LECTERE 5LECTERE 5

Lecturer: Yevheniya B. Dmukhalska

THEME: Classification, structure and biological role of heterocyclic compounds.

PlanPlan1. Classification and nomenclature of heterocycles

compouns.2. Five-membered heterocycles compouns with one

heteroatom. Physical and chemical properties of furan, pyrrole, thiophene. The important derivatives of pyrrole, furan and thiophene.

3. Six-membered heterocycles compouns with one heteroatom.

4. Physical and chemical properties of indole.

Heterocyclic compoundsHeterocyclic compounds are cyclic compounds are cyclic compounds in which one or more ring atoms are not carbon in which one or more ring atoms are not carbon (that is, hetero atoms).(that is, hetero atoms).

As hetero atom can be N, О, S, В, Al, Si, P, Sn, As hetero atom can be N, О, S, В, Al, Si, P, Sn, As, Cu. Bat common is N, О, or S.As, Cu. Bat common is N, О, or S.

ClassificationClassification Heterocycles are conveniently grouped into Heterocycles are conveniently grouped into

two classestwo classes, , nonaromatic:nonaromatic:

and aromatic

By size of ring By size of ring Three-membered Three-membered Four-memberedFour-membered

Five-membered Six-membered Five-membered Six-membered

Nonaromatic heterocyclesNonaromatic 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 Methods of synthesis of five-membered heterocycles compounds with one heteroatom.

1. Cyclization of 1,4-dicarbones compounds (Paale-Knorr synthesis )

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 Paal-Клоrr 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.

O N

H

S

Al2O3

NH3

H2SH2O

H2S

NH3

H2O

Reciprocal transformation of furan, pyrrole, thiophene (Yurie`s cycle reactions)

Formation of furan:Formation of furan:

In laboratory conditions furan is produce by dry distillation of In laboratory conditions furan is produce by dry distillation of mucic acid.mucic acid.

In the industry furan derived from aldopentozesIn the industry furan derived from aldopentozes

CH CH

CH

OH

CHCOOH

COOH

OH

OHOH t

- 3 H2O

O COOHCOOH

t

- CO2- CO2

OO

t

COOH

mucic acid dehydromucic acid furoic acid furan

OH

C H

OC

C

C

C

OH OH

HOH

H

H

H

HC

H

O

O

+ 3H2O

furfural

- CO2

OO

t

COOH

furoic acid furan

(C5H8O4)n nC5H10O5

nH2O

t0

t0

polypentoze pentoza

O

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 Physical properties of furan, pyrrole, thiophene

At room temperature, At room temperature, thiophenethiophene is a colorless liquid with is a colorless liquid with a mildly pleasant odor reminiscent of benzene, with which a mildly pleasant odor reminiscent of benzene, with which thiophene shares some similarities. Like benzene, thiophene shares some similarities. Like benzene, thiophene forms an azeotrope with water.thiophene forms an azeotrope with water.

FuranFuran is typically derived by the thermal decomposition is typically derived by the thermal decomposition of pentose-containing materials, cellulosic solids of pentose-containing materials, cellulosic solids especially pine-wood. Furan is a colorless, flammable, especially pine-wood. Furan is a colorless, flammable, highly volatile liquid with a boiling point close to room highly volatile liquid with a boiling point close to room temperature. It is toxic and may be carcinogenic. temperature. It is toxic and may be carcinogenic.

PyrrolePyrrole is a heterocyclic aromatic organic compound is a heterocyclic aromatic organic compound. . Substituted derivatives are also called pyrroles. Substituted derivatives are also called pyrroles. Porphobilinogen is a trisubstituted pyrrole, which is the Porphobilinogen is a trisubstituted pyrrole, which is the biosynthetic precursor to many natural products biosynthetic precursor to many natural products

Chemical properties of furan, pyrrole, thiophene

The typical reaction of furan, pyrrole, and The typical reaction of furan, pyrrole, and thiophene is thiophene is electrophilic substitution.electrophilic substitution. All three All three heterocycles are much more reactive than benzene. heterocycles are much more reactive than benzene. The reactivity order being is: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. 1. InteractionInteraction with with dilute mineral acidsPyrroles 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)a) NitrationNitration

N

H

(CH3CO)2O + р.HNO3

N

H

NO2

2-nitropyrrole

Further substitution on 2-substituted furans tends to осcur at the other Further substitution on 2-substituted furans tends to осcur at the other -position.-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.

