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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 rin g

are known as heterocyclic compounds. The ring itself is call ed

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. M any are of

fundamental importance to living systems, for examples Chl orophyll

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 prot eins,

three of them are heterocyclic.

H2N CH C

CH2

OH

O

HN

2-amino-3-(1H -indol-3-yl)propanoic acid

Trptophan (Trp)

HN

C

OH

O

Proline (Pro)

pyrrolidine-2-carboxylic acid

H2N CH C

CH2

OH

O

N

NH2-amino-3-(1H-imidazol-4-yl)

propanoic acidHistidine (His)

It has been found that the introduction of hetero-atom in carbocyclic

molecules makes predictable changes in their physical and c hemical

characteristics.

These changes are not only in the behavior of the parent ring b ut also

in the chemical behavior of the functional groups attached t o these

rings X

monosubstituted rings

N N N NX

X

X

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 ut ility

and they are approved by the IUPAC

O

Furan

NH

1H-Pyrrole

NH

Pyrrolidine

NH

Pyrroline

S

Thiophene

Five membered rings containing two heteroatoms

NH

N

N

NH

1H-Pyrazole

N

O

isoxazole

N

S

isothiazole

N

O

oxazole

N

S

thiazoleImidazoleNN

O

Farmazone

NH

NH

Pyrazoline

NH

NH

pyrazolidine

O

NH

isoxazoline

O

NH

isoxazolidine

S

NH

isothiazoline

S

NH

isothiazolidine

Uns a

tura

ted

PartiallyUns at ura

t ed

Satura

ted

Six membered rings

N

N

N

N

N

N

PyrazinePyrimidinePyridazine

NH

NH

O

Piperidine Morphiline

NH

HN

Piperazine

N

Pyridine

O

2H-Pyran

O

4H-Pyran

� 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 pr iority will be as follow:

PrefixValenceElementsPrefixValenceElements

phospha310)Phosphorous (P)floura11) Flour (F)

arse311)Arsenic (As)chlora12) Chlore (Cl)

stilba312)Antimony (Sb)broma13) Bromine (Br)

bisma313) Bismuth (Bi)ioda14) Iodine (I)

sila414) Silicon (Si)oxa25) Oxygen (O)

germa415) Germnium (Ge)thia26) Sulphur (S)

stanna416) Tin (Sn)selena27) Selenium (Se)

plumba417) Lead (Pb)tellura28) Tellurium (Te)

bora318) Boron (B)aza39) Nitrogen (N)

mercura219) Mercury (Hg)

� 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

StemStemStemStemRing sizeRing sizeRing sizeRing size

ir3

et4

ol5

in6*

ep7

The end refers to the degree of unsaturation in the ring

( as shown in the next table)

2: System for Hantzsch-Widman names

Rings containing no NitrogenRings containing Nitrogen

Ring size SaturatedUnsaturatedSaturatedUnsaturated

IraneIreneiridineirine3

etaneeteetidineete4

olaneoleolidineole5

ane***ineane**ine6*

epaneepine****epine7

ocaneocine****ocine8

onaneonine****onin9

ecaneecine****ecin10

Rings containing no NitrogenRings containing no NitrogenRings containing no NitrogenRings containing no NitrogenUnsaturated SaturatedUnsaturated SaturatedUnsaturated SaturatedUnsaturated Saturated

Rings containing NitrogenRings containing NitrogenRings containing NitrogenRings containing NitrogenUnsaturated SaturatedUnsaturated SaturatedUnsaturated SaturatedUnsaturated Saturated

Ring sizeRing sizeRing sizeRing size

IraneIreneIridineIrine3

oxirane

thiirane

Oxirene

thiirene

Aziridineazirine

etaneEteetidineete4

Thietane

oxitane

Thiete

oxete

AzetidineAzete

HNH

NO O

NNH S S

O O

S SO

NH

Oxaziridine

O

NH

2H-[1,2]Oxazete

O

NH

[1,2]Oxazetidine

O

N

Oxazirine

OlaneOleOlidineOle5

Oxolane

thiolane

oxole

thiole

ane***ineane**ine6*

Oxane

thiane

Oxine

thiine

O O

S S

O O

S S

NH

AzoleO

NH

[1,3]-Oxazolidine

N

Azine

� The rings that have one heteroatom, the rings are numbered so that

the heteroatom is given number 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.

