Electronic Structures and Spin Topologies of γ-Picoliniumyl Radicals. A Study of the Homolysis of N-Methyl-γ-picolinium and of Benzo-, Dibenzo-, and Naphthoannulated Analogs


Radicals resulting from one-electron reduction of (N-methylpyridinium-4-yl) methyl esters have been reported to yield (N-methylpyridinium-4-yl) methyl radical, or N-methyl-γ-picoliniumyl for short, by heterolytic cleavage of carboxylate. This new reaction could provide the foundation for a new structural class of bioreductively activated, hypoxia-selective antitumor agents. N-methyl-γ-picoliniumyl radicals are likely to damage DNA by way of H-abstraction and it is of paramount significance to assess their H-abstraction capabilities. In this context, the benzylic C−H homolyses were studied of toluene (T), γ-picoline (P, 4-methylpyridine), and N-methyl-γ-picolinium (1c, 1,4-dimethylpyridinium). With a view to providing capacity for DNA intercalation the properties also were examined of the annulated derivatives 2c (1,4-dimethylquinolinium), 3c (9,10-dimethylacridinium), and 4c (1,4-dimethylbenzo[g]quinolinium). The benzylic C−H homolyses were studied with density functional theory (DFT), perturbation theory (up to MP4SDTQ), and configuration interaction methods (QCISD(T), CCSD(T)). Although there are many similarities between the results obtained here with DFT and CI theory, a number of significant differences occur and these are shown to be caused by methodological differences in the spin density distributions of the radicals. The quality of the wave functions is established by demonstration of internal consistencies and with reference to a number of observable quantities. The analysis of spin polarization emphasizes the need for a clear distinction between "electron delocalization" and "spin delocalization" in annulated radicals. Aside from their relevance for the rational design of new antitumor drugs, the conceptional insights presented here also will inform the understanding of ferromagnetic materials, of spin-based signaling processes, and of spin topologies in metalloenzymes.



Keywords and Phrases

4-methylpyridine; Anti-tumor agents; Anti-tumor drugs; Benzylic; CCSD; Configuration-interaction methods; Density-functional; DNA intercalations; Electron-delocalization; H-abstraction; Heterolytic cleavage; Homolysis; Metalloenzymes; Methyl esters; Methyl radicals; N-methylpyridinium; One-electron reductions; Perturbation theory; Rational design; Signaling processes; Spin delocalization; Spin density distributions; Structural class; Abstracting; Carboxylation; Discrete Fourier transforms; DNA; Electronic structure; Esters; Ferromagnetic materials; Genes; Magnetic materials; Nucleic acids; Organic acids; Organic compounds; Perturbation techniques; Probability density function; Spin dynamics; Toluene; Topology; Wave functions; Density functional theory; benzene; free radical; naphthol derivative; picoline derivative; chemical structure; conformation; electricity; electron; Electrons; Electrostatics; Free Radicals; Models; Molecular; Molecular Conformation; Naphthols; Picolines

International Standard Serial Number (ISSN)

1089-5639; 1520-5215

Document Type

Article - Journal

Document Version


File Type





© 2008 American Chemical Society (ACS), All rights reserved.

Publication Date

01 May 2008