Lecture № 10

Insertion to the chemistry of Insertion to the chemistry of heterocyclic compounds. 3-, 4-Member heterocyclic compounds. 3-, 4-Member

heterocycles. heterocycles.

Fivemember heterocyclic compounds Fivemember heterocyclic compounds with one heteroatomwith one heteroatom..

Ass. Medvid I.I.Ass. Medvid I.I.

OutlineOutline1. Classification and nomenclature of heterocyclic

connections.2. Three- and fourmember heterocyclic compounds

with one heteroatom: a) oxirane and oxetan

b) aziridine and azetidine3. Fivemember heterocyclic connections with one

heteroatom: a) methods of extraction;

b) physical properties of furan, pyrrole, thiophene;c) Chemical properties of furan, pyrrole, thiophene;

1. 1. Classification and nomenclature of Classification and nomenclature of heterocyclicheterocyclic co compoundmpoundss

Heterocyclic compounds are cyclic compounds with one or more ring atoms that are not carbon (that are, hetero atoms). Although heterocycles are known that incorporate many different elements into cyclic structures (for example, N, О, S, В, Al, Si, P, Sn, As, Cu), we shall consider only some of the more common systems in which the hetero atom is N, О, or S. Heterocycles are conveniently grouped into two classes, nonaromatic and aromatic. The nonaromatic compounds have physical and chemical properties that are typical of the particular hetero atom. Thus, tetrahydrofurane and 1,4-dioxane are typical ethers, whereas 1,3,5-trioxane behaves as an acetal.

Pyrrolidine and piperidine are typical secondary amines and Pyrrolidine and piperidine are typical secondary amines and the bicyclic compound quinuclidine is а tertiary amine.the bicyclic compound quinuclidine is а tertiary amine.

Since the chemistry of these compounds parallels the chemistry of реn acyclic relatives, we shall treat them here only briefly. The aromatic heterocycles include such compounds as pyridine, where nitrogen replaces one of the СН groups in benzene, and pyrrole, in which the aromatic sextet is supplied by the four electrons of the two double bonds and the lone pair on nitrogen.

Other aromatic heterocycles contain more than one hetero atom, and still others contain fused aromatic rings. Examples which we will treat in more detail later include.

The nomenclature of these heterocyclic series is а vast' sea of special names for individual ring systems and trivial names for individual compounds. In the course of developing the chemistry of some important groups of compounds we will treat the associated nomenclature. There is only one naming scheme common to all of these compounds that is, unfortunately, used only in cases where alternative nomenclature based on special names is awkward. This scheme is based on the corresponding hydrocarbon. The compound formed by replacing а carbon by а hetero atom is named by an appropriate prefix: aza for nitrogen, оха for oxygen and thia for sulfur.

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.

The commonly used names for monocyclic rings with а single hetero atom will be discussed in the next section.

Nonaromatic heterocyclesNonaromatic heterocycles Names in common use of some fully saturated heterocycles containing only one hetero atom are shown below.

2. Three- and fourmember heterocyclic 2. Three- and fourmember heterocyclic cocompoundmpoundss with with one heteroatomone heteroatom

The common The common threemember heterocyclesthreemember heterocycles are ethylene oxide are ethylene oxide (oxirane), ethyleneimine (aziridine), and ethylene sulfide (oxirane), ethyleneimine (aziridine), and ethylene sulfide (thiirane).(thiirane).

The The fourmember ring heterocyclesfourmember ring heterocycles are rarer, mainly are rarer, mainly because of the greater difficulty of preparing four-because of the greater difficulty of preparing four-membered rings.membered rings.

a)a) Oxirane and oxetaneOxirane and oxetaneMethods of extractionMethods of extraction::

1.1. Cyclization of halogenoalcohols.Cyclization of halogenoalcohols.

2. 2. In the industry of oxirane produce mainly oxidation of In the industry of oxirane produce mainly oxidation of ethylene by oxygen of air at 300-400ethylene by oxygen of air at 300-400°C°C in the presence of in the presence of the silver catalyst.the silver catalyst.

CH2 CH2

OH Cl

+ NaOHH2C CH2

O + NaCl + H2O

2-chlorethanol oxirane

CH2 CH2

OH Cl

+ NaOHH2C CH2

+ NaCl + H2O

3-chlorpropanol oxetane

CH2

H2C O

H2C CH2

O

oxirane

CH2 CH2 + O2

300-400

Ag

Physical and chemical properties of oxirane and oxetanePhysical and chemical properties of oxirane and oxetane

Ethylene oxide, also called oxirane, is the organic compound . This colorless flammable gas with a faintly sweet odor is the simplest epoxide. Most ethylene oxide is consumed as the precursor to ethylene glycol as well as a variety of other chemicals. Ethylene glycol is more commonly known for its use as an automotive coolant and antifreeze. Other chemical applications include ethanolamine, diverse surfactants (see reactions section below), and glycol ethers such as ethoxyethanol. Ethylene oxide is also used as sterilant, although the amount consumed for this purpose is minor compared to the applications in the chemical industry.

