Heterocyclic compound

For other uses of "ring structure", see Ring structure.

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 organic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and applications of organic heterocycles.^[2]

Structures and names of common heterocyclic compounds

Pyridine, a heterocyclic 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. More than half of known compounds are heterocycles.^[3] 59% of US FDA-approved drugs contain nitrogen heterocycles.^[4]

Classification

The study of organic heterocyclic chemistry focuses especially on organic unsaturated derivatives, and the preponderance of work and applications involves unstrained organic 5- and 6-membered rings. Included are pyridine, thiophene, pyrrole, and furan. Another large class of organic heterocycles refers to those fused to benzene rings. For example, the fused benzene derivatives 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 organic compounds. Analogs of the previously mentioned heterocycles for this third family of compounds are acridine, dibenzothiophene, carbazole, and dibenzofuran, respectively.

Heterocyclic organic compounds can be usefully classified based on their electronic structure. The saturated organic heterocycles behave like the acyclic derivatives. Thus, piperidine and tetrahydrofuran are conventional amines and ethers, with modified steric profiles. Therefore, the study of organic heterocyclic chemistry focuses on organic unsaturated rings.

Inorganic rings

Some heterocycles contain no carbon. Examples are borazine (B₃N₃ ring), hexachlorophosphazenes (P₃N₃ rings), and tetrasulfur tetranitride S₄N₄. In comparison with organic heterocycles, which have numerous commercial applications, inorganic ring systems are mainly of theoretical interest. IUPAC recommends the Hantzsch-Widman nomenclature for naming heterocyclic compounds.^[5]

Notes on lists

• "Heteroatoms" are atoms in the ring other than carbon atoms.
• Names in italics are retained by IUPAC and do not follow the Hantzsch-Widman nomenclature
• Some of the names refer to classes of compounds rather than individual compounds.
• Also no attempt is made to list isomers.

3-membered rings

Although subject to ring strain, 3-membered heterocyclic rings are well characterized.^[6]

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 (ethylene sulfide, episulfides)	Thiirene
Three-membered rings with two heteroatoms
Heteroatoms	Saturated	Unsaturated
2 × Nitrogen	Diaziridine	Diazirine
Nitrogen + Oxygen	Oxaziridine	Oxazirine
Nitrogen + Sulfur	Thiaziridine	Thiazirine
2 × Oxygen	Dioxirane (highly unstable)
2 × Sulfur	Dithiirane (highly unstable)

4-membered rings

Four-membered rings with one heteroatom
Heteroatom	Saturated	Unsaturated
Boron	Boretane	Borete
Nitrogen	Azetidine	Azete
Oxygen	Oxetane	Oxete
Phosphorus	Phosphetane	Phosphete
Sulfur	Thietane	Thiete
Four-membered rings with two heteroatoms
Heteroatoms	Saturated	Unsaturated
2 × Nitrogen	Diazetidine	Diazete
2 × Oxygen	Dioxetane	Dioxete
2 × Sulfur	Dithietane	Dithiete

5-membered rings

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. Dithioles have two sulfur atoms.

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 atom.

Five-membered rings with one heteroatom
Heteroatom	Saturated	Unsaturated
Antimony	Stibolane	Stibole
Arsenic	Arsolane	Arsole
Bismuth	Bismolane	Bismole
Boron	Borolane	Borole
Germanium	Germolane	Germole
Nitrogen	Pyrrolidine (Azolidine not used)	Pyrrole (Azole not used) Pyrroline (partially unsaturated)
Oxygen	Oxolane	Furan (Oxole not used)
Phosphorus	Phospholane	Phosphole
Selenium	Selenolane	Selenophene
Silicon	Silolane	Silole
Sulfur	Thiolane	Thiophene (Thiole not used)
Tellurium	Tellurolane	Tellurophene
Tin	Stannolane	Stannole
Five-membered rings with two heteroatoms
Heteroatoms	Saturated	Unsaturated (and partially unsaturated)
2 × Nitrogen	Pyrazolidine Imidazolidine	Pyrazole (Pyrazoline) Imidazole (Imidazoline)
Nitrogen + Oxygen	Oxazolidine Isoxazolidine	Oxazole (Oxazoline) Isoxazole (Isoxazoline)
Nitrogen + Sulfur	Thiazolidine Isothiazolidine	Thiazole (Thiazoline) Isothiazole (Isothiazoline)
Oxygen + Sulfur	Oxathiolane Isoxathiolane	Oxathiole Isoxathiole
2 × Oxygen	Dioxolane	Dioxole
2 × Sulfur	Dithiolane	Dithiole
Five-membered rings with three heteroatoms
Heteroatoms	Saturated	Unsaturated
3 × Nitrogen		Triazole
2 Nitrogen + Oxygen		Oxadiazole
2 Nitrogen + Sulfur		Thiadiazole
Nitrogen + 2 Oxygen		Dioxazole
Nitrogen + 2 Sulfur		Dithiazole
Five-membered rings with four heteroatoms
Heteroatoms	Saturated	Unsaturated
4 × Nitrogen		Tetrazole
3 Nitrogen + Oxygen		Oxatriazole
3 Nitrogen + Sulfur		Thiatriazole
Five-membered rings with five heteroatoms
Heteroatoms	Saturated	Unsaturated
5 × Nitrogen		Pentazole
4 Nitrogen + Oxygen		Oxatetrazole
4 Nitrogen + Sulfur		Thiatetrazole

6-membered rings

The 6-membered ring compounds containing two heteroatoms, at least one of which is nitrogen, are collectively called the azines. Thiazines contain a sulfur and a nitrogen atom in the ring. Dithiines have two sulfur atoms.