NH1

2

34

5

O1

2

34

5

O

N

1

2

3

4 5

NS1

2

3

45

For partially saturated 5-membered rings containing

Nitrogen

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 ).

NH

NH

NH

azole azoline azolidine

NH

O

N

O

N

O1

2

34

5

-1-oxa-3-azoline4

-1-oxa-3-azoline3

-1-oxa-3-azoline2

For full unsaturated rings which contain extra hydr ogens, the

positions of extra hydrogens are indicated as nH in t he 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

N

NH

NH

1

2

34

5

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).

NH

O

1-Oxa-4-azacyclohexane

O

Oxacyclopent-2,4-diene

N

Azabenzene

S

N

1-Thia-2-azacyclopent-2,4-diene

O

N

Oxazacyclopropene

S

1-thiacyclohexa-2,5-diene

N

O N

O

1,7-Dioxo-2,8-diazacyclododeca-2,8-diene

2,3-Dihydro-1,4-dithianaphthalen

N

S

S

N

O

N

2-Azanaphthalene

1

1

2

3

4

1

2

3 4

5

1

2

3

4

4a

5

6

7

4H-4a-Azanaphthalene 1-Oxa-3-azacyclopenta-2,4-diene

2

(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.

O

Cl

3-furanyl chloride

NH

NH2

3-Amino-1H-pyrrole

NH

N

N

COCH3

CN

5-Actyl-4H-1,2,4-triazole-3-carbonitrile

N

N

HN

C2H5

Ph

2-Ethyl-1-phenyl-1,2,4-triazolidine

N

O

NH2

C2H5O2C

Ethyl 5-aminoisoxazol-3-carboxylate

S

NN

SCN

1,3,4-thiadiazol-2-ylthiocyanate

NH

N

NH2

3-Amino-1H-pyrazole-4-carbonitrile

NC

N

NH

NH2NC

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).

N

N

Quinoline Isoquinoline

4

3

2

18

7

6

5

1

2

3

45

6

7

8

N

N

N

N

Peteridine

1

2

3

45

6

7

845

6

7

Phthalazine

N

N

8 1

N

N

Quinoxaline

2

3

45

6

7

8

N

N

NN

QuinazolineCinnoline

1

2

3

45

6

7

81

2

3

45

6

7

8

1

2

3

NH

1

2

3456

7

8

9

4a4b

8a 9a

Carbazole

1H-Indole 1H-Indazole

NH

N1

2

34

5

6

7

NH

12

34

5

6

7

1

2

34

56 7

8

9

Purine

N

HN

N

NN

Indolizine

N

3

2

18

7

6

5

2

1

5

1H-Pyrrolizine

434

6

7

NH

2H-Isoindole

1

2

34

5

6

7

Fusion names� When a heterocyclic ring is fused to a carbocyclic ring, the hetero

ring is chosen as the parent or base component. The n the

systematic name is formulated from the prefix benzo - and the

trivial name of the heterocyclic component as follo ws:

� The bonds between the ring atoms are denoted accord ing to the

successive numbers of the ring atoms by the letters a, b, c, etc.

� The letter must be as early as possible and hence

benzo[ d]thiophene is incorrect.

12

3

5

4

S S

+a

b

c

d

e

benzo[b]thiophene

b

Base component

O

NH

Benzo[b]furanBenzo[b]pyrrole

or Indole

12

3

b

1

2

3

5 4

SS

+a

b

c

d

e

naphtho[2,3-b]thiophenebase component

•Polycyclic systems with two or more heterocycles

The base component is chosen as that in the Hantzsch-Widmannomenclature except that of nitrogen is given the highest priority .

