An Air‐Stable, Neutral Phenothiazinyl Radical with Substantial Radical Stabilization Energy

Abstract

The vital effect of radical states on the pharmacological activity of phenothiazine‐based drugs has long been speculated. Whereas cationic radicals of N‐substituted phenothiazines show high stability, the respective neutral radicals of N‐unsubstituted phenothiazines have never been isolated. Herein, the 1,9‐diamino‐3,7‐di‐tert‐butyl‐N1,N9‐bis(2,6‐diisopropylphenyl)‐10H‐phenothiazin‐10‐yl radical (SQH2.) is described as the first air‐stable, neutral phenothiazinyl free radical. The crystalline dark‐blue species is characterized by means of EPR and UV/Vis/near‐IR spectroscopy, as well as cyclic voltammetry, spectro‐electrochemical analysis, single‐crystal XRD, and computational studies. The SQH2. radical stands out from other aminyl radicals by an impressive radical stabilization energy and its parent amine has one of the weakest N−H bond dissociation energies ever determined. In addition to serving as open‐shell reference in medicinal chemistry, its tridentate binding pocket or hydrogen‐bond‐donor ability might enable manifold uses as a redox‐active ligand or proton‐coupled electron‐transfer reagent.

Thermally encapsulated phenothiazine@MWCNT cathode for aqueous zinc ion battery

“…Of the different cation radicals, the semi benzoquinone-type radical cation species (SQH˙ + & SQ + ) are highly unstable. 50 It is vulnerable to oxidation or disproportionation into the more favorable 14-π electron quinonic (Q + ) cation system, which is stabilized by gaining aromaticity by the Huckel magic number. 51 The chemical stability of phenothiazine was also questionable as they undergo unavoidable side reactions by the radical coupling or oxidation of sulfur to sulfoxide and further to sulfone.…”

Synthesis of Novel Chalcone-Based Phenothiazine Derivatives as Antioxidant and Anticancer Agents

“…It has been reported that the antioxidant activity of phenothiazine and its derivatives is due to the formation of a stable radical cation that becomes stabilized over a large conjugative moiety, and to the change of the phenothiazine butterfly structure to a planar one. In this context, the pharmacological activity of phenothiazine core as an anticancer agent has been attributed to radical stability [ 50 ]. It is worthy of mentioning that chemical antioxidant activity was determined by a simple assay, and in vitro antioxidant activity would better reflect a closer value to the in vivo activity [ 51 , 52 ].…”

Electrochemical Synthesis of the in human S-oxide metabolites of phenothiazine containing Anti-Psychotic Medications

“…Likely due to the deprotonation and one-electron oxidation that occurred. [33] Upon completion of the reaction, a precipitate formed due to the overoxidation product being insoluble in acetonitrile.…”