Transcript Lecture

LECTERE 5
THEME: Classification, structure and
biological role of heterocyclic compounds.
Lecturer: Yevheniya B. Dmukhalska
Plan
1.
2.
3.
4.
Classification and nomenclature of heterocycles
compouns.
Five-membered heterocycles compouns with one
heteroatom. Physical and chemical properties of furan,
pyrrole, thiophene. The important derivatives of pyrrole,
furan and thiophene.
Six-membered heterocycles compouns with one
heteroatom.
Physical and chemical properties of indole.

Heterocyclic compounds are cyclic compounds
in which one or more ring atoms are not carbon
(that is, hetero atoms).
 As hetero atom can be N, О, S, В, Al, Si, P, Sn,
As, Cu. Bat common is N, О, or S.
Classification
 Heterocycles
are conveniently grouped into
two classes, nonaromatic:
and aromatic


By size of ring
Three-membered
Four-membered

Five-membered
Six-membered
Nonaromatic heterocycles
Saturated monocyclic rings are named according to ring size as 3-, iran; 4-, -etan; 5-, -olan; and 6-, -ane. Even this system does not apply
to nitrogencontaining rings and finds only limited use in common
practice.
Fivemembered heterocycles compounds with one
heteroatom.
The structures of these three heterocycles would suggest that they
have highly reactive diene character.
These heterocycles have characteristics associated with aromaticity.
From an orbital point of view, pyrrole has а planar pentagonal structure
in which the four carbons and the nitrogen have sp² hybridization. Each
ring atom forms two sp²—sp²  bonds to its neighboring ring atoms,
and each forms one sp² – s  bond to а hydrogen.
Methods of synthesis of five-membered heterocycles
compounds with one heteroatom.
1. Cyclization of 1,4-dicarbones compounds (Paale-Knorr
synthesis )
H H
C C
H 2C CH 2
R C
C R
R C
C R
OH HO
H
SO
c.
2
4
O O
P 2S 5
NH3
R
O
R
R
R
N
H
R
S
R
Substituted furans, pyrroles, and thiophenes may be prepared by
electrophilic substitution on one of the available materials discussed
or by а variety of cyclization reactions. The most general is the PaalКлоrr synthesis, in which а 1,4-dicarbonyl compound is heated with а
dehydrating agent, ammonia, or an inorganic sulfide to produce the
furan, pyrrole, or thiophene, respectively.
Reciprocal transformation of furan, pyrrole, thiophene
(Yurie`s cycle reactions)
NH3
H2O
O
H2S
Al2O3
H2O
NH3
S
N
H
H2S
Formation of furan:
In laboratory conditions furan is produce by dry distillation of
mucic acid.
OH
OH
CH
CH
CH
CH
CO
OH OH
OH
t
COOH
t
- 3 H2O
O
COOH
O
furan
furoic acid
dehydromucic acid
mucic acid
- CO2
- CO2
COOH
COOH O
t
In the industry furan derived from aldopentozes
H
H
HO
nH2O
(C5H8O4)n
t0
polypentoze
H
nC5H10O5
pentoza
H
- CO2
O
furoic acid
COOH
C
O
furan
H
C
C
t
O
C
OH
OH HO
C
t0
C
O
H
O
furfural
O
H
+ 3H2O
Formation of thiophene
Thiophene is prepared industrially by passing а
mixture of butane, butenes,or butadiene and
sulfur through а reactor heated at 600' for а
contact time of about 1 sec
n- C4H10 + S
=
+ H2 S
Physical properties of furan, pyrrole, thiophene
At room temperature, thiophene is a colorless liquid with
a mildly pleasant odor reminiscent of benzene, with which
thiophene shares some similarities. Like benzene,
thiophene forms an azeotrope with water.
Furan is typically derived by the thermal decomposition
of pentose-containing materials, cellulosic solids
especially pine-wood. Furan is a colorless, flammable,
highly volatile liquid with a boiling point close to room
temperature. It is toxic and may be carcinogenic.
Pyrrole is a heterocyclic aromatic organic compound.
Substituted derivatives are also called pyrroles.
Porphobilinogen is a trisubstituted pyrrole, which is the
biosynthetic precursor to many natural products
Chemical properties of furan, pyrrole, thiophene
