A SYNTHESIS OF BIS(pAMIN0PHENYL) SULFONE FOR LABORATORY CLASSES ROBERT E. BUCKLES The State University of Iowa, Iowa City, Iowa
A THREE-STEPsynthesis of bis(p-aminophenyl) sulfonel bis(p-nitrophenyl) sulfide. The procedure used is a from p-chloronitrobeneene has been devised on a fairly modification of one already de~cribed.~The reaction is amall scale for laboratory classes in beginning organic of particular interest since it demonstrates the ab'ity chemistry. This compound and some of its derivatives of the m-directing nitro group to activate the chloride in the p-position for a displacement process by the -particularly diasone2 (I) and promins (11)-have selective withdrawal of part of the electronic distribeen of interest in chemotherapy for some t i e . bution from the o- and p-positions of the ring. Another interesting and instructive feature of the reaction is that the sulfide ion also acts as a reducing agent so that some of the nitro groups are reduced and highly colored polysulfide ion is formed. A by-product, paminophenyl p-nitrophenyl sulfide,which is the result of such a reduction, can be isolated from the reaction mixture. The isolation of the main product is complicated by the presence of the startingmaterid in the reaction mixture. Their use in the treatment of leprosy has been par- Careful crystallization from acetic acid yields a good ticularly successful, and they have shown some promise crop of crystals, and it is possible to isolate a fair second in tuberc$osis therapy. crop from the mother liquor. The first stev of the synthetic series involves the The second step involves the oxidation of bis(p displacement o i a chloride ion from kaih of two mole- nitrophenyl) sulfide to bis(p-nitrophenyl) sulfone. The cules of p-chloronitrobenzene by a sulfide ion t o form use of sodium hypochlorite in acetic acid for the oxidation as suggested by Weijlard and Messerlyqeads to I This compound has often been designated DDS, yhich is an abbreviationof the name diaminodiphenyl sulfone., GAREL,Y. O.,AND A. L. S a ~ m ~ o ~ , ' Z k u r . ~ P r i k lKhim., ad. 9 Rnrz~ss,G. W., L. W. C ~ K E N C m E ,o M.FREI&LDER, J.Am. P k a m . Assoc., Sci. Ed., 3 3 , 4 3 5 (1944). 8 JAIN, B. C.,,B. R. IYER,AND P. C. G m , Science and C u h r e , 11,568 (1946).
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Chem. Abstracts, 34, 6244 (194I37. WEISLARD,J., AND J. P. MESSERLY, ULS. P ~ h2,385,899, t Oct. 2, 1945; Ckem. Abstracts, 40, 180 (1946). '.
' 12, 1485 (1939);
JANUARY. 1951
virtually quantitative yields of the nitro sulfone. The preparation melts with decomposition around 262" on the Maquenne block. I n fact melting points given in the literature6 ' vary from 225' t o 290'. The nitro sulfone is reduced without further.purification by the action of stannous chloride in concentrated hydrochloric acid. This method was much faster and more clean-cut than those using iron and hydrochloric acid which have been described6for this reduction. The reaction series is very useful for illustrating some of the most important chemical properties of organic compounds containing sulfur. The preparation of either sulfhydryl compounds or sulfides is usually accomplished by a displacement process on a halide involving hydrosulfide ion, sulfide ion, or a mercaptide ion. Such a reaction is demonstrated in the first step of the present series. The type of oxidation reaction peculiar to organic compounds containing sulfur in a relatively reduced form is illustrated in the oxidation of the sulfide to the sulfone. The third step demonstrates the resistance to reduction of sulfur in the oxidized form characteristic of sulfones. Students in the beginning organic laboratory who had completed a t least a semester of the course had no particular difficulty in carrying out the three-step sequence. Of the 150 students who did the experiment none failed to obtain a yield of the final product the first time through. PROCEDURE
