Relative Reactivity of Rings and Ring Positions

Until a few years ago, no quantitative comparison of overall reactivities in electrophilic substitution of the fundamental five-membered rings was available. Only the reactivity of thiophene relative to benzene had been measured quantitatively in several electrophilic substitutions bromination, chlorination, nitration,hydrogen exchange,protodesilylation, and mercura-tion.  

Concerning the comparison among thiophene, furan, and pyrrole, the reactivity order was established mainly on the basis of qualitative criteria. 

This method is of uncertain value since the reactivity of each ring is, at least partially, altered by the electronic effects of the other ring acting as substituent. 

On the basis of these qualitative criteria the following order of reactivity was universally established benzene thiophene furan. Concerning the comparison of furan and p5TroIe, the interpretation of 

Only in recent years has the reactivity sequence of the five-membered rings (including selenophene) been placed on a quantitative basis, by the use of more rigorous kinetic and competitive procedures. 

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III. Monocyclic Azines. Relative Reactivity of Rings and Ring-Positions 262... 

Relative reactivity of ring-positions based on positional selectivity of polychloro-azines must be regarded with caution because of the unequal activating effects of the chlorine substituents on each other. Also, it should be emphasized that one cannot use the positional selectivity in di- and tri-substitutions to assess relative reactivity of different positions. In such substitutions, the reactivity is determined by a complex combination of activating and deactivating effects which are unequal at the ring-positions (cf. Sections II, E, 1, II, E, 2,c, and II,E,2,e). 

In 9-substituted purines, the relative reactivity is 8 > 6 > 2, but in 9//-purines this is modified to 6 > 8 > 2, the demotion of the 8-position being associated with anion formation in the five-membered ring. Conversely, in acidic media the reactivity to nucleophilic displacement at C-8 is enhanced protonation of the five-membered ring facilitates the nucleophilic addition step." The relative reactivities of 2- and 6-positions is nicely illustrated by the conditions required for the reaction of the respective chlorides with hydrazine, a relatively good nucleophile." It is worth noting the parallelism between the relative positional reactivity here with that in halopyrimidines (4 > 2). 

As in pyridine, it is the nitrogen in quinoline which undergoes protonation, alkylation, acylation and, with peroxyacids, oxidation to the A-oxide. S Ar reactions occur on the ring C-atoms, preferentially on those of the more activated benzene moiety. The relative reactivities of the individual heteroaromatic positions were determined by an acid-catalysed H-D exchange with D2SO4. This demonstrated that the SgAr process occurs via the conjugated acid, i.e. the quinolinium ion, and the positional selectivity C-8 > C-5/C-6 > C-7 > C-3 was observed. 

The relative reactivity of azine rings and their ring-positions is determined by a number of factors that are considered in this section. Data and examples are taken up in Sections III and IV on the comparative reactivity of mono- and bi-cyclic azines. It is of interest to note that nucleophilic substitution comprises a sizeable section in the heterocyclic chemistry textbooks by Albert and by Katritzky and Lagowski. ... 

The effects of the nucleophile on aromatic substitution which are pertinent to our main theme of relative reactivity of azine rings and of ring-positions are brought together here. The influence of a nucleophile on relative positional reactivity can arise from its characteristics alone or from its interaction with the ring or with ring-substituents. The effect of different nucleophiles on the rates of reaction of a single substrate has been discussed in terms of polarizability, basicity, alpha effect (lone-pair on the atom adjacent to the nucleophilic atom), and solvation in several reviews and papers. ... 

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