Transcript Heterocycles

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
O
NH
1-oxa-3-azacyclopentane
Hantzsch-Widman (1888)
Suffixes
ring with nitrogen
Ring members unsat’d
sat’d
ring without nitrogen
unsat’d
sat’d
3
-irine
-iridine
irene
irine
4
ete
etidine
ete
etane
5
ole
olidine
ole
olane
6
ine
in
ane
7
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
O
S
* 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
N
H
N
H
N
H
pyrazole
imidazole
1,2,4-triazole
N
N
O
oxazole
N
O
N
isooxazole
S
thiazole
O
O
4-hydropyran
O
O
2-pyrone
* 1,4-dioxane
4-pyrone
H
N
O
O
O
N
H
N
H
* piperidine
piperazine
N
N
N
pyridazine
N
pyrimidine
O
N
* pyridine
N
H
* morpholine
N
N
pyrazine
5
5
4
6
3
6
7
2
7
8
N
1
* quinoline
N
H
* indole
4
3
N
8
2
1
* isoquinoline
Aliphatic heterocyclics, chemistry
Ethers
conc. HBr
O
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
O
+ HBr
HOCH2CH2Br
O
+ NH3
HOCH2CH2NH2
Aromatic heterocycles
N
H
pyrrole
O
S
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
O
250o
Br2, EtOH
0o
N
H
Br
Br
C
CH3
Br
N
H
Br
CH3CO2NO2
O
NO2
O
furan
pyridine:SO3
SO3H
O
C6H5N2+
N
O
(CH3CO)2O, BF3
N
O
O
C
CH3
1. HCN, HCl
O
2. H2O
O
CH=O
furan
Br2
dioxane
O
Br
I2
HgCl2
CH3CO2Na
O
HgCl
CH3COCl
O
O
C
CH3
O
I
less reactive, can use acids
S
H2SO4
S
SO3H
S
NO2
CH3CO2NO2
(CH3CO)2O
Br2, benzene
Br
Br
S
I2, HgO
S
I
Why EAS  2-position?
H
2N
H
Y
H
H
N
H
Y
H
Y
Y
3N
H
N
H
H
N
H
Y
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
5
N
1
6
N


CH3
N
 -picoline
Pyridine
important solvent & base (~ 3o amine)
Reactions:
1) EAS (much less reactive than benzene ~ nitro)
KNO3, H2SO4,
NO2
370o
N
3% yield
N
H2SO4, SO3, HgSO4
220o, 24 hours
SO3
N
H
Br2, 300o
Br
Br
Br
+
N
Friedel-Crafts
no reaction
N
Deactivated to EAS due to electronegativity of Nitrogen
Directs beta due to destabilization of alpha and gamma
H

H
Y
N
H
H
Y
N
H
Y
Y
N
H
Y
Y

N
N
N

H
N
Y
H
N
Y
H
N
Y
Pyridine, reactions
2) Nucleophilic aromatic substitution
NaNH2
N
N
phenyl lithium
N
NH2
H2O
N
NH3, 200o
N
Br
N
Cl
NH2
H
N
NH2
H
Z
Z
NH3, 200o
N
N
Br
N
NH3, 200o
N
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
I
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
4
6
3
6
7
2
7
8
N
NAS
1
4
3
N
8
1
NAS
quinoline
4
5
isoquinoline
3
2
6
7
indole
N
H
1
EAS
2
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+
H
OH
-H2O
EAS
N
H
N
H
NO2
NH2
+
N
OH
H C
CH2
CH2
N
H
Heterocycles as you would expect!
O
N
H
S
O
angle strain
ethers
O
O
NH
amines
N
H
N
H
EAS
O
N
H
S
nucleophilic aromatic substitution
N
NH2
N
N
N
H
N
O
N
N
H
adenine
NH
N
guanine
NH2
O
N
N
H
cytosine
NH2
NH
O
N
H
thymine
O