3.6. Heterocycles

Recall that ring systems do not all need to be made of carbon atoms. Heteroatoms (atoms other than carbon and hydrogen) can also be part of ring structures.

In the vast majority of cases these heteroatoms are part of a functional group that is identical to its non-cyclic counterpart. For example, the nitrogen atoms of both Molecule A and B are part of (secondary) amine functional groups and are both referred to as such (Figure 3.22). However, technically some functional groups get a different name when they are part of a ring system. For example, the nitrogen atoms of both Molecule C and D are part of amide functional groups. However, technically the functional group in Molecule D is properly named as a lactam (a heterocyclic amide).

Figure 3.22 – Examples of Functional Groups and Potential Name Changes for Functional Groups in Heterocycles.

A similar name change happens for several other functional groups when they are part of rings. This text will avoid using specialized names for cyclic functional groups; referring to these functional groups using the standard non-cyclic names is acceptable. However, they are often encountered in other sources. In these cases, searching the functional group name using a resource such as Wikipedia will be a straightforward way of understanding what is being discussed.

3.6.1. Refresher and Expansion: Common Heterocycles

Most heterocyclic compounds were identified and characterized before the IUPAC system was developed. As a result, the use of trivial names for heterocyclic rings remains commonplace and memorizing the more common ones is required for communication. There are hundreds of specifically named heterocyclic rings. For an introductory text only the most common ones will be important (Figure 3.23). Others may be encountered in assignments, labs, discussions, etc. In these cases, searching the ring name using a resource such as Wikipedia will be a straightforward way of understanding what is being discussed.

Figure 3.23 – Select Trivial Names for Common Heterocyclic and Heteroaromatic Rings.

The large variety of heterocycle names is generally frustrating for both communication and learning purposes. However, the specificity is justified given how widespread heterocycles are in important bioorganic molecules (Figure 3.24). Heterocyclic rings are part of almost all major classes of biomolecules, in some cases being the major structural component.

Figure 3.24 – Select Examples of Important Bioorganic Molecules Containing Common Heterocyclic and Heteroaromatic Rings.

3.6.2. Special Properties of Aromatic Heterocycles

Recall that in order for a molecule (or part of a molecule) to be aromatic it must satisfy four conditions: be cyclic, have non-orthogonal p orbitals on all atoms in the ring, be planar, and obey Hückel’s Rule (the number of π electrons in the ring system must be a solution to [4n+2]).

Meeting these conditions makes a molecule (or part of a molecule) aromatic and provides a large amount of stability. This is often referred to as aromatic stabilization energy (Figure 3.25).

Figure 3.25 – Aromatic Stabilization Energy of Benzene.

Both pyrrole and pyridine are aromatic heterocycles with a nitrogen atom in the ring (Figure 3.26). Both nitrogen atoms, as drawn, have a lone pair of electrons. In principle both could be nucleophiles. However, pyridine is a moderate-to-good nucleophile and pyrrole is functionally not nucleophilic.

Figure 3.26 – Contrasting Pyrrole and Pyridine as Aromatic Heterocycles with Differing Nucleophilicities Despite Apparent Similarities.

The hybridization of the nitrogen atom in pyridine is sp²; the lone pair on nitrogen is in an sp² orbital and therefore orthogonal to the π system (Figure 3.27).

Figure 3.27 – Highlighting the Location of Electrons in Pyridine.

As a result, those electrons are not in the π systems of the ring. They can be used for a nucleophilic attack and the product will still be aromatic (Scheme 3.14).

Scheme 3.14 – Generalized Example of Pyridine Acting as a Nucleophile and Being Aromatic Before and After the Nucleophilic Attack.

The hybridization of the nitrogen atom in pyrrole is also sp². This can be seen by drawing the resonance structures and then assigning hybridization (Figure 3.28). The lone pair on nitrogen is in a p orbital and therefore NOT orthogonal to the π system. It is part of the electron cloud that lets the molecule satisfy Hückel’s Rule.

Figure 3.28 – Highlighting the Location of Electrons in Pyrrole.

As a result, those electrons ARE in the π systems of the ring. They could be used for a nucleophilic attack but the product would NOT be aromatic anymore (Scheme 3.15).

Scheme 3.15 – Generalized Example of Pyrrole Acting as a Nucleophile and Being Aromatic Before but not After the Nucleophilic Attack.

Using the lone pair on the nitrogen of pyrrole for a nucleophilic attack breaks the aromaticity of the ring. This loses the aromatic stabilization energy, which means that it costs a lot of energy to do. As a result, pyrrole will not act as a nucleophile.

For aromatic heterocycles it is often extremely helpful to draw out resonance structures to better identify which electrons are available for nucleophilic attacks and which are contributing to aromaticity. For example, there are two nitrogen atoms with lone pairs in an imidazole ring (Figure 3.29). Imidazole is part of the amino acid histidine and involved in catalysis in the active site of some enzymes. At first glance, it may appear that imidazole has two potentially nucleophilic/basic sites. However, one of the lone pairs is in the π system (by being in a p orbital) and one is in an orthogonal sp² orbital. Only one of those two positions is nucleophilic/basic.

Figure 3.29 – Highlighting the Location of Electrons in Imidazole (Part of Histidine) to Show the Difference Between Nitrogen Atoms.