Thiophene aromaticity, comparative

Sulfur. Thiophene and benzo[ >] thiophene are both aromatic heterocycles, as discussed earlier in this review. Isothiazole is a planar molecule with an aromaticity comparable with those of thiazole and pyrazole, and higher than those of isoxazole and oxazole,122 140 as evaluated on the basis of Bird s aromaticity index A, based upon the statistical degree of uniformity of the bond orders of the ring periphery. Theoretical calculations and experimental data in connection with the aromaticity of isothiazole have been reviewed.141 Thiazole is also viewed as an aromatic molecule, similar to thiophene. It lacks an experimental aromaticity value, but the heat of formation together with bond lengths and angles have been calculated by various computational meth-... 

Partial rate factors (/) obtained from deuterium exchange in 2-deuteriated 3- and 5-methylselenophenes and thiophenes were compared with the / values of deuterium exchange in o-, m-, and p-deuteriated toluenes87,88 the comparison shows that the acid- and base-catalyzed exchange of deuterium is similarly affected by methyl substituents in the selenophene, thiophene, and benzene series. Hence, the heterocycles behave here as normal aromatic systems. 

The fact that the lone pair on sulfur contributes to the aromaticity is seen in the lower dipole moment of thiophene as compared to its saturated analogue tetrahydrothiophene (0.52 D vs. 1.90 D) <1972JA8854>. In thiophene, the dipole is directed from the ring toward the heteroatom. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

In the benzene series, an approximately linear relationship has been obtained between the chemical shifts of the para-hydrogen in substituted benzenes and Hammett s a-values of the substituents. Attempts have been made, especially by Taft, ° to use the chemical shifts as a quantitative characteristic of the substituent. It is more difficult to correlate the chemical shifts of thiophenes with chemical reactivity data since few quantitative chemical data are available (cf. Section VI,A). Comparing the chemical shifts of the 5-hydrogen in 2-substituted thiophenes and the parahydrogens in substituted benzenes, it is evident that although —I—M-substituents cause similar shifts, large differences are obtained for -j-M-substituents indicating that such substituents may have different effects on the reactivity of the two aromatic systems in question. Differences also... 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

The heteroaromatic compounds like furans, pyrroles or thiophenes cannot be generally used as dienes in Diels-Alder syntheses, because at the higher temperature required for the addition of less reactive dienophiles, the equilibrium is on the side of the starting materials due to the unfavorable T AS term comparable to the benzenoid aromatic compounds as mentioned. High pressure again shows the two effects already discussed the shift of the equilibrium toward the products and the enhancement of the rate of reaction which allows the temperature of reaction to be lowered. One... 

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%. 

Aromaticity indices based on a statistical evaluation of peripheral bond orders have been derived for five-ring heterocycles a value of 50 for 1,3,4-oxadiazole compares with values of 43 and 66 for furan and thiophene respectively <85T1409>. Somewhat in contrast, O—C, C—N, and N—N bond orders of 1.3124, 1.9062, and 1.3348 (MMX, EXE calculation) for 1,3,4-oxadiazole led to the conclusion that the molecule was not aromatic <91H(32)2023>. 

Aromatic substitution reactions are often complicated and multistep processes. A correlation, however, in many cases can be found between the charged attacking species and the electron density distribution in the molecule attacked during electrophilic and nucleoph c substitution. No such correlation is expected in radical substitution where the attacking particles are neutral, rather a correlation between the reactivities of separate bonds and a free valency index of the bond order. This allows the prediction of the most reactive bonds. Such an approach has been used by researchers who applied quantum calculations to estimate the reactivities of the isomeric thienothiophenes and to compare them with thiophene or naphthalene. " Until recently quantum methods for studying reactivities of aromatics and heteroaromatics were developed mainly in the r-electron approximation (see, for example, Streitwieser and Zahradnik ). The M orbitals of a sulfur atom were shown not to contribute substantially to calculations of dipole moments, polarographic reduction potentials, spin-density distribution, ... 

NMR has been widely invoked in assessing aromaticity. Comparison of the chemical shifts of furan, H-2 7.46 and H-3 6.41, with those observed for 4,5-dihydrofuran, H-2 6.31 and H-3 4.95 (66JCS(B)127), indicates there is ca. 1-1.5 ppm downfield shift attributable to the presence of an aromatic ring current in furan. The same effect is observed for thiophene, H-2 7.35 and H-3 7.13, and 4,5-dihydrothiophene, H-2 6.17 and H-3 5.63 ppm. The similar range of chemical shifts observed for all of the parent heterocycles may be compared with that for benzene, 7.27 8, and further attests to their possessing appreciable ring currents. 

The structural indices of aromaticity, I, of oxadiazoles (145-148), thiadiazoles (150-153) and selenadiazoles (155, 156) are compared with that of the parent furan (144), thiophene (149) and selenophene (154) (Scheme 11). 1,2,3-Oxadiazole (145) is the least stable among them since all attempts to synthesize this compound were unsuccessful, most likely because of its easy isomerization to the acyclic isomer. At the same time its sulfur analogue (150) possesses good stability and has been synthesized. Its 2,4-diaza- (151), 3,4-diaza- (152) and 2,5-diaza-(153) isomers demonstrate even more the extent of n-electron delocalization. There exists a well-known tendency of decreasing aromaticity depending on the type of pyrrole-like heteroatom S > Se > O. However, there is no uniformity in the change in aromaticity in the horizontal rows, i. e., dependence on heteroatom disposition. 

Thiophene S,N-ylides are comparable with the 1-mono- and 1,1-dioxides in that they exhibit diene rather than aromatic properties (86JCS(P 1)233). The S,C-ylides appear to be more sluggish in cycloaddition reactions and are therefore considered more aromatic . 

Concerning the question of phosphole aromaticity there are some indications of 6-rr-delocalization from NMR spectroscopy and other physical methods. The formation of metal complexes with derivatives of Mn, Fe and other metals, however, gives the best chemical proof of such 6ir- delocalization but there are still some doubts arising from the considerable differences in chemical behaviour compared with pyrroles, furans and thiophenes. This once more points to the very different properties of phosphorus, compared to nitrogen in particular. Therefore the problem is still open and much work, both practical and theoretical, remains. 

Magnetic rotation (Faraday) effects have been little used for assessing aromaticity. Furan has only a very weak effect, and when allowance is made for steric strain in the ring the exaltation, Ep> which can be considered to be a measure of aromaticity, is —0 compared with 45 for pyrrole, 52 for thiophene and 182 p,r for benzene (69Mi3iooi). 

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