Chemistry of Heterocyclic compounds

1. Heterocyclic Chemistry 1
CHE 1102-435
Prepared By
Dr. Rabeea Daoub
http://www.nuigalway.ie/chemistry/level2/staff/f_aldabbagh/Fawaz.htm
Cytotoxin- Inhibits DNA-topoisomerase enzymes
Happy Tree
(China)
1

2. Chapter I
INTRODUCTION
• Ordinary organic compounds have a backbone of
carbon atoms, which are bonded to one another and
also to hydrogen or other atoms, or both. The carbon
atoms can join together in a form of open chain,
aromatic ring, or cyclic compound.
• In heterocyclic compounds one or more of the
carbon atoms in the ring is replaced by the atom
(called a hetero-atom) of another element. Most
frequently, the hetero-atoms are oxygen (O), nitrogen (N),
sulfur (S) or phosphorous (P).
• Most heterocycles have the same chemistry as their
open-chain counterparts particularly when the ring is
unsaturated.
2

3. Definition: Heterocyclic compounds are organic
compounds that contain a ring structure containing atoms
in addition to carbon, such as sulfur, oxygen or nitrogen,
as the heteroatom. The ring may be aromatic or non-
aromatic
Significance – Two thirds of all organic compounds are aromatic
heterocycles. Most pharmaceuticals are heterocycles.
Examples
Quinine
Pfizer: Viagra
Treatment of malaria for 400 years (Peru)
Erectile dysfunction 3

4. N
N
Me
N NHMe
N
NC
H
H
Ovarian & lung cancer
GSK - Topotecan
Pfizer - Irinotecan
Camptothecin Analogues
Treating stomach & intestinal ulcers
More soluble & less side-effects
4

5. As in hydrocarbons, the heterocyclic ring atoms may be saturated
(held together by single bonds) or unsaturated (one or more
bonds are double or triple).
Heterocyclic rings may also be aromatic (having alternating single
and double bonds).
The heterocyclic compounds must have the following
properties:
1. Cyclic compounds
2. Containing carbon and other elements as N, O, S, or P.
3. Stable and have aromatic characters.
4. Containing at least two conjugated double bonds.
Importance of Heterocyclic chemistry:
It includes many compounds of biological importance, such as
nucleic acids and certain vitamins, hormones, and pigments. Also
includes significant pharmaceuticals, pesticides, dyestuffs, and
plastics. 5

6. When Is A Molecule Aromatic?
• For a molecule to be aromatic it must:
• Be cyclic
• Have a p-orbital on every atom in ring
• Be planar
• Posses 4n+2 p electrons (n = any integer, 0, 1, 2, 3,….)
benzene naphthalene
+
cyclopropenyl cation
[14]-Annulene
Erich Hückel
6

7. Examples of Heterocyclic Compounds:
There are a number of heterocyclic compounds which are
naturally occurring as: Nicotine, Caffeine, and Haemoglobin.
Nicotine Caffeine Haemoglobin
There are a number of heterocyclic rings which are easily opened
and do not have aromatic characters such as ethylene oxide,
propylene oxide and α-, β-, γ-, and δ-lactones.
ethylene oxide propylene oxide γ -lactones δ-lactones 7

8. Nomenclature of Heterocyclic Compounds:
Heterocyclic Chemistry
Unsat. Unsat.
sat sat
N-present N-absent
irine iridine irene irane
ete ete
etidine etane
ole olidine ole olane
ine a in ane
ocine
epin
ocane
Table 1
a
Ring size
epine
a
ocin
epane
9
10
onine a
ecine a
onin
ecin
onane
ecane
a: Expressed prefixing “perhydro” followed by the name of the
corresponding unsaturated compound.
2.The size of
the monocyclic
ring from 3 to
10 membered
heterocycles is
indicated as in
the table.
1.The name of monocyclic compounds are derived by a prefix indicating the
nature of the heteroatom: oxygen: oxa; sulphur: thia; nitrogen: aza; silicon: sila;
phosphorous: phospha.
8