Oxetane, or 1,3-propylene oxide, is an heterocyclic organic compound, is a liquid with the boiling point47,8 C. Well soluble in a water, ethanol and diethyl ester.

-

H2C CH2

O

H20, H +H2C CH2

OH OHethylenglicol

C2H5OH, H+

H2C CH2

OH OC2H5

2-ethoxiethanol,ethylcelozolHCl

HO CH2 CH2 Cl2-chlorethanol,ethylenchlorhydrine

NH2-RHO CH2 CH2 NH R N-alkylaminoethanol

CH3 MgBrBrMgO CH2 CH2 CH3

HOH, H+

Mg(OH)BrCH3 CH2 CH2 OH

propanol-1propanolyat bromidmagnesium

HO CH2 CH2 O Hbasis

npolyethylenoxide

H2C CH2

OOH CH2 CH2 NH2

H2C CH2

OOH CH2 CH2

OH CH2 CH2

H2C CH2

O

NH3

NH

OH CH2 CH2

OH CH2 CH2

OH CH2 CH2

N

ethanolamine,2-aminoethanol

diethanolamine

triethanolamine

-

H2C CH2

O

CH3OH, H+

CH2 OH

3-meoxypropanol-1

HClHO CH2 CH2 Cl 3-chlorpropanol-1

NH3HO CH2 CH2 NH2

3-aminopropanol-1

CH3 MgBr BrMgO CH2 CH2 CH3HOH, H

+

Mg(OH)BrCH3 CH2

CH2 OH

butanol-1alcoholyat bromidmagnesium

H2C

CH2

CH2

CH2CH2H3CO

CH2CH2

The iThe importantmportant derivativesderivatives of oxirane and oxetane of oxirane and oxetane

EpichlorohydrinEpichlorohydrin (3-chlor-1,2- (3-chlor-1,2-epoxypropan)epoxypropan) is an is an

organochlorine organochlorine compound and an compound and an epoxide. This is a epoxide. This is a colorless liquid with colorless liquid with a pungent, garlic-like odor, insoluble in water, but miscible a pungent, garlic-like odor, insoluble in water, but miscible with most polar organic solvents.with most polar organic solvents. Epichlorohydrin is a highly Epichlorohydrin is a highly reactive compound and is used in the production of glycerol, reactive compound and is used in the production of glycerol, plastics, epoxy glues and resins, and elastomers. In contact plastics, epoxy glues and resins, and elastomers. In contact with water, epichlorohydrin hydrolyzes to 3-MCPD, a with water, epichlorohydrin hydrolyzes to 3-MCPD, a carcinogen found in food.carcinogen found in food.

CH2 CH CH2 Cl

O

β-Propiolactoneβ-Propiolactone (lactone (lactone β-β-hydroxypropionic acid)hydroxypropionic acid) is an is an

organic compound of the organic compound of the lactone lactone family, with a four-family, with a four-membered ring. It is a clear, colorless liquid with a slightly membered ring. It is a clear, colorless liquid with a slightly sweet odor, highly soluble in water and miscible with sweet odor, highly soluble in water and miscible with ethanol, acetone, diethyl ether and chloroformethanol, acetone, diethyl ether and chloroform.. The word The word propiolactonepropiolactone usually refers to this compound, although it usually refers to this compound, although it may also refer to α-propiolactone.may also refer to α-propiolactone. β-Propiolactone is a β-Propiolactone is a disinfectant and has been used to sterilize blood plasma, disinfectant and has been used to sterilize blood plasma, vaccines, tissue grafts, surgical instruments, and enzymes vaccines, tissue grafts, surgical instruments, and enzymes

CH2 CH2

O CO

CH2 CH2

O CO

CH2

OH

CH2 C

NHCH3

OCH3NH2CH3OH

CH2

OH

CH2 C

OCH3

O

methylamide 3-hydroxypropanoic acidmethyl ester 3-hydroxypropanoic acid

b) Aziridine and azetidineb) Aziridine and azetidine

Methods of extractionMethods of extraction::

1.1. Cyclization of halogenoamines.Cyclization of halogenoamines.

2.2. In the industry of aziridine is produced by react of 1,2-In the industry of aziridine is produced by react of 1,2-dichlorethane with an ammonia in the presence of CaO.dichlorethane with an ammonia in the presence of CaO.

