Heterocyclic Aromatic Systems

The concept of aromaticity is not restricted to hydrocarbons. Heterocyclic systems, whether of the pyrrole type 1.38 with trigonal nitrogen in place of one of the C=C double bonds, or of the pyridine type 1.39 with a trigonal nitrogen in place of a carbon atom, are well known. The n orbitals of pyrrole are like those of the cyclopentadienyl anion, and those of pyridine like benzene, but skewed by the presence of the electronegative heteroatom. The energies and coefficients of heteroatom-containing systems like these cannot be worked out with the simple 

The concept of aromaticity is not restricted to hydrocarbons. Heterocyclic systems, whether of the pyrrole type 1.46 with trigonal nitrogen in place of one of the C=C double bonds, or of the pyridine type 1.47 with a 

The replacement of CH groups of benzene by nitrogen leads to the azines. Pyridine, pyrazine and pyrimidine have essentially the same stabilization as benzene. Thus, hydrogen transfer reactions between 1,3-cyclohexadiene and the 

The replacement of -CH=CH- of benzene by BH would lead to a 4 ti-electron system which should be antiaromatic, and it has been calculated to have a paramagnetic shift at the center of its ring, in contrast to the diamagnetic shift characteristic of the 6 n-electron systems.41 

In discussing resonance, Pauling stated The theory of resonance in chemistry is essentially a qualitative theory, which like the classical structural theory, depends for its successful application largely upon a chemical feeling that is developed through practice. 46 The same is true with aromaticity. 

1 Aromatic is defined as a substance characterized by a fragrant smell, and usually a by a warm, pungent taste. (Merriam-Webster New International Dictionary). Reviews Garratt, P. J. Aromaticity, Wiley, NY 1986. Minkin, V. J. Glukhovtsev, M. N. Simkin, B. Y. Aromaticity and Antiaromaticity Electronic and Structural Aspects, Wiley, NY 1994. 

4 Ingold, C. K. Structure and Mechanism in Organic Chemistry, Cornell Univ. Press, Ithaca, NY 1953, p. 238. 

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The classical age of preparative organic chemistry saw the exploration of the extensive field of five-membered heterocyclic aromatic systems. The stability of these systems, in contrast to saturated systems, is not necessarily affected by the accumulation of neighboring heteroatoms. In the series pyrrole, pyrazole, triazole, and tetrazole an increasing stability is observed in the presence of electrophiles and oxidants, and a natural next step was to attempt the synthesis of pentazole (1). However, pentazole has eluded the manifold and continual efforts to synthesize and isolate it. 

To understand the general character of the isoxazole nucleus and to establish its place among the other heterocyclic aromatic systems, it is of the greatest interest to investigate the reactions of isoxazole derivatives in which the heterocyclic nucleus remains intact, especially substitution reactions. 

Some of the new DA agonists do not suffer from these pharmacokinetic problems. Most of the new compounds have bioisosteric heterocyclic aromatic systems instead of the phenolic ring systems in the older analogues. Some examples of these new agonists will be given here. 

Gradually it was recognized that nucleophilic aromatic photosubstitution is a fairly general reaction (Havinga et al., 1967 Havinga and Kronenberg, 1968). It can be realized also with polycyclic and heterocyclic aromatic systems. Various solvents (water, alcohols. 

Scheme 1 Three possible types of heteroatoms and the relationship between carbocyclic and heterocyclic aromatic systems...

Electrostatic effects can be transmitted extremely effectively through aromatic ring systems, a fact that explains some of the significance of heterocyclic aromatic systems in biochemical molecules. Consider the... 

Benzene (CH)6, of course, is the most prototypal aromatic system. When one or more of the CH groups are replaced by other atom(s), a heterocyclic aromatic system is obtained. Well-known examples include pyridine N(CH)5 and pyrimidine N2(CH)4, while lesser known cases are phosphabenzene P(CH)5 and arsabenzene As(CH)s. There are also systems where the heteroatom is a heavy transition metal examples include L Os(CH)s and L Ir(CH)5. 

The isothiazoles possess the typical properties of a heterocyclic aromatic system without the ring lability so characteristic of the analogous isoxazoles.87 The chemistry reflects the relative inertness of the 3-position, the susceptibility of the 4-position to electrophilic attack, and the susceptibility of the 5-position to nucleophilic attack. The ring nitrogen is only weakly basic, but can be induced to form quaternary derivatives, and the N-S bond may be cleaved under certain circumstances. 

Scheme 1 The relationship between carbocyclic and heterocyclic aromatic systems.

N-oxidation can occur in a number of ways to give either hydroxylamines from primary and secondary amines [Eqs. (11) and (12)], hydroxamic acids from amides, or N-oxides from tertiary amines [Eq. (13)]. The enzyme systems involved are either cytochrome P450 or a flavoprotein oxygenase. Hydroxylamines may be further oxidized to a nitro compound via a nitroso intermediate [Eq. (11)]. Oximes can be formed by rearrangement of the nitroso intermediate or N-hydroxylation of an imine, that could in turn be derived by dehydration of a hydroxylamine [Eq. (11)]. N-Oxides may be formed from both tertiary arylamines and alkylamines and from nitrogen in heterocyclic aromatic systems, such as a pyridine ring. 

Some recent investigations of the nitration of heterocyclic aromatic systems such as derivatives of pyrrol should be mentioned, as they seem to support the idea of the additional mechanism of Uot in the sense of fpso-reaction. Thus, Sonnet 45] described the reaction ... 

We have also extended these analyses to heterocyclic aromatic systems, such as azines and N-oxides [98,100-102], In these, it was the influence of the nitrogen(s) or N+-0 upon the remainder of the ring that was being examined by looking for the 7Smin the results were in agreement with what has been observed. 

Five-membered heterocyclic aromatic systems as dienophiles... 

Factor analysis has been used by Cummins et al. to reduce a set of 61 molecular properties to four factors, which were then used to compare the diversity of five chemical databases (see Section 4.6). It was also explored by Gibson et ah in a comparative study of 100 different heterocyclic aromatic systems, but they concluded that FA did not reduce the complexity of the analysis, and did not offer any significant advantages over PCA. 

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