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

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; 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; two heteroatoms
Heteroatoms Saturated Unsaturated
2× Nitrogen Diaziridine Diazirine
Nitrogen + oxygen Oxaziridine Oxazirine
2× Oxygen Dioxirane
(highly unstable)

4-membered rings
Four-membered rings; one heteroatom
Heteroatom Saturated Unsaturated
Nitrogen Azetidine Azete
Oxygen Oxetane Oxete
Phosphorus Phosphetane Phosphete
Sulfur Thietane Thiete
Four-membered rings; 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. Dithiolanes 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; one heteroatom
Heteroatom Saturated Unsaturated
Antimony Stibolane Stibole
Arsenic Arsolane Arsole
Bismuth Bismolane Bismole
Boron Borolane Borole
Nitrogen Pyrrolidine ("Azolidine" not used) Pyrrole ("Azole" 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; two heteroatoms
Heteroatoms Saturated Unsaturated (and partially unsaturated)
2× nitrogen Imidazolidine
Pyrazolidine		 Imidazole (Imidazoline)
Pyrazole (Pyrazoline)
Oxygen + sulfur 1,3-Oxathiolane
1,2-Oxathiolane		 Oxathiole (Oxathioline)
Isoxathiole
Nitrogen + Oxygen Oxazolidine
Isoxazolidine		 Oxazole (Oxazoline)
Isoxazole
Nitrogen + sulfur Thiazolidine
Isothiazolidine		 Thiazole (Thiazoline)
Isothiazole
2× oxygen Dioxolane
2× sulfur Dithiolane Dithiole
Five-membered rings; at least three heteroatoms
Heteroatoms Saturated Unsaturated
N N N Triazoles
N N O Furazan
Oxadiazole
N N S Thiadiazole
N O O Dioxazole
N S S Dithiazole
N N N N Tetrazole
N N N N O Oxatetrazole
N N N N S Thiatetrazole
N N N N N Pentazole

6-membered rings
Six-membered rings; one heteroatom
Heteroatom Saturated Unsaturated Ions
Antimony Stibinin[7]
Arsenic Arsinane Arsinine
Bismuth Bismin[8]
Boron Borinane Borinine Boratabenzene anion
Germanium Germinane Germine
Nitrogen Piperidine
(Azinane not used)		 Pyridine
(Azine not used)		 Pyridinium cation
Oxygen Oxane Pyran
(2H-Oxine not used)		 Pyrylium cation
Phosphorus Phosphinane Phosphinine
Selenium Selenane Selenopyran[9] Selenopyrylium cation
Silicon Silinane Siline
Sulfur Thiane Thiopyran
(2H-Thiine not used)		 Thiopyrylium cation
Tellurium Tellurane Telluropyran Telluropyrylium cation
Tin Stanninane Stannine
Six-membered rings; two heteroatoms
Heteroatom Saturated Unsaturated
Nitrogen / nitrogen Diazinane Diazine
Oxygen / nitrogen Morpholine Oxazine
Sulfur / nitrogen Thiomorpholine Thiazine
Oxygen / Sulfur Oxathiane Oxathiin
Oxygen / oxygen Dioxane Dioxine
Sulfur / sulfur Dithiane Dithiin
Boron / nitrogen 1,2-Dihydro-1,2-azaborine
Six-membered rings; three heteroatoms
Heteroatom Saturated Unsaturated
Nitrogen Triazinane Triazine
Oxygen Trioxane
Sulfur Trithiane
Six-membered rings; four heteroatoms
Heteroatom Saturated Unsaturated
Nitrogen Tetrazine
2 nitrogen, 2 boronCarborazine
Six-membered rings; five heteroatoms
Heteroatom Saturated Unsaturated
Nitrogen 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; one heteroatom
Heteroatom Saturated Unsaturated
Boron Borepin
Nitrogen Azepane Azepine
Oxygen Oxepane Oxepine
Sulfur Thiepane Thiepine
Seven-membered rings; two heteroatoms
Heteroatom Saturated Unsaturated
Nitrogen Diazepane Diazepine
Nitrogen/sulfur Thiazepine

8-membered rings
Heteroatom Saturated Unsaturated
Nitrogen Azocane Azocine
Oxygen Oxocane Oxocine
Sulfur Thiocane Thiocine
4 nitrogen, 4 boronBorazocine

9-membered rings
Heteroatom Saturated Unsaturated
Nitrogen Azonane Azonine
Oxygen Oxonane Oxonine
Sulfur Thionane Thionine

Images of rings with one heteroatom
SaturatedUnsaturated
HeteroatomNitrogenOxygenSulfurNitrogenOxygenSulfur
3-atom ring AziridineOxiraneThiiraneAzirineOxireneThiirene
4-atom ring AzetidineOxetaneThietaneAzeteOxeteThiete
5-atom ring PyrrolidineOxolaneThiolanePyrroleFuranThiophene
6-atom ring PiperidineOxaneThianePyridinePyranThiopyran
7-atom ring AzepaneOxepaneThiepaneAzepineOxepineThiepine
8-atom ring AzocaneOxocaneThiocaneAzocineOxocineThiocine
9-atom ring AzonaneOxonaneThionaneAzonineOxonineThionine

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

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.
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