Aromatic Sulfonamides

Sulfonamides. A/-Halo-A/-alkylsulfonamides, RS02NR X, are relatively stable distillable Hquids. Under the influence of uvlight they form 1 1 adducts with olefins (67,100). Ai-/-Butyl derivatives rearrange forming precursors to cyclopropanes and sultams. A/-Halo-A/-sodioalk5lsulfonamidates, RS02NClNa, have been less extensively studied than their aromatic counterparts (70). The stabiHty of these compounds approaches that of the aromatic sulfonamides (80). The dodecyl compound exhibits properties of both a disinfectant and a surfactant. 

Amino groups bound to sulfur can be replaced by fluorine via diazotization. In contrast to carboxylic acid amides, fluorodediazoniation of aromatic sulfonamides IS readily accomplished to give sulfonyl fluorides in high yields [52, 7S (equation 16) Tetrazotization-fluorination of sulfanilamide can also be effected to give a 38% yield of p-fluorobenzenesulfonyl fluoride [52],... 

The method illustrates the ability of the sodium hydride-dimethylformamide system to effect the alkylation of aromatic sulfonamides under mild conditions and in good yield. The method appears to be fairly general. The submitters have prepared N,N-diethyl- and N,N-di- -butyl- >-toluenesulfonamide as well as 2-(/ -tolyIsuIfonyl)benz[/]isoindoline from 2,3-bis-(bromomethyl)naphthalene, and 1 %-tolylsulfony])pyrrolidine from 1,4-dichIorobutane the yield of purified product exceeded 75% in each case. 

The sulfated alkylbenzenesulfonamides (no. 7-8) and alkylaroylsulfo-propionates (no. 9) were found to be efficient lime soap dispersants [27]. Although the nonionics (nos. 10-11) had low LSDR values they did not potentiate the detergency of soap and exhibited some antagonism. Amphoteric surfactants with alkyl side chains from C12 to C18 (nos. 12-13) possessed the lowest LSDR values, ranging from 2 to 4. The amine oxide derived from an aromatic sulfonamide had a low LSDR of 5 close to that of amphoterics. 

Results obtained in the acylation of aromatic sulfonamides with acetic acid, in the presence of SnOTf based catalysts are presented in Table 48.4. The rate of the sulfonamide acylation follows the seqnence benzenesnlfonamide > p-nitrobenzenesulfonamide > />-methoxybenzenesnlfonamide, and is very sensitive towards the nature of the aromatic hydrogen substituent (the selectivity in acylated />-methoxybenzenesnlfonamide did not exceed 7% irrespective of the catalyst nature this corresponds to an approximate relative yield... 

Metal salt of aromatic sulfonamide (+ metal salt of perfluorometal-ate + halogenated organic compounds) Total 0.01-1.0 26-39... 

The stability of these compounds is maximal at pH 4 - 6, and decreases very sharply at lower and higher pH values, and the mechanism and products of the reaction differed with pH. In the neutral range, hydrolysis yielded the aromatic sulfonamide and the ester, whereas, under acid catalysis in the low pH range, the products were the AT-acyl sulfonamide and an alcohol (R OH, Fig. 11.9). Of particular interest is that the tm values for hydrolysis of the N-sulfonyl imidates in 80% human plasma were 3-150 times lower than in buffer solution at identical pH and temperature. This was taken as evidence for enzymatic hydrolysis by human plasma hydrolases. Hydrolysis under these conditions yielded the sulfonamide and the ester in quantitative amounts. 

The plot in (b) refers to a similar interaction with the carboxymethylated derivative of carbonic anhydrase (Prob. 19). Aromatic sulfonamides are powerful inhibitors of the action of the enzyme and are useful probes of the site characteristics. 

Aromatic sulfonamides are specific inhibitors of carbonic anhydrase (E). The apparent second-order rate constants for association of p-nitrobenzenesulfonamide with (a) carbonic anhydrase-B and (b) the carboxymethylated derivative of the enzyme are shown against pH in Figure 1.14. Estimate using equations (1.225) and (1.226) the values for pAig, and k and he two possible schemes shown for both carbonic... 

Acetazolamide is an aromatic sulfonamide used as a carbonic anhydrase inhibitor. It facilitates production of alkahne urine with an elevated biocarbonate, sodium, and potassium ion concentrations. By inhibiting carbonic anhydrase, the drug suppresses reabsorption of sodium ions in exchange for hydrogen ions, increases reflux of bicarbonate and sodium ions and reduces reflux of chloride ions. During this process, chloride ions are kept in the kidneys to cover of insufficiency of bicarbonate ions, and for keeping an ion balance. Electrolytic contents of fluid secreted by the kidneys in patients taking carbonic anhydrase inhibitors are characterized by elevated levels of sodium, potassium, and bicarbonate ions and a moderate increase in water level. Urine becomes basic, and the concentration of bicarbonate in the plasma is reduced. 

Torok and co-workers312 have reported the one-pot synthesis of /V-arylsulfonyl heterocycles through the reaction of primary aromatic sulfonamides with 2,5-dimethoxytetrahydrofuran. When triflic acid is used in catalytic amount, IV-arylsulfonylpyrroles are formed (Scheme 5.34). Equimolar amount of triflic acid results in the formation of N- ary I s u I fo n y I i n do I e s, whereas /V-arylsu Ifonylcar-bazoles are isolated in excess acid (Scheme 5.34). In the reaction sequence 1,4-butanedial formed in situ from 2,5-dimethoxytetrahydrofurane reacts with the sulfonamide to give the pyrrole derivative (Paal-Knorr synthesis). Subsequently, one of the formyl groups of 1,4-butanal alkylates the pyrrole ring followed by a second, intramolecular alkylation (cyclialkylation) step. 

