Aromatic heterocycles defined

In this chapter we summarize the reactivity of the six-membered heterocyclic compounds. We describe first the aromatic compounds, where aromatic is defined as fully conjugated round the ring, and then the partially and fully saturated compounds. Within each of these sections we discuss first the reactivity at the ring atoms, then the reactivity of substituent groups. 

As often happen with chemistry concepts, atropisomerism was introduced with one example, which was both limited and clear. Then, it expanded to a general concept that lost its clarity. For this reason it is necessary to define clearly the subject of this review. Atropisomerism in heteroaromatic compounds refers to restricted rotation about a sp -sp bond between two rings one of them or both being an aromatic heterocycle. 

The reason why pyrrole is an QlQcixon-excessive aromatic heterocycle is because the electron density on each ring atom is greater than one. Pyrrole has a dipole moment of 1.55 D, similar to that of pyrrolidine in number although with opposite direction. (Here, the direction of the dipole moment vector is represented by an arrow and is properly defined so that the arrow is directed from the positive fractional charge to the negative fractional charge). 

Many of the reactions to sulfonamides involve the skin and mucous membranes. The more severe reactions that occur include potentially lethal toxidermias and a delayed hypersensi-tivity-type syndrome characterized by fever, skin rash, and multi-organ toxicity, hnmediate type I reactions are the most well-defined sulfonamide-induced hypersensitivity reactions with the best defined allergenic drug structmes. Sulfonamides with one methyl substituent on a five- or six-membered aromatic heterocyclic ring on the carbon p to the sulfon-amido substituent are the structmes most complanentary to anti-sulfamethoxazole IgE antibody combining sites. 

On the basis of the reaction of alkyl radicals with a number of polycyclic aromatics, Szwarc and Binks calculated the relative selectivities of several radicals methyl, 1 (by definition) ethyl, 1.0 n-propyl, 1.0 trichloromethyl, 1.8. The relative reactivities of the three alkyl radicals toward aromatics therefore appears to be the same. On the other hand, quinoline (the only heterocyclic compound so far examined in reactions with alkyl radicals other than methyl) shows a steady increase in its reactivity toward methyl, ethyl, and n-propyl radicals. This would suggest that the nucleophilic character of the alkyl radicals increases in the order Me < Et < n-Pr, and that the selectivity of the radical as defined by Szwarc is not necessarily a measure of its polar character. 

The inclusion of aromatic rings as part of the side chains results in quite potent agents, possibly because the rigid rings better define the position of the basic nitrogen. Reaction of para-hydroxyacetanilide (19-1) with formaldehyde and diethylamine affords the corresponding Mannich product (19-2) hydrolysis of the acetamide then leads to the aniline (19-3). Treatment of that compound with dichloro-quinoline (17-6) leads to the displacement of chlorine on the heterocyclic ring and the formation of amodiaquine (19-4) [21]. 

The fifth volume of Advances in Heterocyclic Chemistry surveys the chemistry of four well-defined groups of compounds pyrrolizidines (N. K. Kochetkov and A. M. Likhosherstov), aromatic quinolizines (B. S. Thyagarajan), 1,2,4-thiadiazoles (F. Kurzer), and the amino-chrome pigments (R. A. Heacock). 

For the purposes of this review, aromatic azapentalenes may be broadly defined as heterocyclic analogs of pentalene (I)1 which are aromatic by virtue of a 10- -electron system compounds of this type will thus be iso- -electronic with the pentalene dianion (2).2... 

Aromaticity has been long recognized as one of the most useful theoretical concepts in organic chemistry. It is essential in understanding the reactivity, structure and many physico-chemical characteristics of heterocyclic compounds. Aromaticity can be defined as a measure of the basic state of cyclic conjugated TT-electron systems, which is manifested in increased thermodynamic stability, planar geometry with non-localized cyclic bonds, and the ability to sustain an induced ring current. In contrast to aromatic compounds there exist nonaromatic and antiaromatic systems. Thus, pyrazine (69)... 

The chart in Fig. 99 concerns liquid cyclic compounds (aromatic, hydroaromatic, heterocyclic). In this graph, the curve B limits the area characterizing liquids that produce solutions of relatively low viscosity while the area C again defines liquids that cause swelling only. 

---