Design and Isolation of Stable Nitroxy Radicals

Persistent nitroxyl radicals – stable species that have an N–O• fragment – form one of the more popular classes of radicals. They have many practical uses ranging from oxidation catalysts and living polymerization reagents to radical and spin traps in mechanistic studies to medicinal agents. The archetypical member of this class –TEMPO – is shelf-stable and often the catalyst of choice in many industrial and academic endeavours.

In TEMPO, the otherwise unstable nitroxyl radical moiety is stabilized by being surrounded on either side by two methyl groups. The absence of neighbouring hydrogen atoms precludes the primary decomposition of nitroxyl radicals: disproportionation to give the hydroxylamine and nitrone. There are numerous derivatives related to TEMPO but all maintain the motif of not having any hydrogen atoms next to the nitroxyl radical moiety. Despite its widespread use, it is thought that the efficacy of the TEMPO and related compounds is adversely affected by the steric bulk that partially shields the radical centre. There are a few examples of nitroxyl radicals with a hydrogen atom next to the radical centre, but their numbers are limited and have a number of disadvantages.

In a collaborative project between Prof. Alex Szpilman of the Technion – Israel Institute of Technology’s Schulich Faculty of Chemistry and Dr. Mark Iron of the Weizmann Institute of Science’s Department of Chemical Research Support, whose preliminary findings were recently published online in Nature Communications,[1] the goal was set to find new classes of nitroxyl radicals having a hydrogen atom on one or both sides of the radical centre. By relieving the steric bulk around the nitroxyl radical centre, it was hypothesized that the catalytic efficiency would be significantly improved. Desired properties of the new radicals include easy preparation from readily available starting materials, easy modification to provide a high degree of customization, long shelf-life and high catalytic efficiency.

Two novel classes of nitroxyl radicals were developed, both having hydrogen atoms next to the nitroxyl radical centre and neither involving a bicyclic frame. Isoindoles have one such hydrogen atom, while iso-azaphenylenes have one hydrogen atom on each side of the radical centre. Both are easy to prepare in large quantities and are stable for months in the solid state.

This joint experimental and computational study showed that the stability of the two classes of nitroxyl radicals can be attributed to the steric bulk of the single substitutent next to the hydrogen atom. In a proof-of-concept experiment, the copper co-catalysed oxidation of benzyl alcohol to benzaldehyde was dramatically faster with the two examples of iso-azaphenylene that were prepared than with the previous catalyst of choice, TEMPO.

Further investigation into the development and application of these remarkable new compounds is on-going.

[1] M. Amar, S. Bar, M. A. Iron, H. Toledo, B. Tumanskii, L. J. W. Shimon, M. Botoshansky, N. Fridman and A. M. Szpilman, Nature Communications, 6, 6070 (2015).