Bis(p-nitrophenyl) Sulfide. Set up an apparatus which consists of a 125-ml. Erlenmeyer flask fitted with a short reflux condenser. At the top of the reflux condenser fit a 60-ml. separatory funnel inserted in a cork with a groove cut along its side so that the interior of the apparatus will be open to the atmosphere. Add 12.6 g. of p-chloronitrobenzene (practical grade is satisfactory) and 50 ml. of isopropyl alcohol to the flask. Add a boiling chip and heat the mixture on a steam bath or a water bath. When the solution starts to boil gently, start t o add 24 ml. of 2.5 M sodium sulfide dropwise from the separatory funnel. The total addition should take about half an hour. The mixture will turn dark because of the formation of polysulfide ion soon after the reaction is started. Boil the reaction mixture gently for two hours after the addition of the sodium sulfide is completed. Place about 300 ml. of cold water in a 400-ml. beaker and pour in the reaction mixture with stirring. Stir until the precipitate is coagulated. Filter the solid and wash with 100 ml. of cold water. Mix the solid thoroughly with 120 ml. of 1 N hydrochloric acid in a 250-ml. beaker. Filter the mixture and wash the solid with 20 ml. of cold water. The filtrate should be saved for the isolation of the by-product, p-aminophenyl pnitrophenyl sulfide. H., AND W. A. DAVY,J. Chem. Soc., 1946, 542; MATSUKAWA,T., B. OXTA,mdT. IMAM, J. Pham. Soc. Japan, 70, 77 (1950). "B~TON,
Recrystallize the solid from 50 ml. of glacial acetic acid. Wash the product with 20 ml. of isopropyl alcohol. About 3 g. (14 per cent) of bis(p-Ntrophenyl) sulfide, m. p. 154-6°,7 was obtained a t this point in several sample experiments. The m. p. reporteds is 156-7". Treat the mother liquor with 300 ml. of water. Recrystallize the crude crop of crystals from 50 ml. of isopropyl alcohol. I n several experiments the yield of this second sample of product was about 3 g. (14 per cent) with a melting-. ~ o i n2t to 3" lower than that of the first product. p-Aminophenyl p-Nitrophenyl Sulfide. Neutralize the acidic solution which was obtained when the crude bis(v-nitro~henvl) sulfide was digested with hvdroc h l k a&, wl'th 6 N ammonium hydroxide. Filter the yellow p-aminophenyl pnitrophenyl sulfide. Several experiments gave about 0.8 g. (4 per cent) of product of m. p. 142A0, which checks that r e p ~ r t e d . ~ Bis(pnitropheny1) Sulfone. Fit a 125-ml. Erlenmeyer flask with a reflux condenser to which is connected a glass tube leading to but not touching the surface of some 1 N sodium hydroxide contained in a flask. Then any chlorine gas coming from the reaction mixture will be absorbed by the basic solution, but none of the solution can be sucked into the reaction flask. Add 1.0 g. of bis(p-nitrophenyl) sulfide and 30 ml. of glacial acetic acid to the flask and heat until the solid dissolves. Remove the exit tube from the top of the reflux condenser long enough t o pour 20 ml. (21.1 g.) of 5.25 per cent sodium hypochlorite (commercial laundry bleach) down the condenser. Boil the reaction mixture for half an hour and then add 2 ml. of isopropyl alcohol to destroy the chlorine and the excess hypochlorous acid. Cool the solution and add 50 ml. of cold water. The product obtained by filtration is used directly in reduction to bis(p-aminophenyl) sulfone. A yield of 1.1 g (99 per cent) of bis(p-nitrophenyl) sulfone, m. p. 262' with decomposition on the Maquenne block, was obtained in several sample experiments. Bis(p-aminophenyl) Sulfone. Add the crude bis(pnitrophenyl) sulfone, either moist or dry, to a warm solution of 6 g. of stannous chloride dihydrate in 5 ml. of concentrated hydrochloric acid in a 125-ml. Erlenmeyer flask. Boil the mixture under reflux for about 15 minutes. At the end of this time all solid should be dissolved. Add 20 ml. of water, and then carefully add a solution of 8 g. of solid sodium hydroxide in 20 ml. of water. Filter the solid and wash thoroughly with water. Dissolve the product in 25 ml. of hot isopropyl alcohol, treat with decolorizing carbon, filter, and add 50 ml. of hot water to the filtrate. Cool slowly t o obtain the crystals. Several experiments yielded about 0.4 g. (45 per cent) of bis(p-aminophenyl) sulfone, m. p. 1744", which checks well with that reported.1° All melting points were corrected, See footnote 6. See footnote 4. lo See footnote 6. 8
