Substitution in Pyridine

Though aromatic, pyridine is very resistant to electrophilic aromatic substitution and undergoes reaction only under drastic conditions. For example, nitration or bromina-tion requires high temperatures and strong acid catalysis. 

When substitution does occur, electrophiles attack pyridine mainly at C-3. The cationic intermediate (review Sec. 4.9) is least unfavorable in this case, because it does not put a positive charge on the electron-deficient nitrogen (especially bad if the nitrogen is protonated). 

Draw all contributors to the resonance hybrid for electrophilic attack at C-3 of pyridine. 

PROBLEM 13.2 Repeat Example 13.1, but for electrophilic substitution at C-2 or C-4 of pyridine. Explain why substitution at C-3 (eq. 13.2) is preferred. 

Although resistant to electrophilic substitution, pyridine undergoes nucleophilic aromatic substitution. The pyridine ring is partially positive (due to electron withdrawal by the nitrogen) and is therefore susceptible to attack by nucleophiles. Here are two examples  

---

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

It should be expected that the orientation and rate of electrophilic substitution in the isoxazole nucleus would be affected by both hetero atoms. Because of the electron-accepting effect of the nitrogen atom, electrophilic substitution of the isoxazole nucleus should proceed less readily than in the case of benzene and should occur essentially at the position jS to the nitrogen atom, just as in pyridine and other azoles. Simultaneously the electron-donating oxygen atom should facilitate such reactions in isoxazole as compared with the substitution in pyridine. These predictions are confirmed by the available experimental evidence. 

Displacement of thioether substituents in pyridinium salts can be achieved with amines, and hydroxide will effect a similar substitution in pyridine thioethers, e.g. Scheme 123 (69KGS677). 

Chlorinated Heterocyclics. Substitution in pyridine is more difficult than in benzene hut Cl will enter die ft position slowly. Chlorine will not add to furan to give stable addition products but substitution occurs to give 2-chloro- or 3-chlorofuran. 2.5-dichlorofuran. and 2.3.5-lriehlorofuran. 

For ortho or para substitution in pyridine add — 1.5 kcal mole" 1 per group. 

Fig. 9.2. Plot of

Substitution in pyridine is more consistent with an addition-elimination process (Figure 9.8). 

Regioselective nucleophilic, electrophilic, and radical substitution in pyridines, di-, tri-, and tetrazines 88AHC(44)199. 

Electrophilic C-substitution in pyridines carrying strongly activating substituents (nitrogen and oxygen) is discussed in Sections 8.9.3.1 and 8.9.2.I. 

Substitution in pyridines carrying activating nitrogen and oxygen substituents... 

Boggs J, Pang F (1984) The structural effects of fluorine substitution in pyridine, pyrimidine, and s-triazine an Ah initio study. J Heterocycl Chem 21 1801-1805... 

---