New insights into the iodination mechanism of tyrosine and its dipeptides and comparison with chlorination and bromination reactions†

Abstract

Iodinated aromatic disinfection byproducts have attracted much attention owing to their high toxicity. However, little has been known about the iodination mechanism to date. In this study, the iodination of model aromatic precursors, tyrosine (Tyr) and its model dipeptides, by HOI and other iodinating agents was explored using a quantum chemical computational method, and the halogenation of Tyr by HOX (X = Cl, Br, and I) was compared. The results indicate that the phenolate salt plays a key role in the iodination of the phenol ring in Tyr compounds by HOI via the classic S_EAr mechanism and the second deprotonation becomes the rate-limiting step, which explains why the kinetic isotope effect (KIE) was observed in the iodination of aromatic compounds. Among the seven possible iodinating agents present in chloramination, HOI is the predominant one, and I₂ is the second in the iodination of the phenol ring under typical chloramination conditions. In the further investigation of bromination and chlorination, the KIE was found to also occur in the bromination of Tyr. More importantly, the different reactivity orders of HOX reacting with the phenol ring and the amino group in Tyr are related to the hardness of both HOX and substrates, which can be evaluated from the energy gap (E_LUMO–HOMO) between the LUMO and HOMO energies. Following the “like–attracts–like” principle, the halogenating agent prefers the substrate with a similar E_LUMO–HOMO value. The results are helpful in further understanding the iodination mechanism and identifying various halogenated products.