Aromaticity of five-membered heterocycles

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

Nucleus-independent chemical shift (NICS) values for a number of five-membered heterocycles have been reported and are used as a quantitative magnetic measure of aromaticity. They are a measure of diamagnetic ring current and are not a measure of thermodynamic stability. NICS values are theoretical parameters and the values depend on the computational method used and the position above the ring. Table 2 shows NICS values for a selection of heterocyclic systems where NICS is the value at the centre of the ring. The aromaticity of five-membered heterocycles is discussed in Sections 2.3.4.2 and 2.4.4.2. 

The aromaticity of a heterocycle depends on how effectively the lone-pair of the heteroatom contributes to the aromatic sextet. The aromaticity of five-membered heterocyclic compounds may be estimated from their reactivity in the Diels-Alder reaction.94 Spectrophotometry shows that furan, thiophene, and selenophene resemble benzene in that with maleic anhydride 1 1 complexes are formed which are stable up to 150°C in the case of thiophene, decompose at 150°C with selenophene (whereby selenium is formed together with a diene which gives a further adduct with another molecule of maleic anhydride), and produce the usual adduct at 20°C with furan. Thus, only furan is a normal diene as regards the Diels-Alder reaction. 

To confirm this finding based on the degree of the benzene ring C-C distortion, the magnetic susceptibility anisotropies and the relative energies for the benzene-fused five-membered heterocycles have been computed (Table 68). A similar approach was used by Schleyer et al. <1995AGE337> to evaluate the aromaticity of five-membered heterocycles using the ab initio methods. 

The potential application of C—C coupling constants in assessing the aromaticity of five-membered heterocycles has been discussed. ... 

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. 

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

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... 

Reports on the synthesis of five-membered heterocycles by intramolecular nitrogen—nitrogen bond formation (N1—N5) came some years ago from our laboratory [79CC891 81 JCS(Pl) 1891 83JCS(P1)2273]. Thus, 4-alkyl(aryl)amino-l-azabutadienes 2, which are readily available in large scale from alkyl(aryl)imines 1 and aliphatic or aromatic nitriles (70S 142 ... 

Examples of synthesis of five-membered heterocycles following this strategy are limited in number. An approach to 1,3,4-triazoles involves bonding of C-l and C-3 of vinyl isocyanate 150 to both nitrogen atoms of aromatic hydrazines (78JOC402) (Scheme 37). The reaction was run at room temperature and gave quantitatively regioisomer 151 or a mixture of 151 and 152 when p-nitrophenyl and phenylhydrazine, respectively, were employed. 

No systematic experimental studies on thermodynamic properties of five-membered heterocycles with three or more heteroatoms and at least one tetracoordinated silicon atom were reported. The aromaticity of the fully conjugated germadisiloleanion 21, a heavy congener of the cyclopentadienyl anion, was deduced mainly from its NMR spectroscopic and structural parameters <2005JA13143>. 

A limited amount of energy data is available for this class of heterocycle. Table 38 shows empirical resonance energies (ERE) and Hess-Shaad resonance energies (HSRE) for a limited list of azoles. Also included in Table 38 are aromatic stabilization energies (ASEs). The ASE is a more recent measure of aromaticity based on homodesmotic and isodes-motic reactions. ASE values for a wide range of five-membered heterocycles are available <2003T1657>. 

Aromatic protons of five-membered heterocyclic systems absorb in the same region as the protons of carbocyclic analogs, namely, 6.9to 8.5 S (1.5-3.1 r). Differences, however, between chemical shifts of the protons located at different positions of the heterocyclic rings are greater than those in benzene derivatives. The differences between the chemical shifts of the a and /3 protons in furan, thiophene, and selenophene are 1.05,20 0.12,21 and 0.57 ppm,20,22 respectively the difference is least for thiophene, thus confirming its higher aromaticity as compared with furan or selenophene. 

The computed values were correlated with the experimentally determinated heat of combustion <1949CB358>. An excellent correlation between the computed and the experimental values was obtained, demonstrating that this method can correctly estimate the relative magnetic properties of five-membered heterocycles. It is well known that thiophene is the most aromatic heterocycle in this series. 

In the gas phase, alkylation of five-membered heterocycles by alkyl cations usually occurs via the usual addition-elimination mechanism of aromatic electrophilic substitution. The phenyl cation behaves differently, however although its substrate discrimination is limited, in accord with its exceedingly high reactivity, it has marked selectivity for the a position, which does not conform with the hard character of this cation. It has, therefore, been suggested that an electron-transfer mechanism is followed this is thermodynamically allowed for the phenylium, and likewise for the methyl cation, but not for other alkyl cations (Scheme 28). This SET mechanism applies also for acyl cations [87]. 

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... 

We can now look at specific examples, and see how the principles above can lead to the aromatic heterocycles. In the first of the two broad categories, where only C-heteroatom bonds need to be formed, and for the synthesis of five-membered heterocycles, precmsors with two carbonyl groups related 1,4 are required, thus 1,4-diketones react with ammonia or primary amines to give 2,5-disubstituted pyrroles two successive heteroatom-to-carbonyl carbon additions and loss of two molecules of water produce the aromatic ring, though the exact order of these several steps is never certain. 

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... 

As our computational results presented above demonstrate, it is highly unlikely that heterocycles would be good dienes for Diels-Alder reactions if formation of one or two C-N bonds were involved in the course of the reaction. This automatically eliminates some tautomeric forms of five-membered heterocycles with heteroatoms in 1 and 2 positions as well as five-membered heterocycles with heteroatoms in 1,2,3 and 1,2,5 positions. A major reason for the low reactivity of the heterocycles is because of their high aromaticity. It is obvious that diminishing or eliminating the aromaticity in these heterocycles would make them better dienophiles for Diels-Alder reactions. 

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