SulfonationSulfonation

X

+N

SO3

X SO3H

+

N

X=O, NH pyridinesulfotrioxide

furan-2-sulfoacidpyrrole-2-sulfoacid

pyridine

N

H

N

H

CCH3

O

(CH3CO)2O

SnCl4

2-acetylpyrrole

AcylationAcylation

Because of this high reactivity, even mild electrophiles to Because of this high reactivity, even mild electrophiles to cause reaction. Substitution occurs predominantly at the cause reaction. Substitution occurs predominantly at the αα--position (С-2).position (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.

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.

Halogenation

NH NH NHNH

SO2Cl2

Cl

SO2Cl2 SO2Cl2

Cl Cl

ClCl

ClCl

pyrrole2-chlorpyrrole 2, 5- chlorpyrrole tetrachlorpyrrole

Thiophen are more stable and do not undergo hydrolysis.Reduction of pyrrole:

Reactions of reconstruction

O

+ 2 H2

Ni

O

+ 2 H2

Pd

SS

furantetrahydrofuran

thiophene tetrahydrothiophene

Reactions of oxidation

pyrrole

furan

O

O

V2O5

O OO

maleinic anhydride

maleinmide

O

O O

NHNHH2Cr2O4

 

N

H

NaNH2

CH3 C

O

ClN N

H

C

O

CH3

Na-

; t

+

NCH3 C

O

Cl N

COCH3

t 0 C+

K+

-

2-acetylpyrrolepyrrole

sodium pyrrolide

Potassium pyrrolide

2-methyllpyrrole

-KI,

N-acethylpyrrole

-NaCl

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 For identification of pyrrole and furan used the method coloring of a pine chip. the method coloring of a pine chip. Couples of pyrrole painted a pine chip Couples of pyrrole painted a pine chip soaked in hydrochloric acid in the soaked in hydrochloric acid in the red red colourcolour and furan - in the and furan - in the green colourgreen colour. . Qualitative reaction on thiophene is Qualitative reaction on thiophene is indopheninindophenin`s`s reaction: a mixture of reaction: a mixture of izathine with concentrated sulfuric acid izathine with concentrated sulfuric acid painted in the painted in the blue colourblue colour..

The iThe importantmportant derivativesderivatives of pyrrole, of pyrrole, furan and thiophene.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 Vitamin BB1212 (cyanocobalamin) (cyanocobalamin), , is an especially common vitamer is an especially common vitamer of the vitamin Bof the vitamin B1212 family. family. Cyanocobalamin is usually Cyanocobalamin is usually prescribed for the following prescribed for the following reasons: after surgical removal of reasons: after surgical removal of part, or all of the stomach or part, or all of the stomach or intestine to ensure there are intestine to ensure there are adequate levels of vitamin Badequate levels of vitamin B1212 in in the bloodstream; to treat the bloodstream; to treat

pernicious pernicious anemia; vitamin Banemia; vitamin B1212 deficiency due deficiency due to low intake from to low intake from food; food; thyrotoxicosis, thyrotoxicosis, hemorrhage, hemorrhage, malignancy, liver or malignancy, liver or kidney kidney disease. disease. Cyanocobamide is also Cyanocobamide is also used used to perform the Schilling test to to perform the Schilling test to check your check your ability to absorb vitamin Bability to absorb vitamin B1212

DDerivativeserivatives of furan of furan

Furfural is an industrial chemical compound derived from a variety of Furfural is an industrial chemical compound derived from a variety of agricultural byproducts, including corncobs, oat and wheat bran, and agricultural byproducts, including corncobs, oat and wheat bran, and sawdust. sawdust. IIt is a colorless oily liquid with the odor of almonds, but upon t is a colorless oily liquid with the odor of almonds, but upon exposure to air it quickly becomes yellow.exposure to air it quickly becomes yellow. Furfural's physical Furfural's physical properties are summarized in the table at right. Furfural dissolves properties are summarized in the table at right. Furfural dissolves readily in most polar organic solvents, but is only slightly soluble in readily in most polar organic solvents, but is only slightly soluble in

either water or alkanes.either water or alkanes.

