Why is pyridine less basic than piperidine?

6. Heterocyclic Compounds

As carbocyclic they are called ring molecules whose rings are made up only of carbon atoms. In the so-called Heterocycles at least one carbon of the ring is replaced by a heteroatom such as N, O or S. Over half of all natural products are heterocycles, and heterocyclic rings are contained in an extraordinarily large number of pharmacologically active molecules.

6.1 The nomenclature of the heterocycles

The nomenclature is not that simple because there are several nomenclature systems for heterocycles, and common names are also often used. The type of heteroatom is often indicated by a prefix; Aza- for N, oxa- for O, thia- for S.

Saturated heterocycles :

Aromatic heterocycles:

6.2 Aromatic heterocycles

We cannot discuss the chemistry of aromatic heterocycles in detail here. We shall, however, single out and consider important aspects of their structures and chemical properties.

By replacing a CH unit in benzene with a sp2-hybridized nitrogen, the pyridine molecule is formally obtained:

Pyridine is aromatic (6 & # 960 electrons), but a lone pair of electrons remains on the nitrogen and is located in one of the sp2-Orbitals in the molecular plane.

Because N is more electronegative than C, it draws electron density out of the ring inductively and via resonance:

What consequences does this have for reactivity?

First, since the lone pair of electrons at N does not participate in the conjugation (it is not in a p orbital, and it does not belong to the 6 "aromatic" electrons, see Chapter 5), pyridine reacts as a weak base:

The lone pair of electrons is also accessible to other electrophiles, such as (see Chapter 8):

This results in pyridinium salts, which also occur in nature:

The pyridine nucleotide NAD+ and its 2 "phosphate are coenzymes in a number of enzymatic oxidation and reduction reactions.

Since the pyridine ring is electron-deficient, electrophilic aromatic substitution can only be carried out with great difficulty in this system, and the reactions are orders of magnitude slower than with benzene, e.g .:

2- and 4-Hydroxypyridines are of special interest because they mostly lead to the corresponding 2- or 4-Pyridon tautomerize (see Chapter 12). A resonance structure clearly shows its aromatic character:

Pyridine is the simplest member of the azabenzenes series, which are found quite frequently in important natural products (see also Chapter 16):

The electronic structure of the three heterocycles Pyrrole, furan and thiophene is similar to that of the cyclopentadienyl anion:

In the corresponding heterocycles there is a neutral atom with one or two free electron pairs instead of a negatively charged carbon:

Molecular orbital representation

Resonance structures (valence structure description) :

Two important points follow from this. First: the lone pair of electrons on N is now involved in the aromatic 6 & # 960 electrons (cf. pyridine). i.e. Pyrrole is almost not basic at all, compared to pyridine:

Secondly, There are four dipolar resonance structures in which the positive charge is on the heteroatom and the negative charge is on a different carbon atom (see above). This picture shows that the heteroatom should be relatively electron poor and the carbon atoms should be relatively electron rich. In fact, this is confirmed by the responsiveness of these compounds.

As one would expect for aromatic systems, pyrrole, furan, and thiophene enter into electrophilic aromatic substitution reactions and even more rapidly than benzene.

The most important benzene-fused derivative of the five-membered heterocycles is undoubtedly this Indolewhich is contained in many natural substances:

Molecule orbital image :

Valence structure picture :

Although the resonance structures, in which the cyclic 6 & # 960 electron system of the fused benzene ring is perturbed, are of less importance, they show the electron-donating effect of the heteroatom.

Indoles (like pyrrole) are also very weak bases, but react quickly with electrophiles via electrophilic substitution reactions.

Imidazole is one of the most important small heteroaromatics in nature:

Molecule orbital image: valence structure image :

It comes in the proteinogenic amino acid Histidine (Chapter 15) and is therefore of great importance. Decarboxylation forms what is present in small quantities in all tissues histamine. Excessive amounts of free histamine are considered to be the cause of many allergies:

In contrast to pyrrole and indole, imidazole is clearly basic. Because of the stability of the conjugate acid, imidazole is significantly more basic (pKa = 6.5); the protonation takes place on the lone pair of electrons of the N atom:

Both possible protonated forms of e.g. histidine or histamine will be present in free solution: