PCH 302: PHARMACEUTICAL ORGANIC CHEMISTRY II
CHEMISTRY OF HETEROCYCLIC COMPOUNDS
OJERINDE, O.S.
Heterocycles are ring compounds with elements
other than carbon in the ring.
The most common elements that appear in
heterocyclic compounds are oxygen, nitrogen and
sulphur.
Other elements are selenium, tellurium,
phosphorus, arsenic, silicon and germanium.
Heterocyclic compounds may be classified into
aliphatic and aromatic.
The aliphatic hetero-cyclics are the cyclic
analogues of amines, ethers, thioethers, amides,
etc.
Their properties are particularly influenced by
the presence of strain in the ring.
These compounds generally consist of small (3and 4- membered) and common (5 to 7
membered) ring systems.
The aromatic heterocyclic compounds, in contrast, are
those which have a heteroatom in the ring
Behave in a manner similar to benzene in some of their
properties.
Furthermore, these compounds also comply with the
general rule proposed by Hückel.
This rule states that aromaticity is obtained in cyclic conjugated
and planar systems containing (4n + 2) π electrons.
The conjugated cyclic rings contain six π-electrons as in
benzene
Forms a conjugated molecular orbital system which is
thermodynamically more stable than the non-cyclically
conjugated system.
This extra stabilization results in a diminished tendency
of the molecule to react by addition but a larger tendency
to react by substitution in which the aromatic ring
remains intact.
A heterocyclic ring may comprise of three or more atoms
which may be saturated or unsaturated. Also the ring
may contain more than one hetero atom which may be
similar or dissimilar.
Sources of Heterocycles
Heterocyclic compounds occur widely in nature and in a
variety of non-naturally occurring compounds.
A large number of heterocyclic compounds are essential
to life.
Various compounds such as alkaloids, antibiotics,
essential amino acids, the vitamins, haemoglobin, the
hormones and a large number of synthetic drugs and
dyes contain heterocyclic ring systems.
Heterocyclic Nomenclature
The following rules are employed in the nomenclature of
Heterocycles.
Rule 1: The heteroatom is given a name and is used as a prefix.
Heteroatom
Valence
Prefix
O
2
Oxa
N
3
Aza
S
2
Thia
Se
2
Selena
Te
2
Tellura
P
3
Phospha
As
3
Arsa
Si
4
Sila
Ge
4
Germa
Lowest number assigned to the hetero atom with the highest precedence: O > S >
Rule 2: Ring size is designated by stems that follow the prefix.
Suffixes
ring with nitrogen
Ring members unsat’d
sat’d
ring without nitrogen
unsat’d
sat’d
3
-irine
-iridine
irene
irane
4
ete
etidine
ete
etane
5
ole
olidine
ole
olane
6
ine
ane
ine
inane
7
epine
epane
epin
epane
8
-ocine
-ocin
-ocane
IUPAC and Common Names for Monocyclic Heterocycles
Rule 3: The saturated or hydrogenated ring systems are named
by varying the ending or by placing prefixes such as “dihydro-”,
“tetrahydro-”, “hexahydro-”, etc. The ending of the name will
depend on the presence or absence of nitrogen.
Rule 4: When two or more similar atoms are contained in a ring,
these are indicated by the prefixes ‘di-’, ‘tri-’, etc. placed before the
appropriate ‘a’ term.
Rule 5: When two or more different hetero atoms occur in the ring,
then it is named by combining the prefixes in rule 1 with the ending
in rule 2 in order their preference, i.e. O, S and N.
Rule 6: When substituents are placed on the ring, the hetero atom is assigned position 1 and
the substituents are then counted around the ring in a manner so as to give them the lowest
possible number.
Rule 7: When there is a presence of “EXTRA HYDROGEN” in ring system. The naming of
the isomers is handled by simply adding a prefix that indicates the number of the ring atom
that possesses the hydrogen, thus 1H, 2H, and 3H are used.
Also, a saturated heteroatom with an extra-hydrogen attached is given priority over an
unsaturated form of the same atom and the numbers are grouped together in front of the
heteroatom listings( thus, 1,3-oxazole, not 1-oxa-3-azole)
RINGS WITH MORE THAN ONE HETEROATOM
O
N
N
N
Pyridine
1,2-diazine
(Pyridiazine)
N
N
H
H
Perhydroazine
Perhydro-1,4-oxazine
(Piperidine)
(Morpholine)
N
N
N
N
N
N
N
N
H
H
H
Pyrazole
imidazole
N
1,2,4-triazole
O
O
4-hydropyran
O
2-pyrone
O
O
4-pyrone
O
O
oxazole
isooxazole
Bicyclic compounds or Fused heterocyclic compounds.
A. Carbocycles fused with heterocyclic system.
B. Heterocycle fused with another heterocyclic system.
A. Nomenclature of carbocycles fused with heterocycles IUPAC
names.
1. The parent name(written at the end) is the name of the heterocyclic
ring.
2. The fused name (written at first) is the name of the fused benzene
called “benzo”.
3. The side of fusion of the parent ring with the fused benzene ring is
indicated by alphabetical numbering and put such letter (a, b, c,..etc
between square brackets in between the prefix and parent name. In
this case the parent ring is numbered as usual & the sides 1,2 take
letter (a), sides 2,3 take letter (b), sides 3,4 take letter c,…etc
4.
a.
The total numbering of the complete fused system is done to determine the
position of saturation or substitutions according to the following rules:
The numbering starts from the atom next to the fusion giving the heteroatom
the least possible numbering & continue numbering in an anti-clockwise
direction (whenever possible) & the fused carbons are given the same previous
number adding to its letters (a, b, c,..etc)
N
N
c
a
b
d
N
c
N
benzo[c]pyridazine
b
a
N
N
benzo[d]pyrimidine
benzo[b]pyrazine
(quinazoline)
(quinoxaline)
Cinnoline
9
8
1
7
2
6
3
N
10
5
4
benzo[b]quinoline
9
8
c
d
7
(acridine)
2
a
5
O
b
e
6
dibenzo[b,e]pyridine
1
S
N
10
3
4
H
10H-dibenzo[b,e]1,4-thiazine
(Phenothiazine)
O
benzo[b]pyran-2-one
(coumarin)
O
O
benzo[b]pyran-4-one
(chromone)
N
H
benzo[b]indole , dibenzo[b,d]pyrrole
(carbazole)
B. Nomenclature of heterocycle fused with another heterocycles .
The IUPAC rules for naming such systems are also composed of 4
points.
• The parent atom is given to the more prior heterocycles, is used as
suffix.
• The fused ring(s) name is the less prior rings and is used as prefix.
• The side fusion for both rings
• The numbering of the total systems.
1. The naming of the prefix of fused(less prior) heterocycles is given
as
such:
• Furan
furo
• Pyridine
pyrido
• Pyrrole
pyrrolo
• Pyrimidine
pyrimido
• Pyrazine
pyrazino
• Thiophene
thieno
• Imidazole
imidazo
• Quinoline
quino
2. Determination of the sides of fusion for both sides of the to fused
heterocycles as such:
a.The side of fusion with the parent ring is numbered alphabetically
and the letter of fusion is placed between square brackets at its end.
b. The side of fusion of the prefix ring is indicated by two numbers
denoting the two positions of fusion with the parent ring, these two
numbers are placed at first in the square brackets. The order of
writing these conforms to the direction of lettering of the parent.
3. The selection of the parent ring (as suffix) should be according to
the following order of preferences:
i.The Nitrogen containing ring must be taken as a parent ring.
ii. If NO Nitrogen is present, the ring that contains the more prior
heteroatom (according to table 1) is considered as a parent ring.
iii. The largest ring size is taken as a parent ring if the two rings
contain Nitrogen or does not contain Nitrogen
O
1
3
2
b
2
3
a
O
1
furo[3,2-b]oxepin
iv. The largest number of rings with famous trivial name is always
used as parent name.
v. The ring containing the greatest number of hetero atoms or greatest
varieties of hetero atoms is the parent ring.
vi. A component ring having the more prior hetero atom (according to
table 1) is the parent ring.
vii. The parent ring is the ring containing a more number of carbon
atoms adjacent to the fusion.
4. The peripheral numbering of the total heterocyclic fused molecules
is by the same discussed rule, and considering the following other
rules:
a.Give the lowest number to the more prior hetero atom especially
when present just after fusion. But, if the more prior hetero atom
is not the nearest to the fusion side, the other nearest hetero atoms
after fusion must take the least possible numbering regardless of
priority of table.
b. The hetero atoms in the fusion side are numbered according to the
sequence of numbering, but when carbon atoms in the fusion take
the previous number plus letter a, b, c,..etc and also such carbon
atom follow the least possible numbering.
c. The saturated atoms take the least possible number before other
substitutents.
Radicals derived from Heterocyclic compounds
H
O
N
N
N
S
morpholino
piperazino
2-thienyl
4-morpholinyl
N
N
H
H
4-piperidinyl
3-piperidinyl
Aliphatic heterocyclics, chemistry
Ethers
conc. HBr
O
Amines
CH3
heat
BrCH2CH2CH2CH2Br
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
PYRROLES
N
N
H
Pyrrole
N
 Pyrroline
3,4-Dihydropyrrole
H
2 Pyrroline
2,3-Dihydropyrrole
N
H
3 Pyrroline
2,5-Dihydropyrrole
N
N
H
H

Pyrrolidine
 Pyrryl
Physical Properties
1.
2.
3.
4.
5.
6.
It is a colourless liquid with a boiling point of 1290C
Has an odour resembling that of chloroform
It turns brown on standing in air
It is miscible with most organic solvent
Soluble in water (6%) and dissolves 3% of its weight of water at 250C
It is both a very weak and acid(Pka 17.5) and a very weak base (Pka -3.8).
Chemical Properties
Pyrrole behaves mainly as a very reactive aromatic compound towards electrophilic
Reagents and has been compared to phenol in this respect. It also shows weakly acidic
& basic properties, and it can behave as an enamine (imine), and also as a 1,3-diene
Towards same reactive reagents.
