60th Annual Report on Research 2015

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 p-xylene and the herbicide dimethenamid. The extent to which brominating agents other than HOBr influence bromination rates of organic compounds beyond dimethenamid and p-xylene is currently unknown. Also absent is an understanding of how organic compound structure 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 and alkoxybenzenes. 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 anisole were determined in batch reactors incubated in a water bath at 20.00 ^oC. Reactions were conducted in 40-mL amber glass vials pre-rinsed with aqueous free chlorine (0.6 mM) and ultrahigh-purity deionized water. Solutions for kinetic experiments contained a pH buffer (sodium bicarbonate or sodium borate), sodium nitrate to fix ionic strength, 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 anisole. At time zero for each reactor, anisole was 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 (anisole) and formation of products were concurrently monitored.

RESULTS AND DISCUSSION:

Second-order bromination rate constants (at 20 ^oC) associated with bromination of anisole to give the major product (4-bromoanisole) increased as: HOBr < Br₂O < BrOCl < Br₂ < BrCl. This reactivity trend is consistent with the anticipated trend in leaving group ability among the brominating agents: OH^- (from HOBr) < BrO^- (from Br₂O) < ClO^- (from BrOCl) < Br^- (from Br₂) = Cl^-(from BrCl). The second-order rate constant calculated for net bromination of anisole by HOBr (to give 4-bromoanisole and 2-bromoanisole) is up to 3000-times less than reported in previous studies (which assumed HOBr was the only kinetically-relevant brominating agent). 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.

Under all examined solution conditions, the major product of anisole bromination was 4-bromoanisole. The regioselectivity of anisole bromination varied depending on which brominating agent predominated under any given set of solution conditions, with the extent of bromination para to the methoxy substituent increasing in the order: BrCl < BrOCl < Br₂O = HOBr < Br₂. Preferential substitution para to the methoxy group can be explained by lesser steric hindrance, decreased electrostatic repulsion between the anionic leaving group of the brominating agent and the methoxy group of anisole, and greater stability of the arenium ion intermediate relative to substitution orthoto the methoxy moiety.

Experiments designed to further elucidate the influence of steric effects on bromination rates and regioselectivity (including reactions involving ethylbenzene, isopropylbenzene, and tert-butylbenzene and their alkoxybenzene analogues) are currently in progress.

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 participated in this project during the 12-month period covered by this report. Two served as a co-author on a peer-reviewed publication stemming from this work. Three were co-authors on a presentation derived from this work that was delivered at a national conference. Two of the undergraduate researchers graduated with BS degrees in chemistry; both are currently in doctoral programs (one is a Pharm.D. student, the other is a Ph.D. student in chemistry). The other two undergraduates are continuing on this project during the 2015-2016 academic year.

Impacts on the PI. 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 two 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.