Halogenated diphenyl ethers

Substitution at the 3 and 5 positions with alkyl groups or with halogens large enough to force the diphenyl ether nucleus to adopt a minimum... 

Condensation of aminopyrazole 116 with ethoxy-methylene malonic ester gives the product of addition-elimination (117), which is then cyclized to the piperidone by heating in diphenyl ether. The product tautomerizes spontaneously to the hydroxypyridine 118. The hydroxyl group is then converted to the chloro derivative by means of phosphorus oxychloride (119). Displacement of halogen by n-butylamine gives... 

BFRs are one of the last classes of halogenated compounds that are still being produced worldwide and used in high quantities in many applications. In order to meet fire safety regulations, flame retardants (FRs) are applied to combustible materials such as polymers, plastics, wood, paper, and textiles. Approximately 25% of all FRs contain bromine as the active ingredient. More than 80 different aliphatic, cyclo-aliphatic, aromatic, and polymeric compounds are used as BFRs. BFRs, such as polybrominated biphenyls (PBBs), polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA), have been used in different consumer products in large quantities, and consequently they were detected in the environment, biota, and even in human samples [26, 27]. 

PBBs and PBDEs may also cause toxicity by other mechanisms of action. For example, some PBB congeners can be metabolized to reactive arene oxides (Kohli and Safe 1976 Kohli et al. 1978) that may alkylate critical cellular macromolecules and result in injury. PBDEs may disrupt thyroid hormones by induction of hepatic microsomal UDPGT, which increases the rate of T4 conjugation and excretion, or by mimicking T4 or T3 PBDEs and their hydroxy metabolites are structurally similar to these thyroid hormones which are also hydroxy-halogenated diphenyl ethers (see Section 3.5.2). Clinical interventions designed to interfere with this mechanism or the metabolism of PBBs have yet to be developed. 

Stafford. CJ. 1983. Halogenated diphenyl ethers indentified in avian tissues and eggs by GC/MS. Chemosphere 12(11/12) 1487-1495. 

Gara A, Andersson K, Nilsson C, Norstrom A (1981), Chemosphere 10 365-390.. .Synthesis of halogenated diphenyl ethers and dibenzofurans - a discussion of specific isomers available" Gray AP, Cepa SP, Cantrell JS (1975), Tetrahedron Lett. 33 2873-2876.. .Intervention of the Smiles rearrangement in syntheses of dibenzodioxins 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodi-benzodioxin (HCDD) ... 

The starting substances for the synthesis of the required diphenyl ethers are suitably substituted o-nitrochlorobenzenes, which react with phenols containing in the ortho position a methoxy, nitro, or halogen group. 

PCDEs can be prepared by direct chlorination of diphenyl ether and they were intended to be used for similar purposes as commercial PCB mixtures, chlorination mixtures of biphenyl. Direct chlorination of diphenyl ether at room temperature in acetic acid solution without catalyst yields mainly a monochlorinat-ed diphenyl ether (4-monoCDE) [9], whereas direct halogenation of diphenyl ether with Lewis acid catalysts such as A1C13 results a complex mixture of PCDEs [10]. The synthesis of most individual PCDE congeners can be performed via coupling of biaryliodonium salts and phenols [10]. 

Fish-specific TEFs of halogenated diphenyl ethers have been low also in a rainbow trout early life stage mortality bioassay [85]. Halogenated diphenyl ethers were inactive in this bioassay, whereas polyhalogenated dibenzo-p-dio-xins, dibenzofurans, and biphenyls reduced growth and produced yolk sac edema and craniofacial malformations. PCDEs 71, 77, 102, 118, and 126 and PBDEs 47,85, and 99 were analyzed in this bio assay. 

Neurotoxicity can also occur as a result of indirect effects. For example, damage to hepatic, renal, circulatory, or pancreatic structures may result in secondary effects on the function and structure of the nervous system, such as encephalopathy or polyneuropathy. Secondary effects would not cause a substance to be considered neurotoxic, though at high enough doses, neurotoxicity could be evident. Thus, for the purpose of this review, a substance is defined as neurotoxic when it or its metabolites produce adverse effects as a result of direct interactions with the nervous system. It should be noted, nevertheless, that some chemicals may have multiple modes of action and affect the nervous system directly and indirectly. For example, several halogenated compounds (e.g., polychlorinated biphenyls (PCB), polybrominated diphenyl ethers (PBDE)) may interact directly with brain cells, and also affect the development of the nervous system by altering thyroid hormone homeostasis.7 8... 

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