Heterocyclic compound

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

Structures and names of common heterocyclic compounds
Pyridine, a 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 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
Structure of aziridine Structure of oxirane Structure of thiirane Structure of azirine Structure of oxirene Structure of thiirene
4-atom ring Azetidine Oxetane Thietane Azete Oxete Thiete
Structure of acetidine Structure of oxetane Structure of thietane Structure of azete Structure of oxete Structure of thiete
5-atom ring Pyrrolidine Oxolane Thiolane Pyrrole Furan Thiophene
Structure of pyrrolidine Structure of oxolane Structure of thiolane Structure of pyrrole Structure of furan Structure of thiophene
6-atom ring Piperidine Oxane Thiane Pyridine Pyran Thiopyran
Structure of piperidine Structure of oxane Structure of thiane Structure of pyridine Structure of pyran Structure of thiopyran
7-atom ring Azepane Oxepane Thiepane Azepine Oxepine Thiepine
Structure of azepane Structure of oxepane Structure of thiepane Structure of azepine Structure of oxepine Structure of thiepine
8-atom ring Azocane Oxocane Thiocane Azocine Oxocine Thiocine
Structure of azocane Structure of oxocane Structure of thiocane Structure of azocine Structure of oxocine Structure of thiocine
9-atom ring Azonane Oxonane Thionane Azonine Oxonine Thionine
Structure of azonane Structure of oxonane Structure of thionane Structure of azonine Structure of oxonine Structure of 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

References

  1. ^ IUPAC Gold Book heterocyclic compounds
  2. ^ a b 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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