Sulfa Drugs Experiment

Sulfa Drugs: Preparation of Sulfanilamide
Introduction
The purpose of this experiment is to prepare sulfanilamide from p-Acetamidobenzenesulfonyl chloride. This will be done using reflux, vacuum filtration, and melting point determination.
Experiment Scheme6

Figure 1. Reaction equation.6 A hot water bath was prepared in a fume hood using a 250-mL beaker. 2.5 g of p-acetamidobenzenesulfonyl chloride was placed into a 50 mL Erlenmeyer flask and 11 mL of dilute ammonium hydroxide solution was added to it. The mixture was stirred with a glass stirring rod. The mixture was heated in the hot water bath (70C) for 10 minutes and stirred occasionally. The flask was allowed to cool and placed in an ice water bath for 15 minutes. The p-acetamidobenzenesulfonamide was collected on a Buchner funnel and the flask was rinsed with about 10 mL of ice water. The sold was then transferred to a 25 mL round bottom flask and 5.3 mL of dilute hydrochloric acid was added along with a boiling stone. A reflux condenser was attached to the flask and the mixture was heated using a heating mantle until the solid had dissolved. The solution was then refluxed for an additional 5 minutes. Next, the mixture was allowed to cool to room temperature. Using a Pasteur pipet, the solution was transferred to a 100 mL beaker. While stirring with a glass rod, aqueous saturated sodium bicarbonate was added dropwise to the mixture. This was done until the pH measure between 4 and 6. The mixture was cooled in an ice water bath. The sulfanilamide was collected on a Buchner funnel and rinsed with 5 mL of cold water. The solid was air dried on the Buchner funnel using suction and then placed in a drawer to dry for a week. The next week the sulfanilamide was weighed and the melting point was measured.
Data
Name
Formula
MW (g/mol)
Amount
Moles
State
Density (g/mL)
MP (C)
BP (C) p-Acetamidobenzene-sulfonamide C8H8ClNO3S
233.67
2.5 g
0.011
Solid
1.4683
142-1453
426.83
Ammonium hydroxide
NH4OH
35.05
11 mL
0.31
Liquid
0.911
-771
361
Hydrochloric acid
HCl
36.46
5.3 mL
0.15
Liquid
1.22
-352
572
Sodium bicarbonate
CHNaO3
84.01
20. mL
0.24
Liquid
2.164
>3004
8514
Sulfanilamide
C6H8N2O2S
172.2
0.97 g
0.0056
Solid
1.085
164-1665
4015
Figure 2. Chemical Data.
Name
Hazards p-acetamidobenzensulfonyl chloride corrosive, eye and skin irritant, combustible11
Ammonium hydroxide
Skin and eye irritant, corrosive, permeator, acutely toxic7
Hydrochloric acid
Skin and eye irritant, corrosive, permeator, lung sensitizer8
Sodium bicarbonate
Skin and eye irritant, acutely toxic9
Sulfanilamide
Skin and eye irritant, corrosive, combustible at high temperatures10
Figure 3. Chemical Hazards. The p-acetamidobenzenesulfonyl chloride was a white fine powder while the Ammonium hydroxide was a clear liquid. HCl was also a clear liquid. The p-acetamidobenzenesulfonamide was a white, clumpy solid. During the reflux, the mixture turned to a yellow liquid and the end product (sulfanilamide) ended up being a white, almost flaky powder. The product was weighed to be 0.97 g and the melting point range was 155C-164C. The theoretical yield was 1.9 g. This was calculated by finding the moles of p-acetamidobenzenesulfonyl chloride. This was calculated as follows: 2.5 g (1 mol/233.67 g) = 0.011 moles. Since this reaction has a 1:1 molar ratio the theoretical amount of moles of sulfanilamide would be 0.011 moles as well. Theoretical yield was found as follows: 0.011 mol * 172.2 g/mol = 1.9 g. The experimental yield was 0.97 g; therefore, the percent yield would be calculated as follows: (0.97 g/1.9 g)*100% = 51 %.

