Fused rings, electrophilic aromatic substitution

The polycyclic aromatic hydrocarbons such as naphthalene, anthracene, and phenan-threne undergo electrophilic aromatic substitution and are generally more reactive than benzene. One reason is that the activation energy for formation of the c-complex is lower than for benzene because more of the initial resonance stabilization is retained in intermediates that have a fused benzene ring. 

Electrophilic aromatic substitution of other benzo-fused v-deficient systems generally follows predictable pathways. Thus, benzopyrylium salts are in general resistant to electrophilic substitution even in the benzo-fused ring. Chromones behave somewhat similarly, although substitution can be effected under forcing conditions. Coumarins, on the other hand, undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

The effects of substituent groups in the benzo-fused ring on the ease of electrophilic aromatic substitution are essentially identical to those of the same substituent groups in benzene, so electron-donating groups facilitate reaction while electron-withdrawing groups... 

Appending the quinoxaline ring system to benzazepine 6 required amine protection before the dinitration reaction. The fused bicyclic system imposes close proximity of the nitrogen atom to the aromatic ring. As a result, the amine and sp -protected forms (amides and carbamates) unexpectedly inhibited electrophilic aromatic substitution (equations a and b. Scheme 3.6). We suspected that interactions of electrophilic reagents with the amine or protected amines generated competing... 

Polycyclic benzenoid hydrocarbons contain two or more fused benzene rings fused rings share two adjacent carbons. Polycychc benzenoid hydrocarbons undergo electrophilic aromatic substitution reactions. Naphthalene undergoes irreversible substitution predominantly at the 1-position and reversible substitution predominantly at the 2-position. The nature of the substituent determines which ring of a substi-tuted-naphthalene undergoes electrophilic substitution. 

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. 

An alternate route to fused ring pyrroles involves an interesting cyclization of (5-N-pyrrolyl-2-hydroxypentyl)cobaloxime (31), which proceeds by intramolecular electrophilic aromatic substitution of a cobaloxime n-cation onto the pyrrole ring to provide 6-exo cyclization product 32 enroute to a formal synthesis of (-)-tashiromine (33) <97TL7007>. 

Reactions with Electrophiles. The structure of isoquinoline 1 is the result of fusing benzene and pyridine together. Electrophilic aromatic substitution predominately occurs on the benzene ring under acidic conditions and usually addition takes place at the 5-position but can sometimes add to the 8-position. The rate of electrophilic aromatic substitution is slower for isoquinoline compared to naphthalene. The nitrogen in isoquinoline reacts similar to a pyridine nitrogen and will add a variety of electrophilic species such as 0-(2,4-dinitrophenyl)hydroxylamine 2 to aminate the nitrogen (eq 1). Friedel-Crafts acylation and alkylation do not work due to the formation of IV-acyl or IV-alkyl isoquinolinium salts. 

A novel [3-I-3]-benzannulation process occurs in the coupling of alkynylcarbene complexes (e.g., 160, Scheme 17.27) and heteroaromatic aldehyde-derived imines (e.g., 201) [83]. Furan, benzofuran, and N-substituted indole derivatives led to benzannulation products, heteroaromatic-fused benzenes (e.g., 204). The mechanism proposed involves electrophilic aromatic substitution at the 3-position of the heterocyclic ring, resulting in the complex 202, followed by a simultaneous 1,2-shift of the metal and nucleophilic addition to the iminium salt. 

As discussed in the theoretical section (4.04.1.2.1), electrophilic attack on pyrazoles takes place at C-4 in accordance with localization energies and tt-electron densities. Attack in other positions is extremely rare. This fact, added to the deactivating effect of the substituent introduced in the 4-position, explains why further electrophilic substitution is generally never observed. Indazole reacts at C-3, and reactions taking place on the fused ring will be discussed in Section 4.04.2.3.2(i). Reaction on the phenyl ring of C- and A-phenyl-pyrazoles will be discussed in Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i), respectively. The behaviour of pyrazolones is quite different owing to the existence of a non-aromatic tautomer. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Grimmett, M. R., Advances in Imidazole Chemistry, 12, 103 27, 241 Electrophilic Substitution in the Azines, 47, 325 Halogenation of Heterocycles I. Five-member ed Rings, 57, 291 II. Six and Seven-numbered Rings, 58, 271 III. Heterocycles Fused to Other Aromatic and Heteroaromatic Rings, 59, 245. 

---