OH

C H

OC

C

C

C

OH OH

HOH

H

H

H

H

CH

O

O

(C5H8O4)n nC5H10O5

nH2O

t0

t0

+ 3H2O

polypentozes pentoza

furfural

C

H

O

O

N HCO

N HCO

furfural

2

NaOH

C

O

O

ONa

+CH2OHO

furfurilic alcoholsodium salt of furoic acid

KCN

CHO C O

OH O

furoin

2 NH3+

- 3H2O CHO

hydrofurfuramide

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.

CH

O

OC

OH

O

O

+ 2[Ag(NH3)2]OH + 2Ag +4NH3 + H2O

CH

O

OC N

O

H

H2N-NHNH

Phenylhydrazone furfural

+ + H2O

SynthesisSynthesis of furacilin of furacilin

C

H

O

O

C CH3

C CH3

C

H

O

O

c. HNO3

(CH3CO)20 O2N CHO

O

O

O

O

HOH, H+

O2N

H2N NH NH2

O2N CHO N

C

O

NH C NH2

O

furfural

5-nitrofurfuraldiacetate 5-nitrofurfural

semicarbazone of 5-nitrofurfural,

furacilin

DDerivativeserivatives of thiophene of thiophene

BiotinBiotin (vitamin H) (vitamin H) is a water-soluble B-complex vitamin which is is a water-soluble B-complex vitamin which is composed of an ureido tetrahydroimidizalone) ring used with a composed of an ureido tetrahydroimidizalone) ring used with a tetrahydrothiophene ring.tetrahydrothiophene ring.

Physical and chemical properties of indolePhysical and chemical properties of indole

Indole (benzo [Indole (benzo [bb] pyrrole)] pyrrole) is an aromatic heterocyclic is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. nitrogen-containing pyrrole ring.

Indole is a solid at room temperature. Indole is a solid at room temperature.

The indole structure can be found in many organic The indole structure can be found in many organic compounds like the amino acid tryptophan and in compounds like the amino acid tryptophan and in tryptophan-containing protein, in alkaloids, and in tryptophan-containing protein, in alkaloids, and in pigments. Indole undergoes electrophilic substitution, pigments. Indole undergoes electrophilic substitution, mainly at position 3. mainly at position 3.

N

H

C5H5N SO3

NH

SO3H

SO2Cl2

NH

Cl

C6H5COONO2

NH

NO2

NH

N=N-C6H5

12

34

5

67[C6H5NCl-

+

indole

3-chlorindole

3-nitroindoleindole-3-sulfoacid

3-benzolazoindole

The iThe importantmportant derivativesderivatives of indole. of indole.a) indoxyla) indoxyl

N

C

H

N

C

O

H

OH

keto form enol 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-D-glucose and indoxyl.Indigo dye is a product of the reaction of indoxyl by a mild oxidizing agent such as atmospheric oxygen.

C

C

N

N

C

C

O

O

H

H

N

C

O

H

O

indigoindoxyl

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.

Restoration of indigo and cubic dyeingRestoration of indigo and cubic dyeing

C

C

N

N

C

C

O

O

H

H

C

C

N

N

C

C

OH

OH

H

H

Blue indigo

SnCl2+4NaOH Na2SnO2+2NaCl+2H2O

2SnO22-+2OH- 2SnO3

2-+2[H]

White indigo (leicobasic)

2[H]

[O]

Tryptophan, serotonin, Tryptophan, serotonin, ββ--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.

SerotoninSerotonin

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.

N

СH 2

H

СH 2 NH 2

OH

Serotonin [5-hydroxy-3-( -aminoethyl) іndole]

NH

CH 2-COOH

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 Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyridine.getting and chemical properties of pyridine.

Heterocycles containing as a heteroatom atom of nitrogen, Heterocycles containing as a heteroatom atom of nitrogen, behave to the most widespread representatives of this group of behave to the most widespread representatives of this group of connections (azynes):connections (azynes):

pyridine quinoline isoquinoline acridine

PyridinePyridine is an analog of benzene in which one of the СН is an analog of benzene in which one of the СН units is replaced by nitrogen. The nitrogen lone pair is units is replaced by nitrogen. The nitrogen lone pair is located in an splocated in an sp22 hybrid orbital which is perpendicular to the hybrid orbital which is perpendicular to the system of the ring. Various values have been deduced for system of the ring. Various values have been deduced for the empirical resonance energy of pyridine, but it would the empirical resonance energy of pyridine, but it would appear to be roughly comparable to benzene. The appear to be roughly comparable to benzene. The resonance stabilization is shown by the two equivalent resonance stabilization is shown by the two equivalent Kekule structures and the three zwitterionic forms with Kekule structures and the three zwitterionic forms with negative charge on nitrogen. negative charge on nitrogen.