Discussion The theoretical melting point range of sulfanilamide is 164C-166C. Our experimental calculated value of 155C-164C shows that our product was not very impure. Looking solely at the melting point range, it appears that the experiment was a success. The little bit of impurity could have resulted from possibly heating the solution too long or at too high of a temperature during Reflux. It could also have resulted from adding too much or too little of the base (sodium bicarbonate). Some improvements that could be done to make the product more pure would be to more closely monitor the temperature that the solution was heated. Additionally, the base could have been added more slowly to allow more time for the gas evolution to occur and cease before adding more base. Looking at the percent yield in addition to the melting point range; however, shows that the experiment was most definitely not a success. The percent yield as shown above was only 51 %. While the end product was pretty pure, only half of it was obtained. There are a number of errors that could have resulted in this loss of product. If the solution was heated at too high of a temperature, then some of the product might have boiled out. Additionally, not enough of the base might have been added to fully precipitate the product. These errors could be fixed by monitoring the temperature more closely that the solution was heated at. Additionally, more base could have been added to raise the pH closer to 6 rather than 4. This might have allowed more of the product to precipitate. The p-acetamidobenzenesulfonyl chloride that was one of the starting materials showed para substituents because “the acetomido group directs substitution almost totally to the para position.”6 Therefore, p-acetamidobenzenesulfonyl chloride resulted from the reaction of acetanilide with HOSO2Cl. If the aniline that was used to prepare acetanilide had been used itself in the reaction, problems would have resulted due to aniline being meta directing and due to its lack of a protecting group. The p-acetamidobenzenesulfonyl chloride is used because it has a protecting group that inhibits the reactivity of the amino group. The purpose of adding the p-acetamidobenzenesulfonyl chloride mixture to an ice water bath was to decompose the excess chlorosulfonic acid. After filtration, the intermediate sulfonyl chloride was reacted with aqueous ammonia to produce p-acetamidobenzenesulfonamide. The excess ammonia neutralized hydrogen chloride. Next, acid-catalyzed hydrolysis was used to remove the acetyl protecting group and produce the hydrochloride salt of sulfanilamide which was converted to the final product by adding the base (sodium bicarbonate) slowly. Overall, the experiment as not a success. The steps for producing sulfanilamide were followed; however, some of the possible errors mentioned above must have occurred since there was only a 51% yield produced. On the bright side, the melting point range showed that the product was just slightly impure; therefore, not too many errors occurred to affect the purity of the product. However, there was a major loss of product. Some the possible errors and solutions for this loss of product are listed above.
Questions
2) In the preparation of sulfanilamide, why was aqueous sodium bicarbonate, rather than aqueous sodium hydroxide, used to neutralize the solution in the final step? Aqueous sodium bicarbonate was used instead of sodium hydroxide because sodium bicarbonate is a weaker base than sodium hydroxide is. A weak base is needed to slowly raise the pH to a pH between 4 and 6. With too strong of a base, the pH change would be drastic and would dissolve the compound rather than allowing sulfanilamide to precipitate. This would occur by the strong base deprotonating the sulfanilamide to form a salt. The sulfanilamide salt would then be soluble in water and would therefore not precipitate in the solution.
3) At first glance, it might seem possible to prepare sulfanilamide from sulfanilic acid. When the product is conducted in this way, however, a polymeric product is produced after the first step. What is the structure of the polymer? Why does p-acetamidobenzenesulfonyl chloride not produce a polymer? The structure of the polymer is (-NH-C6H4-SO2-)n. Water forms as a byproduct of this condensation polymerization reaction. The p-acetamidobenzensulfonyl chloride does not produce a polymer because the acetamido group is unreactive and cannot produce a polymer.

Works Cited
ChemicalBook. Ammonium hydroxide; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB1853050.htm (accessed February 17, 2014).1
ChemicalBook. Hydrochloric acid; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB7421538.htm (accessed February 17, 2014).2
ChemicalBook. P-Acetamidobenzenesulfonyl chloride; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB4452614.htm (accessed February 17, 2014).3
ChemicalBook. Sodium bicarbonate; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB7492884.htm (accessed February 17, 2014).4
ChemicalBook. Sulfanilamide; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6212562.htm (accessed February 17, 2014).5
Radke, K., Stolzenberg, G. Organic Chemistry Laboratory Manual; Cengage Learning: Mason, OH, 2009.6

ScienceLab. Ammonium hydroxide MSDS; http://www.sciencelab.com/msds.php?msdsId=9922918 (accessed February 17, 2014).7
ScienceLab. Hydrochloric acid MSDS; http://www.sciencelab.com/msds.php?msdsId=9924285 (accessed February 17, 2014).8
ScienceLab. Sodium bicarbonate MSDS; http://www.sciencelab.com/msds.php?msdsId=9927258 (accessed February 17, 2014).9
ScienceLab. Sulfanilamide MSDS; http://www.sciencelab.com/msds.php?msdsId=9927288 (accessed February 18, 2014).10
TCI America. P-acetamidobenzenesulfonyl chloride; https://www.spectrumchemical.com/MSDS/TCI-A0074.pdf (accessed February 17, 2014).11

Cited: ChemicalBook. Ammonium hydroxide; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB1853050.htm (accessed February 17, 2014).1 ChemicalBook ChemicalBook. P-Acetamidobenzenesulfonyl chloride; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB4452614.htm (accessed February 17, 2014).3 ChemicalBook ChemicalBook. Sulfanilamide; http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6212562.htm (accessed February 17, 2014).5 Radke, K., Stolzenberg, G ScienceLab. Ammonium hydroxide MSDS; http://www.sciencelab.com/msds.php?msdsId=9922918 (accessed February 17, 2014).7 ScienceLab ScienceLab. Sodium bicarbonate MSDS; http://www.sciencelab.com/msds.php?msdsId=9927258 (accessed February 17, 2014).9 ScienceLab TCI America. P-acetamidobenzenesulfonyl chloride; https://www.spectrumchemical.com/MSDS/TCI-A0074.pdf (accessed February 17, 2014).11