Sulphonamides—

Sulphonamides.— Oxidative amidation of sulphinic acids gives primary sulphon-amides, though the severe reaction conditions (18% oleum with NaNj) restrict the potential of this route. Selective amino sulphonation of anilines, using CISOjNCO and AlClj, depends on the formation of cyclic A-carbamoyl-sulphonamides. More conventional preparative methods are covered in the conversion of naphthalene-1-thiol into 4-(2-hydroxyethylsulphonyl)naphthalene-1-sulphonamide (an assessment of standard routes has been made), and in the preparation of alkanesulphonyl- and trifluoromethanesulphonyl-hydroxyl-amines from hydroxylamines and the sulphonyl chlorides. In the latter study,conditions favouring N- rather than 0-sulphonylation were established. 

Sulphonamides.—Preparations of sulphonamides from sulphonyl halides are illustrated with examples of particular interest from the recent literature, viz. a-bromoalkanesulphonaraides RCHBrS02NHBu and iV-alkyl-lViV- 

Yamawaki, H. Morisaki, M. Sawada, and Y. Yukawa, J. Org. Chem., 

Dolyuk, M. M. Kremlev, and M. S. Rovinskii, Voprosy Khim. i khim. Tekhnol., 1975, 

Terauchi and S. Takemura, Chem. and Pharm. Bull. (Japan), 1975, 23, 2410. 

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. 

Many sulphonamides can be extracted with acetone from pharmaceutical preparations. 

For tablets, an amount of powdered sample containing 10 mg sulphonamide is extracted with 50 ml acetone and an amount of solution containing 1—3 [xg of the individual sulphonamides applied to the start. This amount should not be exceeded if critical sulphonamide pairs are to be separated. A method has been described also for concentrating smaller amounts of sulphonamides present in feeding stuffs [3]. 

Silica gel, occasionally also alumina has been the adsorbent principally used in TLC of sulphonamides (cf. Tables 114 and 115). Since many sulphonamides are amphoteric, both acid and basic solvents have found 

Maphenide responds to the Ehrlich reagent only in amounts exceeding 25 [xg, after longer heating at 90° C. It is better detected by spraying with 0.3% ninhydrin solution in butanol and then heating 30 min at 90° C [102, 134]. N4-succinic and phthalic acid derivatives of sulphonamides have been detected through their ability to quench the fluorescence of suitable layers and also with a 0.05% ethanolic solution of bromocresol purple [84]. 

Quantitative evaluation of separated sulphonamides also has been described in detail [168 a]. The best procedure was found to be elution of the sulphonamides with N hydrochloric acid, diazotisation and coupling with N,N-diethyl-N -(l-naphthyl)-ethylenediammonium oxalate. 

Adams and Tjepkema [33] have published the infra-red spectra of sixteen N iV -di-substituted sulphonamides, and noted that a strong band occurs in all cases in the range 1180—1160 cm which they ascribe to the —SO2 — grouping. Schrieber [23] has pointed out that, in addition, these spectra also have a strong band in the 1360— 1330 cm region corresponding to the second sulphone band. 

Further studies by Adams [63] have confirmed his earlier findings, as has an extensive study of this group by Baxter, Cymerman-Craig and Willis [64], who have examined twenty-five 

Perfluoroalkanesulphonyl fluorides give sulphonates and Me SiF with trimethylsilyl ethers, and sulphonamides with bis(trimethylsilyl)amines.  

Sulphonamides.—Cleavage of sulphonamides by alkali metals in HMPA, bis-(2-methoxyethoxy)aluminium hydride, and 40% H2SO4 in AcOH, has been described. 

Shingaki, N. Torimoto, M. Inagaki, and T. Nagai, Chem. Letters, 1973, 1243. 

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C (decomp.) It is made by the oxidation of toluene-o-sulphonamide with alkaline permanganate. Saccharin has about 550 times the sweetening power of sucrose, and is used extensively as a sweetening agent, usually in the form of the sodium salt. The use of saccharin is restricted in the U.S. 

NHCOCH3. White crystals, m.p. 18l-l83"C. Soluble sulphacetamide is the sodium salt which is soluble in water. Il is prepared by acetylating sulphanilamide and hydrolysing one acetyl group. Being more soluble than most of the sulphonamides it is used in treating infections of the urinary tract and of the conjunctiva. 

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. ... 

CqHqNj02S2. Whitc powder, m.p. 200-203 C. Sulphathiazole has the typical actions of sulphonamides, being effective against y -haemolytic Streptococci, Pneumococci, Gonococci and Staphylococci. 

