Transcript Lecture № 20

Lecture № 11
 The
most important derivatives of
the fivemember heterocyclic
compounds with one heteroatom.
Fivemember heterocyclic
compounds with two heteroatoms
Ass. Medvid I.I
Outline:
1.
2.
3.
The important derivatives of pyrrole, furan and thiophene.
Physical and chemical properties of indole.
The important derivatives of indole (indoxyl , indigo, isatin,
tryptophan, serotonin, β- indolyl acetic acid)
4.
Fivemember heterocyclic compounds with two heteroatoms
Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of imidazole. Histamine.
Histidine. Benzimidazole.
Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of pyrazole. Analhine.
Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of oxazole. Isoxazole.
Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of thiazole. Thiamine.
Isothiazole.
5.
6.
7.
8.
1. The important derivatives of pyrrole, furan and
thiophene.
Derivatives of pyrrole
2-Pyrrolidone (2-Pyrrolidinone,2-Pyrol)
is an organic compound consisting of a fiveO membered lactam. It is a colorless liquid
NH
which is used in industrial settings as a highboiling non-corrosive polar solvent for a wide variety of
applications. It is miscible with a wide variety of other
solvents including water, ethanol, diethyl ether,
chloroform, benzene, ethyl acetate and carbon disulfide.
OH
COOH
NH
proline
COOH
NH
oxyproline
Polyvinylpyrrolidone (PVP) is a
water-soluble polymer made from
the monomer N-vinylpyrrolidone.
PVP is soluble in water and
other polar solvents. In water it has the useful
property of Newtonian viscosity. When dry it
is a light flaky powder, which readily absorbs
up to 40% of its weight in atmospheric water.
In solution, it has excellent wetting properties
and readily forms films. This makes it good as
a coating or an additive to coatings.
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.
The oxygen binds to the
hemoglobin molecule in the vicinity of the iron, and the binding
constant is proportional to the partial pressure of oxygen. In the
lungs, where the partial pressure of oxygen is high, hemoglobin
binds oxygen. In the tissues served by the blood stream, the
oxyhemoglobin dissociates back into О, and hemoglobin, which
returns to the lungs for another load. Carbon monoxide is а poison
because it forms а tight complex with the iron of hemoglobin and
prevents it from binding oxygen.
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.
The method of extraction :
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 watersoluble B-complex vitamin
which is composed of an
ureido
tetrahydroimidizalone) ring
used with a
tetrahydrothiophene ring. A valeric acid substituent is
attached to one of the carbon atoms of the
tetrahydrothiophene ring. Biotin supplements are often
recommended as a natural product to counteract the
problem of hair loss in both children and adults. The
signs and symptoms of biotin deficiency include hair loss
which progresses in severity to include loss of eye lashes
and eye brows in severely deficient subjects. Some
shampoos are available that contain biotin, but it is
doubtful whether they would have any useful effect, as
biotin is not absorbed well through the skin.
2. 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. The participation of the
nitrogen lone electron pair in the aromatic ring means that
indole is not a base, and it does not behave like a simple
amine. Indole is a solid at room temperature. At very low
concentrations, however, it has a flowery smell, and is a
constituent of many flower scents (such as orange
blossoms) and perfumes. It also occurs in coal tar. The
indole structure can be found in many organic compounds
like the amino acid tryptophan and in tryptophancontaining protein, in alkaloids, and in pigments. Indole
undergoes electrophilic substitution, mainly at position 3.
Extraction of indole:
1. Cyclization of N-formyl-o-toluidine
CH3
O
NaNH2
N
NH C
H
N-formyl-o-toluidine
indole H
2. Fischer indole synthesis
One of the oldest and most reliable methods for
synthesizing substituted indoles is the Fischer indole
synthesis developed in 1883 by Emil Fischer. Although the
synthesis of indole itself is problematic using the Fischer
indole synthesis, it is often used to generate indoles
substituted in the 2- and/or 3-positions.
