Preparation and Reactions of Amines

Nitrogen Heterocycles

Important nitrogen heterocycles include pyrrole, imidazole, pyridine, pyrimidine, and indole. Two of the significant reactions involving nitrogen heterocycles are both electrophilic aromatic substitution reactions.

A heterocycle is an organic compound containing a ring of atoms of at least two elements (one of which is generally carbon). In most heterocycles, many of the ring atoms are carbon, and only a few are another element, such as oxygen, nitrogen, or sulfur. Replacing one or more of the carbons in an aromatic ring with a nitrogen will have an effect on both the ring's aromaticity and reactivity. Aromaticity is the property of a cyclic compound in which the conjugated (altering single and double bonds) molecule is stabilized by the delocalization of the π\pi electrons.

Heterocycles such as pyrrole, pyridine, indole, imidazole, and pyrimidine are often the base for larger, more complex molecules. They are found predominantly in pharmaceuticals such as those used for high blood pressure, acid reflux, type 2 diabetes, malaria, migraines, and a variety of others. They are also used in other applications, including as a solvent and in small amounts to denature ethanol.

Examples of Nitrogen Heterocycles

Important nitrogen heterocycles include pyrrole, imidazole, pyridine, pyrimidine, and indole.
In nitrogen heterocycles, the addition of the nitrogen to the ring system has a significant effect on molecules' overall reactivity. In pyrrole and pyridine, the addition of nitrogen affects the aromaticity of the ring system and greatly changes the reactivity of those molecules.

In pyrrole, its lone electron pair interacts with the π\pi system of the ring and contributes to the overall aromaticity of the ring. By contrast, pyridine's lone electron pair occupies the space normally occupied by the hydrogen in the carbon-hydrogen bond, making it unavailable to the π\pi system. Therefore, it does not contribute to the overall aromaticity of the ring. This makes pyrrole more reactive toward electrophiles than benzene or pyridine is.

The location of pyridine's lone pair is in the plane of the ring and isolated to the nitrogen, which makes pyridine a stabilized imine and a very good nucleophile but a very bad electrophile, particularly for electrophilic aromatic substitution (EAS) reactions. When pyridine undergoes EAS with Br2, reactions are slow and the results are not good because of the nitrogen's inductive effect. The major product that forms will be bromination at the third position of the pyridine ring. The preference for the bromination is the third position because the nitrogen atom destabilizes the cationic intermediate when the bromine is placed at the two or four position. When the bromine is at either of these positions, resonance would eventually move the cation to the nitrogen, where it would be an electron-deficient and unstable cation. If the bromine is placed at the three position, the cation will move around the ring but will not involve the nitrogen.

When pyrrole undergoes EAS with Br2, halogenation occurs primarily at carbon 2 (C2) because of resonance stabilization of the intermediate. Because the nitrogen can participate in the cation movement, it is possible to place the bromine next to the nitrogen on the pyrrole ring.

EAS Bromination Mechanisms of Pyrrole and Pyridine

When pyrrole undergoes electrophilic aromatic substitution with bromine (Br2), halogenation occurs primarily at carbon 2 of the pyrrole because of resonance stabilization of the intermediate. When pyridine undergoes electrophilic aromatic substitution with bromine (Br2), reactions are very poor because of the nitrogen's inductive effect, and 3-bromination is the major product.