Heterocycles relative aromaticity

Nitrogen. Pyridine is one of the most important heterocycles. The aromaticity of pyridine was intensively connected to structural considerations and chemical behavior. The relative difference between the aromaticity of benzene and pyridine is controversial generally calculations give similar orders of magnitude and differences depend on the criterion of aromaticity considered and the mode of calculation used. A comprehensive review on the theoretical aspects in connection with the aromaticity of pyridine was published.191 Pyridine is about as aromatic as benzene according to theoretical calculations and to experimental data, while quinoline is about as aromatic as naphthalene and more aromatic than isoquinoline.192193 The degrees of aromaticity of pyridine derivatives strongly depend on their substituents. 

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... 

All of the parent heterocycles possess some degree of aromaticity, as based upon chemical behavior such as their proclivity to undergo substitution reactions with electrophilic reagents. Quantification of the relative aromaticities of these heterocycles is less easily achieved. The wide range of potential criteria available for this purpose has been surveyed in Section 2.2.4.2. 

TT-Electron delocalization in isoxazole seems to be more effective than in oxazole however, isothiazole is less aromatic than thiazole thus it is not a general rule that 1,2-diazoles possess higher aromaticity in comparison with 1,3-diazoles. Oxygen-containing heterocycles are always less aromatic than their sulfur and nitrogen counterparts, e.g. thiazole > imidazole > > oxazole. At the same time, the relative aromaticity of S- and N-containing heterocycles can interchange (pyrazole > isothiazole > isoxazole). 

Magnetic criteria have received wide application mainly as a qualitative test for aromaticity and antiaromaticity. The values of the exaltation of diamagnetic susceptibility (in 10-6A cm-3 mol-1), and therefore aromaticity, decrease in the sequence thiazole (17.0) > pyrazole (15.5) > sydnone (14.1). The relative aromaticity of heterocycles with a similar type of heteroatom can be judged from values of the chemical shifts of ring protons. The latter reveals paramagnetic shifts when Tr-electron delocalization is weakened. For example, in the series of isomeric naphthoimidazoles aromaticity decreases in the sequence naphthof 1,2-djimidazole (8 = 7.7-8.7 ppm) > naphtho[2,3- perimidine (8 = 6.1-7.2 ppm). This sequence agrees with other estimates, in particular with energetic criteria. 

The mass spectra of benzo[6]thiophene and several of its derivatives have been recorded,120-124 but only two systematic analyses of such spectra have been made.121,128 The relatively high stability of benzo[6]thiophene to electron impact120,125 has been compared with that of other heterocyclic and aromatic systems.125... 

Azoloazoles represent interesting objects for study. Most of these structures are very unstable and can be regarded only as intermediates <1998JPR687>. Nonetheless, some, for instance pyrrolotetrazole and its derivatives, are relatively stable and can exist as the tautomeric forms 17 and 18 (Equation 2). In these structures only one of the heterocycles remains aromatic, for example, it is the tetrazole ring in the 5//-tautomer 18 and the pyrrole ring in the 1/7-tautomer 17. 

How does this concept of aromaticity apply to typical heterocycles such as pyridine 5.1 and pyrrole 2.1 Pyridine can formally be derived from benzene by replacement of a CH unit by an sp2 hybridised nitrogen atom. Consequently, pyridine has a lone pair of electrons instead of a hydrogen atom. However the six 7t electrons are essentially unchanged, and the pyridine is a relatively aromatic heterocycle. 

In fact the thorny problem as to how aromatic is a particular heterocycle or series of heterocycles has been a preoccupation of physical organic chemists for some time. Bond lengths, heats of combustion, spectroscopic data, and theoretically-calculated resonance energies have all been invoked, but an absolute measure of aromaticity remains elusive. Nevertheless, trends regarding relative aromaticity will be alluded to in this text as they arise. 

