Introduction: Procedure: Step 1

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1 Honors Cup Synthesis Proposal [231-HC-III] Section: 231 (HC-III) Groups Members: Henry Kuang, Holly Williams, Amy Branam, and Eric Jacobstein Title: Synthesis of Sulfanilamide Introduction: Shown above is the mechanism for the synthesis of sulfanilamide, a process which is detailed in the following procedure. Sulfanilamide is an antibacterial drug that blocks the growth of bacteria by interfering with the synthesis of folic acid. It was commonly used during WWII to prevent infection of wounds, but due to its toxicity, it is no longer used except against urinary-tract infections, malaria, and preventing infection of burns. Its antibacterial properties were discovered by Gerhard Domagk and Jacques and Therese Trefouel in Domagk went on to win the Nobel Prize for his work. Procedure: Compound Molecular Formula Boiling Point (ºC) Melting Point (ºC) Density (g/cm 3 ) Solubility in H 2 O g/100ml at 20ºC Acetanilide C 6 H 5 NH(COCH 3 ) Chlorosulfonic acid HSO 3 Cl N/A Water H 2 O N/A Ammonium hydroxide NH 4 OH /0.88 Soluble Hydrochloric acid HCl Sulfanilamide C 6 H 8 N 2 O 2 S N/A Sodium carbonate Na 2 CO Step 1 1

2 Safety Precaution: This reaction step should be carried out under anhydrous conditions as chlorosulfonic acid reacts violently with water. If chlorosulfonic acid should come into contact with your skin, wash immediately with cold water and follow with a rinse using a 5% NaCO 3 solution. Setup: Greasing joints, connect a Claisen adapter to a 50mL round bottom flask. Attach a reflux condenser to the side arm and, using an appropriate size adaptor, connect a separatory funnel to the arm directly above the round bottom flask. The round bottom flask should be set in an ice-water bath to control the reaction rate. (See Figure 1 for illustration) Figure 1: Setup Add g of acetanilide to a 50mL round bottom flask along with a medium-sized magnetic stirring bar. Carefully add 10mL of chlorosulfonic acid into the separatory funnel, ensuring that the stop-cock is closed and the nozzle of the separatory funnel is pointed directly towards the acetanilide. Quickly add the chlorosulfonic acid and begin stirring the reaction mixture. The mixture should darken as the reaction proceeds. After the acetanilide is completely dissolved, allow the reaction mixture to warm to room temperature. Proceed to briefly heat the mixture to ~60 O C for approximately 15 minutes before recooling to room temperature. Add 40g of ice to a 250mL beaker and slowly pour the reaction mixture into the beaker. Rinse the round bottom flask with ice water and pour this into the beaker as well. A white precipitate should form. Collect precipitate by vacuum filtration, washing the solid with small amounts of ice water two or three times. Theoretical Yield: ~85% Step 2 Transfer the N-acetylsulfanilyl chloride (collected from step one) into a 125mL Erlenmeyer flask and add 10mL of ammonium hydroxide. Heat reaction mixture in a sand bath for 30 minutes. Caution: Ammonia vapors will evolve over the course of the reaction, so the reaction must be carried out in the fume hood. After cooling the reaction mixture in an ice-water bath, collect N-(4-sulfamoylphenyl)acetamide through vacuum filtration. Again, wash the precipitate with icewater to ensure purity and dry precipitate completely. Theoretical Yield: ~80% Step 3 Set-up: Attach a reflux condenser to a 25-mL round bottom flask. Transfer N-(4-sulfamoylphenyl)acetamide into a 25-mL round bottom flask with a medium-sized magnetic stir bar. Combine 2mL of concentrated HCl with 2mL of distilled HOH and add mixture to the round bottom flask. Heat the reaction mixture on low heat under reflux for 45 minutes. Cool reaction mixture to room temperature and add one equivalent of distilled water to the cooled mixture. Slowly add a small amount of CaCO 3 to the reaction mixture. A 2

