Quantum Chemical Investigation On Hydrolysis And Direct Photolysis Of Cephradine

Antibiotics are emerging pollutants that are frequently detected in the aquatic environment. The presence of antibiotics in aqueous environments is becoming a major worldwide concern, as they may induce bacterial resistance. Hydrolysis and photolysis are important ways in elimination of many antibiotics. However, due to the large number of micropollutants in the aquatic environment, experimental determination alone cannot determine the hydrolysis and photolysis for so many antibiotics. It is necessary to develop computational prediction methods. It is the purpose of this study to test the feasibility of using quantum chemical calculation to predict hydrolysis and direct photolysis of antibiotics. Cephradine was selected as a case. Cephradine has two hydrolyzable groups, two ionization states (AH± and A-) and two isomers under environmental pH conditions. The calculation results were validated by experimental data. The contents and results are as follows:(1) Density functional theory (DFT) and transition state theory calculations were performed to investigate hydrolysis pathways and kinetics of cephradine. Results showed that the predominant hydrolysis pathway of cephradine is H2O attack on the β-lactam of AH± at acidic conditions; while under neutral and basic conditions, it is the base-catalyzed hydrolysis. The calculated rate constants at different pH conditions were of the same order of magnitude as the experimental values, and the calculated products(diketopiperazine) were confirmed by experiment. This study identified a catalytic role of the carboxyl group in the hydrolysis.(2) The coexistence of transition metal ions and antibiotics in water can lead to their complexing reactions, affecting hydrolysis behavior of antibiotics, but little is known for the mechanism. DFT calculation was performed to obtain Gibbs free energies and stability constants of the complexing reaction between Cu(II) and A- in water. Results show that two complex species are formed, with the binding sites being a) the amino and carbonyl group, and b) the carboxyl group and carbonyl group, respectively. This complexation changes the bond length of lactam, increases the positive formal charge of the hydrolysis site, and reduces both the energy gap of the frontier molecular orbitals for hydrolysis and the activation energy of base-catalyzed hydrolysis. As a result, the hydrolysis of A- was enhanced. The result was confirmed by experiment.(3) DFT and time dependent density functional theory (TD-DFT) calculation were performed to investigate the direct photolysis pathways of AH± and A-. Based on the calculated vertical excitation energies and the potential energy surfaces for excited-state intramolecular proton transfer, it was found that excited-state intramolecular proton transfer of AH± occur via intramolecular hydrogen bond. The calculated Gibbs free energies of activation for the photochemical hydrolysis, decarboxylation and isomerization of cephradine indicate that decarboxylation and isomerization are the photolysis pathways. Photodecarboxylation starts from the lowest excited singlet state (S1) of AH±. While photoisomerization occurs from S1 and the lowest excited triplet state (T1) of A-, or from T1 of AH±. The photodecarboxylation products were confirmed by reported experiment results.In this study, hydrolysis and direct photolysis of cephradine were predicted by quantum chemical calculation. The mechanism of Cu(Ⅱ)-catalyzed hydrolysis of cephradine was revealed. This study lays a foundation for developing quantum chemical calculation-based methods to predict environmental photochemical and hydrolysis behavior of organic micropollutants.