Classification, structure and biological role of heterocyclic compounds and

of nucleic acids

Lecturer: Bekus Iryna

Heterocyclic compoundsHeterocyclic compounds are cyclic are cyclic compounds in which one or more ring atoms compounds in which one or more ring atoms

are not carbon (that is hetero atoms).are not carbon (that is hetero atoms).

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

ClassificationClassification

Heterocycles are Heterocycles are conveniently conveniently grouped into two grouped into two classesclasses, , nonaromatic:nonaromatic:

aromatic

and

By size of ring By size of ring

Three-membered Three-membered Four-Four-memberedmembered

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

TTetrapyrrole compoundsetrapyrrole compounds

blood heme

Five - membered heterocyclic compounds with one heteroatom.

The structures of these three heterocyclic would suggest that they have highly reactive diene character.

These heterocyclic have characteristics associated with aromaticity. From an orbital point of view, pyrrole has a 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 a hydrogen.

Methods of synthesis of Methods of synthesis of five - membered heterocyclec compounds with one heteroatom.

1. Cyclization of 1,4-dicarbones compounds

Formation of furan:Formation of furan:

In laboratory conditions furan is produced by dry In laboratory conditions furan is produced by dry distillation of mucic acid.distillation of 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 thiopheneFormation of thiophene

Thiophene is prepared industrially by passing а Thiophene is prepared industrially by passing а mixture of butane, butene, or butadiene and mixture of butane, butene, or butadiene and sulfur through a reactor heated at 600' for а sulfur through a reactor heated at 600' for а contact time of about 1 seccontact 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, thiopheneChemical 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.

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

NH3

NH3

H2O

H2O

H2S

H2S

FuranFuran

піролпірол

ThiopheneThiophene

1. 1. InteractionInteraction with dilute mineral acids with dilute mineral acidsPyrroles are polymerized by even dilute acids, probably by a Pyrroles are polymerized by even dilute acids, probably by a mechanism such as the followingmechanism such as the following . .

2. Reactions of electrophilic substitution:2. Reactions of electrophilic substitution:This orientation is understandable in terms of the This orientation is understandable in terms of the mechanism of electrophilic aromatic substitution. The mechanism of electrophilic aromatic substitution. The // ratio is determined by the relative energies of the ratio is determined by the relative energies of the transition states leading to the two isomers. As in the transition states leading to the two isomers. As in the case of substituted benzenes, we may estimate the case of substituted benzenes, we may estimate the relative energies of these two transition states by relative energies of these two transition states by considering the actual reaction intermediates produced considering the actual reaction intermediates produced by attack at the by attack at the -or -or -positions.-positions.

a)a) NitrationNitration

N

H

(CH3CO)2O + р.HNO3

N

H

NO2

2-nitropyrrole

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 In the last example, note that 2-iodothiophene is the sole product of iodination, eyeu though the reaction is carried out product of iodination, eyeu though the reaction is carried out in benzene as solvent; that is, thiophene is so much more in benzene as solvent; that is, thiophene is so much more reactive than benzene that no significant amount of reactive than benzene that no significant amount of iodobenzene is formed. iodobenzene is formed.

Halogenation

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 oxidationReactions of oxidation

pyrrole

furan

O

O

V2O5

O OO

maleinic anhydride

maleinmide

O

O O

NHNHH2Cr2O4

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

The iThe importantmportant derivativesderivatives of of pyrrolepyrrole, , furanfuran and and thiophene.thiophene.

The iThe importantmportant derivativesderivatives of pyrrole, furan and of pyrrole, furan and thiophenethiophene..

tetrahidrottetrahidrothhiofeniofenee

biotinbiotin

thiophenethiophene

Five-membered heterocyclec with Five-membered heterocyclec with two heteroatomstwo heteroatoms

pyrazolepyrazole Imidazole thiazoleImidazole thiazole

SSix-membered heterocyclic compoundsix-membered heterocyclic compoundspyridine grouppyridine group

Pyridine

quinoline

nicotinic acid nicotinamide

Six-membered heterocycles with two Six-membered heterocycles with two heteroatomsheteroatoms

pyrazinepyrimidine pirydazine

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

1)1) Reactions which followings with participation of Reactions which followings with participation of heteroatom.heteroatom.

2) Reactions of substituting for the hydrogen atoms of 2) Reactions of substituting for the hydrogen atoms of pyridines ring.pyridines ring.

3) Reactions of reduction and oxidization.3) 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 reduction and oxidization.Reactions of reduction and oxidization. 1.1. Reduction .Reduction .

2. Oxidization .2. Oxidization .

pyperedine

nicotinic acid

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

These ring systems, particularly that of pyrimidine, These ring systems, particularly that of pyrimidine, occur commonly in natural productsoccur commonly in natural products. .

