Five-membered heterocycles aromaticity

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. 

Pyrrole is a nitrogen-containing unsaturated five-membered heterocyclic aromatic compound. It shows aromaticity by delocalization of a lone pair of... 

As a preparative route mercuration of arenes suffers from a lack of selectivity often all possible ring substitution products are formed. The directing influences of substituents operate, but selectivity is poor. The initial products can isomerize. Isomer distributions in mercuration of toluene under different conditions are given in Table 3. These effects coupled with the ease of polymercuration can be disadvantagous. Mild conditions must be used to limit the extent of mercuration of five-membered heterocyclic aromatics such as pyrrole, thiophene, selenophen and furan. These are among the most reactive aromatics toward Hg salts use of HgCl2 in the presence of Na02CCH3 at RT is... 

The improved electrochemical synthesis (7) of poly pyrrole has led to its use as coating for the protection of n-type semiconductors against photocorrosion in photoelectrochemical cells. (8,9) Recently, it was announced that pyrrole was not the only five-membered heterocyclic aromatic ring compound to undergo simultaneous oxidation and polymerization. Thiophene, furan, indole, and azulene all undergo electrochemical polymerization and oxidation to yield oxidized polymers of varying conductivities (5 x 10 3 to 102 cm- ). (10-13) The purpose... 

Five-membered heterocyclic aromatic systems as dienophiles... 

Cycloaddition to five-membered heterocyclic aromatic compounds is well documented. Examples reported this year include the formation of azetidine adducts (67) by irradiation of 3-(p-cyanophenyl)-2-isoxazoline with furan or thiophen (and also with benzene) benzophenone-sensitized reaction of selenophen with dimethylmaleic anhydride (68) to give 1 1 and 1 2 adducts and oxetan formation from benzophenone and 1-acylimidazoles (69), thiazoles, or isoxazoles. ... 

A Hiickel model used for calculating aromaticity indicated that the isoxazole nucleus is considerably less aromatic than other five-membered heterocycles, including oxazole and furan. SCF calculations predicted that isoxazole is similar to oxazole. Experimental findings are somewhat difficult to correlate with calculations (79AHC(25)147). PRDDO calculations were compared with ab initio values and good agreement for the MO values was reported... 

The use of microwaves for the preparation of aromatic five-membered heterocycles has been intensely investigated with excellent results in terms of yields and purities of the products prepared. The Paal-Knorr reaction, namely the cyclocondensation of a 1,4-dicarbonyl compound to give furans, pyrroles and thiophenes has been successfully carried out with the aid of microwaves. 

Tetrazoles are a very interesting family of aromatic five-membered heterocycles for their abiUty to be a mimetic of the carboxy group with metabolic... 

Fig. 1 The aromaticity of five-membered heterocycles characterized by the Bird-Index [32]...

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

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%. 

Scheme 38. Aromaticity Scales in Five-Membered Heterocycles...

Several recent papers analyzed the properties of five-membered heterocycles (azoles, oxoles, thio derivatives) in terms of their higher or lower aromaticity.113-120... 

Among the five-membered heterocycles with three nitrogen atoms, triazoles and benzotriazoles are of significant practical importance. In the case of ben-zotriazole, the aromaticity of the benzenoid 1H-benzotriazole (90A, R = H) has been considered to be greater than that of the quinonoid 2/7-benzotria-zole (90B, R = H) (Scheme 43).134 However, the difference in aromaticity between tautomers is greatly dependent on the dielectric constant of the medium. 

Heterocycles with Arsenic, Antimony, and Bismuth. Arsoles, stilboles, and bismoles (Scheme 54) are five-membered heterocycles for which experimental data do not indicate aromatic properties, while semiempirical calculations (CNINDO or CNDO/ S) showed that the anions are aromatic. The chemistry and theoretical aspects in connection with their... 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

Scheme IV.3). The general scheme of this type of rearrangements in aromatic five-membered heterocycles with an unsaturated side chain is known as the Boulton-Katritzky rearrangement [67JCS(C)2005]. 

While it is clear that 1,2,5-thiadiazoles are clearly aromatic in nature, efforts have been made to quantify the degree of aromaticity. Three detailed comparative studies of relative aromaticity in five membered heterocyclic rings have been carried out by Bird <85T1409>, Katritzky <90JPR885>, and... 

A new index of aromaticity has been proposed and applied to neutral and mesoionic five-membered heterocycles. The aromaticity index is based on data from experimentally determined bond lengths which yield statistically evaluated bond orders. A reasonable parallel exists between the aromaticity index and resonance energies <85T1409>. 

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. 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

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