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Heterocyclic Chemistry Chem. 342 (2013) Prepared by Dr. Ismail Abdelshafy
Chapter 1 Nomenclature of Heterocyclic compounds
Cyclic compounds with at least two different atoms in the ring are known as heterocyclic compounds. The ring itself is called a heterocycle
A hetero atom is an atom other than carbon. The name comes from the Greek word heteros, which means "different". The N-atom is the most common heteroatom. Next in the importance are O- and S-atoms. Heterocycles with Se-, Te-, P-, As-, Sb-, Bi-, Si-, Ge-, Sn-, Pb- or B-atoms are less common.
Heterocyclic compounds are widely distributed in nature. Many are of fundamental importance to living systems, for examples Chlorophyll and heme
Structure of chlorophyll c1
Structure of Heme B
Essential ingradients such as thiamin (Vitamin B1), riboflavin (Vitamin B2), pyridoxal (Vitamin B6), nicotinamide (Vitamin B3), and ascorbic acid (Vitamin C) are heterocyclic compounds. Among the twenty amino acids commonly found in proteins, three of them are heterocyclic. O H2N
CH C
OH
CH2
H N C
O
O H2 N
OH
2-amino-3-(1H -indol-3yl)propanoic acid Trptophan (Trp)
Proline (Pro)
OH
CH2
pyrrolidine-2-carboxylic acid HN
CH C
N NH 2-amino-3-(1H-imidazol-4-yl) propanoic acid Histidine (His)
It has been found that the introduction of hetero-atom in carbocyclic molecules makes predictable changes in their physical and chemical characteristics. These changes are not only in the behavior of the parent ring but also in the chemical behavior of the functional groups attached to these rings
X
monosubstituted rings X X
N
N
X
N
N
There are several methods to nominate heterocycles which can be summarized as follow:
I)Trivial names These names are given to heterocycles and usually arising from the origin of compounds or of their utility and they are approved by the IUPAC
N H
S
O
Thiophene
Furan
N H
Pyrroline
1H-Pyrrole
N H
Pyrrolidine
Five membered rings containing two heteroatoms
Unsaturated
1H-Pyrazole
isoxazole
N
isothiazole N
N
N H N
S
O
N H
N
N
N
S
O
N
Imidazole
Saturated
Farmazone
Partially Unsaturated
O
oxazole
NH
NH S
N H
Pyrazoline
pyrazolidine
NH O
isothiazoline
isoxazoline
NH
NH N H
thiazole
S
isothiazolidine
NH O
isoxazolidine
Six membered rings
O
N
O
4H-Pyran
Pyridine
2H-Pyran
N N N N
Pyridazine
N H
Piperidine
N
N
Pyrimidine
Pyrazine
H N
O
N H
N H
Piperazine
Morphiline
The basis for this system were introduced independently by A. Hantzsch and O. Widman . This system was suggested at the beginning for six and five membered rings and then was extended to include rings from 3 to 10 atoms. The names of the rings is derived by combining a prefix and a suffix ( i.e Name = prefix + suffix ) According to this system a prefix is used to indicate the nature of heteroatom in the ring (O, N, S, P,‌‌) a suffix is used to indicate the size and the degree of saturation in the ring .
