An Air-Stable, Neutral Phenothiazinyl Radical with Substantial Radical Stabilization Energy.

Lukas M Sigmund,Nils Gönnheimer,Jonas Spengler,Fabian Ebner,Christoph Jöst,Deborah Hartmann,Lutz Greb

doi:10.1002/chem.201905238

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‐N 1,N 9‐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.

Highlights

The phenothiazine core structure appears in many pharmacologically active molecules with, for example, anticancerogenic, antipsychotic, or cardiovascular effects.[1]
Whereas the cationic radicals of N-substituted phenothiazines[4] are known for their high stability (Figure 1 b),[5] a substantial drop in stability occurs without the substituent at the nitrogen atom
The N-unsubstituted phenothiazines undergo stepwise two-electron oxidation and deprotonation (Figure 1 a), wherein the semiquinonic radical (SQHC) state is vulnerable for disproportionation or oxidation into the favorable aromatic 14 p-electron quinonic cation (Q+) state

Summary

Introduction

The phenothiazine core structure appears in many pharmacologically active molecules with, for example, anticancerogenic, antipsychotic, or cardiovascular effects.[1]. The N-unsubstituted phenothiazines undergo stepwise two-electron oxidation and deprotonation (Figure 1 a), wherein the semiquinonic radical (SQHC) state is vulnerable for disproportionation or oxidation into the favorable aromatic 14 p-electron quinonic cation (Q+) state. Phenothiazine constitutes the core structure of methylene blue, which is a well-known dye first prepared in 1876 by Caro at BASF (Figure 1 c).[6] Methylene blue was the first synthetic compound ever applied as an antiseptic agent in clinical therapy, even before the advent of sulfonamides or penicillin.[7] The methylene blue radical was postulated in 1939 and later supported by evidence from combined electrochemi-. Cal and EPR studies,[8] which revealed a high tendency toward disproportionation.[9] some persistent N-unsubstituted phenothiazinyl radicals permitted spectroscopic characterization, the isolation of a crystalline and air-stable derivative has, to the best of our knowledge, never been accomplished.[3b, 10]. We describe the air-stable, neutral, N-unsubstituted phenothiazinyl radical SQH2C (Figure 1 d). In addition to serving as a radical reference within the field of phenothiazine-based drugs, dyes, and reagents, SQH2C expands the, to date, limited class of non-heteroatom-substituted aminyl free radicals that can be handled without any precautions.[11]

Results and Discussion

Conclusions

Conflict of interest