Norman C. Rose
and Sanford Rome Portland State University Portland, Oregon 97207
Preparation of 6-Aminosaccharin A multistep synthesis
Students particularly enjoy preparing compounds that they use or encounter in their everyday living. It was hoped initially that a procedure, suitable for the organic laboratory, for the preparation of saccharin might he developed. However, the first step, the chlorosulfonation of toluene, is a reaction that, yields a mixture of o- and ptoluenesulfonyl chloride that is difficult to separate and that gives the desired ortho isomer in low yield. The preparation of 6aminosaccharin does not have the disadvantage of these difficulties, does have relevant associations f& the student, and employs a number of useful reactions and concepts. The synthesis involves the substitution of a chlorosulfonyl group onto an aromatic ring at a pdsitiou predictable on the basis of the directing ability of the groups already present, the oxidation of a methyl group, a cycliaation that is an example of the ease with which five-membered rings are formed, and the reduction of a nitro group. Noyes first prepared 6-amiuosaccharin by converting p-nitrotoluene to 5-nitro-o-toluenesulfonyl chloride and then to 5-nitro-o-toluenesulfonamide, I, (1). Oxidation of I by means of alkaline potassium permanganate acid, 11,which in turn gave Pnitro-2-s~~lfamoylbensoic
was cycliaed to 6-nitrosaccharin, 111, by adding hydrochloric acid to a hot, concentrated solution of the potassium salt of I1 or by maintaining I1 a t a temperature above its melting point (1, 2). Reduction of I11 to 6aminosaccharin, IV, was done with ammonium sulfide (1).
cro, + n,soSO.
O
8
0 1
Y
"0n
SO,NH, 3 WOH .a
0
III
pw.3 H>N@~?~H
o N
Other workers have used the procedure of Noyes to prepare I1 (3, 4). Loev and Kormendy, however, re~ o r t e dthat in their hands the permanganate oxidation
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of I gave quite low yields of I1 (5). Low yields of I1 were also obtained in this laboratory under a variety of conditions and with a variety of modes of addition. In our procedure the preparation of I is based upon the experimental directions of Ullmann and Lehner (6). The organic material from the reaction is taken up in ether. The ether layer is stirred very vigorously while the ammonium hydroxide is added. The heat of the reaction causes the ether to boil and the solution to froth. For this reason, a beaker of a t least 250 ml capacity should be used. During the addition or shortly thereafter, the amide precipitates as it is only slightly soluble in ether. Unreacted p-nitrotoluene remains in the ether. The product is washed with water to remove any residual ammonium hydroxide. The additional washings with ethanol and ether will enable one to dry the product rapidly and are only necessary if the product is to be used immediately after its preparation. The oxidation and cyclization of I to yield I11 is possible in one step and in good yield if a mixture of chromic trioxide and sulfuric acid is used as the oxidizing agent (7). It is essential that the oxidation be carried out a t a temperature of 65'C or higher. The temperitwe is kept in the range of 65-7O0C by the rate of addition of the chromic trioxide. If the temperature does go below 65'C, it must be raised before further additions of chromic trioxide are made. The presence of the potassium hydroxide during the reduction of the nitro group increases the solubility of the F-nitrosaccharin in the aqueous solution by converting the imide nitrogen to its potassium salt. Once the reduction starts, care must be taken not to rush the reduction or the yield will be reduced. The two traps are necessary to prevent the ammonium sulfide from getting out of the system. The 5-nitro-o-toluenesulfonamide and 6-nitrosaccharin are used without further purification. Practical p-nitrotoluene and chlorosulfonic acid and technical chromic trioxide have proved satisfactory. The complete sequence takes 6-7 hr. The preparation of 5-nitro-o-toluenesulfonamide requires 2-3 hr. Average yields of the different products are for I 3.56.0 g, 2040%; for I11 24-3.2 g, 50-90%; and for IV 1.0-1.6 g, 55-90%. The yields of I11 and IV depend upon the care with which the student follows directions. 6-Nitrosaccharin has an initial sweet taste followed by a bitter after taste; fiaminosaccharin has a sweet taste. The sequence can be extended to include a study of the per cent of ortho, meta, and para isomers formed during the nitration of toluene. The analysis of the reaction mixture is done by vapor phase chromatography. Directions for such a study have been given by Dannley and Crum (8). The Experiment PreparaLion of 6-Nilr&olunesdfmarnide (I). Add 18 ml (30 g, 0.15 mole) chlorosulfonic acid to 10 g (0.073 mole) pnitrotoluene contained in a round-bottom flask equipped with a condenser. Place the flask in water that has previously been