Prefixes are formed by changing the terminal (e) of the trivial or theHantzsch-Widman names of the components into (o)

Chose of the base component .

i- Is there only one component which contains nitrog en?

No Yes: choose this as base component

O

N

Base component pyrrole

ii- Is nitrogen absent from all the rings?

NO Yes: choose the ring containing a heteroatom W hich occurs

highest?

S OBase component furan

iii- Are there more than two rings presents?

No Yes: choose the component containing the grea ter

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 heteroa toms?

No Yes: chose the one with the greater number

NO

Base component isoxazole

HN

Vi- Are there differences between the numbers of eac h kind of

heteroatom in the two rings?

No Yes: choose the ring with the greater num ber of atoms

listed first

O

N

Base component oxazole

N

S

Vii- In case of the two rings are of the same size an d contains

the same heteroatoms, how to select the base compon ent?

Rule is to select the base ring to be the one in which

heteroatoms has less separation between the heteroatoms.

Thus:

N

NN

NN

NN

N

NH

N

Base component Pyrazole

N

HN

Base component Pyridazine Base component Pyridazine

Viii- The ring containing the greatest Varity of het eroatom

arranged according to their order priority

Base component Oxazole

N

O

N

HN N

N

S

Base component Thiazole

1- When a heterocyclic ring is fused to a

carbocyclic ring (choose the hetero ring as

the parent or base component

2- One ring only contains N (choose the ring

containing N)

3- No, Nitrogen ( choose according to the

priority O ˃ S )

S

benzo[b]thiophene

b

Base component is thiophene

How to Choose of the base component (Summary)

O

N

Base component pyrrole

S OBase component furan

4- One consists of two or more rings

(Choose one with the greater number of rings)

5- Two rings of different size (choose the

larger)

6- Choose the one with more heteroatoms

N N

N

Base component quinoline

O

N

Base component azepine

7- Same number of heteroatoms (choose O >

S > N)

8- Same type and number of heteroatoms, and

same ring size (choose lower separation

between atoms)

9- Choose the ring containing the greatest

Varity of heteroatom.

O

N

Base component oxazole

N

S

NH

N

Base component Pyrazole

N

HN

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 t he trivial name into <O>

(e.g. pyrazol e is converted to pyrazol o)

� 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 b ase is indicated

by inserting (in square brackets) number for the pr efix and italic

letter for the base component.

�Name = prefix[number, letter ]base

N

N

N

4H-pyrimido[1,2-b]pyridazine

N

N

N

N

Pyrazino[2,3-d]pyrimidineor

pteridine

N

NN

N

Pyrazino[2,3-c]pyridazine

ON

N

O

oxazolo[5,4-d]isoxazole

SN

N

S

thiazolo[5,4-d]isothiazole

N

NN

N

Pyrimido[4,5-c]pyridazine

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

N N

N

N

pyrazolo[1,5-a][1,3,5]triazine

N

N

N

N

pyrazolo[5,1-c][1,2,4]triazine

12

3

45

a

a bc

12

3

45

Other examples for Bridge Specification

N

N

N

pyrido[3,2-d]pyrimidine

1

2

3a

bcd

eN

NH

NN

abc

123 4

5

imidazo[4,5-c]pyrazole

N N

N

pyrido[2,3-d]pyrimidine

1 2

3a

bcd

e

N

N

NN

1

2

3

a

bcd

e

N

NN

N1

2

3a

b c

d

pyrazino[2,3-d]pyridazine

4

5N

NN

N 1

23a

b cd

pyrimido[4,5-d]pyridazinenot

pyrimido[5,4-d]pyridazine

pyrido[3,2-e][1,2,4]triazine

NN

HN

1H-imidazo[1,2-b]pyrazole

N

N

N

4H-pyrimido[1,2-b]pyridazine

N S

NS

thiazolo[5,4-d]isothiazole

N

O

furo[3,4-c]quinoline

ab

c2

3

4

1

Numbering fused heterocycles

The numbering of the complete fused structure does not depend on theoriginal numbering systems of its components .

