https://www.apicmo.com/heterocycles-introduced/ Heterocyclic compounds probably constitute the most varied and the largest number of the family of organic compounds. Heterocycles are useful in several areas of life sciences and technology.

1. Most Influential Heterocycles In The World
info@apicmo.com
Content
Heterocyclic compounds...................................................................................................................1
Classification .....................................................................................................................................2
Preparation and reactions ................................................................................................................2
3-membered rings.....................................................................................................................2
Four-Membered Rings ..............................................................................................................3
Reactions...........................................................................................................................................4
Heteroatom Saturated Unsaturated.........................................................................................5
Four-membered rings compounds with two heteroatoms ......................................................6
5-membered rings with a single heteroatom ...........................................................................6
Five-membered rings compounds with a single heteroatom...................................................8
5-membered rings with 2 heteroatoms....................................................................................8
5-membered rings with 3 heteroatoms....................................................................................9
6-membered rings with 1 heteroatom .....................................................................................9
Pharmaceutically useful pyridines ..................................................................................................11
6-membered rings with 2 or more heteroatoms....................................................................11
7-membered rings...................................................................................................................13
8-membered rings...................................................................................................................13
9-membered rings...................................................................................................................14
Uses of heterocyclic compounds ....................................................................................................14
References ......................................................................................................................................14
Heterocyclic compounds
heterocyclic compound, also known as a ring structure is basically a co
mpound that contains atoms of two distinct elements as members of its
ring/rings. Heterocyclic compounds probably constitute the most varied an
d the largest number of the family of organic compounds.
Regardless of functionality and structure, every carbocyclic compound ma
y be converted into various heterocyclic analogs by just replacing one or
more carbon ring atoms with a different element. As a result, heterocycl
es have offered a platform for exchange of research in different areas in
cluding but not limited to pharmaceutical, medicinal, analytical, and organ
ic chemistry of heterocyclic compounds.
The major examples of heterocyclic compounds are most drugs, nucleic
acids, majority of synthetic and natural dyes, and majority of biomass su
ch as cellulose and related materials.

2. Most Influential Heterocycles In The World
info@apicmo.com
Classification
Even though heterocyclic compounds may be organic or inorganic compo
unds, most have at least one carbon. These compounds can be classifie
d according to their electronic structure. Saturated heterocyclic compound
s behave in the same way as acyclic derivatives. As a result, tetrahydrof
uran and piperidine are conventional ethers and amines with modified st
eric profiles.
The study of heterocyclic chemistry therefore focuses mainly on unsatura
ted derivatives and applications involve unstrained 5 as well as 6 memb
ered rings. This include furan, pyrrole, thiophene, and pyridine. The next
large class of heterocyclic compounds is fused to benzene rings, which
for furan, pyrrole, thiophene, and pyridine are benzofuran, indole, benzot
hiophene, and quinoline, respectively. If two benzene rings are fused, thi
s results to another large family of compounds, which are dibenzofuran,
carbazole, dibenzothiophene, and aridine. Unsaturated rings may be clas
sified based on the participation of a heteroatom in the pi system, conju
gated system.
Preparation and reactions
3-membered rings
Heterocyclic compounds with 3 atoms in a ring are way more reactive c
ourtesy of the ring strain. Heterocycles containing one heteroatom are ge
nerally stable. The ones containing two heteroatoms occur, in general as
reactive intermediates.
Oxiranes, also known as epoxides are the most common 3-membered h
eterocycles. Oxiranes are prepared by reacting peracids with alkenes, wit
h good stereospecificity. Oxiranes are more reactive than unsaturated eth
ers courtesy of the high angle strain of the 3-membered ring. Addition re
actions that proceed by nucleophilic and electrophilic opening of the ring
is the most general reaction class.
A reaction of this kind is involved in nitrogen mustards’ pharmacological
action that were among the very first anticancer drugs developed. Closur
e of intramolecular ring like in the case of anticancer agent mechloretha
mine forms an intermediate aziridium ion. The formed biologically active
agent attacks proliferating cells including cancer cells through inhibition of
their DNA replication. Nitrogen mustards have also been used as antica
ncer agents.