9. Similarity between Heterocyclic and Aromatic Compounds:
The structure of pyridine is completely analogous to that of
benzene.
There is clear similarity between aromatic and heterocyclic
compounds in their reactions because:
1. Both compounds resist oxidation, reduction, and addition
reactions.
2. Both compounds undergo electrophilic substitution reactions.
The heterocyclic compounds are more reactive than benzene in
the electrophilic substitution reactions which shown on the
following example:
Pyridine
Heterocyclic aromatic compound
Aromatic compound
Benzene
Heating 6-7 h
9

10. Classification of Heterocyclic Compounds:
Heterocyclic derivatives as a group, can be divided into two broad
areas: aromatic and non-aromatic. (note aromatic system must
have 4n+2 π-electron)
(I) The Five-Membered Heterocycles rings are shown below (π -
Excessive):
N.B. The lone pair of electrons on the heteroatom in case of 5-
membered heterocycles has to contribute in the conjugated
system.
(II) The six-membered rings below, (π-Deficient):
Pyridine has less electrons than the normal case due to that N is
more electronegative than C and attract more than one electron.
N.B. The lone pair of electrons in case of 6-membered
heterocycles has no contribution in the conjugated system.
10

11. CHAPTER II
THREE MEMBERED RINGS WITH ONE HETERO ATOM
1. The outstanding characteristic of the three-membered hetero
rings is their reactivity to a wide variety of reagents, an effect
undoubtedly resulting from the necessary compression of bond
angles in these molecules.
2. The introduction of a double bond serves to further increase the
strain of the particular system under study.
3. Thus, aziridines are far more reactive than ordinary amines,
and 1H-azirines remain to be synthesized.
4. Of the three saturated analogs, epoxides, aziridines, and
episulfides, the second group is intrinsically interesting because
the substituent on the nitrogen does not lie in the plane of the
ring, leading to the possibility that suitably constructed
derivatives may be subjected to resolution into optically active
enantiomers, for example, [1a] and [1b]
11
N CH3
H3C
H3C N
H3C
CH3
CH3

12. 5. However, because of the ease with which nitrogen undergo
inversion of configuration, [I] exists at room temperature as a
rapidly interconnecting mixture; in fact, the rate of inversion
process is such that substituted aziridines with molecular
asymmetry attributable to trivalent nitrogen.
6. On the other hand, nitrogen inversion in aziridines occurs
sufficiently slowly (in a relative sense) below room temperature
that direct determination of the inversion frequency by nuclear
magnetic resonance (N.M.R.) spectroscopy is feasible.
SYNTHETIC APPROACH
Direct Insertion of the Hetero Atom into a Carbon-Carbon
Double Bond:
1. The direct preparation of epoxides from olefins can be carried
out by a number of methods, the most frequently employed
and generally applicable of which is peracid oxidation.
2. Of the variety of peracids that have been used for this
purpose, m-chloroperbenzoic acid has recently emerged as
the most convenient oxidizing agent. 12

13. 3. This reagent is commercially available, reacts at somewhat
faster rate than either peracetic or perbenzoic acids, and is ideally
suited for epoxidation which require long reaction times to its
excellent stability.
4. Because epoxides readily undergo ring cleavage in the
presence of sufficiently acidic carboxylic acids, reactions
performed with performic, trifluroperacetic. Monopermaleic, and
peracetic acids (in nonbuffered solutions) generally result in
formation of monoesters of 1,2-diols, these reagents are therefore
less satisfactory. 13
C
C
H
O
O C
O
R
O
C
C + RCOH
O