1. Opening of the pyrrole ring.
(a). The pyrrole ring is not readily opened by acids or alkalis, but boiling with alcoholic
Hydroxylamine hydrochloride causes rupture, with the formation of Succinidialdehyde
dioxime.
This opening is facilitated by alkyl groups and hindered by carbonyl and phenyl grps.
(b) Ozonolysis of pyrrole & derivatives at -60oC in chloroform breaks the ring
CHOCHO
+
glyoxal
N
MeCOCHO
+
MeCOOH
+
NH3
methylglyoxal
H
2. Addition reaction
Pyrrole is much more easily hydrogenated over platinium in acid solution than under
Neutral conditions.
Zn
N
H
HOAc
Raney-Nickel
180 o C, High pressure
N
H
3. Substitution reactions of pyrrole.( Electrophilic reaction).
H
2N
H
H
N
H
Y
H
N
H
Y
H
Y
H
Y
3N
H
N
H
(a). At the Nitrogen atom.
-H+
+H
N
H
N
-
more aromatic
than pyrrole
Y
C2H2
N
H
Alkaline catalyst
N
CH=CH2
CH2 =CHCN
N
CH2CH2CN
HCHO
K2CO3 , 40o -55o C
N
CH2OH
1-hydroxymethylpyrrole
, 75o -90o C
HOCH2
CH2OH
N
H
2,5-dihydroxymethylpyrrole
(b). With Grignard reagents.
N
+
CH3MgBr
N
H
MgBr
+
CH3
CH3Br
N
N
MgBr
H
+
CH3COCl
N
N
MgBr
H
+
ClCOOMe
N
N
MgBr
H
COCH3
COOMe
B. At Carbon atoms.
Pyrroles are attacked by electrophilic reagents very rapidly, and mainly at positions
2 &5.
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
pyrrole
HCN, HCl
CH=O
N
H
H2O
(CH3CO)2O
O
250o
Br2, EtOH
0o
N
H
Br
Br
C
CH3
Br
N
H
Br
Friedel-Crafts reaction contd.
Cl3CCOCl
MeOH
K2CO3
Et3N
N
N
H
H
COCCl3
N
COOMe
H
PhCOCl
NaOH
N
H
o
, OC
N
COPh
or
PhCO
H
N
H
3. Mannich reaction.
Formaldehyde + Secondary amine + Ketone/Aldehyde
Imine is formed when amine is primary while Enamine is formed when the amine is
Secondary amine.
HCOH
+
HNMe2
+
N
N
H
H
MeI
N
H
CH2NMe2
NaOH
N
H
CH2OH
CH2NMe2
SYNTHESIS OF PYRROLES
1.
This involves the condensation of α-aminoketone or α-amino-β-keto ester with a
Ketone containing an activated α-methylene group or a keto ester, in presence of a
Base or acid as catalyst. The Knorr process starts with the condensation of the
amino group with the keto group.
Similarly, ethyl acetoacetate is frequently used in the Knorr synthesis, which gives rise
to a pyrrole with a 3-carbethoxy group. However, this can be removed easily if desired,
first by hydrolysis of the ester to the carboxylic acid and then decarboxylation of the
group. 2,4-dimethylpyrrole is a well-known compound easily made by the Knorr
process and elimination of the carbethoxy group.
2. Paal-Knorr synthesis. This is a versatile method of synthesis which involves heating
of a 1,4-dicarbonyl compound with ammonia or primary amine.
The Paal-Knorr method is applied in the pharmaceutical field for the synthesis of
Clopirac- a nonsteroidal anti-inflammatory drugs (NSAIDs).
3. Hantzsch synthesis. This involves a β-keto ester reacting with an α-chloroketone
or aldehyde in the presence of ammonia to give a pyrrole.
Natural occurrence of pyrrole.
It occurs in bone oil, the porphyrins(corrins) which may occur in the free form or as
Complexes with metallic cations, e.g. haemin(Fe2+) a blood pigment, chlorophylls
(a) & (b) (Mg2+) and cyanocobalamin (vitamin B12, an antipernious anaemia factor).
Simplest structure of Porphyrin
Haemin
Chlorophyll a
Chlorophyll b
Chlorophyll d
Chlorophyll c1
Chlorophyll c2
Simplest structure of corrin
cyanocobalamin
FURANS
The name furan comes from the Latin ”furfur” The first furan
derivative to be described was 2-furoic acid. Another important
derivative, furfural. Furan itself was first prepared and it is called
it tetraphenol. Furan is a heterocyclic organic compound consisting
of a five-membered aromatic ring with four carbon atoms and one
oxygen.
.
1.
2.
3.
4.
Physical properties of furan.
colourless, flammable, highly volatile liquid
Has a boiling point close to room temperature.
It is toxic and may be carcinogenic.
It is miscible with most organic solvent and slightly soluble in
water.
5. Furan is a liquid with a chloroform-like smell.
Furan is aromatic because one of the lone pairs of electrons on the oxygen atom
is delocalized into the ring, creating a 4n+2 aromatic system (Hückel's rule)
similar to benzene. Because of the aromaticity, the molecule is flat and lacks
discrete double bonds. The other lone pair of electrons of the oxygen atom
extends in the plane of the flat ring system. The sp2 hybridization is to allow one
of the lone pairs of oxygen to reside in a p orbital and thus allow it to interact
within the pi-system.
