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Mechanism of the reaction between 5-fluorouracil and hypochlorous acid

The reaction between hypochlorous acid (HOCl) and 5-fluorouracil (5-FU) is the fundamental process which can occur in activated neutrophils in cancer patients or during chemical treatment of (hospital) wastewaters . Therefore, the chlorination of 5-FU is of utmost importance in medicinal and environmental chemistry. In this work, it is experimentaly shown that the first product of 5-FU chlorination process is chlorohydrine, which undergoes further chlorination. Structural characteristics of products are determined using 1H, 19F and 13C NMR spectroscopy. Reaction mechanism of chlorination cascade of 5-FU is investigated using quantum chemistry methods. M06–2X/6– 311++G(3df, 2pd)//M06–2X/6–311+G(d) level of theory is applied. The solvent effects are described by the implicit SMD solvation model, using the optimal number of the explicit water molecules. It is shown that 5-FU is chlorinated at the C5 position in the pyrimidine ring. The two-steps reaction in which the first reaction is the addition of Cl+ on N1 anion of 5-FU, yielding the imine intermediate, is determined as the most feasible mechanism. The free energy barrier which corresponds to the addition of chloronium ion is 72, 9 kJ/mol. The addition of water on the imine intermediate (deltaG‡ = 21, 0 kJ/mol), which results in the chlorohydrine, is the second reaction step. The results obtained with quantum chemical methods are in agreement with experimental data. Standard bioassays are preformed in order to determine ecotoxicity of chlorination products of 5-FU. Results of these study play a key role in predicting the environmental fate of 5-FU.

DFT ; pharmaceuticals ; chemical fate ; chlorination

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