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 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 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 an 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 |
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| 4-atom ring | Azetidine | Oxetane | Thietane | Azete | Oxete | Thiete |
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| 5-atom ring | Pyrrolidine | Oxolane | Thiolane | Pyrrole | Furan | Thiophene |
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| 6-atom ring | Piperidine | Oxane | Thiane | Pyridine | Pyran | Thiopyran |
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| 7-atom ring | Azepane | Oxepane | Thiepane | Azepine | Oxepine | Thiepine |
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| 8-atom ring | Azocane | Oxocane | Thiocane | Azocine | Oxocine | Thiocine |
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| 9-atom ring | Azonane | Oxonane | Thionane | Azonine | Oxonine | Thionine |
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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
- ^ IUPAC Gold Book heterocyclic compounds
- ^ a b Thomas L. Gilchrist "Heterocyclic Chemistry" 3rd ed. Addison Wesley: Essex, England, 1997. 414 pp. ISBN 0-582-27843-0.
- ^ Rees, Charles W. (1992). "Polysulfur-Nitrogen Heterocyclic Chemistry". Journal of Heterocyclic Chemistry. 29 (3): 639–651. doi:10.1002/jhet.5570290306.
- ^ 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) - ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "Hantzsch–Widman name". doi:10.1351/goldbook.H02737
- ^ 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
- ^ "Stibinin". chemspider. Royal Society of Chemistry. Retrieved 11 June 2018.
- ^ "Bismin". ChemSpider. Royal Society of Chemistry. Retrieved 11 June 2018.
- ^ "Selenopyranium". ChemSpider. Royal Society of Chemistry. Retrieved 11 June 2018.
- ^ 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.
- ^ "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)
| Authority control databases: National |
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Notes
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