The various sulphonamides differ in their specificity to various bacteria and in their ease of absorption and excretion. They are bacteriostatic (inhibiting growth) and not bactericidal, acting by allowing the natural body mechanisms to destroy the bacteria. 

The action of the sulphonamides is antagonized by p-aminobenzoic acid and they act by inhibiting the uptake and utilization of 1-aminobenzoic acid by bacterial cells, which require this as a precursor of folic acid. 

Jones-Hertzog D K and W L Jorgensen 1997. Binding Affinities for Sulphonamide Inhibitors witl Human Thrombin Using Monte Carlo Simulations with a Linear Response Method. Journal o Medicinal Chemistry 40 1539-1549. 

SULPHANILAMIDE. (Reaction C.) Add 15 g. of the above thoroughly drained sulphonamide to 10 ml. of concentrated hydrochloric acid diluted with 20 ml. water, and boil the mixture gently under reflux for i hour. Then add 30 ml. of water and heat the mixture again to boiling, with the addition of a small quantity of animal charcoal. Filter the boiling solution, and add powdered sodium carbonate in small quantities to the filtrate with stirring until all eflFervescence ceases and the sulphanilamide is precipitated as a white powder. Cool the mixture thoroughly and filter oflF the sulphanilamide at the pump, wash with water and dry. Yield, ca. 10 g. 

Toluene-p-sulphonamide can be similarly converted into the dimethyl-amide, but the methylation now occurs in two definite stages. First the sulphonamide dissolves in the sodium hydroxide to form the mono-sodium salt (see p. 252), which then reacts with the dimethyl sulphate to give the mono-... 

Dissolve log. of powdered toluene-p-sulphonamide in 6o ml. of 10% aqueous sodium hydroxide (2 5 mols.) diluted with 50 ml. of water to moderate the reaction. Then, using the same precautions as in the previous preparation, add 127 ml. (17 g., 2 3 mols.) of dimethyl sulphate and shake the mixture vigorously. The crystalline dimethylamide rapidly separates from the warm... 

The acidic properties of sulphonamides and their mono-substitution derivatives are particularly well illustrated in the alkyl ubstitution compounds, which by reason of these properties can be prepared by two distinct methods. Thus mono- and di-ethylamine, when subjected to the Schotten-Baumann reaction using benzenesulphonyl chloride, gi e benzenesulphonethylamide, and bcnzenesulphondiethylamide respectively. These compounds can also... 

Toluene-/ sulplionamide is almost insolubb in cold water, but dissolves readily in sodium hydroxide solution (as the sodium derivative) aid is immediately reprecipitated on the addition of strong acids. To show the formation of the sodium derivative, dissolve about o-2 g. of metallic sodium in about 10 ml, of ethanol, cool the solution, and then add it to a solution of 1 g. of the sulphonamide in 20 ml. of cold edianol. On shaking the mixture, fine white crystals of the sodium derivative, CH,C,HjSO,NHNa, rapidly separate, and may be obtained pure by filtering at the pump, and washing firet with a few ml. of ethanol, and then with ether. 

Dichloramine-T. Dilute 80 ml, of freshly prepared 2N sodium hypochlorite soluticMi (preparation, p. 525) with 80 ml. of w ter, and then add with stirring 5 g. of finely powdered toluene-p-sulphonamide, a clear solution being rapidly obtained. Cool in ice-water, and then add about 50 ml. of a mixture of equal volumes of glacial acetic acid and water slowly with stirring until precipitation is complete the dichloro-amide separates at first as a fine emulsion, which rapidly forms brittle colourless crystals. Filter off the latter at the pump, wash well with... 

B) SULPHONIC ACIDS. Aliphatic sulphonic acids are rarely encountered, for they are very soluble in water, and many are deliquescent. The aromatic sulphonic acids, although less uncommon, are encountered most frequently as their derivatives e.g.t the sulphonamides, pp. 247, 251), or as nuclear-substituted acids (e.g., sulphanilic acid, p. 384). 

B) Sulphonamides. Mix 0 5 g. of the sulphonic acid or its alkali salt with 15 g. of phosphorus pentachloride, and heat under reflux in a silicone- or oil-bath at 150° for 30 minutes then allow it to cool. 

This method of sulphonamide Tormation may obviously be invalidated by the presence of nuclear —NHj or —OH groups, which could react with ihe phosphorus pentachloride or with the subsequent —SO Cl group. 

Sulphonic Acids. Benzylthiouronium salts (p. 359), Sulphonamides and sulphonanilides (p. 354). 

