When bromide-containing waters are chlorinated, conventional wisdom typically assumes HOBr is the only active brominating agent. Several additional and often-overlooked brominating agents (including BrCl, Br2, BrOCl, Br2O) can form in chlorinated waters, albeit at generally lower concentrations than HOBr. The extent to which these additional brominating agents influence bromination rates of disinfection byproduct precursors is, however, poorly understood. Herein, the influence of BrCl, Br2, BrOCl, Br2O, and HOBr toward rates of sequential bromination of anisole was quantified. Conditions affecting bromine speciation (e.g., pH, concentrations of chloride, bromide, and chlorine) were varied, and regiospecific second-order rate constants were calculated for reactions of each brominating agent with anisole, 2-bromoanisole, and 4-bromoanisole. The regioselectivity of anisole bromination changed with pH, consistent with the participation of more than one brominating agent. Under conditions representative of chlorinated drinking water, contributions to bromination rates decreased as BrCl > BrOCl > HOBr > Br2O (Br2 negligible). The second-order rate constant determined for net bromination of anisole by HOBr is up to 3000-times less than reported in previous studies (which assumed HOBr was the only active brominating agent). Accordingly, models that assume HOBr is the only kinetically relevant brominating agent in solutions of free bromine may be insufficient for reactions involving modestly nucleophilic organic compounds.

Polar molecular surface area provides a valuable metric when optimizing properties as varied as membrane permeability and efflux susceptibility. The EPSA method to measure this quantity has had a substantial impact in medicinal chemistry, providing insight into the conformational and stereoelectronic features that govern the polarity of small molecules, targeted protein degraders, and macrocyclic peptides. Recognizing the value of bioisosteres in replacing permeation-limiting polar groups, we determined the effects of common amide, carboxylic acid, and phenol bioisosteres on EPSA, using matched molecular pairs within the Merck compound collection. Our findings reinforce EPSA's utility in optimizing permeability, highlight bioisosteres within each class that are particularly effective in lowering EPSA and others, which despite widespread use, offer little to no such benefit. Our method for matched-pair identification is generalizable across large compound collections and, thus, may constitute a flexible platform to study the effects of bioisosterism both in EPSA and other in vitro assays.

Polar molecular surface area provides a valuable metric when optimizing properties as varied as membrane permeability and efflux susceptibility. The EPSA method to measure this quantity has had a substantial impact in medicinal chemistry, providing insight into the conformational and stereoelectronic features that govern the polarity of small molecules, targeted protein degraders, and macrocyclic peptides. Recognizing the value of bioisosteres in replacing permeation-limiting polar groups, we determined the effects of common amide, carboxylic acid, and phenol bioisosteres on EPSA, using matched molecular pairs within the Merck compound collection. Our findings highlight bioisosteres within each class that are particularly effective in lowering EPSA and others which, despite widespread use, offer little to no such benefit. Our method for matched-pair identification is generalizable across large compound collections and thus may constitute a flexible platform to study the effects of bioisosterism both in EPSA and other in vitro assays.

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