AB-INITIO MO OPTIMIZATION OF MOLECULAR-STRUCTURES OF FLUOROSUBSTITUTED AND CHLOROSUBSTITUTED DIBENZO-P-DIOXINES AND THE EFFECT OF HALOGEN SUBSTITUTION AT THE 2,3,7,8-POSITIONS ON METABOLIC ATTACK

Full ab initio optimizations were performed on the molecular structure s of 24 fluorinated and chlorinated dibenzodioxines (PFDD/PCDD) and di benzofurans (PFDF/PCDF). Reasonable agreement was found by comparing t he geometries of four calculated structures with known X-ray data from the literature. For the fluorine substituent, calculated electron den sities (Mulliken total charges and pi-electron charges) clearly demons trate the opposite influence of the inductive (I) and mesomeric (M) ef fect. The changes in pi-densities at carbons in ortho-, meta- and pam- position are constant for each fluorine substituent (independent of de gree, pattern, and position of substitution). It is thus possible to c alculate the pi-densities of the substituted dioxines by increments st arting from dibenzodioxine. pi-Charges from quantum mechanical calcula tions and the increment system show good agreement even for OctaFDD (O 8FDD), where eight substituent effects are acting additively. Compared with fluorine, the chlorine substituent exercises a smaller -I-effect and a clearly weaker +M-effect. The HOMO coefficients of the unsubsti tuted dibenzodioxine and dibenzofuran, extracted from nb initio calcul ations, yield a good explanation for the observed regioselective metab olic attack at the 2,3,7,8-positions. The squares of the HOMO-coeffici ents of the 2,3,7,8-positions in dibenzodioxine (DD) are about ten tim es greater than those of the 1,4,6,9-positions. These HOMO coefficient s are practically unaffected by halide substitution. But halogen subst itution reduces strongly the electron density at the halogen-bound car bon, which, however, is a necessary prerequisite for the electrophilic oxygen transfer during metabolism. One would therefore expect halogen substitution of dibenzodioxine and dibenzofuran (DF) at the 2,3,7,8-p osition to hinder metabolism as is indeed found. This provides a plaus ible explanation for the highly selective tissue retention of 2,3,7,8- substituted PCDDs and PCDFs. Our ab initio calculations of five tetra CDDs (T(4)CDDs) confirm the postulate of Kobayashi et al. [1] who, usi ng semiempirical calculations, found a correlation between the toxicit y of a dioxine congener and its absolute molecular hardness. The 2,3,7 ,8-T4CDD also exhibits the smallest absolute hardness (derived from th e HOMO-LUMO energy gap) in our calculations.