61st Annual Report on Research 2016

Constituents of aqueous free bromine (e.g., HOBr and BrO^–) have a well-documented ability to brominate aromatic compounds. Such covalent bond formation between carbon atoms within aromatic structures and electrophilic bromine atoms is an essential step in the synthesis of many commercially-important specialty chemicals, including selected pharmaceuticals, pesticides, flame retardants, and dyes. Bromination of aromatic groups is also associated with the formation of organobromine disinfection by-products (DBPs) in drinking water, wastewater, and recreational waters (e.g., pools and spas). Bromine substitution at aromatic moieties may also contribute to the antimicrobial properties of bromine-containing disinfectants in recreational waters and in household cleaners. Electrophilic bromine species are also generated in vivo via enzyme-mediated oxidation of bromide by H₂O₂ within specific mammalian leukocytes. In addition to killing invading pathogens, these bromine species can also transform endogenous molecules (e.g., via bromination of aromatic compounds). The resulting collateral damage to biomolecules has been linked to several human diseases, including asthma, Alzheimer’s, and atherosclerosis.

Conventional wisdom generally assumes HOBr is the predominant brominating agent in solutions of free bromine. Occasionally, rate constants have also been reported for reactions of BrO^– and Br₂ with aromatic compounds. Several additional bromine species (including BrCl, Br₂O, and BrOCl) can, however, form in solutions of free bromine, albeit at generally lower concentrations than HOBr. Nonetheless, recent findings suggest BrCl, Br₂O, and BrOCl are orders of magnitude more inherently reactive (relative to HOBr) toward anisole and the herbicide dimethenamid. The extent to which brominating agents other than HOBr influence bromination rates of organic compounds beyond anisole and dimethenamid is largely unknown. Also absent is an understanding of how organic compound structure (particularly steric effects) influences the reactivity and regioselectivity of each brominating agent.

The overarching goal of this project is to examine the influence of BrCl, Br₂O, and BrOCl on overall bromination rates of a series of alkylbenzenes. Conditions known to influence free bromine speciation (pH, concentrations of bromide, chloride, and free chlorine) were systematically varied to facilitate calculation of second-order rate constants associated with each brominating agent/aromatic compound pair. Acquisition of second-order rate constants is important because such values are needed in order to predict bromination rates of aromatic compounds under previously unexamined solution conditions.

OVERVIEW OF EXPERIMENTAL METHOD:

Regiospecific bromination rate constants of three alkylbenzenes (ethylbenzene, isopropylbenzene, and tert-butylbenzene) were determined in batch reactors incubated in a water bath at 20.0 °C. Reactions were conducted in 40-mL amber glass vials pre-rinsed with aqueous free chlorine and ultrahigh-purity deionized water. Solutions for kinetic experiments contained a pH buffer, sodium nitrate, sodium chloride, and sodium bromide. Working solutions of free chlorine were added to reactors to achieve targeted initial free chlorine concentrations. Several solution conditions (pH, concentrations bromide, chloride, and free chlorine) are capable of influencing bromination rates. Accordingly, experiments were performed to separately elucidate the effects of each of the aforementioned independent variables on bromination rates of alkylbenzenes. At time zero for each reactor, the three alkylbenzenes were added as a methanolic spike. Aliquots from reactors were periodically obtained, quenched with excess sodium thiosulfate, and extracted into toluene. Toluene extracts were analyzed via gas chromatography/mass spectrometry; loss of parent compound and formation of brominated products were concurrently monitored.

RESULTS AND DISCUSSION:

Rates of alkylbenzene bromination increased with increasing chloride concentration, thereby implicating BrCl as a brominating agent (noting that the concentration of BrCl is proportional to the concentration of chloride). Bromination rates also increased with increasing concentrations of free chlorine (when present in excess relative to added bromide). This finding suggests BrOCl can influence overall bromination rates in these systems. Bromination rates of alkylbenzenes exhibited a dependence on initial added bromide concentration (in the presence of excess free chlorine) that was intermediate between first- and second-order. These findings implicate both HOBr and Br₂O as active brominating agents. That bromination rates are also enhanced by the presence of bromide (in excess of free chlorine) indicates that Br₂can also serve as a brominating agent.

Second-order rate constants (at 20 °C) associated with bromination of each examined aromatic compound increased as: HOBr < Br₂O < Br₂≈ BrOCl < BrCl. Under most examined solution conditions, HOBr accounted for <40% of overall bromination rates. These findings call into question previous models that assumed HOBr is the only active brominating agent of modestly nucleophilic organic compounds in solutions of free bromine.

The regioselectivity of alkylbenzene bromination can be quantified as the para-to-ortho ratio of regiospecific pseudo-first-order rate constants (k_obs,p/k_obs,o). For solution conditions in which rates of bromination para to the alkyl group equal rates of bromination ortho to the alkyl group, k_obs,p/k_obs,o will equal 0.5. For reactions in which BrCl controlled overall bromination rates, k_obs,p/k_obs,o increased in the order: ethylbenzene (0.64) < isopropylbenzene (6.1) < tert-butylbenzene (52). These findings suggest that steric effects are minor for bromination of ethylbenzene; however, steric effects appear to significantly influence bromination reactions involving isopropylbenzene and tert-butylbenzene.

IMPACTS:

Intellectual impacts. The improved understanding of bromination chemistry garnered from this work has multidisciplinary applications, including insights into: (1) production of bromine-containing specialty chemicals, (2) minimization of brominated disinfection by-products in drinking water, and (3) inflammatory diseases in which free bromine can alter biomolecules.

Impacts on participating undergraduate researchers. Four undergraduate chemistry majors have participated in this project during the past 12 months. Two undergraduates delivered poster presentations at an ACS National Meeting in Spring 2016. One undergraduate defended an honors thesis and is currently pursuring a graduate degree in chemistry.

Impacts on PI’s career. Through this project, the PI has already experienced significant career advancement opportunities, including publication of a peer-reviewed article, participation as a panelist at a national conference, and invitations to present seminars at three universities. The PI’s leadership in this project was also noted in his selection as a Jess and Mildred Fisher Endowed Professor of Chemistry by his college in 2015. This project also provided important preliminary data that the PI has incorporated into multiple new extramural funding proposals.