Theoretical Studies On The Hydrolysis Mechanism Of Sulphonamides

Sulfonamides(SAs) are compounds which contain a sulphonamide group and have been extensively used in the areas of medicine and pesticide science. For example, sulfachloropyridazine, sulfathiazole, sulfadiazine are often used as fungicides and florasulam is used as a herbicide. These kinds of sulfonamides are hard to degrade in the environment. The wide use of sulfonamides can lead to the problem of medicine residual in the soil and the development of antibiotic resistant genes. Thus, it is necessary to design and find high effective and easily degradable sulfonamides.With the theoretical progress of quantum chemistry and the rapid development of computer technology, it is possible to explore sulfonamides hydrolysis mechanism by using molecular simulation method. In this thesis, the hydrolysis mechanism of sulfachloropyridazine, sulfathiazole, sulfadiazine and energy barriers were calculated at different p H. In addition, the hydrolysis mechanism of florasulam was also studied.The hydrolysis mechanism of SAs were performed using the Gaussian 09 suite of programs. The geometries of the reactants, intermediates, transition states and products were optimized using the density functional theory with the level B3LYP/6-31+G(d, p). The intrinsic reaction coordinate(IRC) path was carried out to confirm the proposed mechanism. The hydrolysis reactions of SAs with water can occur through two mechanisms. In mechanism I, SAs hydrolysis resembles a nucleophilic acyl substitution but which takes place in the sulphonyl group. Sulphanilic acid and the corresponding heterocyclic base with an amine group are the products of the hydrolysis. The mechanisms II of SAs hydrolysis is one kind of aromatic nucleophilic substitution, which takes place in the heterocyclic aromatic ring and sulfanilamide is the main products of such a hydrolysis.This thesis includes four sections:(1) the hydrolysis mechanism of sulfachloropyridazine, sulfathiazole, sulfadiazine under neutral condition;(2) the hydrolysis mechanism of sulfachloropyridazine, sulfathiazole, sulfadiazine under weak acidic condition;(3) the hydrolysis mechanism of sulfachloropyridazine, sulfathiazole, sulfadiazine under strong acidic condition;(4) the hydrolysis mechanism of florasulam under neutral condition. Firstly, the calculated results show that the mechanisms I has a higher reactivity than the mechanisms II and sulfanilamide, sulphanilic acid are the main products of hydrolysis which is in good agreement with Anna Bialk-Bielinska's experiment results. Secondly, the calculated hydrolysis energy barriers are higher than 46 Kcal?mol-1 in all the sulfachloropyridazine, sulfathiazole, sulfadiazine and florasulam, it indicates that all these compounds are hydrolytically stable at room temperature. Finally, based on the studied hydrolysis mechanism, it is helpful for furtherly designing novel, easily degradable and high effective sulfonamides.