3. Most Influential Heterocycles In The World
info@apicmo.com
Commercially aziridine, and oxirane are essential bulk industial chemicals.
On large scale production of oxirane, ethylene is directly reacted with o
xygen. The chemical reaction, which is the most characteristic of these 3
-membered rings, is that they are susceptible to attack by nucleophilic re
agents in order to open the ring as shown below:
The most common three-membered heterocyclic compounds with one hete
roatom include:
Saturated Unsaturated
Thiirane (episulfides) Thiirene
Phosphirane Phosphirene
Epoxides (oxirane, ethylene oxide) Oxirene
Aziridine Azirine
Borirane Borirene
The most common three-membered heterocyclic compounds with two het
eroatoms include Diaziridine as a saturated derivative and Diazirine as a
n unsaturated derivative as well as Dioxirane and Oxaziridine.
Four-Membered Rings
Various methods of preparation of 4-membered rings heterocycles are sh
own in the diagram below. The process of reacting an amine, thiol or 3-

4. Most Influential Heterocycles In The World
info@apicmo.com
halo with a base is typically effective but with mediocre yields. Dimerizati
on and elimination are usual side reactions. Other functions may also co
mpete in the reaction.
In the first example, cyclization to an oxirane always compete with forma
tion of thietane but the higher nucleophilicity dominates especially if one
uses a weak base.
In the second example, formation of both azetidine and aziridine are pos
sible but only the latter is seen. Example number four shows that this a
pproach to formation of azetidine functions well if there’s no competition.
In the third example, the rigid configuration of the substrate favors forma
tion of oxetane and prevents cyclization of oxirane. In examples 5 and 6,
the Paterno-Buchi photocyclizations are specially suited to formation of
oxetane.
Methods of preparing 4-membered rings heterocycles
Reactions
Reactions of 4-membered heterocyclic compounds also demonstrates ring
strain influence. The following diagram shows some examples. Acid-catal
ysis is a typical feature of various ring-opening reactions shown in exam
ples 1,2, and 3a. in reaction 2 of thietane, sulfur undergoes electrophilic
chlorination leading to formation of chlorosulfonium intermediate and subs
titution of ring-opening chloride ion. In reaction 3b, strong nucleophiles ar
e also seen to open the strained ether. Beta-lactones’ cleavage reactions
may happen either by acid-catalyzed acyl exchange like seen in 4a. It
can also take place by alkyl-O rupture by nucleophiles like in 4b.

5. Most Influential Heterocycles In The World
info@apicmo.com
Example number 6 shows an interesting phenomenon of of intramolecula
r rearrangement the ortho-ester. Reaction 6 shows Beta-lactam cleavage
of penicillin G which shows the enhanced aclylation reaction of the fused
ring system.
Examples of reactions of 4-membered heterocyclic compounds
The most useful heterocyclic compounds with 4-membered rings are two
series of antibiotics, the cephalosporins and penicillins. The two series c
ontain azetidinone ring which is also known as Beta-lactam ring.
Many oxetanes are under investigation as antiviral, anticancer, anti-inflam
matory, and antifungal agents. Oxetanones on the other hand are mostly
applied in agriculture as bactericides, fungicides, and herbicides and in
manufacturing of polymer.
Parent thietane was found in shale oil while its odoriferous derivatives w
ork as scent markers for European polecats,ferrets, and minks. Thietanes
are applied as fungicides and bactericides in paint, as iron corrosion in
hibitors, and in the manufacturing of polymers.
Four-membered rings compounds with a single heteroatom
Heteroatom Saturated Unsaturated
Heteroatom Saturated Unsaturated
Sulfur Thietane Azete
Oxygen Oxetane Oxete
Nitrogen Azetidine Azete

6. Most Influential Heterocycles In The World
info@apicmo.com
Four-membered rings compounds with two heteroatoms
Heteroatom Saturated Unsaturated
Sulfur Dithietane Dithiete
Oxygen Dioxetane Dioxete
Nitrogen Diazetidine Diazete
5-membered rings with a single heteroatom
Thiophene, furan, and pyrrole are the parent aromatic compounds of 5-m
embered rings heterocycles. Here are their structures:
The saturated derivatives of thiophene, furan, and pyrrole are thiophane,
tetrahydrofuran, and pyrrolidine respectively. Bicyclic compounds made of
thiophene, furan, or pyrrole ring fused to a benzene ring are known as
benzothiophene, benzofuran, isoindole (or indole) respectively.
Nitrogen heterocycle pyrrole typically occurs in bone oil that is formed by
decomposition of proteins through strong heating. The pyrrole rings are
found in the amino acids such as hydroxyproline and proline that are co
mponents of various proteins present in high concentrations in structural
protein of ligaments, tendons, skin, and bones and collagen.
Pyrrole derivatives are found in the alkaloids. Nicotine is the most comm
only known pyrrole that contains alkaloid. Hemoglobin, myoglobin, Vitami
n B12, and chlorophylls, are all formed by joining four pyrrole units in a

