4-Acetamidobenzenesulfonyl chloride

The first pyrimidine analogues of sulfanilamide were introduced in 1942, some five years after the start of the bacterial chemotherapy revolution. Sulfadiazine (1018 R = R = H) and sulfamerazine (1018 R = Me, R = H) may be made by treatment of pyrimidin-2-amine or its 4-methyl derivative, either with p-acetamidobenzenesulfonyl chloride followed by... 

Acetamidobenzenesulfonyl chloride (A-acetylsulfanilyl chloride) [121-60-8] M 233.7, 149"(dec). Crystallise the chloride from toluene, CHCI3, or ethylene dichloride. [Beilstein 14IV 2703.]... 

Benzenesulfonyl azide, 4-(acetylamino)- (9) (2158-14-7) p-Acetamidobenzenesulfonyl chloride Sulfanilyl chloride, N-acetyl- (8) Benzenesulfonyl chloride, 4-(acetylamino)- (9) (121-60-8)... 

The following chemicals were obtained from the Aldrich Chemical Company, Inc., and were used without further purification p-acetamidobenzenesulfonyl chloride, 97% acetone, 99.9+%, HPLC grade sodium azide, 99% ethyl acetoacetate, 99% triethylamine, 99% rhodium(ll) acetate dimer phenylacetylene, 98%. The following solvents were obtained from Fisher Scientific and were used without further purification toluene, certified A. C. S. ethyl ether (Solvent grade, Concentrated) petroleum ether, certified A. C. S. Dichloromethane was distilled from calcium hydride. 

In this experiment, you will prepare the sulfa drug sulfanilamide by the following synthetic scheme. The synthesis involves converting acetanilide to the intermediate p-acetamidobenzenesulfonyl chloride in Step 1. This intermediate is converted to sulfanilamide by way of p-acetamidobenzenesulfonamide in Step 2. 

Chlorosulfonic acid must be handled with care because it is a corrosive liquid and reacts violently with water. The p-acetamidobenzenesulfonyl chloride should be used during the same laboratory period in which it is prepared. It is unstable and will not survive long storage. The sulfa drug may be tested on several kinds of bacteria (Instructor s Manual). 

Prepare a hot water bath at 70°C. Place the crude p-acetamidobenzenesulfonyl chloride into the original 5-mL conical vial and add 1.1 mL of dilute ammonium hydroxide solution. Stir the mixture well with a spatula and reattach the air condenser and drying tube (gas trap) using fresh, moistened glass wool. Heat the mixture in the hot water bath for 10 minutes. Allow the conical vial to cool to the touch and place it in an ice-water bath for several minutes. Collect the p-acetamidoben-zenesulfonamide on a Hirsch funnel and rinse the vial and product with a small amount of ice water. You may stop here. 

When the reaction is conducted in this way, however, a polymeric product is produced after Step 1. What is the structure of the polymer Why does p-acetamidobenzenesulfonyl chloride not produce a polymer ... 

The reaction is worked up by pouring it into ice-water, whereupon the 4-acetamidobenzenesulfonyl chloride (8) separates as a white solid. The excess chlorosulfonic acid is hydrolyzed by water (Eq. 21.7). In general, sulfonyl chlorides are much less reactive toward water than are carboxylic acid chlorides, but you should not expose them to water for extended periods of time because they hydrolyze slowly to give the corresponding sulfonic acids according to Equation 21.8. It is unnecessary to dry or purify the 4-acetamidobenzenesulfonyl chloride (8) in this sequence rather, 8 is simply treated directly with aqueous ammonia. 

Reaction, Work-Up, and Isolation Transfer the crude A-acetamidobenzenesulfonyl chloride obtained in the previous experiment to the Erlenmeyer flask, and add 15 mb of concentrated (28%) ammonium hydroxide. A rapid exothermic reaction may occur if the crude 4-acetamidobenzenesulfonyl chloride contains acidic contaminants that were not removed by the aqueous washings in the previous step. Use a stirring rod to break up any lumps of solid that may remain the reaction mixture should be thick but homogeneous. Heat the mixture at 70-80 C for about 0.5 h. Cool the reaction mixture in an ice-water bath and collect the product by vacuum filtration. Wash the crystals with cold water and air-dry them. ... 

Explain why 4-acetamidobenzenesulfonyl chloride (8) is much less susceptible to hydrolysis of the acid chloride function than is 4-acetamidobenzoyl chloride. 

Consider the spectral data for 4-acetamidobenzenesulfonyl chloride (Figs. 21.6 and 21.7). 

Discuss the differences observed in the IR and NMR spectra of acetanilide and 4-acetamidobenzenesulfonyl chloride that are consistent with the formation of the latter in this procedure. 

Concentrated ammonia contains 72% water, yet its reaction with 4-acetamidobenzenesulfonyl chloride (8) produces 4-acetamidobenzenesulfonamide (9) rather than 4-acetamidobenzenesulfonic acid (17). Why is ammonia more reactive than water toward 9 ... 

Using curved arrows to symbolize the flow of electrons, write a stepwise mechanism for the aminolysis of 4-acetamidobenzenesulfonyl chloride (8) to give 4-acetamidobenzenesulfonamide (9). 

Acetylation of aniline produces acetanilide (2) and protects the amino group from the reagent to be used next. Treatment of 2 with chlorosulfonic acid brings about an electrophilic aromatic substitution reaction and yields p-acetamidobenzenesulfonyl chloride (3). Addition of ammonia or a primary amine gives the diamide, 4 (an amide of both a carboxylic acid and a sulfonic acid). Finally, refluxing 4 with dilute hydrochloric acid selectively hydrolyzes the carboxamide linkage and produces a sulfanilamide. (Hydrolysis of carboxamides is much more rapid than that of sulfonamides.)... 

One of the most important examples is the chlorosulfonation of acetanilide 13 to /7-acetamidobenzenesulfonyl chloride 14 (Equation 38), since the latter is used as an intermediate in the manufacture of sulfonamide antibacterial drugs. The optimum reaction conditions were found to be the use of a relatively large excess of the reagent (five equivalents) at 60 °C (2 hours). In acetanilide (A -phenylacetamide) 13, the bulky acetamido (MeCONH) group is electron-donating (+M effect) and its large size virtually excludes o-sulfonation, so the / -sulfonyl chloride 14 is isolated as almost the sole product. 

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