R’-R)-l-naphtho1-3,6-diRed powder > 360 sulfonic acide
74 100 94 88 74 34
7.65
7.72
By the Sheller-Bart reaction. * By coupling. Doak, Eagle and Steinman, THISJOURNAL, 64,1064 (1942), footnotee to Table I. The corresponding arsonic acid was prepared by the method of Barrowcliff, Pyman and Remfry, J . Cltem. SOC.,93, 1893 (1908). e The corresponding arsonic acid was prepared according to German Patent 212,018, Raiziss and Gavron, “Organic Arsenical Compounds,” Chemical Catalog Co., 1923, p. 286. Raney nickel, and the resulting 6-hydroxy-m-arsanilic acid benzenearsonic acid, when oxidized with potassium perreduced in hydrochloric acid solution t o 4-amino-2- manganate gave $-(p-arsonopheny1azo)-benzoic acid. dichloroarsinophenol hydrochloride, m. p. 183-183.4’. The recrystallized compound, suspended in chloroform, Anal. Calcd. for CsH,AsCIaNO.H20: As, 24.3; N, was treated with phosphorus tri- and pentachlorides and the clear orange solution added to aqueous ammonia. 4.54. Found: As, 24.3; N, 4.61. This compound was identical with the compound pre- p-(p-Arsenosopheny1azo)-benzamide precipitated from pared by the reduction of an authentic sample of 6- this solution. No satisfactory means of purifying this hydroxy-m-arsanilic acid, thus establishing that o-hydroxy- compound was found. p-(p-Arsenosophenylazo) -( N-2-hydroxyethyl) -benzbenzenearsonic acid coupled in the 5-position. amide was obtained in a similar manner by using an 5-Hydroxy-2-phenylazobenzenearsonic Acid.-The crude reaction product from the coupling of m-hydroxy- aqueous solution of 2-aminoethanol instead of ammonia. 4-Hydroxy-3-phenylazobenzenearsonic Acid.1a-This benzenearsonic acid and benzenediazonium chloride was purified by dissolving in warm sodium bicarbonate solu- comuound was prepared from the Scheller-Bart reaction tion and precipitating with acid. It was finally recrystal- applied to 4-amino-2-phenylazophenol. This latter comlized several times from water. This was similarly reduced pound was obtained by a slight modification of the method of W0roshzow.1~ The Scheller-Bart reaction was unsucto 5-hydroxy-o-arsanilic acid which gave S-amino
