Heterocyclic compound

Pyridine, a heterocyclic compound

cyclo-octasulfur, a homocyclic compound

A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s).^[1] Heterocyclic chemistry is the branch of chemistry dealing with the synthesis, properties and applications of these heterocycles. In contrast, the rings of homocyclic compounds consist entirely of atoms of the same element.

Although heterocyclic compounds may be inorganic, most contain at least one carbon. While atoms that are neither carbon nor hydrogen are normally referred to in organic chemistry as heteroatoms, this is usually in comparison to the all-carbon backbone. But this does not prevent a compound such as borazine (which has no carbon atoms) from being labelled "heterocyclic". IUPAC recommends the Hantzsch-Widman nomenclature for naming heterocyclic compounds.

Classification based on electronic structure

Heterocyclic compounds can be usefully classified based on their electronic structure. The saturated heterocycles behave like the acyclic derivatives. Thus, piperidine and tetrahydrofuran are conventional amines and ethers, with modified steric profiles. Therefore, the study of heterocyclic chemistry focuses especially on unsaturated derivatives, and the preponderance of work and applications involves unstrained 5- and 6-membered rings. Included are pyridine, thiophene, pyrrole, and furan. Another large class of heterocycles are fused to benzene rings, which for pyridine, thiophene, pyrrole, and furan are quinoline, benzothiophene, indole, and benzofuran, respectively. Fusion of two benzene rings gives rise to a third large family of compounds, respectively the acridine, dibenzothiophene, carbazole, and dibenzofuran. The unsaturated rings can be classified according to the participation of the heteroatom in the pi system.

3-membered rings

Heterocycles with three atoms in the ring are more reactive because of ring strain. Those containing one heteroatom are, in general, stable. Those with two heteroatoms are more likely to occur as reactive intermediates.
Common 3-membered heterocycles with one heteroatom are:

Heteroatom	Saturated	Unsaturated
Nitrogen	Aziridine	Azirine
Oxygen	Oxirane (ethylene oxide, epoxides)	Oxirene
Sulfur	Thiirane (episulfides)	Thiirene

Those with two heteroatoms include:

Heteroatom	Saturated	Unsaturated
Nitrogen	Diaziridine	Diazirine
Nitrogen/oxygen	Oxaziridine
Oxygen	Dioxirane

4-membered rings

Compounds with one heteroatom:

Heteroatom	Saturated	Unsaturated
Nitrogen	Azetidine	Azete
Oxygen	Oxetane	Oxete
Sulfur	Thietane	Thiete

Compounds with two heteroatoms:

Heteroatom	Saturated	Unsaturated
Nitrogen	Diazetidine	Diazete
Oxygen	Dioxetane	Dioxete
Sulfur	Dithietane	Dithiete

5-membered rings

With heterocycles containing five atoms, the unsaturated compounds are frequently more stable because of aromaticity.

Five-membered rings with one heteroatom:

Heteroatom	Saturated	Unsaturated
Nitrogen	Pyrrolidine (Azolidine is not used)	Pyrrole (Azole is not used)
Oxygen	Tetrahydrofuran (Oxolane is rare)	Furan (Oxole is not used)
Sulfur	Thiolane	Thiophene (Thiole is not used)
Boron	Borolane	Borole
Phosphorus	Phospholane	Phosphole
Arsenic	Arsolane	Arsole
Antimony	Stibolane	Stibole
Bismuth	Bismolane	Bismole
Silicon	Silolane	Silole
Tin	Stannolane	Stannole

The 5-membered ring compounds containing two heteroatoms, at least one of which is nitrogen, are collectively called the azoles. Thiazoles and isothiazoles contain a sulfur and a nitrogen atom in the ring. Dithiolanes have two sulfur atoms.

Heteroatom	Saturated	Unsaturated (and partially unsaturated)
Nitrogen/nitrogen	Imidazolidine Pyrazolidine	Imidazole (Imidazoline) Pyrazole (Pyrazoline)
Nitrogen/oxygen	Oxazolidine Isoxazolidine	Oxazole (Oxazoline) Isoxazole
Nitrogen/sulfur	Thiazolidine Isothiazolidine	Thiazole (Thiazoline) Isothiazole
Oxygen/oxygen	Dioxolane
Sulfur/sulfur	Dithiolane

A large group of 5-membered ring compounds with three heteroatoms also exists. One example is dithiazoles that contain two sulfur and a nitrogen atom.

Heteroatom	Saturated	Unsaturated
3 × Nitrogen		Triazoles
2 × Nitrogen / 1 × oxygen		Furazan Oxadiazole
2 × Nitrogen / 1 × sulfur		Thiadiazole
1 × Nitrogen / 2 × sulfur		Dithiazole

Five-member ring compounds with four heteroatoms:

Heteroatom	Saturated	Unsaturated
4 × Nitrogen		Tetrazole

With 5-heteroatoms, the compound may be considered inorganic rather than heterocyclic. Pentazole is the all nitrogen heteroatom unsaturated compound.