(i) Prefix:
is used to indicate the nature of heteroatom in the ring (O,
N, S, P,‌‌) When different heteroatom is present the highest priority will be as follow: Elements
Valence
Prefix
Elements
Valence
Prefix
1) Flour (F)
1
floura
10)Phosphorous (P)
3
phospha
2) Chlore (Cl)
1
chlora
11)Arsenic (As)
3
arse
3) Bromine (Br)
1
broma
12)Antimony (Sb)
3
stilba
4) Iodine (I)
1
ioda
13) Bismuth (Bi)
3
bisma
5) Oxygen (O)
2
oxa
14) Silicon (Si)
4
sila
6) Sulphur (S)
2
thia
15) Germnium (Ge)
4
germa
7) Selenium (Se)
2
selena
16) Tin (Sn)
4
stanna
8) Tellurium (Te)
2
tellura
17) Lead (Pb)
4
plumba
9) Nitrogen (N)
3
aza
18) Boron (B)
3
bora
19) Mercury (Hg)
2
mercura
The Latin numbers (di, tri, tetra,….) are used to indicate the number of heteroatoms. Ex: Tetra + aza ► tetraza When different heteroatom is present the highst periority will be as follow:
O>S>N For a ring has O + N ► Oxaza For a ring has S + N ► thiaza For a ring has O + S ► oxathia
Suffix
is used to indicate the size and the degree of
saturation in the ring Suffix = Stem + end
The end
Ring size
Stem
3
ir
4
et
5
ol
6*
in
7
ep
refers to the degree of unsaturation in the ring
( as shown in the next table)
2: System for Hantzsch-Widman names Ring size
Rings containing Nitrogen
Rings containing no Nitrogen
Unsaturated Saturated
Unsaturated
Saturated
3
irine
iridine
Irene
Irane
4
ete
etidine
ete
etane
5
ole
olidine
ole
olane
6*
ine
ane**
ine
ane***
7
epine
****
epine
epane
8
ocine
****
ocine
ocane
9
onin
****
onine
onane
10
ecin
****
ecine
ecane
Ring size 3
Rings containing Nitrogen Unsaturated Saturated
Rings containing no Nitrogen Unsaturated Saturated
Irine
Iridine
H N
H N
azirine
Aziridine
Oxirene
O
S
O
O
4
ete N
Azete
Oxaziridine
etidine NH
Azetidine
NH
NH
O
O
2H-[1,2]Oxazete
Irane O
oxirane S
NH
N
Oxazirine
Irene
[1,2]Oxazetidine
thiirene
thiirane
Ete
etane
S
Thiete O
oxete
S
Thietane O
oxitane
5
Ole
Olidine
N H
Ole
O
Olane
O
oxole
Oxolane
N H
S
S
[1,3]-Oxazolidine
thiole
thiolane
ine
ane***
Azole O
6*
ine
N
Azine
ane**
O
Oxine
S
thiine
O
Oxane
S
thiane
The rings that have one heteroatom, the rings are numbered so that the heteroatom is given number 1. 4
4
3
5
2
3
5
2
N H
O
1
1
When different heteroatom is present the highest priority will be O > S > N and move in the direction that gives the other heteroatoms the nearest possible numbers. 4
5 O1
3
5
4
1S
N3
N
2
2
For partially saturated 5-membered rings containing Nitrogen
N H
N H
N H
azoline
azole
azolidine
For partially saturated rings we must designate the location of the nearest unsaturated atom by ∆n (where n = the number of the first unsaturated atom). 3
4
N
NH
5
N
2 O
O 4
1 -1-oxa-3-azoline
3
-1-oxa-3-azoline
O 2
-1-oxa-3-azoline
For full unsaturated rings which contain extra hydrogens, the positions of extra hydrogens are indicated as nH in the prefix
When a heterocycle contains two similar atoms,
the
one
carrying
the
heavier
substituent is numbered first. When a heterocycle contains two or more N atoms, we begin numbering from SP3 nitrogen without deviation from the priority
4
3
NH
2 N
5 N H
1
1. Heterocyclic systems are named by considering them to be derived from cyclic hydrocarbons by replacing a carbon corner by heteroatom. 2. The heteroatoms are indicated by the same prefixes
used
in
the
Hantzsch-Widman
nomenclature. 3. When more than one heteroatom is present citation numbers are used (O>S>N).
O
O N H
N
Oxacyclopent-2,4-diene
1-Oxa-4-azacyclohexane
Azabenzene
O N
N
S
S
1-Thia-2-azacyclopent-2,4-diene
Oxazacyclopropene
O
N
N
O
1-thiacyclohexa-2,5-diene
1,7-Dioxo-2,8-diazacyclododeca-2,8-diene
1 1
S
2
N 2
3 S
4
2-Azanaphthalene
2,3-Dihydro-1,4-dithianaphthalen
1
1 O
2
7
5
2 3
N
6
4a 5
3 N
4
4
4H-4a-Azanaphthalene
1-Oxa-3-azacyclopenta-2,4-diene
(iv) Naming substituted monocyclic compounds In case of heterocycles with one heteroatom the hetero atom is given No. 1. Numbers are then given in the way that gives substituents least possible numbers.