Due to its aromaticity, furan's behavior is quite dissimilar to that of the more
typical heterocyclic ethers such as tetrahydrofuran.
It
is
considerably
more
reactive
than benzene
in electrophilic
substitution reactions, due to the electron-donating effects of the oxygen
heteroatom. Examination of the resonance contributors shows the increased
electron density of the ring, leading to increased rates of electrophilic
substitution.
CH3CO2NO2
O
NO2
O
furan
pyridine:SO3
SO3H
O
C6H5N2+
O
(CH3CO)2O, BF3
N
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
Furan serves as a diene in Diels-Alder reactions with electrondeficient dienophiles such as ethyl (E)-3-nitroacrylate. The reaction
product is a mixture of isomers with preference for the endo isomer:
SYNTHESIS OF FURAN
1. Furan can be obtained from furfural by oxidation and decarboxylation of the
resulting furan-2-carboxylic acid, the furfural being derived by destructive
distillation of corn cobs in the presence of sulfuric acid.
heat 200o C
Ag 2 O/Cu 2 O
H3 O+, O2 , NaOH
O
CHO
O
COOH
O
2. The Feist-Benary synthesis is an organic reaction between α-halogen ketones
and
β-dicarbonyl
compounds
to
substituted furan compounds. This condensation reaction is catalyzed by amines
such as ammonia and pyridine. The first step in the ring synthesis is related to
the Knoevenagel condensation. In the second step the enolate displaces an alkyl
halogen in a nucleophilic aliphatic substitution.
3. THE PAAL-KNORR FURAN SYNTHESIS This is normally carried out under
aqueous acidic conditions with protic acids such as aqueous sulfuric or
hydrochloric acid, or anhydrous conditions with a Lewis acid or dehydrating
agent. Common dehydrating agents include phosphorus pentoxide, anhydrides, or
zinc chloride.
The Paal-Knorr reaction is quite versatile. In all syntheses almost all dicarbonyls
can be converted to their corresponding heterocycle. R2 and R5 can be H, aryl or
alkyl. R3 and R4 can be H, aryl, alkyl, or an ester.
The furan synthesis requires an acid catalyst
Other methods include
β-Epoxy Carbonyls
β-Epoxy carbonyls have been known to cyclize to furans. This procedure can use the β-γunsaturated carbonyls as starting materials, which can be epoxidized. The resulting
epoxycarbonyl can be cyclized to a furan under acidic or basic conditions
1,4-Diol-2-ynes
1,4-diol-2-yne systems have also been used to do Paal-Knorr chemistry. Using palladium, a
1,4-diol-2-yne can be isomerized to the corresponding 1,4-diketone in situ and then
dehydrated to the corresponding furan using a dehydration agent.
Microwave Assisted Paal-Knorr. The Paal-Knorr was also considered limited by harsh
reaction conditions, such as prolonged heating in acid, which may degrade sensitive
functionalities in many potential furan precursors. Current methods allow for milder
conditions that can avoid heat altogether, including microwave catalyzed cyclizations.
O
NH
NO2
Furosemide
O
Nitrofurantoin
4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid
Ranitidine
N-(2-[(5-(dimethylaminomethyl)furan- 2-yl)methylthio]ethyl)- N-methyl2-nitroethene- 1,1-diamine
Dehydroascorbic acid
CH = N
N
O
THIOPHENE
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a
flat five-membered ring, it is aromatic as indicated by its extensive substitution
reactions.
Thiophene and its derivatives occur in petroleum, sometimes in concentrations up to
1-3%. The thiophenic content of oil and coal is removed via thehydrodesulfurization
(HDS) process.
Physical properties
1.Thiophene is a colourless liquid with a mildly pleasant odour
reminiscent of benzene, with which thiophene shares some
similarities, at room temperature.
2.Similar boiling points (4 °C difference at ambient pressure).
3.Like benzene, thiophene forms an azeotrope with ethanol.
4.The molecule is flat; the bond angle at the sulphur is around 93
degrees, the C-C-S angle is around 109, and the other two carbons
have a bond angle around 114 degrees.
Chemical properties
Thiophene is considered aromatic, although theoretical calculations suggest that
the degree of aromaticity is less than that of benzene. The "electron pairs" on
sulfur are significantly delocalized in the pi electron system. As a consequence of
its aromaticity, thiophene does not exhibit the properties seen for
conventional thioethers. For example the sulfur atom resists alkylation and
oxidation.
1. Toward electrophiles
Although the sulfur atom is relatively unreactive, the flanking carbon centers,
the 2- and 5-positions, are highly susceptible to attack by electrophiles.
Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes;
perhalogenation is easily accomplished to give C4X4S (X = Cl, Br,
I).Thiophene brominates 107 times faster than does benzene.
Chloromethylation and chloroethylation occur readily at the 2,5-positions.
Reduction of the chloromethyl product gives 2-methylthiophene. Hydrolysis
followed by dehydration of the chloroethyl species gives 2-vinylthiophene.