SO3H
NO2
C6H5COONO2
C5H5N SO3
N
H
4
N
H
3
5
indole-3-sulfoacid
3-nitroindole
+
[C6H5NCl-
N=N-C 6H5
N
H
3-benzolazoindole
6
7
N1
H
2
indole
SO2Cl2
Cl
N
H
3-chlorindole
Oxidation of indole
Due to the electron-rich nature of indole, it is easily
oxidized. Simple oxidants such as N-bromosuccinimide
will selectively oxidize indole 1 to oxindole (4 and 5).
3.The important derivatives of indole.
a) indoxyl
O
OH
C
C
N
N
H
H
enol form
keto form
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-Dglucose and indoxyl.
Indigo dye is a product of the
reaction of indoxyl by a mild
oxidizing agent such as
atmospheric oxygen.
ONa
O
C
ClCH2COONa
NH2
aniline
CH2
NH
NaNH2
O
C
180-200
sodium salt of
N-phenylaminoacetic acid
N
H
indoxyl
b) 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. The indigo molecule is relatively small
with molecular weight of 262.27 atomic units of mass. In the
molecular models illustrated on this page carbon is shown in
grey, oxygen in bright red, nitrogen in blue, bromine in deep
red and hydrogen in white.
indoxyl
O
O
H
C
C
N
O
C
C
N
N
C
H
H
O
indigo
Sulfonation of indigo
O
H
C
N
C
N
C
H
O
blue indigo
HO3S
+2HOSO3H
C
O
H
C
N
C
N
C
C
H
O
5,5-disulfoindigo
(indigocarmine)
SO3 H
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)
Change the colour is, until in a solution is
present a glucose, which in alkaline
medium cans to reduce of indigocarmine.
c) isatin
Isatin is commercially available. It may be prepared from
cyclicizing the condensation product of chloral hydrate, aniline
and hydroxylamine in sulfuric acid. This reaction is called the
Sandmeyer isonitrosoacetanilide Isatin Synthesis and
discovered by Traugott Sandmeyer in 1919.
O
O
C
C
O
OH
N
N
H
lactim form
lactam form
O
O
C
NaOH
C
HCl
NH2
O
C
O
N
H
isatin
sodium salt of
isatinic acid
ONa
O
C6H5NHNH2
C
NH2OH
O
-H20
N
-H20
H
N
OH
C
O
C
O
N
H
oxim isatin
NH
N
isatin
N
H
phenylhydrazon isatin
C6H5
d) 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-(
b -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.
b
CH 2-COOH
a
N
H
b- 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.
4. Fivemember heterocyclic compounds with two
heteroatoms
Azoles are five-membered ring aromatic heterocycles
containing two nitrogens, one nitrogen and one oxygen, or
one nitrogen and one sulfur. They may be considered as aza
analogs of furan, pyrrole, and thiophene, in the same way
that pyridine is an aza analog of benze.
From a molecular orbital standpoint, the azoles are similar to the simpler
aromatic heterocycles. For example, in imidazole, each carboneand
nitrogen may be considered to be spa hybridized. One nitrogen makes two
sp²-sp² σ bonds to carbone and one sp²-s σ bonds to hydrogen. The other
nitrogen has its lone pair in the third spa orbital. The π molecular orbital
system is made up from the рz orbitals from each ring atom. Six 
electrons (one from each carbon and from one nitrogen, two from the other
nitrogen) complete the aromatic shell.
5. Structure, classification, nomenclature, izomery, methods of getting and
chemical properties of imidazole. Histamine. Histidine.Benzimidazole.
Imidazole
IUPAC name
1,3-diazole
Other names
Imidazole
1,3-diazacyclopenta-2,4diene
Molecular formula
C3H4N2
Molar mass
68.08 g/mol
Appearance
white or pale yellow solid
Density
1.23 g/cm3, solid
Melting point
89-91 °C (362-364 K)
Boiling point
256 °C (529 K)
Solubility in water
miscible
Imidazole is a organic compound with the formula C3H4N2. This aromatic
heterocyclic is classified as an alkaloid. Imidazole refers to the parent compound
whereas imidazoles are a class of heterocycles with similar ring structure but
varying substituents.