3 precipitate should form as the solution neutralizes. To ensure maximum precipitation, cool reaction flask in an ice-water bath for five or ten minutes. Using vacuum filtration, followed by two ice-water washes, collect the precipitate. Recrystallization: Dissolve sulfanilamide in the minimum amount of hot water needed and filter through a preheated funnel (this prevents recrystallization of product and removes impurities). Cool the resulting solution and allow the product to re-precipitate out of solution. Finally, use vacuum filtration to recover the pure product. Theoretical Yield: ~80% Safety, Disposal, & Green Issues: Acetanilide: Corrosive, irritant slightly flammable and moderately toxic. Avoid contact with skin and eyes. Do not inhale or swallow. May cause cyanosis. Chlorosulfonic Acid: Corrosive liquid and irritant. Avoid contact with skin and eyes and do not inhale. Quench acid with HOH before disposing in the Aqueous Acid disposal jar. Ammonium Hydroxide: Corrosive, irritant, and very toxic. Avoid contact with skin and eyes. Do not inhale or swallow. Dispose in Aqueous Base disposal jar. Hydrochloric Acid: Poison. Corrosive and irritant. Do not inhale or swallow and avoid contact with skin and eyes. Dispose of in Aqueous Acid disposal jar. Sodium Carbonate: Corrosive and irritant. Do not inhale or swallow and avoid contact with skin and eyes as this may cause eye burns. Dispose in Aqueous Base disposal jar. Sulfanilamide: Corrosive and irritant. Avoid contact with skin and eyes. Do not inhale or swallow. May also cause cyanosis. Budget: Chemical Price Amount Total Cost Source Product No. Acetanilide $33.60/250g g $0.10 Fluka 400 Chlorosulfonic Acid $28.80/100mL 10mL $2.88 Fluka Ammonium hydroxide $53.30/100mL 10mL $5.33 Sigma- Aldrich (28% in HOH) Hydrochloric Acid $42.70/100mL 2mL $0.85 Fluka Solid Sodium Carbonate $53.80/500g 2g $0.22 Sigma- Aldrich Total Cost per Synthesis: $9.38 3

4 References: Step One: 1. Galat, A. Ind. Eng. Chem. 1944, 36, Luk yanov, A. V. Khim. Farm. Zh. 1982, 16, Baine, O. J. Chem. Educ. 1939, 16, 278. Step Two: 1. Hurdis, E. C.; Yang, J. W. J. Chem. Educ. 1969, 46, Shumov, V. N.; Shramova, Z. I.; Shemeryankin, B. V.; Voronin, V. G.; Kuzina, N. G.; Panfilova, Z. A.; Yudin, A. K. Khim. Farm. Zh. 1977, 11, Stewart, J. J. Chem. Soc., 1922, 121, Step Three: 1. Empfield, J. R.; Mayhugh, D.; Ohnmacst, C. J.; Frank, C. A.; Grant, T.; Li, J. Bioorg. Med. Chem. Lett. 1997, 7, Blank, B.; Farina, F. A.; Kerwin, J. F.; Saunders, H. J. Org. Chem. 1961, 26, Supplemental Information: Estimations courtesy of SDBS database (with illustrations via ChemBioDraw). Figure 1: Acetanilide 1 HNMR Shifts at: δ7.79(1h, broad singlet), δ7.49(2h, d), δ7.30(2h, t), δ7.10(1h, t), δ2.138(3h, s) Figure 2: Acetanilide 13 CNMR Shifts at: δ169.48(1c, s), δ138.17(1c, s), δ128.77(2c, d), δ124.23(1c, d), δ120.39(2c, d), δ24.18(1c, q) 4

5 Figure 3: Sulfanilamide 1 HNMR Shifts at: δ7.45(2h, d), δ6.86(2h, broad singlet), δ6.59(2h, d), δ5.76(2h, broad singlet) Figure 4: Sulfanilamide 13 CNMR Shifts at: δ (1C, s), δ129.99(1c, s), δ127.35(2c, d), δ112.41(2c, d) 5