Non-innocent Bromide Redirects Sulfur Oxygenation through O–O Bond Cleavage in a Nonheme Fe(III)–Superoxo System

Abstract Thiol dioxygenase chemistry requires nonheme iron centers to activate triplet O2 while controlling a sequence of short-lived Fe/O2 intermediates, O–O bond cleavage or reorganization, and selective oxygen-atom delivery to sulfur. However, the identity and ordering of these intermediates remain difficult to define, and proposed mechanisms differ in whether sulfur oxygenation precedes, accompanies, or follows O–O bond cleavage. Here, we employ density functional theory (DFT) to interrogate the conversion of a metastable side-on Fe(III)–superoxo intermediate to an FeII–sulfinate product in a sulfur-ligated biomimetic system. The calculations show that the expected oxygenation pathways are kinetically disfavored, as direct sulfur oxygenation from the side-on Fe(III)–superoxo species requires a barrier of 22.4 kcal mol–1 and side-on-to-end-on isomerization does not provide an efficient cysteine dioxygenase (CDO)-like oxygen-transfer pathway. Instead, the reaction proceeds through a bromide-assisted O–O cleavage mechanism, in which outer-sphere Br– promotes O–O bond cleavage to generate an FeIV=O(OBr) intermediate as the competent oxygenating species. Subsequent coordination reorganization and second-sphere hydrogen bonding enable sequential oxygen transfer to sulfur, ultimately forming the FeII–sulfinate product. Reaction-coordinate, bonding, and topological analyses show that O–O cleavage is a cooperative bond-reorganization event involving Br–O interaction formation, O–O weakening, and ferryl-like Fe–O strengthening. Comparative Br-assisted, Cl-assisted, and halide-free models further establish that halide participation lowers the O–O cleavage barrier, with Br-assisted cleavage either kinetically favored over or comparable to its Cl-assisted counterpart. These findings reveal a non-innocent role of outer-sphere bromide in modulating the identity of the oxygenating species and the sequence of sulfur oxygenation in this biomimetic nonheme iron system.