Heterocyclic compounds are cyclic compounds with at least two different elements as ring members atoms. [1] They are the counterparts of homocyclic compounds, which have only ring atoms from the same element.
Although heterocyclic compounds may be inorganic, most contain at least one carbon atom, and one or more atoms of elements other than carbon within the ring structure, such as sulfur, oxygen or nitrogen.[2] Since in organic chemistry non-carbons usually are considered to replace carbon atoms, they are called heteroatoms (meaning 'different from carbon and hydrogen'). Nevertheless, a ring with only heteroatoms is homocyclic. The IUPAC recommends the Hantzsch-Widman nomenclature for naming heterocyclic compounds.
Heterocyclic chemistry is the branch of chemistry dealing with synthesis, properties, and applications of heterocycles.
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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. The study of heterocyclic chemistry therefore 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 are fused to benzene rings, which for pyridine, thiophene, pyrrole, and furan are quinoline, benzothiophene, indole, and benzofuran, respectively. Fusion of two benzene rings gives rise to a third large family of compounds, respectively the acridine, dibenzothiophene, carbazole, and dibenzofuran. The unsaturated rings can be classified according to the participation of the heteroatom in the pi-system.
Heterocycles with three atoms in the ring are 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. Common 3-membered heterocycles are:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Aziridine | Azirine |
Oxygen | Ethylene oxide (epoxides, oxiranes) | |
Sulfur | Thiirane (episulfides) | Thiirene |
Those with two heteroatoms include:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Oxygen | Dioxirane | |
Nitrogen | Diazirine |
Compounds with one heteroatom:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Azetidine | Azete |
Oxygen | Oxetane | Oxete |
Sulfur | Thietane | Thiete |
Compounds with two heteroatoms:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Diazetidine | |
Oxygen | Dioxetane | Dioxetene |
Sulfur | Dithietane | Dithiete |
With heterocycles containing five atoms, the unsaturated compounds are frequently more stable because of aromaticity.
Five-membered rings with a single heteroatom:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Azolidine | Pyrrole |
Oxygen | Oxolane | Furan |
Sulfur | Thiolane | Thiophene |
Phosphorus | Phospholane | Phosphole |
Silicon | Silolane | Silole |
Arsenic | Arsolane | Arsole |
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 |
---|---|---|
Nitrogen | Imidazolidine Pyrazolidine |
Imidazole Imidazoline Pyrazole Pyrazoline |
Nitrogen/oxygen | Oxazolidine Isoxazolidine |
Oxazole Oxazoline Isoxazole Isoxazoline |
Nitrogen/sulfur | Thiazolidine Isothiazolidine |
Thiazole Thiazoline Isothiazole Isothiazoline |
Oxygen | Dioxolane | |
Oxygen/sulfur | Oxathiolane | |
Sulfur | Dithiolane |
A large group of 5-membered ring compounds with three heteroatoms also exists. One example is dithiazoles that contain two sulfur and a nitrogen atom.
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Triazoles | |
Nitrogen/2-sulfur | Dithiazole | |
2-Nitrogen/oxygen | Furazan Oxadiazole |
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2-Nitrogen/sulfur | Thiadiazole |
Five-member ring compounds with four heteroatoms:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Tetrazole |
With 5-heteroatoms, the compound may be considered inorganic rather than heterocyclic. Pentazole is the all nitrogen heteroatom unsaturated compound.
Six membered rings with a single heteroatom:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Piperidine | Pyridine |
Oxygen | Tetrahydropyran | Pyran |
Sulfur | Thiane | Thiopyran |
With two heteroatoms:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Piperazine | Diazines |
Nitrogen / oxygen | Morpholine | Oxazine |
Nitrogen / sulfur | Thiazine | |
Sulfur | Dithiane | |
Oxygen | Dioxane | Dioxin |
With three heteroatoms:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Triazine | |
Oxygen | Trioxane |
With four heteroatoms:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Tetrazine |
The hypothetical compound with six nitrogen heteroatoms would be hexazine.
With 7-membered rings, the heteroatom must be able to provide an empty pi orbital (eg boron) for "normal" aromatic stabilization to be available; otherwise homoaromaticity may be possible. Compounds with one heteroatom include:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Azepane | Azepine |
Oxygen | Oxepane | Oxepine |
Sulfur | Thiepane | Thiepine |
Those with two heteroatoms include:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Diazepine | |
Nitrogen/sulfur | Thiazepine |
Compounds with one heteroatom include:
Heteroatom | Saturated | Unsaturated |
---|---|---|
Nitrogen | Azocane | Azocine |
Oxygen | Oxecane | |
Sulfur | Thiocane |
Saturated | Unsaturated | ||||||
---|---|---|---|---|---|---|---|
Heteroatom | Nitrogen | Oxygen | Sulfur | Nitrogen | Oxygen | Sulfur | |
3-Ring | |||||||
Name | Aziridine | Oxirane | Thiirane | Azirine | Oxirene | Thiirene | |
Structure | |||||||
4-Ring | |||||||
Name | Azetidine | Oxetane | Thietane | Azete | Oxete | Thiete | |
Structure | |||||||
5-Ring | |||||||
Name | Pyrrolidine | Tetrahydrofuran | Tetrahydrothiophene | Pyrrole | Furan | Thiophene | |
Structure | |||||||
6-Ring | |||||||
Name | Piperidine | Tetrahydropyran | Thiane | Pyridine | Pyrylium | Thiopyran | |
Structure | |||||||
7-Ring | |||||||
Name | Azepane | Oxepane | Thiepane | Azepine | Oxepine | Thiepine | |
Structure |
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. Similarly, the compounds with two benzene rings fused to the central heterocycle are carbazole, acridine, and dibenzoazepine.
The history of heterocyclic chemistry began in the 1800's, in step with the development of organic chemistry. Some noteworthy developments:[3] 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, 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.