Almost insoluble in cold water. Higher alcohols (including benzyl alcohol), higher phenols (e.g., naphthols), metaformaldehyde, paraldehyde, aromatic aldehydes, higher ketones (including acetophenone), aromatic acids, most esters, ethers, oxamide and domatic amides, sulphonamides, aromatic imides, aromatic nitriles, aromatic acid anhydrides, aromatic acid chlorides, sulphonyl chlorides, starch, aromatic amines, anilides, tyrosine, cystine, nitrocompounds, uric acid, halogeno-hydrocarbons, hydrocarbons. 

Choice of solvent for recrystallisation. Obtain small samples (about 0 5 g.) of the following compounds from the storeroom (i) salicylic acid, (Li) acetanilide, (iii) m-dinitrobenzene, (iv) naphthalene, and (v) p-toluene-sulphonamide. Use the following solvents distilled water, methylated spirit, rectified spirit, acetone, benzene and glacial acetic acid. 

Amine B.P. M.P < 20 Benzene- sulphonamide />-Toluene- sulphonamide Phenyl- thiourea ot-Naphthyl- thiourea Picrate A-Substltuted Phthallmlde Benzamide... 

Reaction with chlorosulphonic acid ( chlorosulphonyl-ation ). Sulphonamides. Many aryl hahdes, either alone or in chloroform solution, when treated with excess of chlorosulphonic acid afford the corresponding sulphonyl chlorides in good yield (compare Section IV.106) the latter may be readily converted into the aryl sulphonamides by reaction with concentrated ammonia solution or with sohd ammonium carbonate. 

The following give abnormal results when treated with chlorosulphonio acid alone, preferably at 50° for 30-60 minutes —fluobenzene (4 4 -difluorodiplienyl-sulphone, m.p. 98°) j iodobenzene (4 4 -di-iododiphenylsulplione, m.p. 202°) o-diclilorobenzene (3 4 3. -4 -tetrachlorodiphenylsulphone, m.p. 176°) and o-dibromobenzene (3 4 3 4 -tetrabromodiphenylsulphone, m.p. 176-177°). The resulting sulphones may be crystallised from glacial acetic acid, benzene or alcohol, and are satisfactory for identification of the original aryl halide. In some cases sulphones accompany the sulphonyl chloride they are readily separated from the final sulphonamide by their insolubility in cold 6N sodium hydroxide solution the sulphonamides dissolve readily and are reprecipitated by 6iV hydrochloric acid. 

Procedure 1. Dissolve 1 g. of the compound in 5 ml. of chloroform in a test-tube and cool in ice. Add 5 ml. of chlorosulphonic acid CA UTION in handhng) dropwise and with shaking. When the initial evolution of hydrogen chloride subsides, remove the reaction mixture from the ice and, after 20 minutes, pour it into a 50 ml. beaker filled with crushed ice. Separate the chloroform layer, wash it well with water, and evaporate the solvent. Recrystallise the residual aryl sulphonyl chloride from light petroleum (b.p. 40-60°), chloroform or benzene this is not essential for conversion into the sulphonamide. 

To convert the aryl sulphonyl chloride into the sulphonamide, use either of the following methods —... 

If the presence of a sulphone is suspected, treat the product with N sodium hydroxide solution (only the sulphonamide dissolves), filter and reprecipitate the sulphonamide by 6A hydrochloric acid. 

Sulphonamides. Mix together 1 0 g. of the dry acid or 1 - 2 g. of the anhydrous salt with 2 5 g. of phosphorus pentachloride f and heat under a reflux condenser in an oil bath at 150° for 30 minutes. Cool the mixture, add 20 ml. of dry benzene, warm on a steam bath and stir the solid mass well to extract the sulphonyl chloride filter. Add the benzene solution slowly and with stirring to 10 ml. of concentrated ammonia solution. If the sulphonamide precipitates, separate it by filtration if no solid is obtained, evaporate the benzene on a steam bath. Wash the sulphonamide with a little cold water, and recrystallise from water, aqueous ethanol or ethanol to constant m.p. 

Sulphonamides upon heating with acetyl chloride are converted into the A -acetyl derivatives or sulphonacetamides ... 

Reflux 1 g. of the sulphonamide with 2-5 ml. of acetyl chloride for 30 minutes if solution is not complete within 5 minutes, add up to 2-5 ml. of glacial acetic acid. Remove the excess of acetyl chloride by distillation on a water bath, and pour the cold reaction mixture into water. Collect the product, wash with water and dissolve it in warm sodium bicarbonate solution. Acidify the Altered solution with glacial acetic acid Alter oflF the precipitated sulphonacetamide and recrystaUise it from aqueous alcohol. 

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