Heteroaromatic rings reactivity towards electrophiles

The hydrogen-isotope exchange reactions have already been discussed in previous sections. For various aromatic and heteroaromatic substrates, standard reaction rates in protodedeuteration and in nitration have been obtained. A plot of these shows a wide scatter. This means that there is no simple relation between these two measures for the susceptibility to electrophilic attack. No single reactivity index can be used as a measure to derive a unique order of the susceptibility of individual ring positions towards electrophilic attack (75TL1395). 

It is convenient to consider heteroaromatic ligands in two classes - 7t-excessive, five membered rings typified by pyrrole, furan and thiophen, and TC-deficient six-membered rings typified by pyridine. The 7i-excessive heterocycles are usually extremely reactive towards electrophilic attack and, with the exception of thiophen, do not exhibit the chemical inertness often associated with aromatic benzene derivatives. Conversely, the TT-deficient heterocycles are extremely inert with respect to electrophilic attack. Paradoxically, it is the high reactivity of the five-membered rings and the inertness of the six-membered rings that give rise to common synthetic problems. The usual methods for the... 

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... 

Electrophilic Reactions. Further studies aimed at the correlation of the reactivity of five-membered heteroaromatic rings towards electrophiles have been reported. Acid-catalysed hydrogen exchange rates were measured (n.m.r.) for isoxazole, isothiazole, and their 3- and 5-methyl derivatives. Extrapolated values for the rate constants at 100 °C and pH 0 were obtained and compared with those for other ring systems. Quantitative effects of the methyl groups reflect the relative degree of bond fixation, and indicate that the aromaticity increases in the series isoxazole, pyrazole, and isothiazole. ... 

The heteroaromatic substitution reflects the Friedel-Crafts reaction with the opposite reactivity and selectivity. The synthetic advantages and disadvantages are also opposite to those of concern for the selectivity of monosubstitution - whereas introduction of a carbonyl group deactivates the aromatic ring toward further substitution in the electrophilic process, in contrast it activates the heteroaromatic... 

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