Six-membered rings with one heteroatom
Heteroatom	Saturated	Unsaturated	Ions
Antimony	Stibinane	Stibinine[7]	Stibatabenzene cation
Arsenic	Arsinane	Arsinine	Arsatabenzene cation
Bismuth	Bisminane	Bismine[8]	Bismatabenzene cation
Boron	Borinane	Borinine	Boratabenzene anion
Germanium	Germinane	Germine
Nitrogen	Piperidine (Azinane not used)	Pyridine (Azine not used)	Pyridinium cation
Oxygen	Oxane	Pyran (Oxine not used)	Pyrylium cation
Phosphorus	Phosphinane	Phosphinine	Phosphatabenzene cation
Selenium	Selenane	Selenopyran[9]	Selenopyrylium cation
Silicon	Silinane	Siline
Sulfur	Thiane	Thiopyran (Thiine not used)	Thiopyrylium cation
Tellurium	Tellurane	Telluropyran	Telluropyrylium cation
Tin	Stanninane	Stannine
Six-membered rings with two heteroatoms
Heteroatoms	Saturated	Unsaturated
2 × Nitrogen	Piperazine	Pyrazine Pyrimidine Pyridazine
Nitrogen + Oxygen	Morpholine	Oxazine
Nitrogen + Sulfur	Thiomorpholine	Thiazine
Oxygen + Sulfur	Oxathiane	Oxathiin
2 × Oxygen	Dioxane	Dioxin
2 × Sulfur	Dithiane	Dithiin
Six-membered rings with three heteroatoms
Heteroatoms	Saturated	Unsaturated
3 × Nitrogen	Triazinane	Triazine
3 × Oxygen	Trioxane	Trioxin
3 × Sulfur	Trithiane	Trithiin
Six-membered rings with four heteroatoms
Heteroatoms	Saturated	Unsaturated
4 × Nitrogen		Tetrazine
2 Nitrogen + 2 Boron		Carborazine

Six-membered rings with five heteroatoms
The hypothetical chemical compound with five nitrogen heteroatoms would be pentazine.

Six-membered rings with six heteroatoms
The hypothetical chemical compound with six nitrogen heteroatoms would be hexazine. Borazine is a six-membered ring with three nitrogen heteroatoms and three boron heteroatoms.

7-membered rings

In a 7-membered ring, the heteroatom must be able to provide an empty π-orbital (e.g. boron) for "normal" aromatic stabilization to be available; otherwise, homoaromaticity may be possible.

Seven-membered rings with one heteroatom
Heteroatom	Saturated	Unsaturated
Boron	Borepane	Borepine
Nitrogen	Azepane	Azepine
Oxygen	Oxepane	Oxepine
Phosphorus	Phosphepane	Phosphepine
Sulfur	Thiepane	Thiepine
Seven-membered rings with two heteroatoms
Heteroatoms	Saturated	Unsaturated
2 × Nitrogen	Diazepane	Diazepine
Nitrogen + Oxygen	Oxazepane	Oxazepine
Nitrogen + Sulfur	Thiazepane	Thiazepine

8-membered rings

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

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

9-membered rings

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

Images of rings with one heteroatom

	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/condensed 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:^[10]

• 1818: Brugnatelli makes 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 chlorophyll 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.^[11]

See also

• Spiroketals

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. Rees, Charles W. (1992). "Polysulfur-Nitrogen Heterocyclic Chemistry". Journal of Heterocyclic Chemistry. 29 (3): 639–651. doi:10.1002/jhet.5570290306.
4. 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 (24): 10257–10274. doi:10.1021/jm501100b. PMID 25255204.{{cite journal}}: CS1 maint: multiple names: authors list (link)
5. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "Hantzsch–Widman name". doi:10.1351/goldbook.H02737
6. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 978-0-471-72091-1
7. "Stibinin". chemspider. Royal Society of Chemistry. Retrieved 11 June 2018.
8. "Bismin". ChemSpider. Royal Society of Chemistry. Retrieved 11 June 2018.
9. "Selenopyranium". ChemSpider. Royal Society of Chemistry. Retrieved 11 June 2018.
10. Campaigne, E. (1986). "Adrien Albert and the rationalization of heterocyclic chemistry". Journal of Chemical Education. 63 (10): 860. Bibcode:1986JChEd..63..860C. doi:10.1021/ed063p860.
11. "IPEXL.com Multilingual Patent Search, Patent Ranking". www.ipexl.com. Archived from the original on 24 September 2015. Retrieved 8 September 2010.

External links

• Hantzsch-Widman nomenclature, IUPAC
• Heterocyclic amines in cooked meat, US CDC
• List of known and probable carcinogens, American Cancer Society Archived 13 December 2003 at the Wayback Machine
• List of known carcinogens by the State of California, Proposition 65 (more comprehensive)