The typical reaction of furan, pyrrole, and
thiophene is electrophilic substitution. All three
heterocycles are much more reactive than benzene.
The reactivity order being is:
To give some idea of the magnitude of this reactivity order, partial rate
factors (reactivities relative to benzene) for tritium exchange with
fluoroacetic acid.
1. Interaction with dilute mineral acids
Pyrroles are polymerized by even dilute acids, probably by a mechanism
such as the following
.
2. Reactions of electrophilic substitution:
This orientation is understandable in terms of the mechanism of
electrophilic aromatic substitution. The / ratio is determined
by the relative energies of the transition states leading to the
two isomers. As in the case of substituted benzenes, we may
estimate the relative energies of these two transition states by
considering the actual reaction intermediates produced by
attack at the -or -positions.
a)
Nitration
(CH3CO)2O + р.HNO3
N
N
H
H
NO2
2-nitropyrrole
Further substitution on 2-substituted furans tends to осcur at the other
-position.
With 2-substituted pyrroles and thiophenes, attack can occur at С-4
or С-5 when the group present is meta directing, or at С-3 and С-5
when the group present is ortho, раrа directing.
Sulfonation
+
X
X=O, NH
+
N
SO3
pyridine
sulfotrioxide
X
SO3H
furan-2-sulfoacid
pyrrole-2-sulfoacid
N
pyridine
Acylation
(CH3CO)2O
N
H
SnCl4
N
H
C
CH3
O
2-acetylpyrrole
Because of this high reactivity, even mild electrophiles to
cause reaction. Substitution occurs predominantly at the αposition (С-2).
Of these structures, the most important are the two with the positive charge on
sulfur because, in these two sulfonium cation structures, all atoms have octets of
electrons. Nevertheless, as the sets of resonance structures show, the charge on the
cation resulting from attack at the -position is more extensively delocalized than
that for the cation resulting from attack at the -position. The following examples
further demonstrate the generality of -attack.
Halogenation
In the last example, note that 2-iodothiophene is the sole
product of iodination, eyeu though the reaction is carried out
in benzene as solvent; that is, thiophene is so much more
reactive than benzene that no significant amount of
iodobenzene is formed.
Cl
Cl
SO2Cl2
SO2Cl2
NH
pyrrole
NH
Cl
2-chlorpyrrole
SO2Cl2
Cl
NH
Cl
2, 5- chlorpyrrole
Cl
NH
Cl
tetrachlorpyrrole
Reactions of reconstruction
Thiophen are more stable and do not undergo hydrolysis.
Reduction of pyrrole:
Ni
+
2 H2
O
O
tetrahydrofuran
furan
Pd
+
S
thiophene
2 H2
S
tetrahydrothiophene
Reactions of oxidation
O
O
V2O5
O
O
O
maleinic anhydride
furan
O
NH
pyrrole
H2Cr2O4 O
NH
O
maleinmide
O
NaNH2
N
H
;t
H3C C
N
Cl
+
Na
N
-NaCl
H
sodium pyrrolide
pyrrole
C CH3
O
2-acetylpyrrole
H3C C
- + +
NK
O
t 0C
N
Cl
COCH3
Potassium pyrrolide
N-acethylpyrrole
CH 3I
N K+
to -KI,
NH
CH3
2-methyllpyrrole
Pyrrole compounds occur widely in living systems. One of the more
important pyrrole compounds is the porphyrin hemin, the prosthetic
group of hemoglobin and myoglobin. А number of simple
alkylpyrroles have played an important role in the elucidation of the
porphyrin structures. Thus, drastic reduction of hemin gives а complex
mixture from which the four pyrroles, hemopyrrole, cryptopyrrole,
phyllopyrrole, and opsopyrrole, have been isolated.
For identification of pyrrole and furan used
the method coloring of a pine chip.
Couples of pyrrole painted a pine chip
soaked in hydrochloric acid in the red
colour and furan - in the green colour.
Qualitative reaction on thiophene is
indophenin`s reaction: a mixture of
izathine with concentrated sulfuric acid
painted in the blue colour.
The important derivatives of pyrrole,
furan and thiophene.
Condensed of Pyrrole