Discovery
Imidazole was first synthesized by Heinrich Debus in 1858, but various imidazole
derivatives had been discovered as early as the 1840s. His synthesis, as shown
below, used glyoxal and formaldehyde in ammonia to form imidazole. This
synthesis, while producing relatively low yields, is still used for creating Csubstituted imidazoles.
In one microwave modification the reactants are benzil, formaldehyde and
ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine).
Structure and properties
Imidazole is a 5-membered planar ring, which is soluble
in water and other polar solvents. It exists in two
equivalent tautomeric forms because the hydrogen atom
can be located on either of the two nitrogen atoms. The
compound is classified as aromatic due to the presence of
a sextet of π-electrons, consisting of a pair of electrons
from the protonated nitrogen atom and one from each of
the remaining four atoms of the ring.
Some resonance structures of imidazole are shown below:
Amphotericity
Imidiazole is amphoteric, i.e. it can function as both an acid
and as a base.
Preparation
A ball-and-stick model of imidazole, showing carbon-carbon
and a carbon-nitrogen double bonds. Imidazole can be
synthesized by numerous methods besides the Debus method.
Many of these syntheses can also be applied to different
substituted imidazoles and imidazole derivatives simply by
varying the functional groups on the reactants. In literature,
these methods are commonly categorized by which and how
many bonds form to make the imidazole rings. For example,
the Debus method forms the (1,2), (3,4), and (1,5) bonds in
imidazole, using each reactant as a fragment of the ring, and
thus this method would be a three-bond-forming synthesis. A
small sampling of these methods is presented below.
Formation of one bond
The (1,5) or (3,4) bond can be formed by the reaction of an immediate
and an α-aminoaldehyde or α-aminoacetal, resulting in the cyclization of
an amidine to imidazole. The example below applies to imidazole when
R=R1=Hydrogen.
Formation of two bonds
The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane,
at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A
dehydrogenating catalyst, such as platinum on alumina, is required.
The (1,2) and (3,4) bonds can also be formed from N-substituted αaminoketones and formamide and heat. The product will be a 1,4disubstituted imidazole, but here since R=R1=Hydrogen, imidazole itself is
the product. The yield of this reaction is moderate, but it seems to be the most
effective method of making the 1,4 substitution.
Formation of four bonds
This is a general method which is able to give good yields for substituted
imidazoles. It is essentially an adaptation of the Debus method. The starting
materials are substituted glyoxal, aldehyde, amine, and ammonia or an
ammonium salt.
Formation from other heterocycles
Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This
reaction will only give substantial yields if the 1-vinyltetrazole is made
efficiently from an organotin compound such as 2-tributylstannyltetrazole.
The reaction, shown below, produces imidazole when R=R1=R2=Hydrogen.
Imidazole can also be formed in a vapor phase reaction. The
reaction occurs with formamide, ethylenediamine, and hydrogen
over platinum on alumina, and it must take place between 340 and
480 °C. This forms a very pure imidazole product.
chemical properties of Imidiazole

Imidiazole is amphoteric compound. Thanks to pyrrol type
nitrogen atom imidazole has weak acidic properties and by
pyridine type nitrogen atom imidazole – basic properties.
Azol
tautomery is also
peculiar to imidazole, as
a result 4 and 5 location
of imidazole cycle are
equivalent.
Salts of imidazole
Salts of imidazole where the imidazole ring is in the cation
are known as imidazolium salts (for example, imidazolium
chloride). These salts are formed from the protonation or
substitution at nitrogen of imidazole. These salts have been
used as ionic liquids and precursors to stable carbenes. Salts
where a deprotanated imidazole is an anion are also
possible; these salts are known as imidazolide salts (for
example, sodium imidazolide).
