Reaction sites of pyrimidine bases and nucleosides during chlorination: A computational study

As important components of soluble microbial products in water, nucleobases have attracted much attention due to the high toxicity of their direct aromatic halogenated disinfection by-products (AH-DBPs) during chlorination. However, multiple halogenation sites of AH-DBPs pose challenges to identify them. In this study, reaction sites of pyrimidine bases and nucleosides during chlorination were investigated by quantum chemical computational method. The results indicate that the anion salt forms play key roles in chlorination of uracil, thymine, and their nucleosides, while neutral forms make predominant contributions to cytosine and cytidine. In view of both kinetics and thermodynamics, C5 is the most reactive site for uracil and thymine, N3/C5 and N3 for respective uridine and thymidine, N1/C5/N⁴ and N⁴ for respective cytosine and cytidine, whose estimated apparent rate constants k_obs-est of ∼10³, 10³/10², 10⁶/10²/10⁴, and 10³ M^-1 s^-1, respectively, in consistent with the known experimental results. C6 in all pyrimidine compounds is hardly attacked by Cl⁺ in HOCl ascribed to its positive charge, but readily attacked by OH‾ in hydrolysis and the N1=C6 bond was found to possess the highest reactivity in hydrolysis among all double bonds. In addition, the structure-kinetic reactivity relationship study reveals a relatively strong correlation between lgk_obs-est and APT charge in all pyrimidine compounds rather than FED² (HOMO). The results are helpful to further understand the reactivity of various reaction sites in aromatic compounds during chlorination.