(When more than one heteroatom is present the heteroatom of highest priority is numbered 1. Numbering is then made in the way that gives other heteroatoms least possible numbers. This means least difference between the first two atoms and not least algebraic sum of numbers.
According to IUPAC rules the organic compounds are arranged in order of decreasing priority as follow:
a. Cation and anions b. Acids: Carboxylic, peroxycarboxylic, thiocarboxylic, sulfonic, sulfinic,… Etc. c.Derivatives of acids: anhydrides, esters, acyl halides, amides, hydrazides, imides, amidines, …… etc. d. Nitriles: cyanides, isocyanides. e. Aldehydes, thioaldehydes and their derivatives f.Ketones,
thioketones
and
their
derivatives.
g. Alcohols, phenols, thioles, and their esters derivatives with inorganic acids. h. hydroperoxides. i. Amines, imines and hydrazines. j. Ethers, thioethers. k. Peroxides.
All other functional groups, which are included in one of these classes, are then written as prefixes in form of the name in alphabetic order.
Cl
NH2
O
O
C2H5O2C
N H
3-furanyl chloride
3-Amino-1H-pyrrole
N
Ethyl 5-aminoisoxazol-3-carboxylate NH2
NC
NH2
NC N
NH2
N
S
NH
N
SCN
N
N H
1,3,4-thiadiazol-2-ylthiocyanate
3-Amino-1H-pyrazole-4-carbonitrile
COCH3 N
HN
N
NH
N N
CN
5-Actyl-4H-1,2,4-triazole-3-carbonitrile
Ph
C2H5
2-Ethyl-1-phenyl-1,2,4-triazolidine
5-amino-1H-pyrazole-4-carbonitrile
B) Polycycles (A) Trivial names Trivial names approved to be utilized are given below. These were drawn from the IUPAC (Blue Book).
5
4
5 3
6
2
7 N
8 Quinoline
1
4
6
3
7
N 2
8
1
Isoquinoline
5 6 7
3
6
N 3
7
2
N2
7
2
6
3
N
1
Quinazoline
1
5 N N 2
4
Quinoxaline
4
6
N
5
1
8
Cinnoline
7
1
8
N
N
8
8
4
5
4
4
5
6
4b
N3
3
4a
7 6
N 3
5
4
Phthalazine
7
2
2 N
N
8
1
Peteridine
8
8a
N H
9 Carbazole
9a
1
4
4
3
5
4
3
5
5
2
NH 2
1
6
6
N H
N H
7
7 2
Indolizine
1
5
1N
H7 N
8 6
2
N
N
3
1H-Indazole 6
7
5
7
2H-Isoindole 1
4
1
1
1H-Indole
6
N 2
6
7
8
3
5
4
2 N
3
1H-Pyrrolizine
4
3 Purine
N
9
Fusion names When a heterocyclic ring is fused to a carbocyclic ring, the hetero ring is chosen as the parent or base component. Then the systematic name is formulated from the prefix benzo- and the trivial name of the heterocyclic component as follows: The bonds between the ring atoms are denoted according to the successive numbers of the ring atoms by the letters a, b, c, etc. The
letter
must
be
as
early
as
possible
and
benzo[d]thiophene is incorrect. c
+
b
S benzo[b]thiophene
3
b
2
a
4 1
S
d 5
e
Base component
hence
O N H Benzo[b]pyrrole Benzo[b]furan
or Indole
1
a
2
+ 3 5
S
b
1
e
S
2
d c
4
base component
b 3
naphtho[2,3-b]thiophene
•Polycyclic systems with two or more heterocycles The base component is chosen as that in the Hantzsch-Widman nomenclature except that of nitrogen is given the highest priority. Prefixes are formed by changing the terminal (e) of the trivial or the Hantzsch-Widman names of the components into (o)
Chose of the base component. i- Is there only one component which contains nitrogen? No
Yes: choose this as base component
N O Base component pyrrole
ii- Is nitrogen absent from all the rings? NO Yes: choose the ring containing a heteroatom Which occurs highest?
