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

NH
S O
thiacyclobutane 1-oxa-3-azacyclopentane
Hantzsch-Widman (1888)
Suffixes
ring with nitrogen ring without nitrogen
Ring members unsat’d sat’d unsat’d sat’d
3 -irine -iridine irene irine
4 ete etidine ete etane
5 ole olidine ole olane
6 ine perhydro__ine in ane
7 epine perhydro__epine epin epane
You must know the * names

O S N
H
* oxirane * thiirane * aziridine
ethylene oxide ethylene sulfide ethylene imine
oxacyclopropane thiacyclopropane azacyclopropane

H
N N
N N O
diazirane 1-azirine oxaziridine
oxazacyclopropane
 O S NH
oxetane thietane azetidine
oxacyclobutane thiacyclobutane azacyclobutane

N N
azete 1-azetine
azacyclobutadiene 1-azacyclobutene
 O S N
H
* furan * thiophene
oxole
* pyrrole
thiole
oxacyclopentandiene thiacyclopentandiene

O O N
H
1,3-dioxolane * tetrahydrofuran
1,3-dioxacyclopentane * pyrrolidine
azacyclopentane
 N N
N N
N N N
H H H
pyrazole imidazole 1,2,4-triazole

N N
N
O O S
oxazole isooxazole thiazole
 O

O O O O

4-hydropyran 2-pyrone 4-pyrone

H
O N

O N N
H H

* 1,4-dioxane * piperidine piperazine

 N
N
N
N N N

pyridazine pyrimidine pyrazine

N N
H
* pyridine * morpholine
 5 4 5 4
6 3 6 3

7 2 7 N2
N 8 1
8 1

* quinoline * isoquinoline

N
H
* indole
Aliphatic heterocyclics, chemistry
Ethers
conc. HBr
BrCH2CH2CH2CH2Br
heat
O
Amines
O O
CH3 C + HN CH3 C
Cl N
2o amine
sulfides
Three-membered rings undergo additions due to angle
strain, eg. epoxides

O + HBr HOCH2CH2Br

O + NH3 HOCH2CH2NH2
Aromatic heterocycles

N O S
H
pyrrole furan thiophene

Aromatic! EAS very, very reactive

resonance stabilization energy ~ 22-28 Kcal/mole

sp2 6 pi electrons
N no unshared pair on Nitrogen N
H H
very weak base
Kb = 10-14
 strong acids
polymer!
N
H CH3CO2-NO2+
pyrrole (CH3CO)2O, 5oC N NO2
H
SO3
pyridine, 90o SO3H
N
H
C6H5-N2+Cl-

N N N
H
 CHCl3, KOH

N N CH=O
H H
HCN, HCl
pyrrole H2O

(CH3CO)2O O
C
250o N
H CH3

Br Br
Br2, EtOH
0o Br Br
N
H
 CH3CO2NO2
O O NO2

furan
pyridine:SO3

O SO3H

C6H5N2+
N
O N

(CH3CO)2O, BF3
O
O C
CH3
 1. HCN, HCl
O O CH=O
2. H2O
furan
Br2
O Br
dioxane

HgCl2 I2
HgCl O I
O
CH3CO2Na

CH3COCl

O
O C
CH3
 less reactive, can use acids

S H2SO4
S SO3H

CH3CO2NO2

(CH3CO)2O S NO2

Br2, benzene
Br S Br

I2, HgO

S I
Why EAS  2-position?

2- H H H
N Y N Y N Y
H H H
H H
Y Y
3-
N N
H H
 H2, Ni

N 250o N
H H
Kb = 10-14 Kb = 10-3
2o amine

H2, Ni

O 50o O
THF
Pyridine

6 pi electrons, N N N
sp2, flat
aromatic, resonance stabilization energy ~ 23 Kcal/mole
Kb = 2.3 X 10-9
4

CH3
3 5 

2
N 6 N N
1
-picoline
Pyridine important solvent & base (~ 3o amine)
Reactions:
1) EAS (much less reactive than benzene ~ nitro)

NO2
KNO3, H2SO4, 370o
3% yield
N N

H2SO4, SO3, HgSO4

SO3
220o, 24 hours

N
H
Br2, 300o Br Br Br
+
N N

Friedel-Crafts
no reaction
Deactivated to EAS due to electronegativity of Nitrogen
Directs beta due to destabilization of alpha and gamma

H H H
 Y Y Y
N N N

H H Y H Y
Y


N N N

 H H H
N N N
Y Y Y
Pyridine, reactions
2) Nucleophilic aromatic substitution

NaNH2

N N NH2

phenyl lithium H2O

N N
 NH3, 200o
H
N Br N NH2 N
Z

Cl
NH2 H Z
NH3, 200o
N N
N

Br activated to nucl. arom. subts.

NH3, 200o directs alpha & gamma
NR
N
Pyridine, reactions
3) As base
Kb = 2.3 X 10-9

HBr
N N Br
H

CH3I

N N I
CH3
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 EAS

5 4 5 4
6 3 6 3

7 2 7 N2
N 8 1
8 1 NAS
NAS
quinoline
isoquinoline

4 3
5
2 EAS
6 N 1
7 H
indole
Skraup synthesis of quinoline

NH2 NO2
H2C OH H2SO4
+ HC OH + + H2O
H2C OH N
aniline glycerol nitrobenzene

The nitrobenzene is not only the solvent, but is also one of the reactants.
 O
H2C OH HC O H C
H+ CH2
HC OH -H2O CH +
H2C OH CH2
CH2 NH2 N
H
acrolein
H+
OH
H OH H C
-H2O EAS CH2
CH2
N N N
H H H
NO2
NH2

+
N
Heterocycles as you would expect!

O N S angle strain
H

O
ethers
O O
NH
amines
N N
H H
 EAS
O N S
H

nucleophilic aromatic substitution

N
 NH2
O
N N N NH
N N
H N N NH2
H

adenine guanine

NH2 O
N NH
N O N O
H H

cytosine thymine