7. Most Influential Heterocycles In The World
info@apicmo.com
large ring system called porphyrin, like that of chlorophyll B demonstrate
d below.
Bile pigments are formed through decomposition of porphyrine ring and h
ave a chain of 4 pyrrole rings.
Preparation of 5-membered ring heterocycles
Industrial preparation of furan proceeds as shown below by the way of a
ldehyd, furfural, that is generated from pentose that contains raw materia
ls such as corncobs. Similar preparations of thiophene and pyrrole are s
hown in the second row of equations.
The third row of equation one demonstrates the general preparation of s
ubstituted thiophenes, pyrroles, furans from 1,4-dicarbonyl compounds. M
any other reactions leading to formation of substituted heterocycles of thi
s type have been started. Two of these procedures have been shown in
the second and third reaction. Furan is reduced by palladium-catalyze

8. Most Influential Heterocycles In The World
info@apicmo.com
d hydrogenation to tetrahydrofuran. This cyclic ether is a valuable solvent
which can not only be converted to 4-haloalkylsulfonates but also 1,4-di
halobutanes that can be used to prepare thiolane and pyrrolidine.
Five-membered rings compounds with a single heteroatom
Heteroatom Unsaturated Saturated
Antimony Stibole Stibolane
Arsenic Arsole Arsolane
Bismuth Bismole Bismolane
Boron Borole Borolane
Nitrogen Pyrrole Pyrrolidine
Oxygen Furan Tetrahydrofuran
5-membered rings with 2 heteroatoms
The five-membered ring compounds containing 2 heteroatoms and at lea
st one of the heteroatoms is Nitrogen, are known as azoles. Isothiazoles
and thiazoles have a nitrogen and sulfur atom in the ring. Compounds
with two sulfur atoms are known as Dithiolanes.
Heteroatom
Unsaturated (and partial
ly unsaturated)
Saturated
Nitrogen Pyrazole(Pyrazoline) Pyrazolidine

9. Most Influential Heterocycles In The World
info@apicmo.com
/nitrogen Imidazole(Imidazoline) Imidazolidine
Nitrogen/oxygen
Isoxazole
Oxazoline(oxazole)
Isoxazolidine
oxazolidine
Nitrogen/sulfur
Isothiazole
Thiazoline (Thiazole)
Isothiazolidine
Thiazolidine
Oxygen/oxygen Dioxolane
Sulfur/sulfur Dithiolane
Some pyrazoles occur naturally. Compounds of this class are prepared b
y reacting 1,3-diketones with hydrazines. Most synthetic pyrazole compou
nds are used as medicine and dyes. They include fever-reducing analge
sic aminopyrine, phenybutazone used in arthritis treatment, the fibre dye
and yellow food colour tartrazine, and majority of dyes used in colour ph
otography as sensitizing agents.
5-membered rings with 3 heteroatoms
There also exist a large group of five-membered ring compounds with at
least 3 heteroatoms. One example of such compounds is dithiazoles wh
ich contain a nitrogen atom and two sulfur.
6-membered rings with 1 heteroatom
The nomenclature used in monocyclic nitrogen-containing 6-membered rin
g compounds is here below. Positions on the ring for pyridine are shown,
Arabic numerals are more preferred to Greek letters, even though both
systems are used. Pyridones are aromatic compounds courtesy of contrib
utions to resonance hybrid from charged resonance forms as demonstrat
ed for the 4-pyridone.

10. Most Influential Heterocycles In The World
info@apicmo.com
Two major coenzymes involved in various crucial metabolic reactions in
cells, NAD (also known as coenzyme1) and NADP (also known as coen
yme II), are derived from nicotinamide.
The majority of alkaloids contain a piperidine or pyridine ring structure, a
mong them piperine (constitutes one of the sharp-tasting contents of blac
k and white pepper) and nicotine. Their structures are shown below.
Pyridine which was once extracted from coal tar but is now prepared cat
alytically from ammonia and tetrahydrofurfuryl alcohol is a crucial interme
diate and solvent used to manufacture other compounds. Vinylpyridines a
re crucial monomer building blocks of plastics, and fully saturated piperidi
ne, pyridine are used as chemical raw material and rubber processing.

