Introduction to Heterocyclic Compounds

James Richard Fromm

Incorporation of an oxygen, a nitrogen, a sulfur, or an atom of a related element into an organic ring structure in place of a carbon atom gives rise to a heterocyclic compound. Since the heterocyclic atom must form more than one bond in order to be incorporated into a ring structure, halogens do not form heterocyclic compounds although they may be substituents on a heterocyclic ring structure. Heterocyclic compounds, like polycyclic ring compounds, are usually known by non-systematic names.

They may be either simple aromatic rings or non-aromatic rings.  Some examples are pyridine (C₅H₅N), pyrimidine (C₄H₄N₂) and dioxane (C₄H₈O₂).

Pyridine (C5H5N)

Three Pyrimidines (C4H4N2) - Cytosine, Thymine, and Uracil

Note that compounds such as cyclopropane, an anaesthetic with explosive properties, and cyclohexane, a solvent, are not heterocyclic, they are merely cycloalkanes.  The suffix -cyclic implies a ring structure, while hetero- refers to an atom other than carbon.

Cyclopropane	Cyclohexane

Heterocyclic chemistry is the chemistry branch dealing exclusively with synthesis, properties and applications of heterocyclics especially vital to drug design.

3-Membered Rings

Heterocycles with three atoms in the ring are more reactive because of ring strain.   Those containing one heteroatom are generally stable.  Those with two heteroatoms are more likely to occur as reactive intermediates.  Common 3-membered heterocyclics are:

• One N: Aziridine; Azirane; Dimethyleneimine; Ethyleneimine; Ethylimine
• One O: Ethylene Oxide, generally known as epoxides.  The systematic name is oxirane.  The unsaturated ring system is an oxirene (generally unstable).
• One S: Thiirane; Ethylene Sulfide, generally known as an episulfide.

Aziridine	Ethylene Oxide, Oxirane	Ethylene Sulfide, Thiirane

4-Membered Rings

Azetidine, oxetane, and thietane—the four-membered rings containing, respectively, nitrogen, oxygen, and sulfur atoms—are prepared by nucleophilic displacement reactions such as those used to prepare the corresponding three-membered rings

• One N: Azetidine; Trimethylene Imine
• One O: Oxetane; 1,3-Epoxypropane; 1,3-Propylene Oxide; Trimethylene Oxide; Cyclooxabutane; Oxacyclobutane
• One S: Thietane; Trimethylene Sulfide

Trimethylene Imine, Azetidine	1,3-Epoxypropane, Oxetane	Trimethylene Sulfide, Thietane

5-Membered Rings

With heterocyclics containing five atoms, the unsaturated compounds are frequently more stable because of aromaticity.

• With one heteroatom:
  • With N: Pyrrole (aromatic), dihydropyrrole and tetrahydropyrrole
  • With O: Furan (aromatic), dihydrofuran and tetrahydrofuran
  • With S: Thiophene (aromatic), dihydrothiophene and tetrahydrothiophene
  • With As: Arsole and analogues
• With two heteroatoms:
  • One N and one or more of N,S,O: the azoles
  • Two S: Dithiolane

Pyrrole	Furan

Thiophene	Arsole
1,2-Diazole, Pyrazole	1,3-Dithiolane

6-Membered Rings

• With one heteroatom:
  • With N: Pyridine, Piperidine
  • With O: Pyran
  • With S: Thiane
• With two heteroatoms:
  • Two N: Pyridazine, Pyrimidine, Pyrazine are the 1,2-, 1,3-, and 1,4- isomers, respectively.
  • Two N: Piperazine
  • One N and one O: Oxazine, Morpholine
  • One N and one S: Thiazine
  • Two S: Dithiane - 1,2-, 1,3- and 1,4- isomers, respectively
  • Two O: Dioxane - 1,2-, 1,3- and 1,4- isomers, respectively.

Pyridine	Piperidine
Pyran	Tetrahydrothiopyran, Thiane

1,2-Diazine, Pyridazine	1,3-Diazine, Pyrimidine	1,4-Diazine, Pyrazine

Piperazine	Thiazine	Morpholine, Oxazine

1,2-dithiane       1,3-dithiane        1,4-dithiane

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