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A Computational Study of Carbocations from Oxidized Metabolites of Dibenzo[ a , h ]acridine and Their Fluorinated and Methylated Derivatives

2005; American Chemical Society; Volume: 18; Issue: 12 Linguagem: Inglês

10.1021/tx0501841

1520-5010

Gabriela L. Borosky, Kenneth K. Laali,

Synthesis and Biological Evaluation

In a model computational study aimed at understanding structure−reactivity relationships and substituent effects on carbocation stability in aza-polycyclic aromatic hydrocarbons, the epoxides, diol epoxides, and the dihydrodiols of dibenzo[a,h]acridine (DB[a,h]ACR) were studied by density functional theory at the B3LYP/6-31G* level. Bay region carbocations were formed via the O-protonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (polarized continuum model method). Charge delocalization modes in the resulting carbocations were deduced by gauge-independent atomic orbitals (GIAO) NMR (based on Δδ13C values) and via the natural population analysis (NPA)-derived changes in charges. Although the solvent decreases the exothermicity of the epoxide ring-opening reactions due to greater stabilization of the reactants, relative reactivity trends remain the same. Whereas fluorine substitution at ring positions bearing significant positive charge leads to carbocation stabilization by fluorine p-π back-bonding, fluorine substitution at a ring position that presented negative charge density in the unsubstituted compound leads to inductive destabilization. Methylated derivatives exhibit less sensitivity to substituent effects as compared to the fluorinated analogues. A bay region methyl group produces structural distortion, and this deviation from planarity destabilizes the epoxide, favoring ring opening. Relative energies, changes in NPA charges, and GIAO NMR data in the resulting "benzylic" carbocations are examined collectively and discussed, taking into account the available biological activity data on these compounds.