Expanding the Palette of Phenanthridinium Cations

Andrew G Cairns,Michael P Murphy,Hans Martin Senn,Richard C Hartley

doi:10.1002/chem.201304241

Andrew G Cairns, Michael P Murphy + Show 2 more

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https://doi.org/10.1002/chem.201304241

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Abstract

5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. Some properties rely on phenanthridiniums intercalating into DNA, but the use of these cations as exomarkers for the reactive oxygen species (ROS), superoxide, and as inhibitors of acetylcholine esterase (AChE) do not require intercalation. A versatile modular synthesis of 5,6-disubstituted phenanthridiniums that introduces diversity by Suzuki–Miyaura coupling, imine formation and microwave-assisted cyclisation is presented. Computational modelling at the density functional theory (DFT) level reveals that the novel displacement of the aryl halide by an acyclic N-alkylimine proceeds by an SNAr mechanism rather than electrocyclisation. It is found that the displacement of halide is concerted and there is no stable Meisenheimer intermediate, provided the calculations consistently use a polarisable solvent model and a diffuse basis set.

Highlights

5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties
N-Alkylphenanthridinium cations (7) and N-alkyl-dihydrophenanthridines (8) bearing an alkyl or aryl substituent at C-6 can be interconverted by simple redox reactions
A few benzophenanthridiniums have been prepared by cyclisation of N-aryl-N-alkyl-acetamides using POCl3,[32] but the direct synthesis of 5,6-disubstituted phenanthridinium salts by this method is not know

Summary

Introduction

5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. 5,6-Disubstituted dihydrophenanthridines, which are prepared by reduction of the corresponding phenanthridiniums, have useful properties They can be oxidised in vivo to the corresponding phenanthridiniums by reactive oxygen species (ROS).[2] Such ROS are predominantly produced by reduction of oxygen to superoxide in the mitochondria,[18] and underlie much of the damage in cardiovascular disease, stroke and neurodegeneration. They are implicated in the process of ageing.

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