Five-Membered Aromatic Heterocycles with One Heteroatom

1 FIVE-MEMBERED AROMATIC HETEROCYCLES WITH ONE HETEROATOM 

The ring index system combines (I) the prefix oxa- for O. aza- for N or thia- for S and (2) a stem for ring and satuqjtion or unsaturation. These are summarized in Table 20-1. 

The three most common five-membered aromatic rings are furan, with an O atom pyrrole, with an N atom and thiophene, with an S atom. 

Problem 20.1 Name the following compounds, using (i) numbers and (ii) Greek letters. 

Problem 20.2 Write structures for (a) 2-benzoylthiophene, (b) 3-furansulfonic acid, (c) a./f -dichloropyrrole. 

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Pyrrole, furan, and thiophene are five-membered aromatic heterocycles with one heteroatom. In pyrrole, the nitrogen is sp2-hybridized and contributes two electrons to the 6n aromatic ring. Furan and thiophene are isoelectronic with pyrrole, the [—(N )=] unit being replaced by —( 0 )— and -( S )- units, respectively. Pyrrole, furan, and thiophene are electron-rich (there are six n electrons distributed over five atoms) and undergo electrophilic... 

Five-Membered Aromatic Heterocycles with One Heteroatom ... 

We have looked at the five-membered aromatic heterocycles pyrrole, furan and thiophene in Section 11.5. Introduction of a second heteroatom creates azoles. This name immediately suggests that nitrogen is one of the heteroatoms. As soon as we consider valencies, we discover that in order to draw a five-membered aromatic heterocycle with two heteroatoms, it must contain nitrogen A neutral oxygen or sulfm atom can have only two bonds, and we cannot, therefore, have more than one of these atoms in any aromatic heterocycle. On the other hand, there is potential for having as many nitrogens as we like in an aromatic ring. 

Your first chance to devise syntheses for five-membered aromatic heterocycles with one or two heteroatoms. 

The TT-electron excess of the five-membered rings is accompanied by a high rr-donor character. The best measure of rr-donation is the value of first ionization potential, IP, which for all aromatic heterocycles with one heteroatom of pyrrole type reflects the energy of highest occupied rr-orbital. IP, values decrease in the sequence pyrrole > indole > carbazole furan > benzo[/ ]furan > dibenzofuran thiophene > benzo[/ ]thiophene (Section 2.3.3.9, Tables 21 and 23). Thus, the more extensive the rr-system, the stronger is its electron donor ability. Furan and thiophene possess almost equal rr-donation, which is considerably lower than that of pyrrole. 

The five-membered aromatic heterocycles pyrrole (5), furan (6) and thiophene (7) are formally derived from cyclopentadienyl anion by replacement of one CH group with NH, O or S, each of which can contribute two p-electrons to the aromatic ir-electron sextet. Heteroatoms of this type have in classical structures only single bonds and are called pyrrole-like . Other five-membered aromatic heterocycles are derived from compounds (5), (6) and (7) by further replacement of CH groups with N, 0+ or S+. 

The parent compounds of the monocyclic five-membered heterocycles with one heteroatom are aromatic. When considering the three most important systems only, it appears that the aromaticity increases as follows furan < pyrrole < thiophene (< benzene). This sequence also applies to the respective benzo[Z ] condensed systems. 

The fact remains that selenophene and its derivatives have aromatic character. This statement is, however, not easy to substantiate with quantitative data mainly because there are too many ambiguities for parent five-membered ring heterocycles. Some aromaticity indices for five-membered rings with one heteroatom, among them selenophene, were summarized and estimated values for thiophene and selenophene were similar [26], The data obtained from photoelectron ionization energies show that the aromatic stabilization in thiophene is slightly larger than for selenophene [27],... 

The reactivity of five membered heterocycles with two heteroatoms as dienes with at least one nitrogen for Diels-Alder reactions is also very low. In fact, there is not much experimental data in this area of research, except for addition of dienophiles to oxazole, better known as the Kondrateva reaction [57]. The main reason for their low reactivity is high heterocycle aromaticity delocalization of molecular x-orbitals that should be part of the cycloaddition reaction. That can be explained from FMO energy difierences between aromatic heterocycles as well as by bond order uniformity of heterocycles with two heteroatoms... 

With this large group of heterocycles, ring strain is of little or no importance. Ring-opening reactions are, therefore, rarer than in three- and four-membered heterocycles. The crucial consideration is rather whether a compound can be regarded as a heteroarene or whether it has to be classified as a heterocycloalkane or heterocycloalkene (see p 2). Various aromaticity criteria apply to heteroarenes, and as a consequence, different opinions have been expressed on this matter [1]. As will be shown by means of examples of the various systems, the nature and number of heteroatoms are the critical factors. The parent compound of the five-membered heterocycles with one oxygen atom is furan. 

Heterocyclic compounds are ubiquitous in biology, medicine, and biochemistry, and the azoles form an important class of nitrogen heterocyclic compounds with five-membered aromatic rings that can contain one to five nitrogen atoms (other heteroatoms can also be present). Many drugs and pharmaceuticals are derived from azole structures. The structures of representative azoles are shown in Figure 6.1. Note that some of these compounds exist in tautomeric equilibrium in solution. 

Structures and nomenclature for the most important five-membered monocycles with one or more heteroatoms are depicted in Scheme 1. The aromaticity scale in five-membered heterocycles has been long debated.97-101 The decreasing order of aromaticity based on various criteria is (DRE values in kcal/ mol) benzene (22.6) > thiophene (6.5) > selenophene > pyrrole (5.3) > tellurophene > fur an (4.3). Pyrrole and furan have comparable ring strains (Scheme 38). The aromaticity of furan is still controversial 100 the NMR shielding by ring current estimated it at about 60% of the aromaticity of benzene, and other methods reviewed earlier102 estimated it at less than 20%. 

In five-membered heterocycles, formally derived from benzene by the replacement of a CH=CH unit by a heteroatom, aromaticity is achieved by sharing four p-electrons, one from each ring carbon, with two electrons from the heteroatom. Thus in pyrrole, where the heteroatom is N, all the ring atoms are sp hybridized, and one sp orbital on each is bonded to hydrogen. To complete the six 7i-electron system the non-hybridized p-orbital of N contributes two electrons (Box 1.9). It follows that the nitrogen atom of pyrrole no longer possesses a lone pair of electrons, and the compound cannot function as a base without losing its aromatic character. 

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