Theoretical Study of Molecular Structure and Gas-Phase Acidity of Some Biologically Active Sulfonamides

The geometries of substituted sulfonamides [sulfonamide ( I ) sulfamic acid ( II ), sulfamide ( III ), methane sulfonamide ( IV ), 1,1,1-trifluoromethanesulfonamide ( V ), 4-aminobenzenesulfonamide ( VI ), 1,2-benzisothiazol-3-(2H)-one-1,1-dioxide (saccharin) ( VII ), N -(5-sulfamoyl-1,3,4-thiadiazol-2yl)acetamide (acetazolamide) ( VIII ), 4-(aminosulfonyl)- N -[(4-fluorophenyl)methyl]-benzamide (1I9L) ( IX ), ( R )-(+)-4-(ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,-dioxide (brinzolamide) ( X ), and (4 S - trans )-(+)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (dorzolamide) ( XI )] in both neutral and deprotonated forms, were optimized using CBS-QB3 theory (compounds I − IV), the Becke3LYP/6-311+G(d,p) method (compounds I − VIII ), and the two-layered ONIOM(B3LYP 6-311+G(d,p): MNDO) method (compounds VIII - XI ). Sulfamic acid behaves in the gas phase as O-acid. The investigated acids are weak acids with calculated acidity of about 1320−1420 kJ mol -1 . Of the N-acids studied, saccharin possesses the highest gas-phase acidity (1324 kJ mol -1 ). The acidities of phenyl-substituted derivatives computed using the hybrid ONIOM (B3LYP/6-311+G(d,p): MNDO) method are in good agreement with the full DFT ones, and this method can be adopted to model large substituted sulfonamides.