Chemical reactions
1.Interaction of an imidazol with halogenalkanes
(alkylation)
2. Nitrification and sulfonation

3. Interaction with halogens (bromine, iodine)
4. Oxidation
Biological significance and applications
Imidazole is incorporated into many important biological
molecules. The most pervasive is the amino acid histidine,
which has an imidazole side chain. Histidine is present in many
proteins and enzymes and plays a vital part in the structure and
binding functions of hemoglobin. Histidine can be
decarboxylated to histamine, which is also a common biological
compound. It is a component of the toxin that causes urticaria,
which is another name for allergic hives. The relationship
between histidine and histamine are shown below:
One of the applications of imidazole is in the
purification of His-tagged proteins in immobilised metal
affinity chromatography (IMAC). Imidazole is used to elute
tagged proteins bound to Ni ions attached to the surface of
beads in the chromatography column. An excess of
imidazole is passed through the column, which displaces the
His-tag from nickel co-ordination, freeing the His-tagged
proteins. Imidazole has become an important part of many
pharmaceuticals. Synthetic imidazoles are present in many
fungicides and antifungal, antiprotozoal, and
antihypertensive medications. Imidazole is part of the
theophylline molecule, found in tea leaves and coffee beans,
which stimulates the central nervous system. It is present in
the anticancer medication mercaptopurine, which combats
leukemia by interfering with DNA activities.
Industrial applications
Imidazole has been used extensively as a corrosion
inhibitor on certain transition metals, such as copper.
Preventing copper corrosion is important, especially
in aqueous systems, where the conductivity of the
copper decreases due to corrosion. Many compounds
of industrial and technological importance contain
imidazole derivatives. The thermostable
polybenzimidazole PBI contains imidazole fused to a
benzene ring and linked to a benzene, and acts as a
fire retardant. Imidazole can also be found in various
compounds which are used for photography and
electronics.
Histidine is an amino acid that is used to develop and maintain
healthy tissues in all parts of the body, particularly the myelin
sheaths that coat nerve cells and ensure the transmission of
messages from the brain to various parts of the body. It may
be useful for treatment of mental disorders as well as certain
types of sexual dysfunction. Histidine levels in the body must
be balanced to ensure good mental and physical health. High
levels of this amino acid have been linked to the presence of
psychological disorders such as anxiety and schizophrenia,
while low levels of histidine are thought contribute to the
development of rheumatoid arthritis and the type of deafness
that results from nerve damage. Taking histidine supplements
may help relieve symptoms of rheumatoid arthritis. Histidine
is important to normal sexual functioning, because it gets
converted into histamine, a chemical needed to stimulate
sexual arousal. When taken together with vitamin B3 (niacin)
and vitamin B6 (pyridoxine), histidine can increase sexual
pleasure by boosting histamine levels in the body.
Histamine is also needed to help the immune system know when the
body is experiencing an allergic reaction, and for the production of
gastric juices needed for normal digestion. Research suggests that
hsitidine also acts as a natural detoxifier, protecting against radiation
damage, and removing heavy metals from the system. It may even help
prevent the onset of AIDS—histidine is crucial to the production of both
red and white blood cells. Like other amino acids, histidine is found in
many high-protein foods, such as meat and dairy products, as well as
grains such as rice, wheat, and rye. It is not certain if histidine is an
essential or non-essential amino acid—most health experts agree that,
although the body manufactures its own histidine, it is fairly easy for
natural supplies to run short. The chronically ill, post-surgery, or
arthritic individual may wish to consider supplementation with this
amino acid. Histidine is available in both capsule and powder forms, as
well as in combination amino acid formulas. Because it has a proven
effect on the central nervous system and histamine production, people
with manic (bipolar) depression should not take supplemental histidine
without first consulting their physician. Anyone with liver or kidney
disorders should not take histidine without first consulting with a
licensed health care provider. Taking any one amino acid supplement
may cause levels of nitrogen in the body to become imbalanced, as well
as disrupt the Krebs cycle by which toxins are eliminated from the liver
and kidneys.