14. CHAPTER III
THREE - MEMBERED RINGS WITH TWO HETERO ATOMS
1. Where as monohetero atomic three-membered ring systems
were known in the nineteenth century, no three-membered rings
with two hetero atoms had been prepared prior to 1950. Since this
date, however, the chemistry of the oxaziranes [1], diaziridines [2],
and diazirines [3] has rapidly developed.
2. As will be seen in the ensuing section, the unfavorable strain
energy in these molecules is not reflected in the ease with which
they can be prepared. They are nonetheless highly reactive and
possess certain unusual properties. are all relatively stable,
isolable systems.
[1] [2] [3]
SYNTHETIC APPROACH
1. The preparation of the title compounds can be readily achieved
by the direct insertion of an appropriate hetero atom into a
carbonyl or imine double bond.
14
O
N
R
R' R"
H
N
N
R
R'
R"
N
N
R
R'
1
2
3

15. 2. Thus, the oxaziranes are conveniently synthesized by the
oxidation of imines with organic peracids.
3. Because a large variety of imines are amenable to synthesis
(from primary amines and ketones or aldehydes), and because
the oxidation step is general in nature, this reaction represents an
oxazirane synthesis of wide applicability.
4. The main limitation of the process reside in the instability of
certain imines and a few oxaziranes under acidic conditions.
5. This oxidation is remarkably selective for it can be performed in
the presence of functional groups which normally react with
peracids.
6. The reaction of ketones and aldehydes with hydroxylamine-O-
sulfonic acids or chloramines in alkaline solution provides a useful
alternative route to oxaziranes. 15

16. 7. Although many Oxaziranes have limited stability in alkaline
media, such reactions go to completion rapidly at 0ºC (often within
1 minute) and, therefore, can in general compete successfully with
decomposition of the product. This synthetic scheme is a valuable
addition to the peracid-imine reaction for it permits the preparation
of oxaziranes without a substituent on nitrogen.
8. A reaction closely related in mechanistic detail is the addition of
hydroxylamine-O-sulfonic acids or chloramines to Schiff bases
which yields diaziridines. Several variations of this reaction are
known, including generation of the imine in situ, and a few
examples are given below.
9. When aldehydes are treated with ammonia and chloramine, the
resulting diaziridines frequently cannot be isolated because of
further rapid condensation to yield triazolidines such as [5]. 16

17. CHAPTER IV
THE FOUR - MEMBERED HETEROCYCLES
The four-membered hetero rings possess chemical properties that
differ to a significant extent from those of smaller and larger rings.
For example, oxetane [1], azetidine [2], and thietane [3] are, in
general, more stable than their three-membered ring congeners,
and more vigorous condition are required to cause ring cleavage.
[1] [2] [3]
SYNTHETIC APPROACH
Cyclization Reactions:
1. The method most frequently employed at the present time for
the preparation of the four-membered heterocycles is cyclization.
ClCH2CH2CH2OH [1] ClCH2CH2CH2OCOCH3
2. Occasionally, monotosylates and monobrosylates of 1,3-diols
are more accessible, and such functionalized molecules can be
converted successfully to oxetanes.
KOH
H2O 140ºC
(20-25%)
H2O 140ºC
(42-44%)
17

18. 3. Azetidine is best prepared by the dialkylation of trimethylene
chlorobromoide with p-toluenesulfonamide, followed by reduction
of [4] with sodium and amyl alcohol. The conversion of [4] to [2]
can be achieved only by such a reductive procedure because
azetidine rings do not, in general, survive drastic hydrolytic
treatment. Several other approaches to azetidines are exemplified
in the accompanying equations.
ClCH2CH2CH2Br
[4] 55% [2]
4. Although thietane syntheses are subjected to problems similar
to those evidenced with [1] and [2], improved yields can, in
general, be achieved by appropriate modifications.
5. For example, whereas 1,3-dichloropropane reacts with
anhydrous sodium sulfide in ethanol solution to yield [3] in 20-30%
yield, the same product can be obtained consistently in good yield
by prior conversion of 1-bromo-3-chloropropane into its
monothiouronium salt followed by alkaline decomposition of this
intermediate.
ClCH2CH2CH2Br + NaS 20-30%
p-CH3-C6H4-SO3NH2
NaOH/EtOH/reflux
Na/Amyl alcohol
-SO2-C6H4-CH3(p)
EtOH
18

