Heterocyclic compounds, aromatic pyrroles

Cyclic compounds that contain at least one atom other than carbon within their ring are called heterocyclic compounds, and those that possess aromatic stability are called het erocyclic aromatic compounds Some representative heterocyclic aromatic compounds are pyridine pyrrole furan and thiophene The structures and the lUPAC numbering system used m naming their derivatives are shown In their stability and chemical behav lor all these compounds resemble benzene more than they resemble alkenes... 

Other kinds of substances besides benzene-like compounds can also be aromatic. For example, the cyclopentadienyl anion and the cycloheptatrienyl cation are aromatic ions. Pyridine, a six-membered, nitrogen-containing heterocycle, is aromatic and resembles benzene electronically. Pyrrole, a hve-membered heterocycle, resembles the cyclopentadienyl anion. 

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. 

Aromatic sextets can also be present in five- and seven-membered rings. If a five-membered ring has two double bonds and the fifth atom possesses an unshared pair of electrons, the ring has five p orbitals that can overlap to create five new orbitals— three bonding and two antibonding (Fig. 2.6). There are six electrons for these orbitals the four p orbitals of the double bonds each contribute one and the filled orbital contributes the other two. The six electrons occupy the bonding orbitals and constitute an aromatic sextet. The heterocyclic compounds pyrrole, thiophene, and... 

Hoesch reaction. In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds (e.g., pyrrole), but it can be extended to aromatic amines by the use of BCls. Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones " but are attacked at the oxygen to produce imino esters. Many nitriles... 

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as useful starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, and pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromatics (mainly pyrroles and indoles) and saturated nitrogen heterocycles such as pyrrolidines and their derivatives. 

Our study of heterocyclic compounds is directed primarily to an understanding of their reactivity and importance in biochemistry and medicine. The synthesis of aromatic heterocycles is not, therefore, a main theme, but it is useful to consider just a few examples to underline the application of reactions we have considered in earlier chapters. From the beginning, we should appreciate that the synthesis of substituted heterocycles is probably not best achieved by carrying out substitution reactions on the simple heterocycle. It is often much easier and more convenient to design the synthesis so that the heterocycle already carries the required substituents, or has easily modified functions. We can consider two main approaches for heterocycle synthesis, here using pyridine and pyrrole as targets. 

Heterocyclic These are compounds having at least one hetero atom (any other atom but carbon, e.g. O, N and S) within the ring, and conforming to Hiickel s rule. The aromaticity of heterocyclic compounds, e.g. pyridine and pyrrole, can be explained as follows. 

Atoms other than carbon and hydrogen that appear in organic compounds are called heteroatoms. Cyclic organic compounds that contain one or more heteroatoms are called heterocycles. Heterocyclic compounds are the largest class of organic compounds and can be either aromatic (such as pyridine, pyrrole, and furan) or nonaromatic (such as piperidine, pyrrolidine, and tetrahydrofuran). 

Aromatic heterocyclic compounds such as the AMosyl pyrrole 17 can also be used with anhydride catalysis (acid might destroy the pyrrole). Regioselectivity is determined by acylation next to the nitrogen5 and cyclisation follows.6... 

Bonino s first results in this direction were published in four papers, three in Zeitschrifi fur Physikalische Chemie in 1933 and 1934 and one in Memorie della Reale Accademia delle scienze dell istituto di Bologna. [45] Through the study of the constitution and the aromatic character of the heterocyclic compounds, Bonino confronted the classical ideas of structural organic chemistry. In the case of heterocyclic compounds he and his collaborators emphasized that the classical structure formulae of organic chemistry could not account for the new Raman spectroscopic data. According to these, the existence of a double chemical bond for pyrrole, furane, and thiophene was improbable. 

In the Reimer-Tiemann reaction, aromatic rings are formylated by reaction with chloroform and hydroxide ion." ° The method is useful only for phenols and certain heterocyclic compounds such as pyrroles and indoles. Unlike the previous formyla-tion methods (11-18), this one is conducted in basic solution. Yields are generally... 

The anodic methoxylation of aromatic compounds such as naphthalene [41], anthracene [42], alkylbenzenes [31,43], phenols [44-46], anisoles [33,47-54] and other alkoxyben-zenes [53], methoxynaphthalenes [33], methoxyanthracenes [50,54], inden-l-ones [55], / a/r/-substituted anilides [56] and heterocyclic compounds, such as furans [57], thiophenes [58], and pyrroles [59], has received considerable attention. 

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