Substituent effects, benzene rings reactivity ring substituents effect

When a benzene ring bears two or more substituents both its reactivity and the site of further substitution can usually be predicted from the cumulative effects of its substituents In the simplest cases all the available sites are equivalent and substitution at any one of them gives the same product... 

If the reactions of the same substituents on heteroaromatic azoles and on benzene rings are compared, the differences in the reactivities are a measure of the heteroatoms influence. Such influence by the mesomeric effect is smaller when the substituent is /3 to a heteroatom than when it is a or y. The influence by the inductive effect is largest when the substituent is a to a heteroatom. 

Substituents cannot directly conjugate with /3-pyridine-like nitrogen atoms. Azole substituents which are not a or y to a pyridine-like nitrogen react as they would on a benzene ring. Conjugation with an a-pyridine-like nitrogen is much more effective across a formal double bond thus the 5-methyl group in 3,5-dimethyl-l,2,4-oxadiazole (323) is by far the more reactive. 

The effect of substituents in the benzene ring on the reactivity of the halogen atom in 4-chloroquinazolines is worthy of investigation. 

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. 

In common with a number of heterocyclic iodinations, kinetic effects are found in the iodination of indole and 2-methylindole [68AC(R)1435], When the substituent effects for the reaction are examined it is clear that any resonance effects from the fused benzene ring are only poorly relayed to the reactive 3-position, and the rates appear to be controlled by inductive effects. A 5-methyl group was more activating than 5-methoxy [69AC(R)799]. 

When substituted benzene undergoes electrophilic attack, groups already on the ring affect the reactivity of the benzene ring as weU as the orientation of the reachon. A summary of these effects of substituents on reachvity and orienta-hon of electrophihc substituhon of substituted benzene is presented below. 

The difference in the reactivities of the same substituents on heteroaromatic nuclei and on benzene rings are a measure of the influence of the heteroatom(s). For six-membered heteroaromatic rings, the typical effect of the heteroatom(s) is to attract electrons away from the carbon atoms of the ring. This influence is relatively small when the heteroatom is p to the substituent, but large for the a- and y-orientations. 

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