The Eu(III) and Tb(III) complexes of 36, developed by Parker et al., showed modulation of the lanthanide emission caused by changes in pH [139]. The coordinating antenna was covalently attached to the complex but only coordinates to the metal centre under specific pH conditions. This was demonstrated on a cyclen complex where three carboxylate pendant arms were attached, allowing coordination to take place, and resulted in the formation of a charge-neutral complex. The fourth position contained an aromatic sulfonamide tethered via an ethyl carbon chain, 36a-36c. Studies showed that luminescence was switched on when the complexes were in alkaline conditions because the two metal-bound waters (q = 2) were displaced. This led to a situation where the pendant aryl sulfonamide groups were coordinated... 

Chlorobenz[d]isothiazole-l, 1-dioxide ( pseudosaccharin chloride ) (6)3,24.25, lee, 25i, 26i, 262 displays the reactivity of a cyclic imidoyl chloride263 resembling very much carboxylic acid halides. In previous sections preparation of 3, 4, 5, 13, 68, 86, 89 from 6 has been mentioned. Derivatives of 6 substituted in the phenyl ring have been described.250 Interestingly, Meadow observed231 that crude 6 and material that contained phosphorus pentachloride reacted with thiols more readily than the pure compound. In the reaction of 6 with aromatic sulfonamides, aluminum chloride had been added for activation.252... 

Aromatic sulfonamides Pyrene Cleavage of N—S bond (deprotection of amines synthesis of polyamines as macro ligands) [31]... 

The ability of zinc in carbonic anhydrase to become five-coordinate is also confirmed by the structural studies on enzyme-inhibitor complexes discussed in Section 62.1.4.2.1. There is much evidence for the coordination of anionic inhibitors to the metal, while the competitive inhibitor imidazole gives a five-coordinate centre. Sulfonamides are powerful inhibitors which bind directly to the zinc and also interact with the protein. The sulfonamide acetazolamide has significant affinity for the apoenzyme. It is probable " that the first interaction between the enzyme and aromatic sulfonamides is a hydrophobic interaction between the aromatic ring and residues in the active site cavity, followed by ionization of the SO2NH2 group prior to complex formation. Sulfonamides only bind to the zinc and cobalt enzymes, i.e. the two metals that give an active enzyme. 

Aliphatic and aromatic sulfonamides are prepared from the corresponding sulfonyl halide (RSO2X) and ammonia, 1°- or 2°-amines.The reaction requires alkaline conditions and thus a stoichiometric amount of additional base to neutralize the by-product hydrohalide (see below Eq. (27)). This base may be a second molecule of the reactive amine, a 3°-amine, or an inorganic base. The reaction can be performed in organic or aqueous solvents, although excessive temperatures must be avoided in water to prevent hydrolysis of the... 

Figure 15. Chemical structures of the carbonic anhydrase inhibitors 15-21. The small aromatic sulfonamides 15 and 16 bind with nanomolar affinity to carbonic anhydrase. Methazolamide 18 was used for a long time to treat glaucoma. 19 was the first topically active inhibitor. Structure-based drug design at Merck first led to 20 and then to the marketed drug, dorzolamide 21.

Kumar K, King RW, Carey PR. Carbonic anhydrase—aromatic sulfonamide complexes a resonance Raman study. FEBS Lett 1974 48 283-287. 

Aromatic Sulfonamides. A considerable volume of biological and clinical literature continues to appear regarding furosemide (ll) which was made available to the United States market in I966. In addition to... 

The fluorinated aromatic sulfonamides (31) bind tightly to carbonic anhydrase (CA) II enzyme and show their inhibitory activity. The activities for fluorinated inhibitors of carbonic anhydrase increase in the order of non-F, 2-F, 2,5-F2, 3,4,5-F3, 2,3,5,6-F4, and 2,3,4,5,6-Fs in 31 (1.8, 0.73, 0.55, 0.55, 0.53, 0.44 nM, respectively). The increased activity is due to their hydrophobicity and specific contacts between the fluoroaromatic ring and the Phe131 site of the protein [11]. The octanol/water partition coefficients (log P) measure the hydrophobicity of each compound and increase with the level of fluorine substitution. 

In the search for more desirable agents with a more favorable electrolyte excretion pattern, our investigation (59) turned to the aromatic sulfonamides more closely related to sulfanilamide. Emphasis was placed on animal (dog) excretion data rather than in vitro enzyme inhibition results (4). One analog of sulfanilamide, p-carboxybenzenesulfonamide (CBS), a relatively weak car-... 

A second type of behavior occurs for weak acids like HCN, H2S, and aromatic sulfonamides (ArS02NH2). Assuming that the anions (conjugated bases) bind the low-pH species of the enzyme, the bell-shaped plot of log K versus pH (Figure 2.15) can be accounted for. In fact, at low pH, the inhibitors are in the protonated form, which is not suitable for metal binding. At high pH the concentration of the low-pH species of the enzyme decreases. The maximal apparent affinity is experimentally halfway between the p/fa of the inhibitor and the p Ta of the enzyme, treated as if it were only one. The same type of curve is also expected if the high-pH species of the enzyme binds the weak acid. Indeed, kinetic measurements seem to favor this hypothesis for sulfonamides. ... 

---