S
O
Base component furan
iii- Are there more than two rings presents? No
Yes: choose the component containing the greater number of rings
N
N
N
Base component quinoline
iv- Are the two rings of different size? No
Yes: choose the larger one
O N Base component azepine
V- Do the rings contain different numbers oh heteroatoms? No
Yes: chose the one with the greater number
H N N O Base component isoxazole
Vi- Are there differences between the numbers of each kind of heteroatom in the two rings? No
Yes: choose the ring with the greater number of atoms listed first
N
S N
O Base component oxazole
Vii- In case of the two rings are of the same size and contains the same heteroatoms, how to select the base component? Rule is to select the base ring to be the one in which heteroatoms has less separation between the heteroatoms. Thus:
N
H N
N N
N H Base component Pyrazole
N
N
N
N N
Base component Pyridazine
N N
Base component Pyridazine
Viii- The ring containing the greatest Varity of heteroatom arranged according to their order priority
O
H N
S
N N
N
N Base component Oxazole
Base component Thiazole
How to Choose of the base component (Summary) 1- When a heterocyclic ring is fused to a b
carbocyclic ring (choose the hetero ring as
S
the parent or base component
benzo[b]thiophene Base component is thiophene
2- One ring only contains N (choose the ring
N
containing N)
O Base component pyrrole
3- No, Nitrogen ( choose according to the priority O ˃ S )
S
O
Base component furan
N
4- One consists of two or more rings (Choose one with the greater number of rings) N
N
Base component quinoline
O
5- Two rings of different size (choose the larger)
6- Choose the one with more heteroatoms
N Base component azepine
N
7- Same number of heteroatoms (choose O >
S N
S > N)
O Base component oxazole
8- Same type and number of heteroatoms, and
N
H N N
same ring size
(choose lower separation
N H
between atoms) Base component Pyrazole
9- Choose the ring containing the greatest Varity of heteroatom.
Bridge Specification Adding prefixes to the name of a base component The base component is chosen as before Prefixes are formed by changing the terminal e of the trivial name into <O> (e.g. pyrazole is converted to pyrazolo) Some prefixes are formed as in the following table
Acenaphthylene Acenaphtho Naphthalene Naphtho Anthracene
Anthra
Perylene
Perylo
Benzene
Benzo
Pyridine
Pyrido
Furan
Furo
Pyrimidine
Pyrimido
Imidazole
Imidazo
Quinoline
Quino
Isoquinoline
Isoquino
Thiophene
Thieno
The position of fusion between the prefix and the base is indicated by inserting (in square brackets) number for the prefix and italic letter for the base component.
Name =
prefix[number, letter]base
N
N
N
N
N
N
N
N
4H-pyrimido[1,2-b]pyridazine
N
N
N
N
Pyrazino[2,3-d]pyrimidine or pteridine
Pyrimido[4,5-c]pyridazine
N
N
N N
N
Pyrazino[2,3-c]pyridazine
S
O
N
O
oxazolo[5,4-d]isoxazole
N
S
thiazolo[5,4-d]isothiazole
If a position of fusion is occupied by a heteroatom, the names of the two component rings are chosen in a way that both contain this heteroatom.
Symmetric and Asymmetric Heterocycle 4
5
N
a N
3 N
1
N
2
pyrazolo[1,5-a][1,3,5]triazine
5
N N
a
4
b c
3 N
1
N
2
pyrazolo[5,1-c][1,2,4]triazine
Other examples for Bridge Specification
N b a N c
N 4 3 2
1
1
N
1 5
2
N H
3
N d
2
a c
N
b
3
a N e b d c
N
N
imidazo[4,5-c]pyrazole
pyrido[3,2-d]pyrimidine
3 1 2
pyrido[3,2-e][1,2,4]triazine
1
e
N
N
e
N d
a c
b
N
pyrido[2,3-d]pyrimidine
b
N a
N
N
c d
2
N a
3
N N
pyrazino[2,3-d]pyridazine
N1
5 d b c
4
3
2
N pyrimido[4,5-d]pyridazine not pyrimido[5,4-d]pyridazine
H N
N
N
N
N
N
1H-imidazo[1,2-b]pyrazole
4H-pyrimido[1,2-b]pyridazine
O1
N S
4
2 c b
N
S
a
N thiazolo[5,4-d]isothiazole
furo[3,4-c]quinoline
3
Numbering fused heterocycles The numbering of the complete fused structure does not depend on the original numbering systems of its components .
