Inhibition of Hydrocarbon Autoxidation by Nitroxide Catalyzed Cross Dismutation of Alkylperoxyl and Hydroperoxyl Radicals & a Novel Approach Toward Fluorinated Polyunsaturated Lipids

Abstract

Nitroxides are intermediates in the accepted reaction mechanisms of the antioxidant activity of diarylamines and hindered alkyl amines. The parent amines are used as additives to preserve synthetic and natural hydrocarbon-based materials from oxidative degradation. New methodology which enables monitoring of hydrocarbon autoxidations at low rates of radical generation has revealed that diarylnitroxides and hindered nitroxides are far better inhibitors of unsaturated hydrocarbon autoxidation than their precursor amines, implying intervention of a previously overlooked mechanism. Experimental and computational investigations suggest that the nitroxides catalyze the cross-dismutation of alkylperoxyl and hydroperoxyl radicals to yield a hydroperoxide and O2, thereby halting the autoxidation chain reaction. The hydroperoxyl radicals – key players in hydrocarbon combustion, but essentially unknown in autoxidation – are proposed to derive from a tunneling-enhanced intramolecular (1,4)- hydrogen-atom transfer/elimination sequence from oxygenated radical addition intermediates. These insights suggest that nitroxides are preferred additives for the protection of unsaturated hydrocarbonbased materials from autoxidation since they exhibit catalytic activity under conditions where their precursor amines are less effective and/or inefficiently converted to nitroxides in situ. Polyunsaturated fatty acids (PUFAs) are highly autoxidizable lipids that are integral structural components of biological membranes as well as substrates for enzymes the produce inflammatory mediators implicated in a host of degenerative diseases. In particular, the interactions between these substrates and their respective native enzymes are hotly pursued since elucidation of the underlying mechanisms could lead to the discovery of better small molecule inhibitors for the ailments to which they contribute. In the past decade, an additional mode of cellular degeneration has been unveiled in the process of ferroptosis whose hallmark includes a sharp increase in the cellular pool of PUFA derived hydroperoxides. As a result, there is further incentive to uncover all mechanisms by which these inflammatory precursors are developed. Herein, progress toward the synthesis of fluorinated PUFAs is presented. These are proposed to be useful to probe the interactions of PUFAs with lipoxygenase enzymes, which metabolize polyunsaturated fatty acids to their hydroperoxide derivatives.