6-membered rings

Six-membered rings with a single heteroatom:

Heteroatom	Saturated	Unsaturated
Nitrogen	Piperidine (Azinane is not used)	Pyridine (Azine is not used)
Oxygen	Oxane	Pyran (2H-Oxine is not used)
Sulfur	Thiane	Thiopyran (2H-Thiine is not used)
Silicon	Salinane	Siline
Germanium	Germinane	Germine
Tin	Stanninane	Stannine
Boron	Borinane	Borinine
Phosphorus	Phosphinane	Phosphinine
Arsenic	Arsinane	Arsinine

With two heteroatoms:

Heteroatom	Saturated	Unsaturated
Nitrogen / nitrogen	Piperazine	Diazines
Oxygen / nitrogen	Morpholine	Oxazine
Sulfur / nitrogen	Thiomorpholine	Thiazine
Oxygen / oxygen	Dioxane	Dioxine
Sulfur / sulfur	Dithiane	Dithiine

With three heteroatoms:

Heteroatom	Saturated	Unsaturated
Nitrogen		Triazine
Oxygen	Trioxane
Sulfur	Trithiane

With four heteroatoms:

Heteroatom	Saturated	Unsaturated
Nitrogen		Tetrazine

With five heteroatoms:

Heteroatom	Saturated	Unsaturated
Nitrogen		Pentazine

The hypothetical compound with six nitrogen heteroatoms would be hexazine.

7-membered rings

With 7-membered rings, the heteroatom must be able to provide an empty pi orbital (e.g., boron) for "normal" aromatic stabilization to be available; otherwise, homoaromaticity may be possible. Compounds with one heteroatom include:

Heteroatom	Saturated	Unsaturated
Nitrogen	Azepane	Azepine
Oxygen	Oxepane	Oxepine
Sulfur	Thiepane	Thiepine

Those with two heteroatoms include:

Heteroatom	Saturated	Unsaturated
Nitrogen	Homopiperazine	Diazepine
Nitrogen/sulfur		Thiazepine

8-membered rings

Heteroatom	Saturated	Unsaturated
Nitrogen	Azocane	Azocine
Oxygen	Oxocane	Oxocine
Sulfur	Thiocane	Thiocine

9-membered rings

Heteroatom	Saturated	Unsaturated
Nitrogen	Azonane	Azonine
Oxygen	Oxonane	Oxonine
Sulfur	Thionane	Thionine

Images

Names in italics are retained by IUPAC and they do not follow the Hantzsch-Widman nomenclature

	Saturated			Unsaturated
Heteroatom	Nitrogen	Oxygen	Sulfur	Nitrogen	Oxygen	Sulfur
3-Atom Ring	Aziridine	Oxirane	Thiirane	Azirine	Oxirene	Thiirene
4-Atom Ring	Azetidine	Oxetane	Thietane	Azete	Oxete	Thiete
5-Atom Ring	Pyrrolidine	Oxolane	Thiolane	Pyrrole	Furan	Thiophene
6-Atom Ring	Piperidine	Oxane	Thiane	Pyridine	Pyran	Thiopyran
7-Atom Ring	Azepane	Oxepane	Thiepane	Azepine	Oxepine	Thiepine

Fused rings

Heterocyclic rings systems that are formally derived by fusion with other rings, either carbocyclic or heterocyclic, have a variety of common and systematic names. For example, with the benzo-fused unsaturated nitrogen heterocycles, pyrrole provides indole or isoindole depending on the orientation. The pyridine analog is quinoline or isoquinoline. For azepine, benzazepine is the preferred name. Likewise, the compounds with two benzene rings fused to the central heterocycle are carbazole, acridine, and dibenzoazepine.

History of heterocyclic chemistry

The history of heterocyclic chemistry began in the 1800s, in step with the development of organic chemistry. Some noteworthy developments:^[2]
1818: Brugnatelli isolates alloxan from uric acid
1832: Dobereiner produces furfural (a furan) by treating starch with sulfuric acid
1834: Runge obtains pyrrole ("fiery oil") by dry distillation of bones
1906: Friedlander synthesizes indigo dye, allowing synthetic chemistry to displace a large agricultural industry
1936: Treibs isolates chlorophyl derivatives from crude oil, explaining the biological origin of petroleum.
1951: Chargaff's rules are described, highlighting the role of heterocyclic compounds (purines and pyrimidines) in the genetic code.

Commercial use

Leading companies with a vast number of patents related to heterocyclic compounds are Bayer, Merck, Ciba-Geigy, Pfizer, Eli Lily, BASF, Hoffmann La Roche, ER Sqibb, Warner Lambert and Hoechst.^[3]

References

1. IUPAC Gold Book heterocyclic compounds
2. E. Campaigne "Adrien Albert and the Rationalization of Heterocyclic Chemistry" J. Chemical Education 1986, Volume 6, 860. doi:10.1021/ed063p860
3. Companies with the highest number of patents related to heterocyclic compounds.

External links

• Hantzsch-Widman nomenclature, IUPAC
• Heterocyclic amines in cooked meat, US CDC
• List of known and probable carcinogens, American Cancer Society
• List of known carcinogens by the State of California, Proposition 65 (more comprehensive)