2. Desulfurization by Raney nickel
Desulfurization of thiophene with Raney nickel affords butane. When coupled
with the easy 2,5-difunctionalization of thiophene, desulfurization provides a
route to 1,4-disubstituted butanes
3. Lithiation
Not only is thiophene reactive toward electrophiles, it is also readily lithiated
with butyl lithium to give 2-lithiothiophene, which is a precursor to a variety of
derivatives, including dithienyl.
4. Polythiophene
The polymer formed by linking thiophene through its 2,5 positions is
called polythiophene. Polythiophene itself has poor processing properties. More
useful are polymers derived from thiophenes substituted at the 3- and 3- and 4positions. Polythiophenes become electrically conductive upon partial oxidation,
i.e. they become "organic metals.
5. Coordination chemistry
Thiophene exhibits little thioether-like character, but it does serve as a pi-ligand
forming piano stool complexes such as Cr(η5-C4H4S)(CO)3.
Others are
less reactive, can use acids
S
H2SO4
S
SO3H
S
NO2
CH3CO2NO2
(CH3CO)2O
Br2, benzene
Br
Br
S
I2, HgO
S
I
Synthesis and production
The Gewald reaction is an organic reaction involving the condensation of
a ketone (or aldehyde when R2 = H) with a α-cyanoester in the presence of
elemental sulfur and base to give a poly-substituted 2-amino-thiophene.
The reaction mechanism of the Gewald reaction has only recently been elucidated.
The first step is a Knoevenagel condensation between the ketone (1) and the αcyanoester (2) to produce the stable intermediate 3. The mechanism of the addition
of the elemental sulfur is unknown. It is postulated to proceed through
intermediate 4. Cyclization and tautomerization will produce the desired product
(6).
The Volhard-Erdmann cyclization is an organic synthesis of alkyl and aryl thiophenes
by cyclization of disodium succinate or other 1,4-difunctional compounds (γ-oxo acids,
1,4-diketones, chloroacetyl-substituted esters) with phosphorus heptasulfide.The reaction
is named after Jacob Volhard and Hugo Erdmann.
An example is the synthesis of 3-methylthiophene starting from itaconic acid
Thiophenes are important heterocyclic compounds that are widely used as
building blocks in many agrochemicals and pharmaceuticals. The benzene
ring of a biologically active compound may often be replaced by a
thiophene without loss of activity. This is seen in examples such as the
NSAIDs lornoxicam, the thiophene analog of piroxicam.
Lornoxicam
Piroxicam
4-(4-Bromophenyl)thiophene-2-carboxylic acid
Pyridine
 a basic heterocyclic organic compound with
the chemical formula C5H5N.
 structurally related to benzene, with one C-H
group replaced by a nitrogen atom.
 pyridine ring occurs in many important
compounds, including azines, antimalarial,
vitamins nicotinamide, pyridoxal and several
other drugs.
N
pyridine
N
H
piperidine
Pyridine replaces the CH of benzene by a N atom (and a
pair of electrons)
Hybridization = sp2 with similar resonance stabilization
energy
Lone pair of electrons are not involved in aromaticity.
Physical properties
1.It is a colourless,
2.highly flammable,
3.weakly alkaline,
4.water-soluble liquid with a distinctive, unpleasant fishlike odor.
5.boils at 115.2 °C and freezes at −41.6 °C.
6.Its density, 0.9819 g/cm3, is close to that of water.
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
Chemical Properties
Pyridine is miscible with water and virtually all organic
solvents.
It is weakly basic, and with hydrochloric acid it forms a
crystalline hydrochloride salt which melts at 145–147 °C.
Most chemical properties of pyridine are typical of
a heteroaromatic compound.
In organic reactions, pyridine behaves both as a
tertiary amine,
undergoing protonation, alkylation,
acylation, and N-oxidation at the nitrogen atom, and as
an aromatic
compound,
undergoing nucleophilic
substitutions.
Due to the presence of the electronegative nitrogen in the
pyridine ring,
the molecule is relatively electron deficient.
It therefore enters less readily electrophilic aromatic
substitution reactions,
which are characteristic of benzene derivatives.
However, unlike benzene and its derivatives, pyridine is
more prone to nucleophilic substitution and metalation of
the ring by strong organometallic bases.
The reactivity of pyridine can be distinguished for
three chemical groups:
1.With electrophiles: electrophilic substitution takes
place where pyridine expresses aromatic properties.
2.With nucleophiles: pyridine reacts via its 2nd and 4th
carbon
atoms
and
thus
behaves
similar
to imines and carbonyls.
3.The reaction with many Lewis acids: this results in the
addition of the substituents to the nitrogen atom of
pyridine, which is similar to the reactivity of tertiary
amines. The ability of pyridine and its derivatives to
oxidize, forming amine oxides (N-oxides), is also a feature
of tertiary amines.
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
N
H
Y
N
H
Y
N
H
Y
Pyridine is an important solvent & base (~ 3o amine)
Reactions:
1)Electrophilic aromatic substitutions (much less reactive than
benzene ~ nitro)
 Many electrophilic substitutions on pyridine either do not
proceed or proceed only partially;
 the heteroaromatic character can be activated by electrondonating groups CH3, OH, NH2,
 Common alkylations and acylations, such as Friedel–Crafts
alkylation or acylation, usually fail for pyridine
 because they only lead to the addition at the nitrogen atom.