Histamine forms colorless hygroscopic crystals that melt at 84°C, and
are easily dissolved in water or ethanol, but not in ether. In aqueous solution
histamine exists in two tautomeric forms, Nπ-H-histamine and Nτ-Hhistamine.
Tautomers of histamine
Histamine has two basic centres, namely the aliphatic amino group
and whichever nitrogen atom of the imidazole ring does not already
have a proton. Under physiological conditions, the aliphatic amino
group will be protonated, whereas the second nitrogen of the
imidazole ring will not be protonated. Thus, histamine is normally
protonated to a singly-charged cation. Istidine was first isolated by
German physician Albrecht Kossel in 1896.
Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid histidine, a
reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic
vasoactive amine.
Conversion of histidine to histamine by histidine decarboxylase
Once formed, histamine is either stored or rapidly inactivated.
Histamine released into the synapses is broken down by
acetaldehyde dehydrogenase. It is the deficiency of this enzyme that
triggers an allergic reaction as histamines pool in the synapses.
Histamine is broken down by histamine-N-methyltransferase and
diamine oxidase.
Benzimidazole is a heterocyclic aromatic organic compound.
This bicyclic compound consists of the fusion of benzene and
imidazole. The most prominent benzimidazole compound in
nature is N-ribosyl-dimethylbenzimidazole, which serves as an
axial ligand for cobalt in vitamin B12. Benzimidazole, in an
extension of the well-elaborated imidazole system, has been used
as carbon skeletons for N-heterocyclic carbenes. The NHCs are
usually used as ligands for transition metal complexes. They are
often prepared by deprotonating an N,N'-disubstituted
benzimidazolium salt at the 2-position with a base.
Preparation
Benzimidazole is commercially available. The usual synthesis
involves condensation of o-phenylenediamine with formic acid, or
the equivalent trimethoxymethyl:
C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH +
+ 3 CH3OH
Benzimidazole
IUPAC name
1H-benzimidazole
Properties
Molecular formula
C7H6N2
Molar mass
118.14 g mol−1
Melting point
170–172 °C
Submitted by E. C. Wagner and W. H. Millett.
Benzimidazoles are a large chemical family used to treat nematode and
trematode infections in domestic animals. However, with the widespread
development of resistance and the availability of more efficient and easier to
administer compounds, their use is rapidly decreasing. They are
characterized by a broad spectrum of activity against roundworms
(nematodes), an ovicidal effect, and a wide safety margin. Those of interest
are mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole,
albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel,
netobimin, and triclabendazole. Netobimin, albendazole, and
triclabendazole are also active against liver flukes; however, unlike all the
other benzimidazoles, triclabendazole has no activity against roundworms.

Benzimidazole gives a similar reactions of electrophilic
substitution as imidazole, radicals direct in 5 or 6 location
of benzole cycle.
6. Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of pyrazole. Analhine.
Pyrazole refers both to the class of simple aromatic ring organic compounds of
the heterocyclic series characterized by a 5-membered ring structure
composed of three carbon atoms and two nitrogen atoms in adjacent positions
and to the unsubstituted parent compound. Being so composed and having
pharmacological effects on humans, they are classified as alkaloids, although
they are rare in nature. Pyrazoles are produced synthetically through the
reaction of α,β-unsaturated aldehydes with hydrazine and subsequent
dehydrogenation.

In the industry pyrazole also produces by
interaction of diazoalkans with acetylene
and by interaction hydrazine,
alkylhydrazine or arylhydrazine with 1,3dicarbonyl componds
Pyrazoles react with potassium borohydride to form a class of ligands known
as Scorpionates. Structurally related compounds are pyrazoline and
pyrazolidine.
Heterocycle formation from 1,3-dinitroalkanes. A novel pyrazole
synthesis .