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heated to boiling and heet for I/, hr. Cool the reaction flmk well in an ice bath. While working in a hood, carefully pour the reaction mixture into 100-150 ml of ice. Stir the ice rapidly during the addition. Extract the resulting mixture with 50 ml ether. While stirring the ether layer very vigorously in a beaker of s t least 250 ml capacity, add 25 ml concentrated ammonium hydroxide. Continue the stirring until a. tan solid forms. Remove the solid by suction filtration. Wash the precipitate with 25 ml cold ether, and 50 ml cold water. (Unreacted p-nitrotoluene may precipitate in the filtrate during the course of washing the precipitate.) Dry the solid in air. (If the product is to be used immediately in the next step, use the wash procedure outlined above and then in addition wash the precipitate with cold, 95% ethanol and cold ether and air dry.) Yield is 3.5-6 g. The crude product which may have black particles in it is used in the next step. The sulfonamide may be recrystallized from water. Lit. mp 186-187T (I). P~epamLionof 6-Nit~osaccharin(111). Add 4.3 g (0.02 mole) dry 5-nitro-o-toluenesulfonamide to 25 ml concentrated sulfuric acid contained in a dry beaker of at least 250 ml capacity. Heat to 65°C. While stirring the acid solution, add 6 g chromic triovide in small portions at such a. rate that the temperature is msintained between 65-70%. It may be necessary attimes to cool the reaction mixture or to heat it to maintain the desired temperature range. Do not add chromic trioxide unless the temperature is at least 65°C. Stir the mixture during the entire period of addition (2&30 min). During the addition the reaction mixture turns green, becomes very viscous, and foams due to the relesse of a gas. When the addition is complete, stir for an additional ten minutes at 65-70°C and cool in an ice bath. Pour the cold reaction mixture into 100 ml of water. Filter with suetion. Wash the precipitate well with cold water. About 2-3 g of solid 6-nitrosaccharin is obtained. Taste the solid. The crude product is used in the next step. The product can he recrystallized from water. Lit. mp 209°C ( I ) . Preparation of 6-Aminosaccharin (IV). A 100-ml distilling apparatutus is fitted with a. thermometer that reaches nearly to the bottom of the distilling flask, a condenser and an adapter that goes into a small flask used as a trap. All connections must be air tight. Dilute sodium hydroxide solution is placed in the trap to trap hydrogen sulfide. A second trap containing dilute hydrachlorio acid to trap ammonia is attached to the first trap. Place 0.6 g potassium hydroxide, 10 ml water, 2.1 g (0.92 male) 6-nitrosaccherin, and 15 ml ammonium sulfide, 207& light, in the distilling flask. Heat until sulfur begins to farm in quantity. The temperature of the reaction mixture will bc approximately 9S°C. Carefully maintain the temperature within a two degree range, i.e., approximately 9,&97"C, for a. couple of minutes. Raise the temperature until the mixture distills. The quantity of liquid remaining becomes very small, and the contents of the flask begin to spatter within the flask (the temperature of the reaction mixture will be around 103-105'C); stop the distillation. During the distillation, the bulb of the thermometer is kept near the bottom of the flask in the reaction mixture. Cool the disiilling flask. Add 10 ml water to the distilling flask, heat to boiling, and filter the hat solution. Wash the precipitate twice with 5 ml hot water. Add concentrated hydrochloric acid to the filtrate to precipitate the 6-aminosaccharin. Cool the solution to room temperature, filter by suction, and wash the precipitate well with cold water. Dry. Taste the product. The product may be recrystallized from water. Lit. mp 2 7 9 T (9).
Literature Cited (1) Norzs, W. A,, Am. Chcm. J., 8,167 (1886). (2) N o r m W. A,. AND W1ra;r. W. B.. Am. Chcm. J.. 11. 161 (1889). C.. A N D COLONNA, M., 0 0 s ~ Chim. . Ilal., 68, 132 (1938). (3) FINZI, 14) SzA80. L.. Bull. Sac. Chim. Froncs. 771 119.53). isi L O E V . B . , ' A N D KORMENDT, M..J.'OW. c h & i 27.2177 (1962). (6) ULLMANN. F.. A N D LEHNER, A,, Chsm. Be?., 38,729 (1905). (7) ROBE.N. C., J . Helero. Chsm., 6,745 (1969). (8) DANNLBI. R. L.,AND CROM.I. D.. "Exoerimental Organia Chemistm: T h e Maomillan Company, New York, 1968, D. 329.
