Interrupted Homolytic Substitution Enables Organoboron Compounds to Inhibit Radical Chain Reactions Rather than Initiate Them

Abstract

The reactions of organoboranes with peroxyl radicals are key to their use as radical initiators for a vast array of radical chain reactions – particularly at low temperatures where high stereoselectivity and/or regioselectivity is desired. While these reactions generally proceed via concerted homolytic substitution (SH2) mechanisms, organoboranes which bear groups that can stabilize tetracoordinate boron radical “ate” complexes (e.g. catecholboranes) undergo this reaction via a step-wise addition / fragmentation sequence, and serve as useful stoichiometric alkyl radical precursors. Here we show that arylboronic esters and amides derived from catecholborane and diaminonaphthaleneborane, respectively, are potent radical-trapping antioxidants (RTAs). Mechanistic studies reveal that this is because the radical “ate” complexes derived from peroxyl radical addition are sufficiently persistent to trap another radical, in an interrupted SH2 reaction. Remarkably, the reactivity of these organoboranes as inhibitors of autoxidation was shown to translate from simple hydrocarbons to the phospholipids of biological membranes, such that they can inhibit ferroptosis, a cell death modality driven by lipid autoxidation and relevant in neurodegeneration and other major pathologies. The unique mechanism of these organoboranes is one of only a handful of RTA mechanisms that are not based on H-atom transfer processes and provide a new dimension to boron chemistry and its applications.

Keywords: organoboranes, radicals, chain reactions, autoxidation, antioxidants, mechanisms