Electronic structures and spin topologies of gamma-picoliniumyl radicals. A study of the homolysis of N-methyl-gamma-picolinium and of benzo-, dibenzo-, and naphthoannulated analogs

Abstract

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-gamma-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-gamma-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), gamma-picoline (P, 4-methylpyridine), and N-methyl-gamma-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.

Figure 1

Molecular models of the MP2/6-31G* optimized structures of 4-methylpyridine P (a.k.a. γ-picoline), 1,4-dimethylpyridinium 1c (a.k.a. 1-methyl-γ-picolinium), 1,4-dimethylquinolinium 2c, 9,10-dimethylacridinium 3c, 1,4-dimethylbenzo[g]quinolinium 4c, and of the corresponding radical cations PR and 1rc – 4rc.

Figure 2

Electrostatic potentials of toluene T and benzyl radical TR (left), of 4-methylpyridine P and 4-methylpyridinium-4-yl PR (center), and of 1,4-dimethylpyridinium 1c and 1,4-dimethylpyridinium-4-yl 1rc. The QCI/6-31G*//MP2/6-31G* potentials are shown, their values are color-coded (−0.05 to 0.15 a.u.), and they are displayed on isosurfaces of the electron densities (ρ = 0.0004 a.u.).

Figure 3

Spin polarization in (from top) methyl radical (CH₃, ²A₂), radical cations of ethene (C₂H₄⁺, ²B_2u), acetylene (C₂H₂⁺, ²B_u), and dinitrogen (N₂⁺, ²Σ_g), and triplet oxygen (³O₂, ³Σ_g). Electron density isosurface for ρ = 0.04; spin density isosurfaces for ρ^S = ±5·10⁻⁴.

Figure 4

Spin density distributions of benzyl radical and its pyridine and pyridinium derivatives. Spin densities are color-coded (−4.432·10⁻³ to 4.432·10⁻³ a.u.) and displayed on isosurfaces of the electron densities (value 0.04 a.u.).

Figure 5

Annulation effects on spin density distributions of radical cations 2rc – 4rc computed with the B3LYP/6-31G* and QCI/6-31G* densities. Spin densities are color-coded (−4.432·10⁻³ to 4.432·10⁻³ a.u.) and displayed in isosurfaces of the electron densities (value 0.04 a.u.).

Scheme 1

Radicals formed under hypoxic conditions.

Scheme 2

Homolyses of toluene (T → TR + H), γ-picoline (P → PR + H), N-methyl-γ-picolinium (1c → 1rc + H), and annulated 1c-derivatives 2c – 4c.

Chart 1

Electron delocalization in the parent and benzoannulated benzyl radical (Y = CH) and their hetero-analogs (Y = N, NR⁺).

Chart 2

Avoidance of benzyl delocalization as primary stabilization mode: Alternative homoallyl systems, diphenylmethyl systems, and remote spin appearance.

Chart 3

Polarities of toluene T, γ-picoline P, and N-methyl-γ-picolinium 1c and their homolysis products benzyl TR, γ-picolinyl PR, and N-methyl-γ-picoliniumyl 1rc, respectively.

Chart 4

Spin dipole and spin quadrupole polarizations in localized and delocalized MOs.

Chart 5

Spin quadrupole polarization of allyl’s “π₁-electron pair” by the unpaired electron in the π₂-SMO.

Chart 6

“Electron delocalization” and “spin delocalization” in the regions C(CH₂), C_oH, C_mH, and Y. Each set contains data for TR (Y = C_pH), PR (Y = N), and 1rc (Y = NCH₃) on differences between ROHF and QCI data.

Chart 7

Strategies to control the stabilities and reactivities of N-alkyl-γ-picoliniumyl radicals aim at the manipulation the C_o–C_m bond polarity.