Reactivity of Polycyclic and Heteroaromatic Compounds

The polycyclic aromatic hydrocarbons such as naphthalene, anthracene, and phenanthrene undergo the various types of EAS and are generally more reactive than benzene. One reason for this is that the localization energy for formation of the cationic intermediate is lower than for benzene because more of the initial resonance stabilization is retained in intermediates that have a fused benzene ring. CNDO calculations provide estimates of the localization energies. For benzene, naphthalene, and anthracene, these are, respectively, 36.3, 15.4, and 8.3 kcal/mol.  

The relative stability of the TSs determines the position of substitution under kinetically controlled conditions. For naphthalene, the preferred site for electrophilic attack is the 1-position, which is the result of the greater stability of the cationic intermediate for 1-substitution. 

Two factors can result in substitution at the 2-position. If the electrophile is very bulky, the hydrogen on the adjacent ring may cause a steric preference for attack at C(2). Under conditions of reversible substitution, where relative thermodynamic stability is the controlling factor, 2-substitution is frequently preferred. An example of this behavior is in sulfonation, where low-temperature reaction gives the 1-isomer, but at elevated temperatures the 2-isomer is formed.  

CerfoviXam, Mechanistic Aspects in Aromatic Sulfonation and Desulfonation, Interscience, New York, 1968, pp. 68-69. 

Both phenanthrene and anthracene have a tendency to undergo addition reactions under the conditions involved in certain electrophilic substitutions. For example, an addition product can be isolated in the nitration of anthracene in the presence of hydrochloric acid. This is a result of the relatively close balance in resonance stabilization to be regained by elimination (giving an anthracene ring) or addition (resulting in two benzene rings). 

Molecular orbital calculations provide estimates of the localization energies. For benzene, naphthalene, and anthracene these are, respectively, 36.3, 15.4, and 8.4 kcal/mol.  

Phenanthrene and anthracene both react preferentially in the center ring. This behavior is expected from simple resonance considerations. The cr complexes that result from substitution in the center ring have two intact benzene rings. The total resonance stabilization of these intermediates is larger than that of the napththalene system that results if substitution occurs at one of the terminal rings. 

---

As can be seen from reaction (1), these compounds can include groups that would be reactive toward organolithiums or organomagnesium halides and hence prohibit the use of such metal-Hg exchanges for their formation. Polycyclic aromatics , heteroaromatics ... 

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. 

---