Heterocycles

Ring compounds with elements other than carbon in the

ring. The most common elements to appear in
heterocyclic compounds are oxygen, nitrogen and sulfur.
The aliphatic heterocycles are similar to the open chain
analogues, ethers, amines and sulfides.
The aromatic heterocycles are similar to other aromatic
compounds.

Heterocyclic Nomenclature
Replacement nomenclature (IUPAC recommended 1957)
Oxygen

oxa

Sulfur

thia

Nitrogen

aza

Lowest number assigned to the hetero atom with the highest

precedence: O > S > N

S
thiacyclobutane

NH

1-oxa-3-azacyclopentane

Hantzsch-Widman (1888)
Suffixes
ring with nitrogen
Ring members unsatd
satd

ring without nitrogen

unsatd
satd

-irine

-iridine

irene

irine

ete

etidine

ete

etane

ole

olidine

ole

olane

ine

in

ane

epine perhydro__epine epin

perhydro__ine

epane

You must know the * names

O
* oxirane
ethylene oxide
oxacyclopropane

N
N
diazirane

S
* thiirane
ethylene sulfide
thiacyclopropane

N
H
* aziridine
ethylene imine
azacyclopropane

H
N
1-azirine

N
O
oxaziridine
oxazacyclopropane

O
oxetane
oxacyclobutane

N
azete
azacyclobutadiene

S
thietane
thiacyclobutane

N
1-azetine
1-azacyclobutene

NH
azetidine
azacyclobutane

* furan
oxole
oxacyclopentandiene

* thiophene
thiole
thiacyclopentandiene

N
H
* pyrrole

O
O
1,3-dioxolane
1,3-dioxacyclopentane

O
* tetrahydrofuran

N
H
* pyrrolidine
azacyclopentane

N
N

N
H

N
H

N
H

pyrazole

imidazole

1,2,4-triazole

N
O
oxazole

isooxazole

S
thiazole

O
4-hydropyran

2-pyrone

* 1,4-dioxane

4-pyrone

H
N

O
O

N
H

N
H

* piperidine

piperazine

N
N

pyridazine

N
pyrimidine

O
N
* pyridine

N
H
* morpholine

N
N
pyrazine

N
1

* quinoline

N
H
* indole

4
3

N
8

* isoquinoline

Aliphatic heterocyclics, chemistry

Ethers
conc. HBr

heat

BrCH2CH2CH2CH2Br

Amines

CH3

O
C
+ HN
Cl
2o amine

sulfides

CH3

O
C
N

Three-membered rings undergo additions due to angle

strain, eg. epoxides

+ HBr

HOCH2CH2Br

+ NH3

HOCH2CH2NH2

Aromatic heterocycles

N
H
pyrrole

furan

thiophene

Aromatic! EAS very, very reactive

resonance stabilization energy ~ 22-28 Kcal/mole
sp2
N
H

6 pi electrons
no unshared pair on Nitrogen
very weak base
Kb = 10-14

N
H

strong acids
N
H
pyrrole

polymer!

CH3CO2-NO2+
(CH3CO)2O, 5oC

N
H

NO2

N
H

SO3H

SO3
pyridine, 90o
C6H5-N2+ClN
H

N N

CHCl3, KOH
N
H

HCN, HCl

pyrrole

CH=O

N
H
H2O

(CH3CO)2O

250o

Br2, EtOH
0o

N
H
Br
Br

C
CH3
Br

N
H

Br

CH3CO2NO2
O

NO2

furan
pyridine:SO3
SO3H

O
C6H5N2+

N
O

(CH3CO)2O, BF3

O
O

C
CH3

1. HCN, HCl
O

2. H2O

CH=O

furan
Br2
dioxane

Br

I2

HgCl2
CH3CO2Na

HgCl
CH3COCl
O

C
CH3

less reactive, can use acids

S

H2SO4
S

SO3H

NO2

CH3CO2NO2
(CH3CO)2O
Br2, benzene
Br

Br

I2, HgO
S

Why EAS 2-position?

2N
H

Y
H

H
N
H

Y
H

3N
H

N
H

H
N
H

H2, Ni
N
H

250o

N
H
Kb = 10-3
2o amine

Kb = 10-14

H2, Ni
O

50o

O
THF

Pyridine
N
N
N
6 pi electrons,
sp2, flat
aromatic, resonance stabilization energy ~ 23 Kcal/mole
Kb = 2.3 X 10-9

4
3
2

N
1

CH3
N

-picoline

Pyridine

important solvent & base (~ 3o amine)

Reactions:
1) EAS (much less reactive than benzene ~ nitro)
NO2

KNO3, H2SO4, 370

3% yield

N
H2SO4, SO3, HgSO4
220o, 24 hours

SO3
N
H

Br2, 300o

Br

Br

Br

+
N
Friedel-Crafts

no reaction

Deactivated to EAS due to electronegativity of Nitrogen

Directs beta due to destabilization of alpha and gamma
H

H
Y

H
Y

N
H

Y
N
H

H
N

H
N

H
N

Pyridine, reactions
2) Nucleophilic aromatic substitution
NaNH2
N

phenyl lithium
N

NH2

H2O
N

NH3, 200o
N

Br

Cl

NH2

NH2
H

Z
Z

NH3, 200o
N

Br
N

NH3, 200o

activated to nucl. arom. subts.

directs alpha & gamma
NR

Pyridine, reactions
3) As base
Kb = 2.3 X 10-9
HBr
N

N
H

Br

N
CH3

CH3I
N

4o salt

Pyridine, reactions
4) reduction

H2, Pt
N

HCl, 25o, 3 atm.

N
H
piperidine
Kb = 2 X 10-3
aliphatic 2o amine

Polynuclear Heteroaromatics
EAS
5

EAS
5

NAS

4
3

N
8

NAS
quinoline
4
5

isoquinoline

3
2

6
7

indole

N
H

EAS

Skraup synthesis of quinoline

NO2

NH2
+
aniline

H2C OH
HC OH
H2C OH
glycerol

H2SO4

+ H2O
N

nitrobenzene

The nitrobenzene is not only the solvent, but is also one of the reactants.

H2C OH
HC OH
H2C OH

H+
-H2O

HC O
CH +
CH2

O
H C
CH2
CH2
N
H

NH2

acrolein

H+

OH

-H2O

EAS

N
H

N
H

NO2
NH2
+
N

OH
H C
CH2
CH2
N
H

Heterocycles as you would expect!

N
H

angle strain

ethers
O

NH

amines
N
H

N
H

EAS
O

N
H

nucleophilic aromatic substitution

N

NH2
N

N
H

O
N
N
H

adenine

NH
N

guanine

NH2

N
N
H
cytosine

NH2

NH
O

N
H
thymine