Heteroaromatic reactivity, quantitative substituent effects

Reactions involving monocyclic six-membered heteroaromatic rings have not been studied sufficiently extensively to allow a quantitative treatment of substituent effects. However, comparison with aza-naphthalene reactivities indicates that aza- and polyaza-benzene systems must also be highly selective. 

The recognition of the species which is undergoing reaction, of the quantitative effects of heteroatoms, of interactions between heteroatoms and substituents, and of the importance of hydrogen bonding have made possible, for the first time, a rational, quantitative, overall treatment of heteroaromatic reactivity patterns. 

A quantitative study has been made on the effect of a methyl group in the 2-position of five-membered heteroaromatic compounds on the reactivity of position 5 in the formylation and trifluoroacetylation reaction. The order of sensitivity to the activating effect of the substituent is furan > tellurophene >selenophene = thiophene (77AHC(2l)ll9). 

There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. The quantitative estimation of the role of steric strain in reactivity was first made mostly with the help of linear free energy relationships. This method remains easy and helpful, but the basic observation is that the description of a substituent by only one parameter, whatever its empirical or geometrical origin, will describe the total bulk of the substituent and not its conformationally dependent shape. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. 

However, few parameters of this kind have so far been determined experimentally. Therefore, in heteroaromatic chemistry the quantitative investigation of reactivity remains a needed area of research. Also, being in a large measure of a formalized character, the equations obtained require a detailed analysis, which should reveal the peculiarities of transmission of electronic effects in various organic families, and allow understanding of the role played by the heteroatom in electronic effect transmission and the details of the subtle structure of interacting substituents. In this task, there is still an acute problem in quantifying the effect of solvent on the reactivity of heterocyclic compounds of different classes. 

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