19. CHAPTER V
FIVE-MEMBERED HETEROCYCLIC COMPOUNDS
A. FURAN:
Nomenclature:
Synthesis of Furan:
1. By dehydration of 1,4-dialdehydes or 1,4-diketones with P2O5:
19

20. 20

21. 2. By dry distillation of mucic acid:
Fuoric acid is formed as an intermediate; it gives furan by heating
at its boiling point.
3. From ethylacetoacetate (CH3COCH2COOEt = EAA):
21

22. Structure of Furan:
1. Furan has two conjugated double bonds.
2. Oxygen has two lone pair of electrons, one pair enter into
resonance with the ring to form six Π-electrons like benzene.
3. Furan has aromatic character with five resonating structures.
Resonating structures of Furan:
Electrophilic Substitution Reactions of Furan:
 Nitration of furan give more than 90% α-nitrofuran and less than
10% β-nitrofuran.
 This means that the resonating structure (III + IV) > 90%, while
(II = V) < 10%.
 The lone pair of electrons of oxygen enter into resonance with
the two double bonds producing six π-electrons, so it gives
closed circle of 6 π-electrons and the electron density at each
position is large.
22

23.  The electron density at α-position is more than β-position, so
the electrophilic substitution of furan leads mainly to α-
substitution.
 The furan is more reactive than benzene in electrophilic
substitution reaction (Nitration of furan occur by acetylnitrate
CH3COONO2 at room temperature).
Reactions of Furan:
1. Reduction:
2. Nitration:
Acetylnitrate
Furan α-nitrofuran
3. Sulphonation:
α-Furansulphonic
acid
23

24. 4. Halogenation:
The formed, HCl, cause polymerization of furan. So, the reaction
occur at -40ºC to avoid the polymerization process.
5. Indirect Methods for Halogenation:
6. Reactions with Maleic anhydride:
24
O
Cl2
-400
C
O
Cl
Furan -Chlorofuran
(i)
O
COOH
Br2
O
Br
COOH
-CO2

Br
-Bromofuran
Fuoric acid
(ii)
O
HgCl2
-HCl
HgCl
Cl2
-HgCl2
Cl
-Chlorofuran
Furan

25. 7. Friedel-Crafts Acylation:
25
O
Furan
CH3COCl
Acetyl chloride
O
COCH3
-Acetylfuran

26. Furfural (Furan-2-aldehyde):
Synthesis:
Furfural is obtained by heating of pentoses with H2SO4:
Reactions of Furfural:
(i) Cannizaro’s Reaction:
(ii) Benzoin Condensation:
26
HNO3
Oxidation
O
C
O
C
O
O
Furil

27. Mechanism (Very very important):
(iii) Aldol Condensation:
Mechanism:
(iv) Perkin Condensation:
27
O
CHO
CH3CHO
NaOH
O
COOH
Furfural Furylacrylic acid

28. B. THIOPHENE
Properties of Thiophene:
1. Colourless liquid.
2. Has boiling point = 84ºC like benzene.
3. Obtained by distillation of coal.
Separation of Thiophene from Benzene:
Benzene is always contaminated with large amount of thiophene
which could be separated as follows:
The mixture of benzene and thiophene is allowed to react with
dil. H2SO4. Thiophene reacts readily with dil. H2SO4 while
benzene is not reacted. The formed thiophene-α-sulphonic acid is
soluble in water, while benzene is immiscible with water. The
water layer containing thiophene-α-sulphonic acid can be easily
separated.
28

29. Synthesis of Thiophene
1. By passing a stream of acetylene and H2S through red hot
tube in presence of Al2O3:
2. From n-butane and sulphur:
3. From 1,4-dialdehyde or ketone by reaction with P2S5:
CH3-CH2-CH2-CH3 + 4 S
S
560 + 3 H2S
n- butane
29

