Kinetic Isotope Effects in Electrophilic Aromatic Halogenation of Dimethenamid in Chlor(am)inated Water Demonstrate Unique Aspects of Iodination

Abstract

Electrophilic aromatic substitution reactions can initiate halogenated disinfection byproduct (DBP) formation. The rate-controlling step (RCS) of electrophilic aromatic halogenation is commonly assumed to be halogen addition (vs proton removal), although this assumption has not been previously assessed under water disinfection conditions. Herein, the herbicide dimethenamid (DM) was used as a model aromatic compound to examine the RCS of halogenation in water treated with free chlorine (chlorination), free chlorine and bromide (bromination), or monochloramine and iodide (iodination). Hydrogen–deuterium kinetic isotope effects (KIEs) were determined using DM (k H) and deuterated DM (k D) in separate reactors. DM chlorination and bromination exhibited no KIE (k H/k D ≈ 1), supporting halogen addition as the RCS. Iodination did, however, exhibit primary KIEs (k H/k D > 1.4), demonstrating some degree of proton removal in the RCS. Increasing the pH (5.2–8.9) and I– concentration (10–100 μM) suppressed iodination rates but did not significantly affect KIEs (1.47–2.06), suggesting that iodine addition is rate-controlling under these conditions ([Cl–] = 15 μM). In contrast, adding 25–100 mM Cl– increased the KIE in iodination (2.85–3.42), reflecting a shift in kinetic control toward proton removal. This study delineates how chloride can both enhance and inhibit electrophilic aromatic iodination, which has implications for I-DBP formation in halide-rich water.

Formation Mechanism of Iodinated Aromatic Disinfection Byproducts: Acid Catalysis with H2OI+

“…Accordingly, we concluded that H 2 OI + could participate in the iodination mechanism before rate-controlling proton removal, which agrees with the experimental results in a previous study. 25 Comparing the most favorable route for the Tyr-Gly and HOI reaction (R B in Figure 1) with the Tyr-Gly and H 2 OI + reaction (R E in Figure 3), the energy barrier of the H 2 OI + reaction route R E is 31.4 kcal mol −1 lower than that of the HOI route R B . Furthermore, the calculated rate constant of route R E is 6.15 × 10 7 M −1 s −1 , and its reaction rate is 1.93 × 10 −3 M s −1 , which is 23 orders of magnitude higher than that of the HOI reaction (route R B ).…”

“…In light of previous studies reporting that H 2 O could be involved in the iodination processes, 25,32 route R E in Figure 3 examines the involvement of the solvent water molecule acting as a weak Brønsted base for the leaving proton in the H 2 OI + and Tyr-Gly reaction. This reaction is a stepwise mechanism with fast formation of complex (Com1) [H 2 OI + •••Tyr-Gly] followed by a rate-controlling deprotonation reaction that resulted in the formation of I-Tyr-Gly.…”

“…Other proton acceptors such as a second Tyr-Gly molecule exist in the system, but some proton acceptors (e.g., OH − ) do not participate in the rate-controlling step of iodination since the KIE is independent of pH. 25 Compared to route R E , route R F allows the release of H 2 OI + , which can be recycled for the next iodination of Tyr-Gly. Due to the thermodynamic limitation, the H 2 OI + concentration is approximately 6−11 orders of magnitude lower than that of HOI in chloraminated water in a pH range of 6−10.…”

“…These data indicate that H 2 OI + has a higher reactivity than ICl for the formation of I-Tyr-Gly, which is also observed in the iodination of dimethenamid in a previous study. 25 pH Effect on Iodination Mechanisms. The iodination of dipeptides and the formation of I-DBPs could be affected by water pH.…”

“…In this case, the primary hydrogen−deuterium kinetic isotope effects (KIEs = k H /k D , Section S1 and Scheme S2) are not typically observed in S E Ar reactions, which lead to the conclusion that deprotonation of the σ-complex is not involved in the rate-controlling step. 23−25 However, previous studies have also shown that this mechanism cannot explain iodination of several aromatic compounds due to their primary KIE (k H / k D ), including 1.47−2.06 for dimethenamid, 25 3.8 for 2,4,6trideuterioanisole, 26 3.97 for 2,4,6-trideuterophenol, 27 2.3−5.4 for 4-nitrophenol, 28 and 4.4 for Ni(II)-coordinated pyrazole. 29 Additionally, the σ-complex intermediate was not observed in the formation of aromatic I-DBPs.…”