11. Most Influential Heterocycles In The World
info@apicmo.com
Pharmaceutically useful pyridines
Pharmaceutically useful pyridines include the isonicotinic acid hydrazide (t
uberculostat isoniazid), the anti-AIDS-virus drug known as nevirapine, nico
randil – avasodilator used for controlling angina, phenazopyridine-the urin
ary-tract analgesic as well as the anti-inflammatory sulfa drug. Diflufenican,
clopyralid, paraquat, and diquat are popular pyridine derivatives which a
re used as herbicides.
6-membered rings with 2 or more heteroatoms
The 3 monocyclic six-membered ring heterocycles with 2 nitrogen hetero
atoms (diazines) are numbered and named as shown below.
Maleic hydrazide is a pyridazine derivative used as a herbicide. Some p
yrazines such as aspergillic acid occur naturally. Here are the structures
of the aforementioned compounds:

12. Most Influential Heterocycles In The World
info@apicmo.com
Pyrazine ring is a component of various polycyclic compounds of industri
al and biological importance. Important members of pyrazine family are p
henazines, alloxazines, and pteridines. Pharmacologically and biologically,
the most crucial diazines are pyrimidines. Cytosine, thymine, and uracil
are the 3 of the 5 nucleotide bases which constitute the genetic code in
RNA and DNA. Below are their structures:
Vitamin thiamin have a pyrimidine ring and in addition to synthetic barbit
urates including amobarbital are commonly used drugs. Morpholine (pare
nt tetrahydro-1,4-oxazine) is produced on large scale for use as a fungici
de, corrosion inhibitor, and a solvent. Morpholine ring is also found in th
e sedative-hypnotic drug trimetozine and some fungicides like fenpropimo
rph and tridemorph. Here’s the structural formula for morpholine:

13. Most Influential Heterocycles In The World
info@apicmo.com
7-membered rings
As the ring size increases, the variety of the compounds that may be ob
tained by varying the location, type, and the number of heteroatoms incr
eases enormously. However, the chemistry of heterocycles with 7-membe
red rings or more is less developed than that of 6 and 5-membered ring
heterocyclic compounds.
Oxepine and Azepine rings are crucial constituents of various naturally o
ccurring metabolic products of marine organisms and alkaloids. The azep
ine derivative known as caprolactam is commercially produced in bulk for
use in the manufacture of nylon-6 as an intermediate and in production
of synthetic leather, coatings, and films.
7-membered heterocyclic compounds with two or one nitrogen atom in th
eir ring are structural units of broadly used psychopharmaceuticals Praze
pine (tricyclic antidepressant) and tranquilizer diazepam also known as v
alium.
8-membered rings
Examples of heterocyclic compounds in this class include azocane, oxoc
ane, and thiocane with Nitrogen, oxygen, and sulfur being the respective
heteroatoms. Their respective unsaturated derivatives are azocine, oxoci
ne, and thiocine respectively.

14. Most Influential Heterocycles In The World
info@apicmo.com
9-membered rings
Examples of heterocyclic compounds in this class include azonane, oxon
ane, and thionane with Nitrogen, oxygen, and sulfur being the respective
heteroatoms. Their respective unsaturated derivatives are azonine, oxoni
ne, and thionine respectively.
Uses of heterocyclic compounds
Heterocycles are useful in several areas of life sciences and technology.
As we have already seen in our discussion, many drugs are heterocycli
c compounds.
References
IUPAC Gold Book, heterocyclic compounds. Link:
W. H. Powell: Revision of the extended Hantzsch-Widman System of No
menclature for Heteromonocycles, in: Pure Appl. Chem.1983, 55, 409–41
6;
A. Hantzsch, J. H. Weber: Ueber Verbindungen des Thiazols (Pyridins de
r Thiophenreihe), in: Ber. Dtsch. Chem. Ges. 1887, 20, 3118–3132
O. Widman: Zur Nomenclatur der Verbindungen, welche Stickstoffkerne e
nthalten, in: J. Prakt. Chem. 1888, 38, 185–201;