1
associate. prof. Ye. B. Dmukhalska, assistant. I.I. Medvid

1.
2.
3.
4.
5.
6.
7.
8.
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)
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.

1. The important derivatives of pyrrole, furan and thiophene.
Derivatives of pyrrole
2-Pyrrolidone (2-Pyrrolidinone,2-Pyrol)
O is an organic compound consisting of a fivemembered 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
NH proline
COOH
NH oxyproline
COOH

Polyvinylpyrrolidone ( PVP ) is a water-soluble polymer made from the monomer N -vinylpyrrolidone.

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 О
2 per iron.

Vitamin B
12
(cyanocobalamin) , is an especially common vitamer of the vitamin B
12 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 B
12 in the bloodstream; to treat pernicious anemia; vitamin B
12 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 B
12

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 :
(C
5
H
8
O
4
) n polypentozes nH
2
O
nC t 0
5
H
10
O
5
pentoza
H
H O
C
H
C
H H
C
OH H O
C
OH
H
O
C
H t 0
O furfural
C
O
H
+ 3H
2
O

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.
2
O furfural
O
C
H
NaOH
O
O
C
ONa sodium salt of furoic acid
+
KCN
+ 2 NH
3
- 3H
2
O
O
CH C
OH O furoin
O
O
O CH
N HC
N HC hydrofurfuramide
O
O
CH
2
OH furfurilic alcohol

O
C
O
H
+ 2[Ag(NH
3
)
2
O
]OH + 2Ag +4NH
3
+ H
2
O
O
OH
O
C
O
+
H H
2
N-NH
H
C N NH
O
Phenylhydrazone furfural
+ H
2
O

O furfural
H
2
N NH
O
O c. HNO
3
O C CH
3
C
O
C
H
(CH
3
CO)
2
0
O
2
N O
CH O
NH
2
O
2
N
CH
O C CH
3
5-nitrofurfuraldiacetate
O
N NH C NH
2 O semicarbazone of 5-nitrofurfural,
furacilin
HOH, H
+
O
2
N
O
5-nitrofurfural
C
O
H

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.

1. Cyclization of N-
CH
3
O
NaNH
2
NH C
H indole
N
H
N-formyl-o-toluidine

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 .

SO
3
H
NO
2
N
H
3-nitroindole
+
[C
6
H
5
N

Cl -
N=N-C
6
H
5
C
6
H
5
COONO
2
5
6
4
7
N
H
1
2 indole
3
C
5
H
5
N SO
3
N
H indole-3-sulfoacid
SO
2
Cl
2 Cl
N
H
N
H
3-benzolazoindole
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 ).

O
C
N
H keto form
C
N
H enol form
OH
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.
aniline
ClCH
2
COONa
NH
2
O ONa
C
NaNH
2
NH
CH
2 180-200 sodium salt of
N-phenylaminoacetic acid
O
C
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.
N indoxyl
H
O
C
O
N
H
O
C
C
H
N
C
C
O indigo

O H
C N
C C
+2HOSO
N C
HO
3
S
H blue indigo
O
O H
C N
C C
N C
H O
5,5-disulfoindigo
(indigocarmine)
3
H
SO
3
H

O
SnCl
2
+4NaOH Na
2
SnO
2
+2NaCl+2H
2
O
2SnO
2
2+2OH - 2SnO
3
2+2[H]
H OH H
C N
2[H]
C N
C C C C
[O]
N C N C
H O H OH
Blue indigo White indigo
(leicobasic)

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
C
N
H lactam form
O
C
O
N lactim form
OH isatin
N
H
O
C
O
NaOH
HCl
C
O
O
C ONa
N H
2 sodium salt of isatinic acid

NH
2
OH
-H
2
0
N OH
C
O
N
H oxim isatin isatin
N
H
O
C
O
C
6
H
5
NHNH
2
-H
2
0
N
H
C
N NH C
6
H
5
O phenylhydrazon isatin

H O
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.

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
Other names
Molecular formula
Molar mass
Appearance
Density
Melting point
Boiling point
Solubility in water
1,3-diazole
Imidazole
1,3-diazacyclopenta-2,4diene
C3H4N2
68.08 g/mol white or pale yellow solid
1.23 g/cm3, solid
89-91 °C (362-364 K)
256 °C (529 K) miscible

Imidazole is a organic compound with the formula C
3
H
4
N
2
. 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:

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=R
1
=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=R
1
=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=R
1
=R
2
=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).

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:

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
IUPAC name 1 H -benzimidazole
Properties
Molecular formula C
7
H
6
N
2
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 .

 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



 1. Interaction with alkyl- and acylradicals
2. Nitrification and sulfonation


4. Reduction

 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.

Antipyrine – colorless crystal compound with bitter taste, which is soluble in water. Used in medicine as antipyretic and analgesic agent.

Amidopyrine and analgine used in medicine as antipyretic and analgetic drugs. Analgine has biggest analgetic properties and amidopyrine – antipyretic

NaO
3
S CH
2
CH
3
N
CH
3
O
N
N
C
6
H
5
CH
3
Analgin
2,3-dymethyl-4-methylamino-
1-phenilpyrazolone-5-Nmethansulfonate of sodium

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.



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.

3.
4.
5.
1.
2.
6.
Reactions :
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
Molecular formula
Molar mass
Density
Boiling point isoxazole
Properties
C
3
H
3
NO
69.06202
1.075 g/ml
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.



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.

 1. Thiazole is a weak base and can reacts with halogenalkans and mineral acids
2. With amides
3. Oxidation by peroxiacids

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
Penicillin – widely used antibiotic

Thiamine
Thiamine is a colorless compound with a chemical formula
C
12
H
17
N
4
OS. 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.

Isothiazole
IUPAC name
Other names
Molecular formula
Molar mass
Isothiazole
1,2-thiazole
Properties
C
3
H
3
NS
85.13 g/mol
Boiling point 114 °C