Arenes toxicity

Although many of the aromatic compounds based on benzene have pleasant odors, they are usually toxic, and some are carcinogenic. Volatile aromatic hydrocarbons are highly flammable and burn with a luminous, sooty flame. The effects of molecular size (in simple arenes as well as in substituted aromatics) and of molecular symmetry (e.g., xylene isomers) are noticeable in physical properties [48, p. 212 49, p. 375 50, p. 41]. Since the hybrid bonds of benzene rings are as stable as the single bonds in alkanes, aromatic compounds can participate in chemical reactions without disrupting the ring structure. 

Daly JW, DM Jerina, B Witkop (1972) Arene oxides and the NIH shift the metabolism, toxicity and carcinogenicity of aromatic compounds. Experientia 28 1129-1149. 

A successful designer of a toxic laboratory will find it necessary to refine most of the elements of the traditional chemical laboratory. Many details which aren t directly associated with the toxic operations will impact on the safety of these operations. Because common laboratory mishaps will be far more serious where toxics are used, it makes sense to invest every effort to preclude such accidents through careful design. 

There are people in the Washington Toxics Coalition—which I m a member of—who aren t chemically injured but who are really supportive of us and advocate for us. 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

This section is dedicated to arene oxides of bicyclic and tricyclic arenes (e.g., naphthalene, anthracene, and phenanthrene oxides), whereas higher arenes and particularly benzo[a]pyrene (one of the most toxic and intensively investigated PAHs) are examined in Sect. 10.4.4. 

BA undergoes metabolism in animals and humans to intermediates responsible for its toxicity. These metabolic intermediates include arene oxides, dihydrodiols, and diol epoxides such as BA 3,4-dihydrodiol and BA 3,4-diol-l,2-epoxide. ... 

The first systematic investigations of the catalytic Friedel-Crafts-type reaction with alcohols and olefines were performed by Yamamoto and colleagues. After reporting the development of a Pd-catalyzed method for the allylation of different naphthol derivatives [24], the authors used Mo(CO)g for the Friedel-Crafts-type alkylation of electron-rich arenes with allyl acetates [25], The same molybdenum catalyst was additionally used for a Friedel-Crafts-type alkylation of arenes using 1-phenylethanol and styrene as alkylating reagents [26], However, Mo(CO)g is toxic and must be handled under strictly inert conditions. Thus, more stable Lewis acids were necessary. 

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. 

The pleasant odors of the derivatives of many arenes is the origin of the name aromatic hydrocarbons. The arenes themselves generally are quite toxic some are carcinogenic and inhalation of their vapors should be avoided. The volatile arenes are highly flammable and burn with a luminous sooty flame, in contrast to alkanes and alkenes, which usually burn with a bluish flame leaving little carbon residue. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

For alkene dihydroxylations, heavy metal oxides such as 0s04 and Ru04 can be applied. They are efficient catalysts but their toxitity makes their use less desirable and there is a dear need for non-toxic metal catalysts. Nevertheless, only a few reports have focused on the use of iron catalysts for alkene dihydroxylations. All systems described so far try to model the naturally occurring Rieske dioxygenase, an enzyme responsible for the biodegradation of arenes via cis-dihydroxylation by soil baderia [66]. 

One of the most important reactions in arene synthesis is the halogenation of arenes. Conventionally, these reactions are performed directly by bromine or chlorine [7]. However, on the laboratory scale chlorine is not easily manageable and is a toxic gas. Therefore, it is not often used in academic research. For iodinations normally a strong oxidizing agent is required. In halogenations, often unintentional side-chain... 

Aryl and heteroaryl (furyl, thienyl) boronic acids are especially suitable for the preparation of their iodonium salts, having the added advantage of better yields and lack of toxicity [108]. Tetraarylborates (sodium or potassium) reacted with (diacetoxyiodo)arenes in acetic acid to afford diaryliodonium salts in excellent yield (Scheme 37). It appears that triarylboranes formed upon reaction of the borates with acetic acid serve actually as the real arylating agents [109]. 

Ethoxylates Many cosmetic ingredients are created with the help of these toxic petroleum-derived surfactants. Polyethylene glycols are among the most common, and each is identified on labels as PEG, followed by a number. There are literally hundreds of PEGs on your cosmetic labels. (BDIH Certified Natural Cosmetics aren t allowed to contain ethoxylated ingredients.)... 

The most serious toxicities associated with carbamazepine use are idiosyncratic skin rashes, hematological disorders, hepatotoxicity, and teratogenicity (80). On the basis of studies with mice, teratogenicity is most likely related to formation of arene oxide and/or quinone-like metabolites of carbamazepine (83),... 

Perhaps the most widely reported use of silver acetylides is in the deprotection of 1-trimethylsilyl-l-alkynes. Schmidt and Arens first reported the treatment of 1-trimethylsilyl-l-alkynes with silver nitrate to give the silver acetylide in situ, which, when treated with potassium cyanide, is converted to the free alkyne (Scheme 1.63).137 This very mild and selective, but toxic, means for the selective... 

There is some evidence that particular calixarene derivatives have direct therapeutic properties. The antitubercular action of 4-octylcalix[8]arenes with pendent polyether chains was determined by Cornforth s group in the early 1950s where the compound, then of unknown composition and called Macrocyclon, was shown to be generally non-toxic to mammals and yet more potent than streptomycin in the treatment of tubercular bacilli [32],... 

Sodium thiophenoxide and bis phenyliodonium acetylene triflate afforded cleanly l,2-bis(phenylthio)acetylene [6]. Alkynyl iodonium salts have alkynylated several arene sulphonates which were converted into alkynyl aryl sulphones. The process is probably the best among other methods, as far as yield, availability of starting materials, non-toxicity and ease of handling are concerned. 

Akira Suzuki, from Kurashiki University, Japan, is one of the great names of arene chemistry due to his outstanding reaction that bears his name. As expected, his chapter (No. 3) deals with the Suzuki reaction with arylboron compounds and its synthetic applications in arene chemistry. The Suzuki reaction is now becoming all the more important as requirements for organic synthesis will necessarily have to take ecological aspects ( green chemistry ) into account and use of a number of toxic metals is phased out. 

Alkane hydroxylation is carri out in nature by a variety of enzymes, but the ones that have attracted most attention are the cytochrome P-450 dependent systems found, for example, in mammalian liver. In the liver they serve to detoxify lipid soluble species, such as drugs, by making them more water soluble and hence more easily eliminated. For some substrates, such as certain arenes, the hydroxylation in fact makes these substrates more toxic, by converting them to epoxides which then alkylate liver DNA. The ultimate source of the 0-atom used in the hydroxylation is O2, but only one of the two 0-atoms of the O2 is incorporated in the substrate, the other is reduced to H2O. This means two reducing equivalents are also required. Because they introduce only one 0-atom from O2 into the substrate, these enzymes are called monooxygenases (equation 59). 

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