The pyrimidines, cytosine, thymine, and uracil are The pyrimidines, cytosine, thymine, and uracil are especially important because they are components especially important because they are components of nucleic acids, as are the purine derivatives of nucleic acids, as are the purine derivatives adenine and guanine.adenine and guanine.

Nucleic acidsNucleic acids A Nucleic acids are polymers of nucleotides joined by 3',5' -phosphodiester bonds; that is, a phosphate group links the 3' carbon of a sugar to the 5' carbon of the next sugar in the chain. A phosphate group is often found at the 5' end, and a hydroxyl group is often found at the 3' end.

Types of nucleic acids.Types of nucleic acids.

Two types of nucleic acids are found within Two types of nucleic acids are found within cells of higher organisms: deoxyribonucleic cells of higher organisms: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nearly acid (DNA) and ribonucleic acid (RNA). Nearly all the DNA is found within the cell nucleus. Its all the DNA is found within the cell nucleus. Its primary function is the storage and transfer of primary function is the storage and transfer of genetic information. This information is used genetic information. This information is used (indirectly) to control many functions of a living (indirectly) to control many functions of a living cell. In addition, DNA is passed from existing cell. In addition, DNA is passed from existing cell to new cells during cell division RNA occurs cell to new cells during cell division RNA occurs in all parts of a cell. It functions primarily in in all parts of a cell. It functions primarily in synthesis of proteins, the molecules that carry synthesis of proteins, the molecules that carry out essential cellular functions. out essential cellular functions.

The monomers for nucleic acid polymers, The monomers for nucleic acid polymers, nucleotides, have а more complex nucleotides, have а more complex structure than polysaccharide monomers structure than polysaccharide monomers (monosacharides) or protein monomers (monosacharides) or protein monomers (amino acids). Within each nucleotide (amino acids). Within each nucleotide monomer are three subunits. А monomer are three subunits. А nucleotidenucleotide is, а molecule composed of a pentose is, а molecule composed of a pentose sugar bonded to both a group and a sugar bonded to both a group and a nitrogen-containing hetero-cyclic base. nitrogen-containing hetero-cyclic base.

• Pentose sugars. • The sugar unit of а nucleotide is either the

pentose ribose or the 2-deoxyribose.

Nitrogen-containing bases.Nitrogen-containing bases. Five nitrogen-containing bases are nucleotide Five nitrogen-containing bases are nucleotide

components. Three of them are derivatives of components. Three of them are derivatives of pyrimidine, а monocyclic base with а six-pyrimidine, а monocyclic base with а six-membered ring, and two are derivatives of membered ring, and two are derivatives of purine, а bicyclic base with fused five- and six-purine, а bicyclic base with fused five- and six-membered rings.membered rings.

NucleosidesNucleosides

are compounds formed when a are compounds formed when a base is linked to a sugar via a base is linked to a sugar via a

glycosidic bond.glycosidic bond.

                                                                                                            

                          

CytidineCytidine ThymidineThymidineUridineUridine

NucleotideNucleotide

A A nucleotide nucleotide results when phosphoric results when phosphoric acid is esterified to a sugaracid is esterified to a sugar OOH OOH group ofgroup of a a nucleosidenucleoside. . The nucleoside ribose ring has The nucleoside ribose ring has threethree OOH OOH groups available for groups available for esterificationesterification, , atat C-2, C-3, C-2, C-3, andand C-5 C-5 ((althoughalthough 2-deoxyribose 2-deoxyribose has only twohas only two).). The The vast majority of monomeric nucleotides in vast majority of monomeric nucleotides in the cell are the cell are ribonucleotides ribonucleotides having having 5-5-phosphate phosphate groupsgroups..

Nucleotide formation.Nucleotide formation. The formation of а nucleotide from The formation of а nucleotide from

sugar, base, and phosphate can be sugar, base, and phosphate can be visualized as occurring in the following visualized as occurring in the following manner:manner:

Nucleotide nomenclature.Nucleotide nomenclature.

There are two major classes of nucleic acids – There are two major classes of nucleic acids – DNA and RNA.DNA and RNA.