Physical properties of pyrazole

Pyrazole is a colorless crystal compound
with weak pyridine smell, which is soluble in
water, ethanol and ether. In inpolar solvents
pyrazole forms dimers and trimers through
formation intermolecular hydrogen bonds.
Chemical properties of pyrazole

Pyrazole is amphoteric compound. Thanks to pyrrol type
nitrogen atom imidazole has weak acidic properties and by
pyridine type nitrogen atom imidazole – basic properties
Hence, pyrazole can react with acids and bases
 Azol
tautomery is also peculiar to
pyrazole, as an imidazole, as a result 3
and 5 location of pyrazole cycle are
equivalent.
Chemical reactions

1. Interaction with alkyl- and acylradicals
2. Nitrification and sulfonation
 3.
Halogenation of pyrazole
4. Reduction
Aliphatic nitro compounds have proved to be useful
starting materials in organic synthesis. When the nitro
compounds are properly substituted they can cyclise,
yielding heterocyclic compounds. 1,3-Dinitroalkanes
can be viewed as synthetic equivalents for 1,3dicarbonyl compounds through a Nef, or equivalent,
reaction, and therefore could be ultimately converted
into azole heterocycles. Application of the Nef reaction
under the usual conditions (NaOH; conc. H2SO4) to 1,3dinitroalknes gives only trace amounts of the anticipated
dione, although the yields can be increased (up to 40%)
using a secondary amine as the base. We now find that
1,3-dinitroalkanes react with hydrazines giving rise to
pyrazoles.The title compounds are five-membered
heterocycles having two adjacent nitrogen atoms within
the ring. Pyrazoles have two endocyclic bonds and
possess aromatic and tautomeric properties.
Pyrazolones also have two double bonds, one of which is attached to an
exocyclic oxygen atom. Pyrazolines have only one endocyclic double bond. The
structural elucidation of pyrazoles and derivatives has been greatly aided by
nuclear magnetic resonance spectroscopy, especially for distinguishing between
isomeric structures. Pyrazoles are stable compounds and their boiling points
increase with an increase in the number of alkyl groups on carbon; solubility in
organic solvents is also increased. Substitution on nitrogen decreases the boiling
point because of the elimination of hydrogen bonding. Pyrazolines are usually
liquids having high boiling points and low water solubility, and are basic in
nature. Pyrazolones are often crystalline solids and their characteristics are
strongly influenced by the predominant tautomeric form. Pyrazoles can react
with both acids and bases, and can be halogenated, nitrated, and acylated on
both N and C. Pyrazolines are much less stable, resulting in facile ring opening.
Pyrazolones react with diazonium salts, an important process in the dye
industry. The preferred synthetic method for the title compounds utilizes the
reaction of hydrazines with bifunctional compounds, such as β-diketones and
esters, and β-keto acetylenic compounds. In an alternative procedure, diazo
compounds replace hydrazines and ring formation takes place via 1,3-dipolar
cycloaddition. Pyrazoles and pyrazolones are widely used in the
pharmaceutical industry to alleviate inflammation, fever, pain, and infections.
To a lesser extent, they are also used as insecticides and herbicides. Pyrazolones
linked to azo compounds are extensively used in the dye industry; some
pyrazolines display insecticidal activity. In medicine, pyrazoles are used for
their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing,
muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase
inhibiting, antidiabetic and antibacterial activities.
Main derivatives of pyrazole

Pyrazolone-5 is colorless crystal compound, which is
soluble in water and ethanol, bad soluble in ether and
toluene. Pyrazolone-5 is tautomeric compound and can
exists in CH2-, OH- and NH-forms.
Main derivatives of pyrazole are antipyrine, amidopyrine and
analgine. As primery compound for obtaining medicine of
pyrazolone chain using 3-methyl-1-phenylpyrazolone-5.
Obtaining of antipyrine
Antipyrine – colorless crystal compound with bitter taste, which is
soluble in water. Used in medicine as antipyretic and analgesic
agent.
