introductory heterocyclic chemistry
TRANSCRIPT
(3,4,5 and 6-
membered ring of
O,N, S. Heterocyclic
compounds and di-
heteroatoms)
OS N
O N
CH3
N
N
CN
O
N
OH
CH3
N
NO
CHO
N N
SAc
N
OPh
NN
N
NO2
N N
NNEt
N
O Cl
NH
O S
O
O
N
N N
O O
S O
Introductory Heterocyclic Chemistry
Heterocycles
Ring compounds with elements other than carbon in the
ring. The most common hetero elements 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 compounds are frequently abundant in plants and
animal products; and they are one of the important constituent of
almost one half of the natural organic compounds known.
Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the
some important class of natural heterocyclic compounds.
• Heterocyclic compounds can be easily classified based on
their electronic structure.
• Heterocyclic compounds are primarily classified as saturated
and unsaturated.
• The saturated heterocyclic compounds behave like the acyclic
derivatives with modified steric properties. Piperidine and
tetrehydrofuran are the conventional amines and ethers of this
category.
• However, unsaturated heterocyclic compounds of 5- and 6-
member rings have been studied extensively because of their
unstrained nature.
• The unstrained unsaturated heterocyclic compounds include
Pyridine, Thiophene, Pyrrole, Furan and their benzo fused
derivatives. Quinoline, Isoquinoline, Indole, Benzothiophene,
and Benzofuran are some important example of benzo fused
heterocycles.
• Heterocyclic compounds have a wide application in
pharmaceuticals, agrochemicals and veterinary products.
Many heterocyclic compounds are very useful and essential
for human life.
• Various compounds such as hormones, alkaloids antibiotic,
essential amino acids, hemoglobin, vitamins, dyestuffs and
pigments have heterocyclic structure.
Nomenclature of Heterocyclic
Compounds
The IUPAC rules for Heterocyclic compounds allow three
nomenclatures.
I. The Hantzsch-Widman Nomenclature.
II. Common Names or trivial Names
III. The Replacement Nomenclature
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
ONH
1-oxa-3-azacyclopentane
• In replacement nomenclature, the heterocycle's name is
composed of the carbocycle's name and a prefix that
denotes the heteroatom.
• Notice that heterocyclic rings are numbered so that the
heteroatom has the lowest possible number.
• The Hantzsch-Widman nomenclature is based on the
type (Z) of the heteroatom; the ring size (n) and
nature of the ring, whether it is saturated or
unsaturated.
• This system of nomenclature applies to monocyclic
three-to-ten-membered ring heterocycles.
Hantzsch-Widman
nomenclature
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
Some of the syllables are derived from Latin numerals,
namely ir from tri, et from tetra, ep from hepta, oc from octa,
on from nona, ec from deca.
The ring size is indicated by a suffix according to Table
below.
The endings indicate the size and degree of
unsaturation of the ring.
• According to this system heterocycles are named by
combining appropriate prefix/prefixes with a stem
from the table above. The letter “a” in the prefix is
omitted where necessary.
• Each suffix consists of a ring size root and an ending
intended to designate the degree of unsaturation in
the ring.
• It is important to recognize that the saturated suffix
applies only to completely saturated ring systems,
and the unsaturated suffix applies to rings
incorporating the maximum number of non
cumulated double bonds.
• Systems having a lesser degree of unsaturation
require an appropriate prefix, such as "dihydro"or
"tetrahydro".
• Saturated 3, 4 & 5-membered nitrogen
heterocycles should use respectively the
traditional "iridine", "etidine" & "olidine" suffix.
EXAMPLES
O S N
H
* oxiraneethylene oxideoxacyclopropane
* thiiraneethylene sulfidethiacyclopropane
* aziridineethylene imineazacyclopropane
N
N
N O
NH
diazirane 1-azirine oxaziridineoxazacyclopropane
You must know the * names
O S NH
N N
oxetaneoxacyclobutane
thietanethiacyclobutane
azetidineazacyclobutane
azeteazacyclobutadiene
1-azetine1-azacyclobutene
O
O NH
O
O S NH
* furanoxoleoxacyclopentandiene
* thiophenethiolethiacyclopentandiene
* pyrrole
1,3-dioxolane1,3-dioxacyclopentane
* tetrahydrofuran* pyrrolidineazacyclopentane
N
O
N
SON
NH
N
N
NH
N
NH
N
pyrazole imidazole 1,2,4-triazole
oxazole isooxazole thiazole
O O O
O
O
NH
NH
HN
O
O
4-hydropyran 2-pyrone 4-pyrone
* 1,4-dioxane * piperidine piperazine
N
N
NN
N
N
N NH
O
pyridazine pyrimidine pyrazine
* pyridine * morpholine
6
7
8
5
N1
2
34
6
7
8
5
1
N 2
34
NH
* quinoline * isoquinoline
* indole
• In case of substituents, the heteroatom is designated
number 1, and the substituents around the chain are
numbered so as to have the lowest number for the
substituents.