DNA has only one biological role, but it is the more central one. DNA has only one biological role, but it is the more central one. The information to make all the functional macromolecules of The information to make all the functional macromolecules of the cell (even DNA itself) is preserved in DNA and accessed the cell (even DNA itself) is preserved in DNA and accessed

through transcription of the information into RNA copies. through transcription of the information into RNA copies. Coincident with its singular purpose, there is only a single DNA Coincident with its singular purpose, there is only a single DNA

molecule (or “chromosome”) in simple life forms such as molecule (or “chromosome”) in simple life forms such as viruses or bacteria. Such DNA molecules must be quite large in viruses or bacteria. Such DNA molecules must be quite large in

order to embrace enough information for making the order to embrace enough information for making the macromolecules necessary to maintain a living cellmacromolecules necessary to maintain a living cell RNA has a RNA has a

number of important biological functions, and on this basis, number of important biological functions, and on this basis, RNA molecules are categorized into several major types: RNA molecules are categorized into several major types: messenger RNA, ribosomal RNA, messenger RNA, ribosomal RNA, and and transfer RNA. transfer RNA.

Eukaryotic cells contain an additional type, Eukaryotic cells contain an additional type, small nuclear RNA small nuclear RNA (snRNA).(snRNA).

DNADNAThe DNA isolated from The DNA isolated from different cells and viruses different cells and viruses characteristically consists of characteristically consists of two polynucleotide strands two polynucleotide strands wound together to form a wound together to form a long, slender, helical molecule, long, slender, helical molecule, the the DNA double helix. DNA double helix. The The strands run in opposite strands run in opposite directions; that is, they are directions; that is, they are antiparallel antiparallel and are held and are held together in the double helical together in the double helical structure through structure through interchain interchain hydrogen bondshydrogen bonds

DNA molecules are the carriers of the genetic information within а cell; DNA molecules are the carriers of the genetic information within а cell; that is, they the molecules of heredity. Each time а cell divides, an exact that is, they the molecules of heredity. Each time а cell divides, an exact copy of the DNA of the present cell is needed for the new daughter cell. The copy of the DNA of the present cell is needed for the new daughter cell. The process by which new DNA molecule generated is DNA replication DNA process by which new DNA molecule generated is DNA replication DNA replication is the process by which DNA molecules produce exact duplicates replication is the process by which DNA molecules produce exact duplicates of themselves. The key concept in understanding DNA replication is the of themselves. The key concept in understanding DNA replication is the base pairing associated with the DNA double helix.base pairing associated with the DNA double helix.

We can divide the overall process of protein synthesis into two steps. The We can divide the overall process of protein synthesis into two steps. The first step is called transcription and the second translation. first step is called transcription and the second translation. TranscriptionTranscription is the process by which DNA directs the synthesis of RNA molecules that is the process by which DNA directs the synthesis of RNA molecules that carry the coded information needed for protein synthesis. carry the coded information needed for protein synthesis. TranslationTranslation is is the process by which the codes within RNA molecules are deciphered and а the process by which the codes within RNA molecules are deciphered and а particular protein molecule is formed. The following diagram summarizes particular protein molecule is formed. The following diagram summarizes the relationship between transcription and translation.the relationship between transcription and translation.

DNA to RNA TranscriptionDNA to RNA TranscriptionThe DNA contains the master plan for the creation of The DNA contains the master plan for the creation of

the proteins and other molecules and systems of the the proteins and other molecules and systems of the cell, but the carrying out of the plan involves transfer cell, but the carrying out of the plan involves transfer of the relevant information to RNA in a process of the relevant information to RNA in a process called transcription. The RNA to which the called transcription. The RNA to which the information is transcribed is messenger RNA information is transcribed is messenger RNA (mRNA).(mRNA).

Ribonucleic acids (RNA).Ribonucleic acids (RNA). Four major differences exist between RNA molecules and DNA Four major differences exist between RNA molecules and DNA

molecules.molecules.1.1. The sugar unit in the backbone of RNA is ribose; it is The sugar unit in the backbone of RNA is ribose; it is

deoxyribose in DNA.deoxyribose in DNA.2.2. The base thymine found in DNA is replaced by uracil in RNA. The base thymine found in DNA is replaced by uracil in RNA.

Uracil, instead of thymine, pairs with (forms hydrogen bonds Uracil, instead of thymine, pairs with (forms hydrogen bonds with) adenine in RNA.with) adenine in RNA.

3.3. RNA is а single-stranded molecule; DNA is double-stranded RNA is а single-stranded molecule; DNA is double-stranded (double helix). Thus RNA, unlike DNA, does not contain (double helix). Thus RNA, unlike DNA, does not contain equal amounts of specific bases.equal amounts of specific bases.

4.4. RNA molecules are much smaller than DNA molecules, RNA molecules are much smaller than DNA molecules, ranging from as few as 75 nucleotides to а few thousand ranging from as few as 75 nucleotides to а few thousand nucleotides.nucleotides.

Differences exist between RNA Differences exist between RNA molecules and DNA molecules.molecules and DNA molecules.

Types of RNATypes of RNA

Thank you for attentionThank you for attention