Obtaining of amidopyrine
Synthesis of analgine
Amidopyrine and analgine used in medicine as antipyretic and
analgetic drugs. Analgine has biggest analgetic properties and
amidopyrine – antipyretic
CH 3
NaO 3S CH 2 N
O
CH 3
N
N CH 3
C 6H 5
Analgin
2,3-dymethyl-4-methylamino1-phenilpyrazolone-5-Nmethansulfonate of sodium
7. Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of oxazole. Isoxazole.
Oxazole is the parent compound for a vast class of heterocyclic
aromatic organic compounds. These are azoles with an oxygen and
a nitrogen separated by one carbon. Oxazoles are aromatic
compounds but less so than the thiazoles.
Preparation
Classical oxazole synthetic methods in organic chemistry are:
a) the Robinson-Gabriel synthesis by dehydration of 2acylaminoketones;
b) the Fischer oxazole synthesis from cyanohydrins and aldehydes;
c) the Bredereck reaction with α-haloketones and formamide;
d) in one reported oxazole synthesis the reactants are a nitrosubstituted benzoyl chloride and an isonitrile.
The Fischer oxazole synthesis is a chemical
synthesis of the aromatic heterocycle oxazole from
cyanohydrins and aldehydes in the presence of anhydrous
hydrochloric acid. This method was discovered by
Hermann Emil Fischer in 1896.
 Method
of getting oxazole by
cyclodehydratation of α-acylaminoketons
at the presents of mineral acids
Biosynthesis
In biomolecules, oxazoles result from the cyclization and oxidation of serine or
threonine nonribosomal peptides:
Where X = H, CH3 for serine and threonine respectively, B = base.
(1) Enzymatic cyclization. (2) Elimination. (3) [O] = enzymatic
oxidation.
Reactions :
1.
2.
3.
4.
5.
6.
Deprotonation of oxazoles at C2 is often accompanied by ring-opening to the
isonitrile.
Electrophilic aromatic substitution takes place at C5 requiring activating
groups.
Nucleophilic aromatic substitution takes place with leaving groups at C2.
Diels-Alder reactions with oxazole dienes can be followed by loss of oxygen to
form pyridines.
The Cornforth Rearrangement of 4-acyloxazoles is a thermal rearrangement
reaction with the organic acyl residue and the C5 substituent changing
positions.
Various oxidation reactions. One study] reports on the oxidation of 4,5diphenyloxazole with 3 equivalents of CAN to the formamide and benzoic acid:
Isoxazole
IUPAC name
isoxazole
Properties
Molecular formula
C3H3NO
Molar mass
69.06202
Density
1.075 g/ml
Boiling point
95 °C
Isoxazole is an azole with an oxygen atom next
to the nitrogen. Isoxazoles are found in some
natural products, such as ibotenic acid. Isoxazoles
also form the basis for a number of drugs,
including the COX-2 inhibitor valdecoxib (Bextra).
Furoxan is a nitric oxide donor.
Synthesis of isoxazole
 Reaction
of 1,3-dicarbonil compounds with
hydroxylamine
8. Structure, classification, nomenclature, izomery, methods of
getting and chemical properties of thiazole. Thiamine.
Isothiazole.
Thiazole, or 1,3-thiazole, is a clear to pale yellow flammable liquid with a
pyridine-like odour and the molecular formula C3H3NS. It is a 5-membered
ring, in which two of the vertices of the ring are nitrogen and sulfur, and the
other three are carbons . Thiazole is used for manufacturing biocides, fungicides,
pharmaceuticals, and dyes. Thiazoles are a class of organic compounds related to
azoles with a common thiazole functional group. Thiazoles are aromatic. The
thiazole moiety is a crucial part of vitamin B1 (thiamine) and epothilone. Other
important thiazoles are benzothiazoles, for example, the firefly chemical
luciferin. Thiazoles are structurally similar to imidazoles. Like imidazoles,
thiazoles have been used to give N-S free carbenes nd transition metal carbene
complexes.