1. The greatest number of rings should be on a horizontal line, then the maximum number of rings should be above and to the right of this a horizontal line. 2. Numbering is carried out usually in a clockwise (Not in all cases) starting with the atom not engaged in the ring fusion in the most counter-clockwise position of the uppermost ring. 2 1
N b c
a
d e
h g
f
benzo[h]isoquinoline
3
3 2
2
4
N 1
b c
a
CH3
d e
g
4a 4b
H3C h
1
3
f
13
N
13b 13a
5 6
12 7
11 8
10
9
4,9-dimethylbenzo[h]isoquinoline 2
2
1
1 HN 11
10
4
11c 11a 11b
3 c
4a
7a
N
6a
6
2
NH
b a
5
9 8
3
3
N
7
1H-pyrido[3,2-c]carbazole
4H-pyrido[2,3-c]carbazole
4
a)- Give low numbers to the heteroatoms 6
1
S
O
2 3
5
1 2
N H
O
4
3
4H-[1,3]oxathiolo[5,4-b]pyrrole Benzo[b]furan (N.B: 1,3,4 is lower than 1,3,6)
b) Give low number to heteroatoms in the order O> S> N
6 S
1 O
5
2 4
3
Thieno[2,3-b]furan
1
O
H 6 N
2
5
N
N
3
4
6H-imidazo[4,5-d]oxazole
6 1
O
H N 5
2
N 3
Me
N 4
5-methyl-6H-imidazo[4,5-d]oxazole
c) Give hydrogen atom the lowest numbers 6 O
1
5
2 4
O
3
4H-cyclopenta[d][1,3]dioxole 6 N
O
5
1 2
N H
4
O
3
4H-[1,3]dioxolo[4,5-d]imidazole
A carbon atom common to two or more rings is given a lower case letter after the numeral of the atom immediately proceeding. A heteroatom common to two or more rings receives an individual locant.
1 7
8
N
2
N
6
3 N
5
4a
N
4
Imidazo[1,2-b][1,2,4]triazine
1 7 1
N
N N 3
N a 2
b c N
6
8
N 2
N
H3C 4
3
N 4a N 5 6-methylimidazo[1,2-b][1,2,4]triazine
2 1
CH3 9 9a
8
O 3
9b 3a
7 5a 6
1
CH3 4
5 N
2
9
N
8
3
5
4
3,9-dimethylfuro[3,4-c]quinoline
S
6
NH2
1 2N
5 5
7a
CH3
N 6
7-methyl-4H-pyrimido[1,2-b]pyridazine
NC 7
7
N
NH2 6
O 7
4
4a 3
4
N thieno[3,4-d]pyridazin-5-amine
3
NH 1
N 2 6-amino-1,4-dihydropyrano[2,3-c]pyrazole -5-carbonitrile
H3C N
N
N
N CH3 N
N 3,6-dimethyl-3H-imidazo[1,2-b]pyrazole
NC
7
Pyrrolo[3,2-e][1,3,4]oxadiazine
COOC2H5
6
8
O
O 5 1 S
N
2
3
4
NH2
Ethyl 5-amino-8-cyano-7Hthiazolo[3,2-a]pyridine-6-carboxylate
N
N N
Pyrrolo[2,3-e][1,3,4]oxadiazine
The names originally for hydrocarbons, converted heterocycles by application of replacement principals.
into
names
of
This method is highly convenient for naming bicyclic saturated heterocycles. prefix (bicyclo )followed in square brackets by the number of carbon atoms separating the bridgeheads on three possible routes from one bridgehead to the other, followed by the name of alkane containing the same number of atoms in the chain as the whole bicyclic skeleton.
O
3 2
4
1
5 6
bicyclo[3.1.0]hexane
2 1 6
3
N4 H 2-thia-4azabicyclo[3.1.0]hexane 5
3-oxabicyclo[3.1.0]hexane
S
O O
7-oxa-bicyclo[2.2.1]heptane
S
2-oxa-bicyclo[2.2.1]heptane
O
2-oxa-6-thia-bicyclo[2.2.1]heptane
O Cl O
2-oxa-bicyclo[4.2.2]decane
O
7-oxa-bicyclo[4.2.2]decane
9-chloro-7-oxa-bicyclo[4.2.2]decane
O Cl
7-chloro-11-oxa-bicyclo[4.3.2]undecane