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 1935. Domagk went on to win the Nobel Prize for his work.
Procedure:
Compound
Acetanilide
Chlorosulfonic acid
Water
Ammonium hydroxide
Hydrochloric acid
Sulfanilamide
Sodium carbonate
Molecular Formula
C6H5NH(COCH3)
HSO3Cl
H2O
NH4OH
HCl
C6 H8 N2 O2 S
Na2CO3
Boiling Point
(ºC)
304
151-52
100
37.7
48
N/A
1600
Melting
Point (ºC)
113.7
-80
0
-91.5
-27.32
165
851
Density
(g/cm3)
1.219
1.753
0.995
0.91/0.88
1.18
1.08
2.54
Solubility in H2O
g/100mL at 20ºC
0.4
N/A
N/A
Soluble
62
7.5
22
Step 1
1
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% NaCO3 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 0.7214g 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 ~60OC 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 CaCO3 to the reaction mixture. A
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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:
Amount 0.7214g 10mL 10mL 2mL Total Cost $0.10 $2.88 $5.33 $0.85 2g $0.22 Chemical Acetanilide Chlorosulfonic Acid Ammonium hydroxide (28% in HOH) Hydrochloric Acid Solid Sodium Carbonate Price $33.60/250g $28.80/100mL $53.30/100mL $42.70/100mL $53.80/500g Source Fluka Fluka Sigma-­‐Aldrich Fluka Product No. 400 26388 338818 84415 Sigma-­‐Aldrich 57795 Total Cost per Synthesis: $9.38 3
References:
Step One:
1. Galat, A. Ind. Eng. Chem. 1944, 36, 192.
2. Luk’yanov, A. V. Khim. Farm. Zh. 1982, 16, 904-910.
3. Baine, O. J. Chem. Educ. 1939, 16, 278.
Step Two:
1. Hurdis, E. C.; Yang, J. W. J. Chem. Educ. 1969, 46, 679-698.
2. 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, 95-100.
3. Stewart, J. J. Chem. Soc., 1922, 121, 2555-2561.
Step Three:
1. Empfield, J. R.; Mayhugh, D.; Ohnmacst, C. J.; Frank, C. A.; Grant, T.; Li, J. Bioorg. Med. Chem. Lett. 1997,
7, 775-778.
2. Blank, B.; Farina, F. A.; Kerwin, J. F.; Saunders, H. J. Org. Chem. 1961, 26, 1551–1553.
Supplemental Information:
Estimations courtesy of SDBS database (with illustrations via ChemBioDraw).
Figure 1: Acetanilide 1HNMR
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 13CNMR
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)
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Figure 3: Sulfanilamide 1HNMR
Shifts at: δ7.45(2H, d), δ6.86(2H, broad singlet), δ6.59(2H, d), δ5.76(2H, broad singlet)
Figure 4: Sulfanilamide 13CNMR
Shifts at: δ151.82 (1C, s), δ129.99(1C, s), δ127.35(2C, d), δ112.41(2C, d)
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