Electrophilic aromatic substitution of pyridine

Electrophilic aromatic substitution of pyridine takes place at C-3 because the most stable intermediate is obtained by placing an electrophilic substituent at that position (Figure 20.2). When the substituent is placed at C-2 or C-4, one of the resulting resonance contributors is particularly unstable because its nitrogen atom has an incomplete octet and a positive charge. 

The electron-withdrawing nitrogen atom makes the intermediate obtained from electrophilic aromatic substitution of pyridine less stable than the carbocation intermediate obtained from electrophilic aromatic substitution of benzene. Pyridine, therefore, is less reactive than benzene. Indeed, it is even less reactive than nitrobenzene. (Recall from Section 19.14 that an electron-withdrawing nitro group strongly deactivates a benzene ring toward electrophilic aromatic substitution.)... 

Explain why electrophilic aromatic substitution of pyridine occurs at C3. 

Electrophilic aromatic substitution of the 4-aminobenzofuran 1103 with the complex salt 602 afforded the iron complex 1109 in quantitative yield. Cyclization of the complex 1109 with concomitant aromatization was achieved by oxidation with an excess of iodine in pyridine at 90 °C in air to afford directly furostifoline (224) (688,689) (Scheme 5.179). 

Electrophilic substitutions Pyridine s electron-withdrawing nitrogen causes the ring carbons to have significantly less electron density than the ring carbons of benzene. Thus, pyridine is less reactive than benzene towards electrophilic aromatic substitution. However, pyridine undergoes some electrophilic substitution reactions under drastic conditions, e.g. high temperature, and the yields of these reactions are usually quite low. The main substitution takes place at C-3. 

The effect of the heteroatom is to make the pyridine ring very unreactive to normal electrophilic aromatic substitution. Conversely, pyridines are susceptible to nucleophilic attack. These topics are discussed later. 

A theme of this section is making reactions work. Usually that means making reactions that already work quite well work much better. But we start with a reaction - electrophilic aromatic substitution on pyridines and related heterocycles - that, doesn t really work at all. We shall see why not and how the reaction can be successfully realised. This involves some serious mechanistic thinking and questions of regioselectivity are vital to the solution. This is new chemistry with a great future. 

The electrophilic aromatic substitution of the pyridine ring continues to be explored as a way to prepare substituted pyridines. Bw-( 5y w-collidine)-iodine(I) and bromine (I) are effective iodinating or brominating agents, respectively, of pyridinols, although the di- or tri-halogenated products are obtained <97TL2467>. lodination of 3-pyridinol produces 5-hydroxy-... 

Both pyrimidine and purine aie planai. You will see how important this flat shape is when we consider the structure of nucleic acids. In tenns of their chemistry, pyrimidine and purine resemble pyridine. They are weak bases and relatively unreactive toward electrophilic aromatic substitution. 

The reactivity of pyridine relative to that of benzene has been measured using the competitive technique developed by Ingold and his schoool for corresponding studies of electrophilic aromatic substitution. The validity of the method applied to free-radical reactions has been discussed. Three sources of the phenyl radical have been used the results obtained are set out in Table II. 

Problem 24.22 Electrophilic aromatic substitution reactions of pyridine normally occur at C3. Draw... 

The effect of heteroatoms on electrophilic aromatic substitution, e.g. the reactions of pyridine, will be considered separately in Chapter 11. 

The empirical data for electrophilic aromatic substitution on benzocycloalkenes over a variety of reactions and conditions show a consistent trend of increased Cp selectivity due primarily to C deactivation, with some indication that Cp activation occurs in benzobicycloalkenes. Acidity work on the benzocycloalkenes and related pyridines demonstrates clearly the extent of deactivation. The rehybridization model of Finnegan and Streitweiser has been postulated to account for the deactivation. Thummel s correlation of C y -H P a provided the necessary link between rehybridization and deactivation. Theories involving bond fixation in the Wheland intmnediate deserve some further consideration but are not essential to an understanding of the present empirical data. 

Electrophilic aromatic substitutions The chemistry of pyrimidine is similar to that of pyridine with the notable exception that the second nitrogen in the aromatic ring makes it less reactive towards electrophilic substitutions. For example, nitration can only be carried out when there are two ring-activating substituents present on the pyrimidine ring (e.g. 2,4-dihydroxypyrimidine or uracil). The most activated position towards electrophilic substitution is C-5. 

Electrophilic aromatic substitutions Quinoline and isoquinoline undergo electrophilic aromatic substitution on the benzene ring, because a benzene ring is more reactive than a pyridine ring towards such reaction. Substitution generally occurs at C-5 and C-8, e.g. bromination of quinoline and isoquinoline. 

Predict the product of electrophilic aromatic substitution reactions of pyridine and quinoline. 

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