While there are no extensive reports on the relative aromaticity of the heterocycles covered in this chapter, the general reactivity of these systems can be predicted based on first principles. By assuming that these fused systems are comprised of a five-membered rc-excessive heterocyclic system and a five-membered -deficient heterocyclic system, electrophilic agents are expected to react on the n-excessive subunit. Ab initio calculations on the thienothiazoles and furothiazoles predicted that electrophilic substitutions should occur exclusively on the furan or thiophene subunit with the regioselectivity being a function of the resonance-stabilization of the reactive intermediates <76KGS1202>. A priori, C-H deprotonation by a nonnucleophilic base should occur preferentially on the -deficient heterocyclic component. 

Since there are no extensive studies on the relative aromaticity of the heterocycles covered in this chapter, the relative order of aromaticity of these systems has been gleaned from disparate studies. A priori, the combined effects of the 7i-electron-deficient five-membered heterocycles annelated to a pyridine nucleus provides a series of bicyclic heterocycles with low reactivity towards electrophiles. In the presence of suitable leaving groups, they are prone to undergo nucleophilic substitution. Since these heterocycles are readily obtained from either appropriately substituted pyridines or five-membered heterocycles, methods for direct functionalization of the parent heterocycles are not frequently studied. Based on the diversity of reactions these heterocycles undergo, it can be inferred that the pyridofuroxans are the least aromatic. 

The relative aromaticities of isomers of oxygen and sulfur heterocycles can be predicted in a similar way, e.g., thiatriazoles . Of course, the most stable isomer of a pair, as measured by heat of formation, is not necessarily the most aromatic in fact, imidazole (A7/f = 132.9 kj mol ) is thermodynamically more stable than pyrazole (Hf= 179.4 kj mol-1) <1999JPCA9336>. Nevertheless, the empirical rule that 1,2-nitrogen interactions are more favorable for aromaticity than 1,3-nitrogen interactions is a convenient guide to the relative stabilities of closely related azole isomers in the gas phase <2010T2695>. 

In Tables 126,37- 1,43,46,56,73-115 and n 57.90.9.4,..6-.34 pKr+ values currently available for heterocyclic cations are listed in order of increasing complexity of the heterocyclic system. Aromatic and nonaromatic heterocyclic cations are considered separately in Tables I and II, respectively. Only data for strictly aqueous solutions or for aqueous solvents containing small proportions of nonnucleophilic organic solvents are included in Tables I and II. A number of data reported for aqueous alcoholic solutions are discussed separately in Section VI,A. Equilibrium constants in such media can only be considered as apparent constants since no allowance is made for the existence of the pseudobases in these solutions as mixtures of the corresponding hydroxide and alkoxide adducts. The presence of an organic solvent is sometimes necessary to promote sufficiently the solubility of the pseudobase for pXR+ determination. In such cases, interpretation of data relative to strictly aqueous solutions is more straightforward if nonnucleophilic cosolvents such as acetonitrile and dioxane, are chosen in preference to alcohols. 

The increased susceptibility to pseudobase formation for O-heterocyclic relative to the corresponding N-heterocyclic cations that was noted above for the aromatic series is also seen in the l//-isobenzofurylium (25 X = O) and N-phenyl 1 //-isoindolium (25 X = NPh) series in Table II. For these cases ApKR. (NPh - O) 11.5, which may be converted to ApXR. (NMe - O) % 15.5 using the difference noted previously for N-methyl- and N-phenyl-3,4-dihydroisoquinolinium derivatives. This difference is in reasonable agreement with ApXR + (NMe - O) % 18.5 observed for aromatic cations (Table IV). The low stability of the cation relative to the pseudobase for O-heterocycles is also present in the 2H-furylium cations (26). Although... 

On the other hand, all the sulfur-containing heterocycles are located in the close vicinity of the model aromatic structure, the cyclopentadienyl anion 131. Thus, one can assign higher aromaticity to the sulfur-containing heterocycles relative to the oxygen-containing ones, not only on the basis of geometric criteria but also from the 2-D dimensional perspective. 

Table VI. Relative Concentrations of Heterocyclics in Aromatic, Polar, and Asphaltene Fractions from EDS Asphaltenes...

The relative aromaticity of common heterocycles is shown below ... 

Relative Aromaticity of Five-Membered Ring Heterocycles ... 

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