Facile synthesis of bromo- and mixed bromo/chloro dibenzo-p-dioxins and [14C]-labeled 1,3,7,8-tetrabromodibenzo-p-dioxin

Abstract

Polybrominated dibenzo-p-dioxins (PBDDs) and mixed bromo/chloro dibenzo-p-dioxins (PXDDs) are persistent organic pollutants that can possess the same toxicity as their fully chlorinated analogs (PCDDs) and have been identified in the same matrices. Herein a general synthetic methodology is described to produce multiple congeners of PBDDs and PXDDs with varying degrees of halogenation and substitution patterns for use as analytical and/or internal standards, and for absorption, disposition, metabolism, and excretion (ADME) studies. The syntheses of PBDDs and PXDDs were accomplished by condensing a common precursor, 4,5-dibromo catechol, with variable precursors, i.e., polychlorinated 1-chloro-2-nitrobenzenes or polybrominated 1-fluoro-2-nitrobenzenes, to introduce a desired number of halogens and specific substitution patterns. Initial attempts to synthesize PBDDs and PXDDs were performed in potassium carbonate with DMSO at 145–150 °C. PXDDs syntheses resulted in formation of the desired products at >90% purity but attempts at higher brominated PBDDs syntheses resulted in dehalogenated by-products. To preclude by-product formation, additional syntheses for some PBDDs were conducted by refluxing the precursors in acetonitrile, which resulted in pure products at higher yield. Six PXDDs ranging from four to six halogens were synthesized (20–84% yield), of which three contained the halogen substitution pattern of 2,3,7,8. Five PBDDs ranging from four to six bromines were produced in 23–83% yield, three of which were toxic. Using the initial DMSO method, [14C]-1,3,7,8-tetrabromodibenzo-p-dioxin (0.26 μCi/μmol; 11% overall yield) was synthesized from commercially available [14C]-phenol to allow an ADME study to be conducted.