CHARACTERISTICS OF HETEROATOMS IN RINGS

The replacement of two CH groups in benzene by a neutral NR, O or S introduces into the new ring an electron-donating heteroatom. This electron-donor character is accentuated in the pyrrole anion where N is introduced. Thus the five-membered rings with one heteroatom are electron rich (ir-excessive), and the chemistry of pyrrole, furan and thiophene is dominated by this effect and is again considered together as a whole in Part 3. 

However, five-membered rings containing two or more heteroatoms necessarily possess both a pyridine-like heteroatom and a pyrrole-like heteroatom. Thus their chemistry shows similarities to both those of the six-membered rings and of the five-membered rings with one heteroatom this is dealt with in Part 4. 

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Substitutive Nomenclature. The first step is to determine the kind of characteristic (functional) group for use as the principal group of the parent compound. A characteristic group is a recognized combination of atoms that confers characteristic chemical properties on the molecule in which it occurs. Carbon-to-carbon unsaturation and heteroatoms in rings are considered nonfunctional for nomenclature purposes. 

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... 

The introduction of heteroatoms into cyclic systems produces significant variations in the molecular geometry that reflect the changes in covalent radii, relative electronegativity and effective hybridization. Consequently, there are changes in the bonding and the physico-chemical characteristics of these heterocyclic systems—particularly in small ring systems. 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

As mentioned earlier, nucleophilic attack at ring carbon atoms a and y to a heteroatom is a reaction characteristic of the ir-deficient six-membered heterocycles. Within this context we do not regard hydrogen atoms attached to ring carbon atoms as substituent groups, and hence proton removal to generate a carbanionic centre is classified as a reaction at a ring carbon atom. There are thus six major reaction types, summarized in equations (21)—(26) in terms of the initial mechanistic steps. 

A characteristic feature of a second type of [2.3.3]cyclazines is an odd number of peripheral heteroatoms contributing a pair of electrons to the 7r-system. The synthesis of cyclazines with a heteroatom in the five-membered ring (260) starting from 2,5-diaminoazoles (261) an ethyl 2-cyano-3-ethoxyacrylate has been described (Scheme 41) (76ACS(B)468). 

It appears that the only known representative of this family is the heavily annulated substance depicted in 65, which was synthesized as shown.82 Being an even-membered ring and incorporating but a single -excessive heteroatom in its periphery, the twelve-membered monocyclic moiety of 65 is somewhat unorthodox in the sense that it contains an odd number of electrons, thirteen to be exact. As a result, the central 17-ribbon of 65 cannot sustain delocalization without experiencing the ill effects of a w-electronic open shell. It is hardly surprising, therefore, to find that 65 exhibits UV and 1H NMR characteristics that are indicative of a nonplanar, strictly atropic, central frame. 

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