 Substitutions usually occur at the 3-position which is the
electron-richest carbon atom in the ring and is therefore more
susceptible to an electrophilic addition.
 Direct nitration of pyridine requires harsh conditions
and has very low yields.
 Direct sulphonation of pyridine is even more difficult
than direct nitration.
 In contrast to the nitration and sulphonation, the
direct bromination and chlorination of pyridine proceed
well.
NO2
KNO3, H2SO4, 370o
N
3% yield
N
H2SO4, SO3, HgSO4
220o, 24 hours
SO3
N
H
Br2, 300o
Br
Br
+
N
Friedel-Crafts
N
no reaction
ii
N+
_
AlCl3
Br
N
ii, AlCl3, RCOCl
O
ii
R
N
Pyridine, reactions
2) Nucleophilic aromatic substitution
In contrast to benzene, pyridine efficiently supports several nucleophilic
substitutions, and is regarded as a good nucleophile. The reason for this is
relatively lower electron density of the carbon atoms of the ring. These
reactions include substitutions with elimination of a hydride ion and
elimination-additions with formation of an intermediate arine configuration, and
usually proceed at 2- or 4-position.
 Many nucleophilic substitutions occur easier not with
bare pyridine, but with pyridine modified with
bromine, chlorine, fluorine or sulphonic acid fragments
which then become a leaving group.
 So fluorine is the best leaving group for the
substitution with organolithium compounds.
 The nucleophilic attack compounds may be alkoxides,
thiolates, amines, and ammonia (at elevated pressures).
NaNH2
N
N
phenyl lithium
NH2
H2O
N
N
NH3, 200o
N
Br
N
Cl
NH2
H
N
NH2
H
Z
Z
NH3, 200o
N
N
Br
NH3,
N
200o
NR
N
activated to nucl. arom. subts.
directs alpha & gamma
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
H2, Pt
4) reduction
HCl, 25o, 3 atm.
N
H2/PtO2
AcOH
N
H
AlCl3
ROH
N
Piperidine
N
H
1,2-Dihydropyridine
N
H
3 -Tetrahydropyridine
piperidine
Kb = 2 X 10-3
aliphatic 2o amine
LiAlH4
LiAlH4
N
H
3 Tetrahydropyridine
N
H
1,4-Dihydropyridine
N
H
Piperidine
5. Dimerization reaction.
N
Raney Ni
Na/THF
+
Heat
N
N
N
2,2-Bipyridyl
Zn/Ac2O
25oC
N
4,4-Dipyridyl
Ac
N
N
Dimeric product.
Me
N+
Paraquat (weed killer)
+N
Me 2Cl-
Ac
2NaH.
Synthesis of pyridine.
1. Chichibabin synthesis
condensation reaction of aldehydes, ketones, α,β-Unsaturated carbonyl
compounds, or any combination of the above, in ammonia or ammonia
derivatives.
unsubstituted pyridine is produced from formaldehyde and acetaldehyde,
First, acrolein is formed in a Knoevenagel condensation from the acetaldehyde
and formaldehyde. It is then condensed with acetaldehyde and ammonia
into dihydropyridine, and then oxidized with a solid-state catalyst to pyridine.
This process is carried out in a gas phase at 400–450 °C. The product consists
of a mixture of pyridine, simple methylated pyridines (picoline) and lutidine;
2. Dealkylation of alkylpyridines
Pyridine can be prepared by dealkylation of alkylated pyridines, which are
obtained as by-products in the syntheses of other pyridines. The oxidative
dealkylation is carried out either using air over vanadium(V) oxide catalyst, by
vapor-dealkylation on nickel-based catalyst, or hydrodealkylation with
a silver or platinum based catalyst. Yields of pyridine up to be 93% can be
achieved with the nickel-based catalyst.
3. Hantzsch pyridine synthesis
The Hantzsch pyridine synthesis typically uses a 2:1:1 mixture of a β-keto acid
(often acetoacetate), an aldehyde (often formaldehyde), and ammonia or its salt
as the nitrogen donor. First, a double hydrogenated pyridine is obtained, which is
then oxidized to the corresponding pyridine derivative.
3. Bönnemann cyclization
The trimerization of a part of a nitrile molecule and two parts of acetylene into
pyridine is called Bönnemann cyclization. A series of pyridine derivatives can be
produced in this way. When using acetonitrile as the nitrile, 2-methylpyridine is
obtained, which can be dealkylated to pyridine
Other methods
The Kröhnke pyridine synthesis involves the condensation
diketones with ammonium acetate in acetic acid followed by oxidation.
of
1,5-
4. The Ciamician-Dennstedt rearrangement entails the ring-expansion
of pyrrole with dichlorocarbene to 3-chloropyridine.
5. Gattermann-Skita synthesis,
A malonate ester salt reacts with dichloromethylamine.
CONEt2
CONHNH2
N
NH2
N
Nikethamide
Stimulant
SO2NH
N
Isoniazid
Anti-tubercular agent.