Pyrrole compounds occur widely in living systems. One of
the more important pyrrole compounds is the porphyrin
hemin, the prosthetic group of hemoglobin and myoglobin.
А number of simple alkylpyrroles have played an important
role in the elucidation of the porphyrin structures. Thus,
drastic reduction of hemin gives а complex mixture from
which the four pyrroles, hemopyrrole, cryptopyrrole,
phyllopyrrole, and opsopyrrole, have been isolated.
Tetrapyrrole compounds
The function of hemoglobin in an
organism is to transport oxygen.
1 g of hemoglobin absorbs 1.35
ml of oxygen at STP,
corresponding to exactly one
molecule of О2 per iron.
Tetrapyrrole ancyclic compounds
Vitamin B12 (cyanocobalamin),
is an especially common vitamer
of the vitamin B12 family.
Cyanocobalamin is usually
prescribed for the following
reasons: after surgical removal of
part, or all of the stomach or
intestine to ensure there are
adequate levels of vitamin B12 in
the bloodstream; to treat pernicious
anemia; vitamin B12 deficiency due
to low intake from food;
thyrotoxicosis, hemorrhage,
malignancy, liver or kidney
disease. Cyanocobamide is also
used to perform the Schilling test to
check your ability to absorb vitamin B12
Derivatives of furan
Furfural is an industrial chemical compound derived from a variety of
agricultural byproducts, including corncobs, oat and wheat bran, and
sawdust. It is a colorless oily liquid with the odor of almonds, but upon
exposure to air it quickly becomes yellow. Furfural's physical
properties are summarized in the table at right. Furfural dissolves
readily in most polar organic solvents, but is only slightly soluble in
either water or alkanes.
H
H
HO
(C5H8O4)n
polypentozes
nH2O
t0
C
H
nC5H10O5
pentoza
C
C
O
furfural
O
H
H
C
C
H
OH
OH HO
+ 3H2O
C
t0
O
H
Chemically, furfural participates in the same kinds of reactions as other
aldehydes and other aromatic compounds. The aromatic stability of
furfural is not as great as in benzene, and furfural participates in
hydrogenation and other addition reactions more readily than many other
aromatics.
NaOH
O
+
C
O
O
CH2OH
ONa
furfurilic alcohol
sodium salt of furoic acid
O
2
O
KCN
C
O
H
furfural
CH
C
O
O
OH
furoin
O
+ 2 NH3
- 3H2O
N
O
HC
CH
O
N
hydrofurfuramide
HC
O
O + 2[Ag(NH ) ]OH
3 2
C
H
C
O
O
+ 2Ag +4NH3 + H2O
OH
H
C
O
O
+
H H2N-NH
C N
NH
O
Phenylhydrazone furfural
+ H2O
Synthesis of furacilin
O
O
C
O
H
c. HNO3
O
(CH3CO)20
O2N
furfural
NH
C
CH3
CH O
O
NH2
O2N
O
CH
N
NH
C
semicarbazone of 5-nitrofurfural,
furacilin
+
HOH, H
O2N
O C CH3
5-nitrofurfuraldiacetate
O
O
H2N
C
NH2
O
O
C
H
5-nitrofurfural
Derivatives of thiophene
Biotin (vitamin H) is a water-soluble B-complex vitamin which is
composed of an ureido tetrahydroimidizalone) ring used with a
tetrahydrothiophene ring.
Physical and chemical properties of indole
Indole (benzo [b] pyrrole) is an aromatic heterocyclic
organic compound. It has a bicyclic structure, consisting of
a six-membered benzene ring fused to a five-membered
nitrogen-containing pyrrole ring.
Indole is a solid at room temperature.
The indole structure can be found in many organic
compounds like the amino acid tryptophan and in
tryptophan-containing protein, in alkaloids, and in
pigments. Indole undergoes electrophilic substitution,
mainly at position 3.
SO3H
NO2
C6H5COONO2
C5H5N SO3
N
H
4
N
H
3
5
3-nitroindole
indole-3-sulfoacid
+
[C6H5NCl-
N=N-C 6H5
N
H
3-benzolazoindole
6
7
N1
H
2
indole
SO2Cl2
Cl
N
H
3-chlorindole
The important derivatives of indole.
a) indoxyl
Indoxyl is isomeric with oxindol and is obtained as an
oily liquid. Indoxyl is obtained from indican, which is a
glycoside. The hydrolysis of indican yields β-D-glucose
and indoxyl.
Indigo dye is a product of the reaction of indoxyl by a
mild oxidizing agent such as atmospheric oxygen.
O
OH
C
C
N
N
H
H
keto form
enol form
Indigo is a powder, insoluble in water, with a melting point
higher than 300C. It absorbs light in the yellow region of the
spectrum (maximum at 602 nm), which gives it its intense
blue colour.
indoxyl
O
O
H
C
C
N
O
C
C
N
N
C
H
H
O
indigo
Restoration of indigo and cubic dyeing
SnCl2+4NaOH
Na2SnO2+2NaCl+2H2O
2SnO22-+2OHO
H
C
N
C
C
2SnO32-+2[H]
2[H]
OH
H
C
N
C
[O]
C
N
C
N
C
H
O
H
OH
Blue indigo
White indigo
(leicobasic)
Tryptophan, serotonin, β-indolyl acetic acid
For many organisms (including
humans), tryptophan is an
essential amino acid. This
means that it cannot be
synthesized by the organism
and therefore must be part of
its diet. Amino acids, including
tryptophan, act as building
blocks in protein biosynthesis.
In addition, tryptophan
functions as a biochemical
precursor for the following
compounds.
Serotonin
HO
СH 2 СH 2 NH 2
N
H
Serotonin [5-hydroxy-3-(
 -aminoethyl) іndole]
Serotonin is a monoamine neurotransmitter synthesized in
serotonergic neurons in the central nervous system (CNS)
and enterochromaffin cells in the gastrointestinal tract of
animals including humans. Serotonin is also found in
many mushrooms and plants, including fruits and
vegetables.

