Aromatic compounds, fused reactivity

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Few of these species are strictly aromatic, but reactivity with electrophiles resembles that of aromatic compounds. Much of the discussion that follows will be devoted to the pyrones and thiopyrones (the fused benz-derivatives, coumarins, chromones, flavones, and isoflavones, will be covered in Part 3). 

CAS 135-48-8. C22H14. Highly reactive aromatic compound consisting of five fused benzene rings. 

Pyrrole, furan, and thiophene are aromatic compounds that undergo electrophilic aromatic substitution reactions preferendally at C-2. These compounds are more reactive than benzene toward electrophiles. When pyrrole is protonated, its aromahcity is destroyed. Pyrrole polymerizes in strongly acidic solutions. Indole, benzofuran, and benzothiophene are aromatic compounds that contain a five-membered aromatic ring fused to a benzene ring. 

This Report follows the pattern established by the previous Reporter in Volume 1. The section dealing with fused 5,6-systems is chiefly concerned with the chemistry of purine and purine analogues and that on fused 6,6-systems with the chemistry of pteridines and flavins. Within the discussion of a given ring system, reference is made to synthetic methods before physical properties and reactivity. Where appropriate, fully aromatic compounds are discussed before those of an increased level of saturation. Because of the limits of space imposed on the Senior Reporters of this volume, it has been necessary to omit reference to much interesting work. 

Taylor has collected the above and similar data and compared the ratio of reactivities of the ortho and para positions of compounds of type 19 (expressed as log/odog/p) with the ratio of reactivities of the equivalent positions, a and c, in compounds of type 20 and found that the latter ratio was lower, i.e., a relative increase in the reactivity of the para position (c) has occurred upon ring formation. This fall in the ratio log fa log fc increases along the series X = S < 0 (< NH < CHg) in 20. As this trend parallels the increase in strain in the fused bridging ring it was argued that ring strain was the primary cause of the reduction in ratio. Position a is a-aromatic and position c is j8-aromatic therefore the above concept represents an extension by Taylor of an earlier explanation of the Mills-Nixon effect in indane. Further substitution... 

Recent work ( ) with model organosulphur compounds has shown that at temperatures above 350 C and pressures in excess of 100 atm (1500 psig), the hydrolytic desulphurisation reaction occurs readily with thioethers, mercaptans and other non-thio-phenic types of organosulphur compounds. Thiophene itself is more resistant to this type of reaction but desulphurisation is significant in the 450 - 500 C range. More complex fused ring sulphur containing aromatic structures, can, however, be more reactive. 

Chls and all tetrapyrroles are heteroaromatic compounds and the aromatic character of the underlying tetrapyrrole moiety and the reactivity of the functional groups in the side chains govern their chemistry. Three different classes of tetrapyrroles, differentiated by their oxidation level, occur in nature porphyrins (11, e.g. hemes), chlorins (12, e.g. chls) and bacteriochlorins (13, e.g. bchls). As a cyclic tetrapyrrole with a fused five-membered ring, the overall reactivity of chi is that of a standard phytochlorin 7. Such compounds are capable of coordinating almost any known metal with the core nitrogen atoms. Together with the conformational flexibility of the macrocycle and the variability of its side chains, this accounts for their unique role in photosynthesis and applications ... 

In a fused system there are not six electrons for each ring.8" In naphthalene, if one ring is to have six, the other must have only four. One way to explain the greater reactivity of the ring system of naphthalene compared with benzene is to regard one of the naphthalene rings as aromatic and the other as a butadiene system.81 This effect can become extreme, as in the case of triphenylene.82 For this compound, there are eight canonical forms like A. 

In this section the reactivity of aromatic and non-aromatic systems are treated separately as in Chapter 4.02. For convenience, the former group is taken to comprise all compounds of structural types (5)-(ll), including benzo fused derivatives, even when there is little evidence of aromaticity as is the case with dioxazoles. Likewise, the nonaromatic systems will include dihydro and tetrahydro derivatives of structural types (16)-(24). 

In each of the five sections of Chapter 3, the chemistry is reviewed in the following order (1) Reactivity of aromatic rings (thermal reactions not involving reagents, substitutions at carbon, additions to nitrogen, metallations) (2) Reactions of nonaromatic compounds (this enormous area, which overlaps extensively with nonheterocyclic chemistry, is reviewed with emphasis on the heterocyclic aspects) (3) Reactions of substituents (with emphasis on situations in which substituents behave somewhat differently when attached to a heterocycle note that for benzene-fused heterocycles, the benzene ring is treated as a substituent). 

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