S
400C
S
 H2S
Thiophene
S
400C

Al2O3
Thiophene
Acetylene
H2S

30. Structure of Thiophene:
1. Thiophene has two conjugate double bonds.
2. Sulphur has two lone pair of electrons; one pair enter into
resonance with the ring to form six p-electrons like benzene.
3. Thiophene has aromatic character with five resonating
Structures.
Resonating Structures of Thiophene:
30

31. S
S
S
S
COCH3
NO2
HO3S
2-thiophene-2- sulfonic acid
S
NO
2
O2N
HNO3
S
S
S S S
Br
Br
Br
Cl Cl
Cl
Cl
Cl Cl
Cl
Cl2
50
major minor
Reactions of Thiophene:
Sulfonation
Acetylation
Nitration
Halogenation
31

32. 32

33. 33

34. C. PYRROLE
Pyrrole nucleus exist in a number of natural occurring substances as
chlorophyll, coal tar, and animal bones.
Separation of Pyrrole from bones:
1. Bones are washed carefully with water and then crushed to small
particles.
2. The bones washed again with water, then with dil. NaOH to remove
the acidic compounds.
3. The bones washed with dil. H2SO4 to remove the basic compounds.
4. The bones are then covered with conc. KOH, where the potassium salt
of pyrrole is precipitated.
5. Pyrrole is obtained by filtration of the potassium salt and then
acidification with dil. HCl.
6. The pure pyrrole is then obtained as clean liquid by distillation.
Pyrrole
34

35. 35
N
H
Pyroole contained
animal bones
1.H2O
2.NaOH
3.H2SO4
4.KOH
N
K
Pyrrole potassium
salt
dil. HCl
N
H
Pyrrole distilled
in pure state

36. Synthesis of Pyrrole:
1. By passing a stream of acetylene and NH3 through red hot
tube containing alumina Al2O3
2. From succinimide by treatment with Zn/HCl:
3. General Method: Pyrroles can also be synthesized from
condensation between a 1,4-dialdehyde or ketone with NH3
ammonia or ammonia derivatives:
36

NH3
Red hot tube
Al2O3 N
H
Pyrrole
Acetylene

37. Structure of Pyrrole:
1. As furan and thiophene, pyrrole is aromatic heterocyclic
compound with six π-electrons.
2. It exist in five resonating structures and undergo electrophilic
substitution mainly at α-position and minor at β-position.
3. When the α-position is occupied, substitution occur at β-
position.
37

38. Basicity of Pyrrole:
Pyrrole
1. Pyrrole is a very week base as the lone pair of electrons of
nitrogen sharing with the two conjugated double bonds to form
closed circle of 6 π-electrons.
2. Thus the lone pair of nitrogen are less available to accept
proton than pyrrolidine and pyrroline.
3. The order of basicity is:
> >
Pyrrolidine Pyrroline Pyrrole
Completely saturated Partially saturated Aromatic compound
38

39. Reactions of pyrrole:
N
H
N
H
N
H
N
H
N
H
N
H
OHC
COCH3
C
O
C
O
O
H3C
H3C
NO2
HO3S
2-nitropyrrole
pyrrolidine
2-pyrrole sulfonic acid
2-acetylpyrrole
pyrrole-2-carboxaldehyde
acetic anhydride
Acetylation
Vilsmier Rex
Nitration
Reduction
Sulfonation
39

40. 40

41. CHAPTER VI
FIVE-MEMBERED RINGS FUSED WITH BENZENE RING
1. Benzofuran (Coumaron):
Benzofuran (Coumaron)
Synthesis of Benzofuran (Coumaron):
(i) From Coumarin:
(ii) From Salicylaldehyde and Chloroacetic acid:
41

42. (iii) From o-Hydroxychlorostyrene:
(iv) General Method:
From phenolic aldehydes or ketones with halogen derivatives
in the presence of sodium carbonate NaCO3:
42
OH
Cl
o-Hydroxychlorostyrene
alc. KOH
 HCl
O
Coumaron