CH 2-COOH

N
H
- indolyl acetic acid
(heteroauxin)
It is a heterocyclic compound
that is an phytohormone
called auxins. This colourless
solid is probably the most
important plant auxin.
Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of pyridine.
Heterocycles containing as a heteroatom atom of nitrogen,
behave to the most widespread representatives of this group of
connections (azynes):
pyridine
quinoline
isoquinoline
acridine

Pyridine is an analog of benzene in which one of the СН
units is replaced by nitrogen. The nitrogen lone pair is
located in an sp2 hybrid orbital which is perpendicular to
the  system of the ring. Various values have been
deduced for the empirical resonance energy of pyridine,
but it would appear to be roughly comparable to benzene.
The resonance stabilization is shown by the two
equivalent Kekule structures and the three zwitterionic
forms with negative charge on nitrogen.

Derivatives of pyridine are biological active
compounds, such as nicotine amide, nicotinic acid
(vitamin PP).
nicotinic acid
Characteristic for pyridine reactions can be divided into
three groups:
Reactions which followings with participation of
heteroatom.
Reactions of substituting for the hydrogen atoms of
pyridines ring.
Reactions of reduction and oxidization.
Reactions which followings with participation of heteroatom.
1. Cooperating with acids.
Due to the indivisible pair of electrons atom of nitrogen of
pyridine shows weak basic properties. At cooperating with strong
mineral and organic acids he forms soluble salt of pyridine.
pyridine bromide
2. Reaction with the oxide of sulphur (VI).
Reactions of substituting for the hydrogen atoms of pyridines
ring.
1. Reactions of electrophilic substitution (SE).
The reactions of nitration, sulphonation and halogenation pass
slowly drastic and with low exits. Thus an electrophilic reagent is
direct in position 3.
3-nithropyridine
3-pyridinesulphure acid
Reactions of nucleophilic substitution.
The substitution goes on positions 2,4,6, most easy of nucleophilic
reagent is entered in position of 2,6 (α-position ). The prime
example of reaction of this type is an amination of pyridine with
sodium of amide on Chychybabyne. The reaction flows to the
mechanism SN2:
σ- complex
2- aminopyridine
Reactions of reduction and oxidization.
1.
Reduction .
pyperedine
2. Oxidization .
nicotinic acid

These ring systems, particularly that of pyrimidine, occur
commonly in natural products. The pyrimidines, cytosine,
thymine, and uracil are especially important because they
are components of nucleic acids, as are the purine
derivatives adenine and guanine.



Diazines
In this section, we shall take а brief look at another class of
heterocycles, the diazines. The three types of
diazabenzenes are:
In addition to these three diazines, the bicyclic tetraaza
compound, purine, is an important heterocyclic system.
Aminopurines
aminoderivatives of purine –
adenine and guanine present in nucleinic
acids as purine’s bases.
 Maine

The рininе nucleus also occurs in such compounds as
caffeine (coffee and tea) and theobromine (cacao beans).
 Hypoxantine
and xantine have the same
chemical properties as uric acid
N-methyl derivatives of hypoxantine and
xantine widely used in pharmacy
Murexidne’s reaction is the qualitative
reaction on uric acid

By heating uric acid with nitrate acid and next
adding of ammonium observe purpur-violet color
Thanks you for attention!!!