Design concept for α-hydrogen-substituted nitroxides

Stable nitroxides (nitroxyl radicals) have many essential and unique applications in chemistry, biology and medicine. However, the factors influencing their stability are still under investigation, and this hinders the design and development of new nitroxides. Nitroxides with tertiary alkyl groups are generally stable but obviously highly encumbered. In contrast, alpha-hydrogen- substituted nitroxides are generally inherently unstable and rapidly decompose. Herein, a novel, concept for the design of stable cyclic alpha-hydrogen nitroxides is described, and a proof-of-concept in the form of the facile synthesis and characterization of two diverse series of stable alpha-hydrogen nitroxides is presented. The stability of these unique alpha-hydrogen nitroxides is attributed to a combination of steric and stereoelectronic effects by which disproportionation is kinetically precluded. These stabilizing effects are achieved by the use of a nitroxide co-planar substituent in the gamma-position of the backbone of the nitroxide. This premise is supported by a computational study, which provides insight into the disproportionation pathways of alpha-hydrogen nitroxides.