Six-membered rings with one heteroatom

What are six-membered rings with one heteroatom?

Hexagonal heterocycles with one heteroatom are six-membered cyclic organic compounds with one atom in the ring other than carbon.

A CH in the benzene can be replaced by a nitrogen atom or by another of the group 15 elements without substantially altering the character of the π-orbitals. That is, hexagonal heterocycles of this type can be considered benzene analogs.

Among these, pyridine is one of the most abundant and well-known heterocycles.

Next, pyridine and the two benzopyridines (quinoline and isoquinoline) along with other hexagonal heterocycles are discussed.

Pyridines

Quinolines and isoquinolines

Other fused quinolines

Quinolizines

Quinolizines (quinolizinium salts and their derivatives) are stable, water-soluble crystalline solids, which can be considered aromatic.

fig-01

They are prepared by different synthetic routes from pyridines substituted at the C2 position.

fig-02

This ring system normally occurs in nature in partial or completely reduced form.

fig-03

Lupine is a plant alkaloid of the genus Lupinus.

Quinolizinium salts retain many properties of the pyridinium salts. Thus, they are resistant to electrophilic attack, but susceptible to nucleophilic attack, especially at the C4 position.

Nucleophiles easily subdue the ring system. In addition, the hydride at the C4 position is not displaced, because the intermediate (I) can undergo electrophilic ring opening.

fig-04

4-chloro-quinolizinium perchlorate can lose chlorine.

fig-05

The hydroxy-, amino- and alkyl- substituents at C2 and C4 positions are ativated in the same way as in the pyridinium salts. For example, 2-hydroxy-quinolizinium salts readily deprotonate to give 2-quinolizones.

fig-06

Acridines

Acridine is a linear tricyclic heterocycle with a structure similar to anthracene.

fig-07

Some amino-acridines, especially 9-amino acridine and 3,6-diamino-acridine (proflavine) have antiseptic properties. Other amino-acridines are used as dyes, e.g. acridine orange.

fig-08

In this compound, the positive charge is widely delocalized.

A general method of synthesis of this ring system is by cyclization of 2-phenyl-amino benzoic acids.

fig-09

The 9-chloro-acridine obtained in this way can be converted to C9-substituted acridines by nucleophilic displacement.

fig-10

Acridine is found in coal tar and is a crystalline solid with a melting point of 110°C. It is also basic in character with pKa values of 5.60, comparable in strength to pyridine.

The C9 position of acridine is activated by the nitrogen atom of the ring.

In this way, acridine is easily reduced to 9,10-dehydro-acridine with potassium cyanide (KC≡N).

fig-11

In addition, a methyl group in the C9 position is sufficiently activated to give copulation reactions with diazonium salts. Thus, when the nitrogen atom is quaternized, a methylide is easily formed by reaction with an alkali.

Phenanthridines

Phenanthridine is the heterocyclic analog of phenanthrene, with a nitrogen atom in the N5 position. It is a solid with a melting point of 108 °C, weakly basic with pKa values of 4.52. It can be N-alkylated and N-oxidized in the same way as the other fused pyridines.

The ring system can be prepared by various cyclization reactions.

fig-12

The activated position for phenanthridines is C6 and the properties of the substituents on that carbon atom differ in relation to other positions.

The chloride at C6 is displaced without difficulty by nucleophiles, and 6-methylphenanthridine can be lithiated and alkylated at the methyl group.

For example, phenanthridine is reduced to the 5,6-dihydro-derivative with lithium aluminum hydride (LiAlH4).

fig-13

Indolizines

Indolizine consists of a 5-membered ring fused at the N1—C2 bond of the pyridine.

fig-14

It occurs in nature in fully reduced form, as the alkaloid δ-conicein.

fig-15

Indolizine gives rise to a family of heterocyclic compounds in which one or more of the remaining CH groups are replaced by nitrogens.

Compounds of this type can be classified as aromatic, because it comprises a 10-electron π-conjugated system.

Indolizine has significant resonance energy and its ultraviolet (UV) spectrum resembles that of naphthalene.

The synthesis can be carried out by different routes. One of them is the Chichibabin synthesis.

This method starts from a pyridine with an activated methylene group at C2.

fig-16

Indolizine is an air-sensitive solid with a melting point of 75 ºC, which exhibits some pyrrole-like properties.

For example, it is a weak base (pKa = 3.94) and the most stable cation (I) is formed by protonation at C3 which is equivalent to the C2 position of pyrrole.

fig-17

Indolizine undergoes electrophilic substitution preferentially at the C3 position and, if this is blocked, at C1.

The ring system is preferably hydrogenated on the 6-membered ring. However, if the reduction is carried out in an acidic medium, the cation (I) is selectively hydrogenated at the C1—C2 double bond.

Six-membered rings with one oxygen