Research Proposal for Synthesis of Sulfanilamide

I propose to synthesize sulfanilamide, one of a class of sulfa drugs used as antibacterial agents (1). I will begin the synthesis with nitrobenzene, a chemical that is in stock in the laboratory. The reaction mechanism for synthesis of sulfanilamide from nitrobenzene can be found in appendix. I will need the following chemicals. Also listed are the location of the chemicals in the lab, the quantities needed of each chemical for myself and for the group as a whole, the amount available in the lab, safety protocols, and clean-up and disposal procedures. Tin powder (20 mesh), located on shelf #11 in the stock room, 250 grams available, 150 grams needed for myself, 1.5kg needed for the group, need to order more. Wear gloves and goggles when handling, and approved NIOSH respirator may also be used, dispose of in trash. See MSDS for additional safety information. Chlorosulfonic acid 97%, located in the acid cabinet in the stock room,800mL available, 37.5mL needed for myself, 375mL needed for the group, wear gloves, goggles, and smock when handling and use extreme caution, and conduct reaction under hood, be careful not to let it come in contact with water, as it is highly reactive with water producing HCl. In case of spill neutralize with sodium bicarbonate then dispose of in trash, sink. If any is inhaled or touches your skin, neutralize with sodium bicarbonate immediately. See MSDS for additional safety information. Zinc powder (20 mesh), located on shelf #11 in the stock room, 250 grams available, 0.1 grams needed for myself, 1 gram needed for the group, wear gloves and goggles when handling, dispose of in trash. See MSDS for additional safety information. Nitrobenzene 99%, located in the flammable cabinet in the stock room, 1 2/3 L available, 65mL needed for myself, 650mL needed for the group, wear gloves and goggles when handling, keep under hood at all times, nitrobenzene is flammable, keep away from open flames, in case of contact with skin, flush area with water. Dispose of in non-halogenated waste container. See MSDS for additional safety information. Acetic anhydride, located in acid cabinet in the stock room, 250 mL available, 37.2mL needed for myself, 372 mL needed for the group, need to order more. Wear gloves and goggles when handling, and approved NIOSH respirator may also be used, dispose of in trash. See MSDS for additional safety information.

Sodium Acetate, located on shelf #16 in the stock room, 15/6 lbs. available, 31.8 grams needed for myself, 381g needed for the group. Wear gloves and goggles when handling. Dispose of in trash. See MSDS for additional safety information.

Hcl 12 Molar, located in the acid cabinet in the stock room, 1 L available, 372 mL needed for myself, 3.72 L needed for the group, need to order more. Wear gloves and goggles when handling, use under the hood to avoid inhalation, be very careful not to spill. If a spill occurs neutralize with sodium bicarbonate, HCl can burn skin quickly, if exposed to skin, neutralize area immediately and wash off. Neutralize with sodium bicarbonate and dispose of in sink. See MSDS for additional safety information. Ammonium Hydroxide, located in the hood, 1 L available, 90 mL needed for myself, 0.9 L needed for the group. Wear gloves and goggles when handling, corrosive do not allow to contact skin. In case of skin contact, flush area with water. For spills, dilute with water or neutralize with acetic acid and dispose of in sink. See MSDS for additional safety information. Sodium Hydroxide, located on shelf #16 in the stock room, 1 lb. available, 240 grams needed for myself, 2.4kg needed for the group, need to order more. Wear gloves and goggles when handling, corrosive do not allow to contact skin. In case of skin contact, flush area with water. For spills, dilute with water or neutralize with acetic acid and dispose of in sink. See MSDS for additional safety information. Sodium Bicarbonate, located on the lab bench, 0 lbs. available, 100 grams needed for myself, 1kg needed for the group, need to order more. Safe to handle, use to neutralize clean up acid spills, dispose of in trash. See MSDS for additional safety information.

Equipment Needed: 800mL beaker for ice bath

500mL round bottom flask 100 mL round bottom flask Buchner funnel and filter flask Filter paper Drying tube/condenser tube with inlet and outlet 3-way adapter Claisen adapter rubber stoppers rubber tubing litmus paper IR spectrometer IR spectroscopy sample press Erlenmeyer flask nest from lab drawer Glass stir rod metal spatula heating plate graduated cylinders 10 and 50 mL Theoretical Yield: Nitrobenzene MW=123.11 Aniline MW=93.12 Acetanilide MW=135.16 p-Acetaminobenzenesulfonyl chloride MW=233.68 p-Acetaminobenzenesulfonamide MW=214.25 Sulfanilamide MW=172.20 (3) Assuming a yield of 40%: 123.11g/mol / 12g Nitrobenzene = 0.0975 moles 0.0975 mol Nitrobenzene (40% yield)=0.0390 moles Aniline 0.0390 moles Aniline (40% yield)=0.0156 moles Acetanilide 0.0156 moles Acetanilide (40% yield)=0.0062 moles p-Acetaminobenzenesulfonyl chloride 0.0062 moles p-Acetaminobenzenesulfonyl chloride (40% yield)=0.0025 moles pAcetaminobenzenesulfonamide 0.0025 moles p-Acetaminobenzenesulfonamide (40% yield)=0.0010 moles Sulfanilamide 172.20 g/mol * 0.0010 moles Sulfanilimide = 0.172g In order to get 1 gram of Sulfanilamide, I will have to multiply the suggested quantity of Nitrobenzene by about 6, the procedure will reflect this.

Experimental Procedure: Synthesis of Aniline 1. Prepare an ice-water bath. 2. Place 150 g granulated tin and 72.0 g nitrobenzene in a 500 mL round bottom flask. 3. Add 330 mL HCl, slowly, to round bottom flask, insert thermometer, and swirl to mix. 4. Allow reaction to proceed for ~ 20 min. while keeping temperature between 5560C by using the ice-water bath. 5. Remove thermometer, rinse it with water, and fix flask with a reflux condenser, see appendix for setup. 6. Transfer mixture to 100mL round bottom flask, heat reaction mixture using a heating mantle for ~ 15 min. 7. Meanwhile, dissolve 240 g NaOH in 600 mL water and cool to room temperature. 8. When the refluxing reaction mixture no longer has visible droplets of nitrobenzene and a discoloration from the reaction intermediatesremove the heat source and cool the mixture on ice. 9. Slowly add the NaOH solution to the cooled reaction mixture. 10. Steam distill using internal steam distillation and collect 600-720 mL distillate in an Erlenmeyer Flask, see appendix for setup. (Obtain an estimate of distillate volume, by comparing with an identical flask filled with the same amount of water.) Synthesis of Acetanilide 11. Meanwhile, prepare a solution of 31.8 g anhydrous sodium acetate in 180 mL water. 12. Add 27 mL conc. HCl to the aniline distillate and mix using a magnetic stirrer. 13. Add 37.2 mL acetic anhydride to the mixture and then immediately add the sodium acetate solution. 14. Stir the solution for several minutes, cool on ice, and collect the product. 15. Transfer product to a tared flask and allow to dry. 16. When dry, determine melting point and obtain an IR spectrum, see appendix. Synthesis of Sulfanilamide. 1. Melt the acetanilide product, which is still in the flask, and swirl until an even layer of acetanilide covers the bottom surface of the flask. 2. Perform the next series of events in the hood and use gloves. 3. Cool flask on ice and slowly add chlorosulfonic acid (12.5 mL for every 5.0 g of acetanilide). 4. Swirl flask to promote the reaction. 5. Remove from ice-water bath and swirl. 6. If reaction begins to proceed vigorouslyplace back into ice-water bath. 7. When the reaction subsides (5-10 min) there will be a few lumps of acetanilide still remaining. 8. Now, heat the mixture for about 10 minutes, in order to complete the reaction. 9. Cool the flask under a stream of water (under the tap).

10. Transfer the solution dropwise into a beaker containing 75 mL ice water, which is also being cooled in an ice-water bath. 11. Rinse the flask with cold water and stir the precipitated product until an even suspension of granular white solid is obtained. 12. Collect and wash the solid on a Buchner funnel, see appendix for setup. 13. Press and drain the filter cake, then transfer the solid to the rinsed flask. 14. Add 30 mL conc. aqueous ammonium hydroxide for every 5.0 g acetanilide. 15. Heat the mixture (just below boiling) with occasional swirling for ~ 5 min. 16. Note a change in appearance of the mixture. 17. Cool the suspension in an ice bath and collect the product. 18. Dry your sample as thoroughly as possible. 19. Transfer the moist amide product back into the reaction flask and add 5 mL HCl and 10 mL water (for every 5.0 g acetanilide). 20. Gently boil the mixture until the solid has dissolved (5-10 min)then heat at the boiling point for another 10 minutes (do not evaporate to dryness). 21. Cool solution to room temperature (if there are any solids left, continue heating the sample) and add a pinch of decolorizing charcoal and filter. 22. Transfer solution to a beaker and add aqueous sodium bicarbonate until the solution is neutral. 23. Cool mixture on ice and collect product. 24. Recrystallize product using ethanol. 25. Determine melting point and obtain an IR spectrum, see appendix. (2)

Bibliography 1.

Brewster, Ray Q., McEwen, William E., and Vanderwerf, Calvin A. United Experiments in Organic Chemistry 2nd ed.; D. Van Nostrand Company, Inc.: Princeton, NJ, 1964 2. Fieser, Louis F. and Williamson, Kenneth L. Organic Experiments, 5th ed.; D. C. Heath and Company: Toronto, 1983 3. Hodgman, Charles D. editor-in-chief. Handbook of Chemistry and Physics, 42nd ed.; The Chemical Rubber Publiching Company: Cleveland, Ohio, 1960 4. McMurry, John. Organic Chemistry, 7th ed.; Thomson Brooks/Cole: United States, 2008 5. Zubrick, James W. The Organic Chem Lab Survival Manual, 6th ed.; John Wiley and Sons, Inc.: HVCC, 2004