Hydrolysis of sulphonamides

A. 6 Intramolecular nucleophilic catalysis of the hydrolysis of sulphonamides 238 B Reactions of the hydroxyl group 239... 

A.6 Intramolecular nucleophilic catalysis by the carboxyl group of the hydrolysis of sulphonamides ... 

Hydrolysis of sulphonamides, 1077 Hydroqumone diacetate, 664, 677 Hydroqumones, 749 Hydroxamic acid test for esters, 1062, 1063 ... 

Hexamethylphosphoramide has found important uses as a solvent in various organic reactions, such as carboxylic ester formation, hydrolysis of sulphonamides, alkylation of ketones, decyanation of nitriles, the Beckmann rearrangement and so on. HMPA may be used to make cyclodiphospha-zanes (7.250). 

Hydrolysis of a sulphonamide. Mix 2 g. of the sulphonamide with 3-5 ml. of 80 per cent, sulphuric acid in a test-tube and place a thermometer in the mixture. Heat the test-tube, with frequent stirring by means of the thermometer, at 155-165° until the solid passes into solution (2-5 minutes). Allow the acid solution to cool and pour it into 25-30 ml. of water. Render the resulting solution alkaline with 20 per cent, sodium hydroxide solution in order to liberate the free amine. Two methods may be used for isolating the base. If the amine is volatile in steam, distil the alkaline solution and collect about 20 ml. of distillate extract the amine with ether, dry the ethereal solution with anhydrous potassium carbonate and distil off the solvent. If the amine is not appreciably steam-volatile, extract it from the alkaline solution with ether. The sulphonic acid (as sodium salt) in the residual solution may be identified as detailed under 13. 

An unusual oxidation reaction is that of sulphonamides with nitric acid in the presence of concentrated sulphuric or hydrochloric acid to yield an amount of nitrous oxide claimed to be proportional to the amount of sulphonamide411,412. Probably, the ammonia formed by hydrolysis reacts to give ammonium nitrate, which is known to yield nitrous oxide on heating ... 

Reaction of some of the less common derivatives of sulphonic acids also may lead to sulphonamides. For example, hydrolysis of sulphonyl isocyanates4,418 and the reduction of sulphonyl azides with zinc in acetic acid498 lead to sulphonamides, as depicted in equations 124 and 125, respectively, in good yields. 

A plethora of insoluble sulphonamide analogues, for instance phthalylsulfathiazole and succinylsulfathiazole, are not readily absorbed from the gastrointestinal tract. However, the release of active sulphonamide in high concentration, obtained due to hydrolysis in large intestine, enables their application for intestinal infections and also for pre-operative preparation of the bowel for surgery. A few examples of sulphonamides belonging to this specific use will be discussed here. 

A detailed study of the intramolecular catalysis of the normally very slow acid hydrolysis of a sulphonamide has been described. Where a carboxy-group is suitably placed, e.g. in c -H02CCH=CHS02NMePh, substantial rate enhancement is observed. 

The sulphonamides have been used in the treatment of intestinal infections. Substitution of the aniline N with a succinyl group produces an acidic compound which is fully ionised at intestinal pH and is therefore not appreciably absorbed into the bloodstream. Slow enzjmatic hydrolysis of the product in the intestine releases the free primary amine group which is essential for activity. This concept of prodmg design has been exploited in the sjmthesis of succinyl-sulfathiazole (p/Gt 4.5) from sulfathiazole (p/Gt 7.1) (Fig. 22.42). 

The mode of action of sulphonamides was greatly clarified by Woods in 1940. It had been shown that tissue extracts, pus, bacteria, and particularly yeast extract contained a heat-stable substance of low molecular weight which would inhibit the action of sulphonamides on bacteria (Stamp, 1939). Woods, recalling that enzymes are inhibited by substances which chemically and sterically resemble their substrates (see Section 9.3a), adopted this hypothesis that the inhibitory substance in yeast is the substrate of an enzyme widely distributed in nature, and that it resembles sulphanilamide chemically. He found activity was concentrated in an alkali-soluble fraction of yeast, and that it ran parallel to a colour test for an aromatic amino-group. Activity was lost on esterification or acetylation, recovered on hydrolysis, and lost again on treatment with nitrous acid (Woods, 1940). Thus he made it clear that the active substance was an aromatic aminoadd. Because p-aminobenzoic add (pAB) (2.13 p. 28) is the aromatic aminoadd that most resembles sulphanilamide (2,12) he tried it as an inhibitor of bacteriostasis, and found that one molecule could prevent 5000 to 25 000 molecules of sulphanilamide from functioning. 

C10H10N4O2S. White powder, which darkens on exposure to light m.p. 255-256 C. Prepared by condensing p-acet-amidobenzenesulphonyl chloride with 2-aminopyrimidine and subsequent hydrolysis. Soluble sulphadiazine is the sodium salt. Sulphadiazine is the least toxic of the more potent sulphonamides. ... 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

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