• Use fully unsaturated name with
dihydro, tetrahydro, etc
Rings With More Than One Heteroatom
If more than one hetero atom occur in the ring,
then the heterocycle is named by combining
the appropriate prefixes with the ending in the
table above in order of their preference, O > S
> N.
• Identical systems connected by a single bond
• Such compounds are defined by the prefixes bi-,
tert, quater-, etc., according to the number of
systems, and the bonding is indicated as follows:
• When naming such compounds the side of the
heterocyclic ring is labeled by the letters a, b, c, etc.,
starting from the atom numbered 1. Therefore side ‘a’
being between atoms 1 and 2, side ‘b’ between atoms
2 and 3, and so on as shown below for pyridine.
Naming Hetrocycles with fused rings
• The name of the heterocyclic ring is chosen as the parent
compound and the name of the fused ring is attached as
a prefix. The prefix in such names has the ending ‘o’,
i.e., benzo, naphtho and so on.
EXTRA HYDROGENS
Aliphatic heterocyclics, chemistry
Ethers
Amines
sulfides
O
conc. HBr
heatBrCH2CH2CH2CH2Br
HNCH3 C
Cl
O
+ CH3 C
N
O
2o amine
Three-membered rings undergo additions due to angle
strain, eg. epoxides
O
O
+ HBr
+ NH3
HOCH2CH2Br
HOCH2CH2NH2
Aromatic heterocycles
NH
O S
pyrrole furan thiophene
N
H
Aromatic! EAS very, very reactiveresonance stabilization energy ~ 22-28 Kcal/mole
sp2 6 pi electrons
no unshared pair on Nitrogen
very weak base
Kb = 10-14
NH
NH
strong acidspolymer!
CH3CO2-NO2
+
(CH3CO)2O, 5oC NH
NO2
SO3
pyridine, 90o
NH
SO3H
C6H5-N2
+Cl-
NH
N N
pyrrole
NH
NH
CH=O
NH
C
NH
Br
pyrrole
CHCl3, KOH
HCN, HClH2O
(CH3CO)2O
250o
CH3
O
Br2, EtOH
0o
BrBr
Br
O
furan
CH3CO2NO2
O NO2
pyridine:SO3
O SO3H
C6H5N2+
O NN
(CH3CO)2O, BF3
O CO
CH3
O
furan
O CH=O
O Br
O HgCl O I
1. HCN, HCl
2. H2O
Br2
dioxane
HgCl2
CH3CO2Na
I2
CH3COCl
O CO
CH3
S
less reactive, can use acids
H2SO4
S SO3H
CH3CO2NO2
(CH3CO)2O S NO2
Br2, benzene
S BrBr
I2, HgO
S I
N
H
N
H
N
H
N
H
N
H
YH
YH
Y
H
Y
H
Y
H
Why EAS 2-position?
2-
3-
NH
O
H2, Ni
250o
H2, Ni
50o
NH
O
Kb = 10-14 Kb = 10-3
2o amine
THF
Pyridine
N N N6 pi electrons,
sp2, flat
aromatic, resonance stabilization energy ~ 23 Kcal/mole
Kb = 2.3 X 10-9
3
2N
1
6
54
N
N
CH3
-picoline
Pyridine important solvent & base (~ 3o amine)
Reactions:
1) EAS (much less reactive than benzene ~ nitro)
N
KNO3, H2SO4, 370o
N
NO2
3% yield
H2SO4, SO3, HgSO4
220o, 24 hours
N
SO3
H
Br2, 300o
N N
Br Br Br
+
Friedel-Craftsno reaction
N
N
N
H Y
Y
H
Y
HN
Y
HN
Y
H
N
Y
H
N
Y
H
N
H Y
N
H Y
Deactivated to EAS due to electronegativity of NitrogenDirects beta due to destabilization of alpha and gamma
Pyridine, reactions
2) Nucleophilic aromatic substitution
N
NaNH2
N NH2
phenyl lithium H2O
NN
N
N
N
Br
Cl
Br
NH3, 200o
NH3, 200o
NH3, 200o
NR
N NH2
N
NH2
N
N
H Z
Z
H
activated to nucl. arom. subts.directs alpha & gamma
Pyridine, reactions
3) As base
Kb = 2.3 X 10-9
N
N
HBr
CH3I
N
H
Br
N
CH3
I
4o salt
Pyridine, reactions
4) reduction
N
H2, Pt
HCl, 25o, 3 atm. NH
piperidine
Kb = 2 X 10-3
aliphatic 2o amine
Polynuclear Heteroaromatics
6
7
8
5
N1
2
34
6
7
8
5
1
N 2
34
quinolineisoquinoline
EAS EAS
NAS
NAS
5
6
7
4
NH 1
2
3
indole
EAS
EAS -Electrophilic Aromatic Substitution
NAS – Nucleophilic aromatic Substitution