Electrophilic aromatic substitution chlorosulfonation

Molten 2-ethoxybenzoic acid (7) was added to a mixture of chlorosulfonic acid and thionyl chloride while keeping the reaction temperature below 25 °C. In this straightforward electrophilic aromatic substitution the ethoxy group directs the electrophile towards the ortho and para position whereas the carboxylic acid directs meta giving an overall selectivity for the attack at C-5. It was necessary to add thionyl chloride to transform the intermediate sulfonic acid into... 

Furosemide can also be synthesized starting with 2,4-dichlorobenzoic acid (formed by chlorination and oxidation of toluene). Reaction with chlorosulfonic acid is an electrophilic aromatic substitution via the species -S02C1 attacking ortho and para to the chlorines and meta to the carboxy-late. Ammonolysis to the sulfonamide is followed by nucleophilic aromatic substitution of the less hindered chlorine by furfurylamine (obtained from furfural—a product obtained by the hydrolysis of carbohydrates). 

The second route utilizes the introduction of the chlorosulfonyl substituent directly onto the aromatic nucleus. The reaction of substituted benzenes with chlorosulfonic acid gives good yields of arylsulfonyl chlorides however, the aryl substituent dictates the position of attachment of the chlorosulfonyl function in this electrophilic aromatic substitution.7 The method described herein allows replacement of a diazotized amine function by the chlorosulfonyl group. The ready availability of substituted anilines makes this the method of choice for the preparation of arylsulfonyl chlorides. 

Acetanilide reacts with chlorosulfonic acid in an electrophilic aromatic substitution ... 

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/>-acetamidobenzene-sulfonyl 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.)... 

As shown here, the sulfonyl chloride group (—SO2CI) can be conveniently introduced to an aromatic ring via an electrophilic aromatic substitution reaction using chlorosulfonic acid. The reaction is usually referred fo as chlorosul-fonation. It has been determined that two equivalents of fhe acid are required per equivalent of the aromatic compound. In the initial attack the system first forms the corresponding sulfonic acid, which in turn is converted to the sulfonyl chloride. If is believed fhat the initial stage of the reaction involves SO3 as the electrophile. It is likely that this reagent results from the establishment of fhe equilibrium reaction shown here ... 

Direct preparation of aryl sulfonyl chlorides from arenes has been achieved through electrophilic aromatic substitution with excess chlorosulfonic acid. ° This method was used in the initial medicinal chemistiy route for the preparation of Viagra, which relied on a penultimate chloro-sulfonylation reaction with chlorosulfonic acid (Scheme 13.3). ... 

In aromatic carboxylic acids, the carboxylic acid group (CO2H) is an electron-withdrawing moiety (-1, —M effects), hence it reduces the reactivity of the attached aromatic nucleus towards electrophilic substitution. So like aromatic carbonyl compounds (Section 7), aromatic carboxylic acids are more resistant towards sulfonation than the parent aromatic hydrocarbons. The reaction therefore generally requires rather forcing conditions, e.g. the use of a large excess of chlorosulfonic acid at temperatures of more that 120 °C. The reactions of benzoic, cinnamic and phenylacetic acid with chlorosulfonic acid were reported by Suter. ... 

In comparison with alkyl halogenides, halides bound to aromatic nuclei are less reactive, and, unless activated by the presence of other substituents (for example, reactive chlorine in 2,4-dinitrochlorobenzene), nucleophilic substitution reactions cannot be used for their identification. For the identification, electrophilic substitution reactions on aromatic nuclei are used predominantly, such as nitration and chlorosulfonation. Only in exceptional and special cases are other procedmes used [preparation of Grignard reagent and the conversion to anilides (12) preparation of addition compounds with picric acid-chloronaphthalenes, see p. 127 oxidation of side chains-oxidation of chlorotoluene to the corresponding chlorobenzoic acid, see p. 129]. 

---