Structure of thiazoles (left)
and thiazolium salts (right)
Organic synthesis
Various laboratory methods exist for the organic synthesis of thiazole.
1. The Hantzsch thiazole synthesis (1889) is a reaction between haloketones
and thioamides. Example is given below:
2. In an adaptation of the Robinson-Gabriel
synthesis, a 2-acylamino-ketones reacts with
phosphorus pentasulfide.
3. In the Cook-Heilbron synthesis, an αaminonitrile reacts with carbon disulfide.
4. Certain thiazoles can be accessed though
application of the Herz reaction.
Reactions
Thiazoles are characterized by larger pi-electron delocalization
than the corresponding oxazoles and have therefore greater
aromaticity. This is evidenced by the position of the ring
protons in proton NMR (between 7.27 and 8.77 ppm), clearly
indicating a strong diamagnetic ring current.
The calculated pi-electron density marks C5 as the primary
electrophilic site, and C2 as the nucleophilic site.
Chemical reactions

1. Thiazole is a weak base and can reacts with
halogenalkans and mineral acids
2. With amides
3. Oxidation by peroxiacids
4. Electrophilic aromatic substitution at C5
requires activating groups such as a methyl
group in this bromination:
5.Nucleophilic aromatic substitution often requires an
electrofuge at C2, such as chlorine with
6. Organic oxidation at nitrogen gives the thiazole N-oxide;
many oxidizing agents exist, such as mCPBA; a novel one
is hypofluorous acid prepared from fluorine and water in
acetonitrile; some of the oxidation takes place at sulfur,
leading to a sulfoxide :
Main derivatives of thiazole
2-aminothiazole
Penicillin – widely used antibiotic
Thiamine
Thiamine is a colorless compound with a chemical formula
C12H17N4OS. Its structure contains a pyrimidine ring and a thiazole
ring linked by a methylene bridge. Thiamine is soluble in water,
methanol, and glycerol and practically insoluble in acetone, ether,
chloroform, and benzene. It is stable at acidic pH, but is unstable in
alkaline solutions. Thiamine is unstable to heat, but stable during
frozen storage. It is unstable when exposed to ultraviolet light and
gamma irradiation. Thiamine reacts strongly in Maillard-type
reactions.
Thiamine, or thiamin, sometimes called aneurin, is a watersoluble vitamin of the B complex (vitamin B1), whose phosphate
derivatives are involved in many cellular processes. The best
characterized form is thiamine diphosphate (ThDP), a coenzyme in
the catabolism of sugars and amino acids. In yeast, ThDP is also
required in the first step of alcoholic fermentation.
Thiamine is synthesized in bacteria, fungi and plants. Animals
must cover all their needs from their food and insufficient intake
results in a disease called beri-beri affecting the peripheral nervous
system (polyneuritis) and/or the cardiovascular system, with fatal
outcome if not cured by thiamine administration. In less severe
deficiency, nonspecific signs include malaise, weight loss, irritability
and confusion. Today, there is still a lot of work devoted to
elucidating the exact mechanisms by which thiamine deficiency
leads to the specific symptoms observed (see below). Finally, new
thiamine phosphate derivatives have recently been discovered,
emphasizing the complexity of thiamine metabolism and the need
for more research in the field.
Isothiazole
IUPAC name
Isothiazole
Other names
1,2-thiazole
Properties
Molecular formula
C3H3NS
Molar mass
85.13 g/mol
Boiling point
114 °C
An isothiazole is a type of organic compound containing a
five-membered aromatic ring that consists of three carbon
atoms, one nitrogen atom, and one sulfur atom. Isothiazole
is a member of a class of compounds known as azoles. In
contrast to the isomeric thiazole, the two heteroatoms are
in adjacent positions. The ring structure of isothiazole is
incorporated into larger compounds with biological
activity such as the pharmaceutical drugs ziprasidone and
perosiprone.
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