Heteroaromatic reactivity, quantitative

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). 

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 term aromatic will be used in a strict non-historical sense to mean possessing a cyclic 7r-electron system (6 and 10 electrons for the mono- and bi-cyclic rings discussed in this review). Heteroaromatic compounds, like carboaromatics, have widely different degrees and types of electronic dissymmetry and polarizabihty. Consequently, their reactivity varies tremendously with any one reagent and their relative reactivity changes drastically with the type of reagent. In this sense, aromatic compounds show differences in reactivity but not in aromaticity. The virtues of this qiuilitative concept of aromaticity and the pitfalls of trying to use it as a quantitative concept in modern context have been ably presented by Peters and by Balaban and Simon. ... 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

Electrochemical induction of the reaction (Pinson and Saveant, 1974), as shown to occur in a number of cases with aromatic and heteroaromatic substrates (Saveant, 1980a, 1986, 1988), also provides evidence for the Sr I mechanism. The electrochemical approach allows, in addition, a quantitative analysis of the mechanism and reactivity problems and will be described in this connection in the next subsection. 

There is current interest in the quantitative comparison of electrophilicities and nucleophilicities, particularly in carbon-carbon bond-forming reactions. The rates of a-adduct formation in acetonitrile of 10 electron-deficient aromatics and heteroaromatics with a series of reference carbon nucleophiles have been used to compare their electrophilicities, E. Values of E ranging from —13.2 for 1,3,5-trinitrobenzene, the least reactive studied, to -4.7 for 4,6-dinitrotetrazolo 1,5-a Ipyridinc, the most reactive, were determined.52 A reasonable correlation was found between electrophilicities and pA a values for water addition (eq. 1). These pA a values have also been found to... 

Understanding, rationalizing, and predicting both reactivity and the energetics of dynamic stereochemistry are of major importance in heterocyclic chemistry and one or both of these topics are a concern of the majority of the contributions in Advances in Heterocyclic Chemistry. No previous systematic study has been reported which treats quantitatively steric effects in heteroaromatics this is the purpose of this article. 

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. 

This group constitutes a virtually infinite class of heteroaromatic ring systems. However, relatively few of the parent compounds have yet been made, and fewer still have had their quantitative (or indeed qualitative) reactivities measured. The compounds described in this chapter are subdivided as follows Section 2, compounds with one five- and one six-membered ring Section 3, compounds with one five and two six-mem-bered rings Section 4, compounds with two five- and one six-membered rings Section 5, compounds with two five-membered rings and Section 6, compounds with three or more five-membered rings. 

To determine a constants for heteroaromatic substituents, use is made of various physical parameters, as well as quantitative data on the reactivity of hetaryl, aliphatic, and aromatic compounds. Wide use has been made of NMR a constants for heteroaromatic groups are often determined by using and F chemical shifts in spectra of substituted benzenes (63JA709 72BCJ1519 79ZOR1737 80AJC1763 82MI1). 

This article has shown that, despite the diversity of heterocyclic systems and the complications involved in developing general concepts, it is possible to find for heteroaromatic systems certain quantitative dependences permitting correlation of the data on the reactivity of aromatic and heteroaromatic compounds on the basis of well-developed approaches. 

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. 

Reaction indices have been frequently used to analyze and predict positional selectivity of S Ar reactions. The average local ionization energy, 7(r), seems to have the best predictive power for this reaction type among the commonly used descriptors. Local minima in /(r) reflect both the positional selectivity for S Ar and the relative reactivity in aromatic and heteroaromatic systems. The 7(r) approach generally has quantitative predictive capacity for nitrations and halogenation, but it has problems for systems where steric hindrance is of key importance for the regioselectivity. 

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