Synthesis of polybrominated dibenzo-p-dioxins and mixed bromo/chloro dibenzo-p-dioxins

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

Submitted to: American Chemical Society National Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 12/13/2017
Publication Date: 3/18/2018
Citation: Singh, A., Hakk, H., Lupton, S.J. 2018. Synthesis of polybrominated dibenzo-p-dioxins and mixed bromo/chloro dibenzo-p-dioxins [abstract]. American Chemical Society 255th National Meeting. Marach 18-22, 2018. New Orleans, LA. Paper No. ORGN 691.

Interpretive Summary:

Technical Abstract: Polychlorinated dibenzodioxins (PCDDs) are considered to be persistent organic pollutants and their adverse health effects are intensively documented. Polybrominated (PBDD) and mixed bromo/chloro dibenzo-p-dioxins (PXDD) by-products are formed during brominated flame retardant (BFR) synthesis and during BFR-treated plastics incineration. PBDDs and PXDDs possess the same high in vitro toxicity as their chlorinated relatives, and the World Health Organization has recommended the same toxicity equivalent factors (TEFs) be applied to them. The PBDD/PXDD compounds have also been identified in the same matrices as PCDDs, i.e. flue gas and incineration ash, marine organisms, sewage sludge, and house dust. Despite the in vitro toxicity results, very little is known about the pharmacokinetic behavior of this class of chemicals. In order to facilitate future adsorption, disposition, metabolism and excretion (ADME) animal studies, it is required that they be synthesized at sufficient mass, and preferably, as radiochemicals. Herein we report a new, but simple and convenient, method to synthesize a library of PBDDs, as well as mixed PXDDs, in moderate to high yields. The first step involved the synthesis of properly-halogenated precursor molecules, i.e. o-catechol and 1-nitro-2-fluorobenzene. Di, tri, or tetrahalogenated o-catechol congeners were synthesized by bromination of o-catechol carefully controlling bromine stoichiometry, or chlorination by sulfuryl chloride. The synthesis of 1-fluoro-2-nitro bromobenzene congeners proceeded by bromination of 1-fluoro-2-nitrobenzene utilizing N-bromosuccinimide, while chlorinated congeners were purchased. The second step involved nucleophilic substitution of halogenated o-catechol with the halogenated 1-fluoro-2-nitrobenzene in the presence potassium carbonate base in DMSO at 150 'C (Scheme 1). Ten PBDD/PXDD molecules were synthesized by these methods, 6 toxic and 4 non-toxic (30-77% yield), although the approach is general enough that most mono-to-octa-halogenated dioxin molecules could be synthesized by these methods.