Sulphapyridine (Antibacterial)
H
CH3
Ho
N
N
H
COOMe
COOEt
H 3C
N
Mefloquine (Antimalarial)
CF3
N
Ph
Pethidine (Analgesic)
OCOPh
Cocaine (Topical anaesthetic).
Pyridine is used as a solvent to make esters
O
R
X
+
O
Pyr
R1-OH
1
R
O
R
X = OAc, Cl, Br
O
O
O
OH
+
Pyr
O
O
N+
O
R
Acyl pyridinium ion
Reactive intermediate
Polynuclear Heteroaromatics
EAS
6
5
7
8
EAS
5
4
N
3
6
2
7
NAS
1
5
7
indole
N
8
2
1
isoquinoline
3
2
6
3
NAS
quinoline
4
4
N
H
1
EAS
EAS Electrophilic Aromatic Substitution
NAS Nucleophilic Aromatic Substitution
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
O
angle strain
ethers
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
OXIDATION-REDUCTION
• In organic chemistry, oxidation is seen as –
addition of oxygen and/or removal of
hydrogen. Reduction is viewed as – addition
hydrogen and/or removal of oxygen
RCH2OH [O] RCHO
R2CO
[H]
R2CHOH
• Oxidizing agents bring about oxidation while
reducing agents effect reduction. However in
organic chemistry, substrate is the focus
OXIDATION REACTIONS
• Alcohols: RCH2OH [O]
RCHO [O]
RCOOH
R2CH-OH [O]
R2C=O
R3C-OH [O]
Difficult to oxidize
• Oxidizing agent is usually alkaline KMnO4 or chromic acid H2CrO4 (generated in situ by K2Cr2O7/ H2SO4 or CrO3/ H2SO4).
H2CrO4 is especially useful for 2ry alcohols with α,β-unsaturation.
H+
RCH2OH + KMnO4 KOH (aq) RCOO-K+ + MnO2
RCOOH
3R2CHOH + 2 H2CrO4 + 6H+  3R2C=O + 2Cr3+ + 8H2O
• For 1ry alcohols it is difficult to stop the reaction at aldehyde stage,
except if the aldehyde is removed as soon as it is formed, usually by
distillation (since aldehydes often have lower b.p. than acids).For
the production of aldehydes only PDC or DCC is used.
• Benedict’s & Fehling’s reagents give +ve test with aldehydes and αhydroxyketones (i.e. aldoses and ketoses). The reagents, which
contain Cu2+ (citrate in Benedict’s; tartrate in Fehling’s), is reduced
to Cu2O – seen as a brick-red precipitate
• Also, Tollens’ reagent (AgNO3/aq. NH3) generates [Ag(NH3)2]+
which, tho’ a weak oxidizing agent, oxidizes aldehydes and αhydroxyketones. In the process, Ag metal is deposited on the test tube
wall, appearing like a mirror (silver mirror test). Ketones do not react
RCHO + [Ag(NH3)2]+  RCOO- + Ag
R-CO-CH(OH)R' + [Ag(NH3)2]+  R-CO-CO-R' + Ag
• Oppenauer oxidation: process by which 2ry alcohols are oxidized to
ketones using Al alkoxide (usually t-butoxide) in the presence of a
large excess of acetone (to drive the equilibrium in the forward
direction). The process involves an initial alkoxy exchange followed
by hydride ion transfer. The reverse reaction (i.e. reduction of ketone
to 2ry alcohol) is known as Meerwein-Ponndorf-Verley (MPV)
OP
reduction.
3R2CHOH + (Me3C-O-)3Al
(R2CH-O-)3Al + Me3C-OH
(R2CH-O-)3Al + Me2C=O
MPV
3R2C=O + (Me2CH-O-)3Al
Side chain oxidation of alkylbenzenes
• Alkylbenzenes can be oxidized to benzoic acid using: hot,
dil.HNO3; hot chromic acid; OR hot, alkaline KMnO4 (best).
Oxidation always occurs at the benzylic carbon
CH3
CH2CH2CH3
1. KMnO 4/ O H-, hea t
2. H+
1. KMnO 4/ O H-, hea t
2. H+
CO O H
CO O H
Oxidative cleavage of alkenes
• Hot KMnO4: yields carboxylic acids. If terminal alkene is
involved, CO2 is formed. Rxn used to locate double bond position
in alkenes
RCH=CHR' hot KMnO4 RCOO-K+ + R'COOH H+ RCOOH
RCH=CH2 hot KMnO4 RCOOH + CO2 + H2O
• Ozonolysis: addition of ozone, 1st yields molozonide, then ozonide.
Because ozonide is unstable and may explode it is not usually
isolated but reduced to carbonyl. This reaction can also be used to
R R''
R O
R''
R
locate position
of
double
bonds
in
alkenes.
R''
C
C
R' C C R'''
+
C C
R'''
R'
Alke ne
Zn/ H2O
O3
O
o zo ne
O
R'
O
O
o zo nid e
mo lo zo nid e
R
R'
C O
+
O
R''
O C
R'''
+
Zn(OH)2
R'''
Oxidative coupling
• Alkynes: undergo oxidative coupling and dimerize to form diynes
R-CΞCH Cu Cl /NH /O R-CΞC-CΞC-R
• Phenols: oxidative coupling of phenols is very important in
biosynthesis of alkaloids. Loss of a proton and an electron results in
radical which may couple ortho-ortho, ortho-para, or para-para
2
2
3
2
O.
