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The chlorination of barbiturates. Quantum-chemical study of the reaction mechanism

Barbiturates are drugs that act as central nervous system depressants. They are used as anxiolytics, hypnotics, anticonvulsants and intravenous anesthetics. The chlorination of barbiturates by hypochlorous acid (HOCl) is very important reaction in biochemistry and environmental chemistry. The barbiturates show high stability over a extended period of time and resistance to both biological and chemical degradation, which is why they accumulate in the environment retaining their pharmacological properties. In order to explain why barbiturates are chemically inert to chlorination by HOCl, standard quantum chemical methods have been used to describe the reaction of most common barbiturates used in medical practice. The chlorination reaction of pharmaceutically relevant 5, 5-disubstituted barbiturates has been compared with the parent barbituric acid. It has been shown that barbituric acid easily undergoes chlorination to give the C5-chlorinated product (Figure 1). Chlorination of 5, 5-disubstituted barbiturates is not possible in the C5-position, but only in the N-position. However, calculated energy barriers for those processes are prohibitively high (ΔG#298 > 200 kJ/mol). To undergo N- chlorination, the tautomerization of corresponding barbiturates to their iminol forms is required (Figure 2). As expected [1], the calculated energy barrier for chlorination of the iminol form is lower than the direct N- chlorination of the amide form, but exceeds 150 kJ/mol, which indicates the recalcitrant properties of barbiturates under chlorination conditions.

DFT ; psychopharmaceutical ; chemical fate ; chlorination

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