Organic Chemistry: Concepts and Applications - Headley Allan D. 2020

Aromaticity and Aromatic Substitution Reactions
17.11 Electrophilic Substitution Reactions of Pyridine

Even though pyridine looks a lot like benzene, the products of the reaction of pyridine with electrophiles are slightly different from those of benzene, polycyclic aromatic compounds, or pyrrole. To fully understand why the difference, we need to examine an important property of pyridine and that is the dipole moment. Pyridine has a dipole moment of 2.26 debyes and the direction of the dipole is away from the aromatic ring and toward the nitrogen, as shown below.

Based on this dipole moment, the electron density is toward the nitrogen atom and away from the aromatic ring. Reactions (17-69)—(17-71) give the resonance structures of the intermediates that result from the RDS step of the reaction mechanism after the addition of an electrophile.

(17-69)

(17-70)

(17-71)

You will notice that for the addition to positions #2 and #4 (Reactions (17-70) and (17-71)), there is a resonance structure in each that is not stable since the positive charge is on the very electronegative nitrogen. Since the pathway that leads to the more stable intermediate is the attraction of the electrophile to the #3 position of the pyridine ring, the major product will be the substitution in the #3 position. The final step in the reaction mechanism to give the major product is shown in Reaction (17-72). Note that the major product shown is typically formed in very low yields since pyridine is less reactive, compared to the other aromatic molecules.

(17-72)

If the least stable intermediates were to form products, the final steps in the reaction mechanism to give the minor products would be as shown in Reactions (17-73) and (17-74).

(17-73)

(17-74)

The overall aromatic substitution reaction is shown in Reaction (17-75).

(17-75)

An example of the electrophilic substitution involving pyridine and showing only the major organic product is given in Reaction (17-76).

(17-76)

Problem 17.13

Give the major organic product for the reaction of pyridine with Br₂/FeBr₃.

It should be noted that since pyridine has a pair of electrons on the nitrogen that is not involved in the aromaticity, it is nucleophilic and in the presence of an electrophile, the possibility exists for a substitution reaction as shown in the examples below.

(17-77)

(17-78)