OH
O
O
.
[O ]
.
-e - , -H+
O
.
O
.
O
O
.
H H
O
OH
OH
e no liza tio n
O
O
. .
OH
H
O
O
OH
H
H
O
. .
O
O
O
H
HO
OH
Oxidation of ketones.
O
O
PhCOO.OH
CF3COOH
RCOR
O
RCOOR
This reaction is called Baeyer-Villiger oxidation.
REDUCTION
• Alkenes:
RR'C=CR''R''' + H2
• Aldehydes RCHO
RR'CH-CHR''R'''
Ni, Pd, or Pt
RCH2OH;
[H]
•
Ketones: RR'C=O [H] RR'CHOH
• Acids: RCOOH [H] RCH2OH ;
• Esters: RCOOR'
RCH2OH + R'OH
[H]
• Amides: RCONHR'
• Nitriles: R-CΞN
[H]
RCH2NHR' or
[H]
• Nitro compounds: PhNO2
RCH2NH2
PhNH2
• Epoxides
• Lactones
• Acid Chlorides : RCOCl
RCH2OH
• Anhydrides, (RCO)2O
RCH2OH
O
RCH2NH2
OH
CH2OH
O
Reagents used
• H2/catalyst: catalysts include Ni, Pd, Pt
• Metal/Acid: Examples include: Zn-Hg/HCl (Clemmensen
reduction); Fe/HCl; Fe/glacial AcOH; Sn/HCl
• Na/alcohol (Hydrogenolysis): High pressure hydrogenation.
Usually an industrial process employed in reduction of esters
RCOOR' [Na/EtOH] RCH2OH + R'OH
• Metal hydrides: Most widely used are LiAlH4 & NaBH4
- LiAlH4 is powerful and unselective (reduces virtually all
groups)
- NaBH4 is mild and selective (reduces only aldehydes and
ketones)
- LiAlH4 must be used in anhydrous condition because it reacts
violently with water (water is added cautiously after the reaction to
break down the Al complex). NaBH4 is used in aqueous medium
- Mechanism: Always involves hydride ion transfer to the carbonyl
carbon. The process is repeated until all the hydride from the
reducing agent has been transferred. The complex formed is then
decomposed by water. Using NaBH4 the process is shown below
R
C O
R'
H
H
B
H
Na +
H
R C OBH3 Na +
C O
R'
R C O B -Na +
4
3H2O
H
R C O B-Na +
R'
H
R'
3
H
R
R'
H
4 R C OH
R'
+
Na H2BO 3
4
Other Reduction Reactions
• Nitro reduction: Nitro groups are usually reduced by metal/acid or
H2/catalyst. However selective nitro reduction can be achieved by
using H2S in aqueous alcoholic ammonia
N H2
NO2
Fe / HCl
NO2
H2S
NO2
N H2
N H3 / EtO H
N H2
• Wolff-Kishner reduction: Used when Clemmensen reduction fails
or when strongly acidic conditions cannot be used because acidlabile groups are present. It involves heating the hydrazone or
semicarbazone formed from a carbonyl with KOH or NaOEt
Ph(R)C=O H NNH Ph(R)C=N-NH2 KOH PhCH2R + N2
2
2
Hydrazine
Hydrazone
• Huang-Minlon modification (of Wolff-Kishner reduction): The
hydrazone is formed in situ by refluxing the carbonyl in diethylene
glycol with hydrazine and KOH. Advantages of this method are:
- No need to isolate the hydrazine
- Reaction time is reduced
- Reaction can be carried out at atmospheric pressure, & large scale
- Good yield obtained
• Meerwein-Ponndorff-Verley (MPV) reduction: is the reverse of
Oppenauer oxidation. The alkoxide commonly used is Al
isopropoxide. In order to favour the formation of alcohol, acetone
formed is removed by distillation (drives equilibrium to the right).
MPV reduction is also very selective for carbonyls (i.e. groups such
as conjugated double bond, nitro or halogen are unaffected).
3 R(R')C=O + (Me2CH-O-)3Al
(RR'CH-O-)3Al + Me2C=O
• Reductive amination: process by which aldehydes and ketones are
converted to 1ry amines thro’ catalytic or chemical reduction in the
presence of ammonia. An imine is formed as intermediate.
R
C O +
R'
N H3
- H2O
R
C NH
H2/N i
R'
H
R
C N H2
R'
• Birch Reduction: Benzene is reduced to 1,4-cyclohexadiene by
treating it with an alkali metal (Na, K or Li) in a mixture of liquid
NH3 & an alcohol
Na
N H3 / EtO H
• Note that when benzene is hydrogenated under pressure using H2/
metal catalyst, cyclohexane is the final product. The intermediates –
1,3- and 1,4-cyclohexadiene, & cyclohexene cannot be isolated since
they undergo hydrogenation faster than benzene
H2 / N i
+
H2 / N i
H2 / N i