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

Authors: Singh, Anuradha; Hakk, Heldur; Lupton, Sara

Submitted to: Chemosphere
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2019
Publication Date: 8/27/2019
Citation: Singh, A., Hakk, H., Lupton, S.J. 2019. Facile synthesis of bromo- and mixed bromo/chloro dibenzo-p-dioxins and [14C]-labeled 1,3,7,8-tetrabromodibenzo-p-dioxin. Chemosphere. 239. https://doi.org/10.1016/j.chemosphere.2019.124626.
DOI: https://doi.org/10.1016/j.chemosphere.2019.124626

Interpretive Summary: Persistent organic pollutants (POPs) are toxic chemicals usually containing bromine or chlorine atoms that accumulate and persist in the environment and food chain, and they are known to be globally transported. Human exposure most commonly occurs through consumption of food, particularly meat and milk products. Humans are exposed to new classes of POPs constantly, and risk assessments are needed to estimate exposure to these new chemicals. An important element of risk assessments is data on the absorption, disposition, metabolism, and excretion (ADME) of each chemical or chemical class within a food-producing animal. ADME studies can be conducted in a laboratory setting very easily with radiolabeled versions of these chemicals; however, these radiolabeled compounds are generally not commercially available. We developed a general method for the synthesis of POPs containing a varying number of chlorine and/or bromine atoms which will prove useful to make compounds to administer in ADME studies or to serve as internal standards when quantifying levels of these compounds in food. The developed method was general enough to create various unlabeled POPs, and was also used to successfully create a specific radiolabeled POP, which will be used in a future ADME study.

Technical 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. The development of a general synthetic method was undertaken 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 achieved 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 accomplished in potassium carbonate with DMSO at 145-150 °C. PXDD syntheses resulted in formation of the desired products at >90% purity, but attempts at higher brominated PBDD syntheses resulted in dehalogenated by-products. To limit by-product formation, additional syntheses for some of the PBDDs were conducted by refluxing the precursors in acetonitrile, which resulted in pure products at similar yield. Six PXDDs ranging from four to six halogens were synthesized (20-84% yield), of which 3 contained the toxic halogen substitution pattern of 2,3,7,8. Five PBDDs ranging from tetra- to hexa-bromo 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.