1. The greatest number of rings should be on a horizontal line , thenthe maximum number of rings should be above and to the right ofthis 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 mostcounter-clockwise position of the uppermost ring.

1

2

3a b

c

d

N

benzo[h]isoquinoline

h e

fg

N

HN

1H-pyrido[3,2-c]carbazole

1

23

4

5

67

8

9

1011

4a

6a7a

11a 11b11c

1

2

3a b

c

d

N

4,9-dimethylbenzo[h]isoquinoline

CH3h e

fg

H3C

N

NH

4H-pyrido[2,3-c]carbazole

1

2 3

423

a

bc

N

1

23

4

5

6

7

8910

11

12

13

4a

4b

13a13b

a)- Give low numbers to the heteroatoms

O

Benzo[b]furan

NH O

S

4H-[1,3]oxathiolo[5,4-b]pyrrole

(N.B: 1,3,4 is lower than 1,3,6)

1

2

3 4

5

61

2

3

b) Give low number to heteroatoms in the order O> S> N

SO

Thieno[2,3-b]furan

1

2

34

5

6

N

O

N

HN

6H-imidazo[4,5-d]oxazole

N

O

N

HN

Me

5-methyl-6H-imidazo[4,5-d]oxazole

1

2

3 4

5

6

1

2

3 4

5

6

c) Give hydrogen atom the lowest numbers

O

O6

4H-cyclopenta[d][1,3]dioxole

N

NH O

O

5

6

4H-[1,3]dioxolo[4,5-d]imidazole

1

2

34

5

1

2

34

A carbon atom common to two or more rings is given a lower case

letter after the numeral of the atom immediately pr oceeding. A

heteroatom common to two or more rings receives an individual

locant.

N

N

N

N

1

2

3

45

6

7 8

4a

Imidazo[1,2-b][1,2,4]triazine

1

2

3

45

6

1

2

3a

b

c

N

N

N

N

6-methylimidazo[1,2-b][1,2,4]triazine

H3C

7 8

N

N

NN

N4a

12

3

456

N

O

3,9-dimethylfuro[3,4-c]quinoline

75a

CH3

CH3

3a8

99a

9b 1

2

3 N

N

N

7-methyl-4H-pyrimido[1,2-b]pyridazine

CH345 6

7

8

9

1

2 3 4

5

67

7a

4a

NN

S

NH2

thieno[3,4-d]pyridazin-5-amine

1

2

3

4

5 6

7

NNH

O

NH2NC

6-amino-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

NN

N

CH3

3,6-dimethyl-3H-imidazo[1,2-b]pyrazole

H3C

1

2 3

4

5

67

8

NS NH2

COOC2H5NC

Ethyl 5-amino-8-cyano-7H-thiazolo[3,2-a]pyridine-6-carboxylate

N O

NN

Pyrrolo[3,2-e][1,3,4]oxadiazine

Pyrrolo[2,3-e][1,3,4]oxadiazine

O

NNN

This method is highly convenient for naming bicycli c saturated heterocycles.

The names originally for hydrocarbons , converted into names ofheterocycles by application of replacement principals .

prefix ( bicyclo )followed in square brackets by the number of carbon atomsseparating the bridgeheads on three possible routes from on e bridgehead tothe other , followed by the name of alkane containing the same number ofatoms in the chain as the whole bicyclic skeleton.

1

2

3

4

5

6bicyclo[3.1.0]hexane

O

3-oxabicyclo[3.1.0]hexane

12

3

45

6

NH

S

2-thia-4-azabicyclo[3.1.0]hexane

O

O

O OS

O O

O

7-oxa-bicyclo[2.2.1]heptane 2-oxa-bicyclo[2.2.1]heptane 2-oxa-6-thia-bicyclo[2.2.1]heptane

2-oxa-bicyclo[4.2.2]decane 7-oxa-bicyclo[4.2.2]decane

Cl

9-chloro-7-oxa-bicyclo[4.2.2]decane

Cl

7-chloro-11-oxa-bicyclo[4.3.2]undecane