Heterocyclic 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 organic chemistry dealing with the synthesis, properties, and applications of these heterocycles.[2]

structures and names of common heterocyclic compounds

Pyridine, a heterocyclic compound

cyclo-Octasulfur, a homocyclic compound

Examples of heterocyclic compounds include all of the nucleic acids, the majority of drugs, most biomass (cellulose and related materials), and many natural and synthetic dyes. 59% of US FDA-approved drugs contain nitrogen heterocycles.[3]

Classification

Although heterocyclic chemical compounds may be inorganic compounds or organic compounds, 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.[4]

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 refers to those fused to benzene rings. For example, the fused benzene analogs of pyridine, thiophene, pyrrole, and furan are quinoline, benzothiophene, indole, and benzofuran, respectively. The fusion of two benzene rings gives rise to a third large family of compounds. Analogs of the previously mentioned heterocycles for this third family of compounds are acridine, dibenzothiophene, carbazole, and dibenzofuran, respectively. The unsaturated rings can be classified according to the participation of the heteroatom in the conjugated pi system.

3-membered rings

Heterocycles with three atoms in the ring are higher in energy and 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. The C-X-C bond angles (where X is a heteroatom) in oxiranes and aziridines are very close to 60° and the peripheral H-C-H bond angles are near to 180°.

Three-membered rings with one heteroatom

Heteroatom	Saturated	Unsaturated
Boron	Borirane	Borirene
Nitrogen	Aziridine	Azirine
Oxygen	Oxirane (ethylene oxide, epoxides)	Oxirene
Phosphorus	Phosphirane	Phosphirene
Sulfur	Thiirane (episulfides)	Thiirene

Three-membered rings with two heteroatoms

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

4-membered rings

Four-membered rings with one heteroatom

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

Four-membered rings with two heteroatoms

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

5-membered rings

Five-membered rings with one heteroatom

Heteroatom	Saturated	Unsaturated
Antimony	Stibolane	Stibole
Arsenic	Arsolane	Arsole
Bismuth	Bismolane	Bismole
Boron	Borolane	Borole
Nitrogen	Pyrrolidine ("Azolidine" is not used)	Pyrrole ("Azole" is not used)
Oxygen	Tetrahydrofuran	Furan
Phosphorus	Phospholane	Phosphole
Selenium	Selenolane	Selenophene
Silicon	Silacyclopentane	Silole
Sulfur	Tetrahydrothiophene	Thiophene
Tellurium		Tellurophene
Tin	Stannolane	Stannole

Five-membered rings with two heteroatoms

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

Five-membered rings with at least three heteroatoms

A large group of 5-membered ring compounds with three or more heteroatoms also exists. One example is the class of dithiazoles, which contain two sulfur atoms and one nitrogen atoms.

Heteroatom	Saturated	Unsaturated
3 × Nitrogen		Triazoles
2 × Nitrogen / 1 × oxygen		Furazan Oxadiazole
2 × Nitrogen / 1 × sulfur		Thiadiazole
1 × Nitrogen / 2 × oxygen		Dioxazole
1 × Nitrogen / 2 × sulfur		Dithiazole
4 × Nitrogen		Tetrazole
4 × Nitrogen/1 × Oxygen		Oxatetrazole
4 × Nitrogen/1 × Sulfur		Thiatetrazole
5 × Nitrogen		Pentazole

6-membered rings

Six-membered rings with one heteroatom

Heteroatom	Saturated	Unsaturated	Ions
Antimony		Stibinin[5]
Arsenic	Arsinane	Arsinine
Bismuth		Bismin[6]
Boron	Borinane	Borinine	Boratabenzene anion
Germanium	Germinane	Germine
Nitrogen	Piperidine (Azinane is not used)	Pyridine (Azine is not used)	Pyridinium cation
Oxygen	Tetrahydropyran	Pyran (2H-Oxine is not used)	Pyrylium cation
Phosphorus	Phosphinane	Phosphinine
Selenium			Selenopyrylium cation
Silicon	Silinane	Siline
Sulfur	Thiane	Thiopyran (2H-Thiine is not used)	Thiopyrylium cation
Tin	Stanninane	Stannine

Six-membered rings with two heteroatoms

Heteroatom	Saturated	Unsaturated
Nitrogen / nitrogen	Diazinane	Diazine
Oxygen / nitrogen	Morpholine	Oxazine
Sulfur / nitrogen	Thiomorpholine	Thiazine
Oxygen / oxygen	Dioxane	Dioxine
Sulfur / sulfur	Dithiane	Dithiin
Boron / nitrogen		1,2-Dihydro-1,2-azaborine

Six-membered rings with three heteroatoms

Heteroatom	Saturated	Unsaturated
Nitrogen	Triazinane	Triazine
Oxygen	Trioxane
Sulfur	Trithiane

Six-membered rings with four heteroatoms

Heteroatom	Saturated	Unsaturated
Nitrogen		Tetrazine

Carborazine is a six-membered ring with two nitrogen heteroatoms and two boron heteroatom.

Six-membered rings with five heteroatoms

Heteroatom	Saturated	Unsaturated
Nitrogen		Pentazine

Six-membered rings with six heteroatoms

The hypothetical compound with six nitrogen heteroatoms would be hexazine.

Borazine is a six-membered ring with three nitrogen heteroatoms and three boron heteroatom.

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
Boron		Borepin
Nitrogen	Azepane	Azepine
Oxygen	Oxepane	Oxepine
Sulfur	Thiepane	Thiepine

Those with two heteroatoms include:

Heteroatom	Saturated	Unsaturated
Nitrogen	Diazepane	Diazepine
Nitrogen/sulfur		Thiazepine

8-membered rings

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

Borazocine is an eight-membered ring with four nitrogen heteroatoms and four boron heteroatom.

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
8-Atom Ring	Azocane	Oxocane	Thiocane	Azocine	Oxocine	Thiocine
9-Atom Ring	Azonane	Oxonane	Thionane	Azonine	Oxonine	Thionine

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. Thienothiophene are the fusion of two thiophene rings. Phosphaphenalenes are a tricyclic phosphorus-containing heterocyclic system derived from the carbocycle phenalene.

History of heterocyclic chemistry

The history of heterocyclic chemistry began in the 1800s, in step with the development of organic chemistry. Some noteworthy developments:[7]
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.

Uses

Heterocyclic compounds are pervasive in many areas of life sciences and technology.[2] Many drugs are heterocyclic compounds.[8]

References

1. IUPAC Gold Book heterocyclic compounds
2. Thomas L. Gilchrist "Heterocyclic Chemistry" 3rd ed. Addison Wesley: Essex, England, 1997. 414 pp. ISBN 0-582-27843-0.
3. Edon Vitaku, David T. Smith, Jon T. Njardarson (2014). "Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals". J. Med. Chem. 57: 10257-10274. doi:10.1021/jm501100b. PMID 25255204.CS1 maint: multiple names: authors list (link)
4. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "Hantzsch–Widman name". doi:10.1351/goldbook.H02737
5. "Stibinin". chemspider. Royal Society of Chemistry. Retrieved 11 June 2018.
6. "Bismin". ChemSpider. Royal Society of Chemistry. Retrieved 11 June 2018.
7. Campaigne, E. (1986). "Adrien Albert and the rationalization of heterocyclic chemistry". Journal of Chemical Education. 63 (10): 860. doi:10.1021/ed063p860.
8. "IPEXL.com Multilingual Patent Search, Patent Ranking". www.ipexl.com.

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)