 

Derivatives of pyridine are biological active Derivatives of pyridine are biological active compounds, such as nicotine amide, nicotinic acid compounds, such as nicotine amide, nicotinic acid (vitamin PP).(vitamin PP).

nicotinic acid

Characteristic for pyridine reactions can be divided into Characteristic for pyridine reactions can be divided into three groups:three groups:

Reactions which followings with participation of Reactions which followings with participation of heteroatom.heteroatom.

Reactions of substituting for the hydrogen atoms of Reactions of substituting for the hydrogen atoms of pyridines ring.pyridines ring.

Reactions of reduction and oxidization.Reactions of reduction and oxidization.

Reactions which followings with participation of heteroatom.Reactions which followings with participation of heteroatom.

1. Cooperating with acids. 1. Cooperating with acids.

Due to the indivisible pair of electrons atom of nitrogen of Due to the indivisible pair of electrons atom of nitrogen of pyridine shows weak basic properties. At cooperating with strong pyridine shows weak basic properties. At cooperating with strong mineral and organic acids he forms soluble salt of pyridine.mineral and organic acids he forms soluble salt of pyridine.

2. Reaction with the oxide of sulphur (VI). 2. Reaction with the oxide of sulphur (VI).

pyridine bromide

Reactions of substituting for the hydrogen atoms of pyridines Reactions of substituting for the hydrogen atoms of pyridines ring.ring.

1. Reactions of electrophilic substitution (S1. Reactions of electrophilic substitution (SEE).). The reactions of nitration, sulphonation and halogenation pass The reactions of nitration, sulphonation and halogenation pass slowly drastic and with low exits. Thus an electrophilic reagent is slowly drastic and with low exits. Thus an electrophilic reagent is direct in position 3.direct in position 3.

3-nithropyridine

3-pyridinesulphure acid

Reactions of nucleophilic substitution.Reactions of nucleophilic substitution.

The substitution goes on positions 2,4,6, most easy of nucleophilic The substitution goes on positions 2,4,6, most easy of nucleophilic reagent is entered in position of 2,6 (α-position ). The prime reagent is entered in position of 2,6 (α-position ). The prime example of reaction of this type is an amination of pyridine with example of reaction of this type is an amination of pyridine with sodium of amide on Chychybabyne. The reaction flows to the sodium of amide on Chychybabyne. The reaction flows to the mechanism Smechanism SNN2:2:

σ- complex 2- aminopyridine

Reactions of reduction and oxidization.Reactions of reduction and oxidization. 1.1. Reduction .Reduction .

2. Oxidization .2. Oxidization .

pyperedine

nicotinic acid

These ring systems, particularly that of pyrimidine, occur These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, commonly in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they thymine, and uracil are especially important because they are components of nucleic acids, as are the purine are components of nucleic acids, as are the purine derivatives adenine and guanine.derivatives adenine and guanine.

DiazinesDiazines In this section, we shall take а brief look at another class of In this section, we shall take а brief look at another class of

heterocycles, the diazines. The three types of heterocycles, the diazines. The three types of diazabenzenes are:diazabenzenes are:

In addition to these three diazines, the bicyclic tetraaza In addition to these three diazines, the bicyclic tetraaza compound, purine, is an important heterocyclic system. compound, purine, is an important heterocyclic system.

AminopurinesAminopurines Maine aminoderivatives of purine – Maine aminoderivatives of purine –

adenine and guanine present in nucleinic adenine and guanine present in nucleinic acids as purine’s bases.acids as purine’s bases.

The рininе nucleus also occurs in such compounds as The рininе nucleus also occurs in such compounds as caffeine (coffee and tea) and theobromine (cacao beans).caffeine (coffee and tea) and theobromine (cacao beans).

Hypoxantine and xantine have the same Hypoxantine and xantine have the same chemical properties as uric acidchemical properties as uric acid

N-methyl derivatives of hypoxantine and xantine widely used in pharmacy

Murexidne’s reaction is the qualitative Murexidne’s reaction is the qualitative reaction on uric acidreaction on uric acid

By heating uric acid with nitrate acid and next By heating uric acid with nitrate acid and next adding of ammonium observe purpur-violet color adding of ammonium observe purpur-violet color

Thanks you for attention!!!