CH2 CH2

Cl

+ NaOHH2C CH2

+ NaCl + H2O

2-chlorethylamine aziridine,ethylenimine

NH2NH

CH2 CH2

Cl

+ NH3

H2C CH2

+ CaCl2 + H2O

1, 2-dichlorethane aziridine,ethylenimine

NHCl

CaO

CH2 CH2

Cl

+ NaOHH2C CH2

+ NaCl + H2O

3-chlorpropylamine

CH2

H2CNH2

NH

azetidine,trimethylenimine

Physical and chemical properties of aziridine and Physical and chemical properties of aziridine and azetidineazetidine

Aziridine is a group of organic compounds sharing the aziridine functional group which is a three membered heterocycle with one amine group and two methylene groups. The bond angles in aziridine are around 60° which is considerably less than the bond angle of 109.5° found in ordinary hydrocarbons and this results in angle strain just like in the comparable cyclopropane and oxirane molecules. Bonding in this type of compound can be explained by invoking a banana bond model. Aziridine is less basic than acyclic aliphatic amines with a pKa of 7.9 for the conjugate acid due to increased character of the nitrogen free electron pair. Increased angle strain in aziridine is also responsible for increased barrier for nitrogen inversion.

AzetidineAzetidine is a colorless liquid with the ammonia`s smell. The well soluble in a water and alcohols.

H2C CH2

RNH2 NH2

diamine

HClCl CH2

2-chlorethane amine NH3

H2N CH2 NH2etane diamide-1,2

HOH HO CH2 CH2

CH2

CH2

CH2CH2HN

NH

R

NH2

NH2

2-aminoethanol

The iThe importantmportant derivativesderivatives of aziridine and azetidine of aziridine and azetidine

A beta-lactam ring (β-lactamA beta-lactam ring (β-lactam or azetidinon- or azetidinon- 2 2)) is a lactam with a heteroatomic ring is a lactam with a heteroatomic ring

structure, consisting of three carbon atoms and structure, consisting of three carbon atoms and

one one nitrogen atomnitrogen atom. . A lactam is a cyclic amide. A lactam is a cyclic amide. The The beta-lactam ring is part of the structure of several antibiotic beta-lactam ring is part of the structure of several antibiotic families, principally the penicillins, cephalosporins, families, principally the penicillins, cephalosporins, carbapenems and monobactams, which are therefore also carbapenems and monobactams, which are therefore also called called beta-lactam antibioticsbeta-lactam antibiotics. These antibiotics work by . These antibiotics work by

inhibiting the bacterial cell wall synthesis.inhibiting the bacterial cell wall synthesis.

CH2 CH2

CO

N

H

HOH, HNH3CH2

NH2

CH2 C

NH2

O

2-aminopropanoic acidamide of 2-aminopropanoic acid

CH2 CH2

CO

N

H

CH2

NH2

CH2 COH

O+

3. Fivemember heterocyclic compounds with one heteroatom.

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

However, like benzene, many of their chemical properties are not typical of dienes. They undergo substitution rather than addition reactions, and they show the effect of а ring current in their nmr spectra. In short, 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.

The remaining рz, orbitals on each ring atom overlap to form а The remaining рz, orbitals on each ring atom overlap to form а molecular system in which the three lowest molecular orbitals are molecular system in which the three lowest molecular orbitals are bonding. The six bonding. The six electrons (one for each carbon and two for electrons (one for each carbon and two for nitrogen) fill the three bonding orbitals and give the molecule its nitrogen) fill the three bonding orbitals and give the molecule its aromatic character. Pyrrole is isoelectronic with cyclopentadienyl aromatic character. Pyrrole is isoelectronic with cyclopentadienyl anion, an unusually stable carbanion that also has а cyclic anion, an unusually stable carbanion that also has а cyclic electronic system with six electrons.electronic system with six electrons.

Furan and thiophene have similar structures. In these cases, the Furan and thiophene have similar structures. In these cases, the second lone pair on the heteroatom may be considered to occupy second lone pair on the heteroatom may be considered to occupy an span sp²² orbital that is perpendicular to the orbital that is perpendicular to the system of the ring. system of the ring.

The aromatic character of these heterocycles may also be expressed using resonance structures, which show that а pair of electrons from the hetero atom is delocalized around the ring.

Although руrrole is an amine, it is an extremely nonbasic one Although руrrole is an amine, it is an extremely nonbasic one because the nitrogen lone pair is involved in the aromatic sextet because the nitrogen lone pair is involved in the aromatic sextet and is thereby less available for bonding to а proton. The pKa of and is thereby less available for bonding to а proton. The pKa of its conjugate acid is 0.4. In fact, this pKa corresponds to а its conjugate acid is 0.4. In fact, this pKa corresponds to а conjugate acid in which protonation has occurred predominantly conjugate acid in which protonation has occurred predominantly on carbon rather than on nitrogen.on carbon rather than on nitrogen.

a) Methods of extraction of a) Methods of extraction of fivemember heterocyclic compounds with one heteroatom.

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

CH2 CH2

C C RR

OOP2S5

CR

CH

CH

C R

OH OH

NH3

H2SO4 c.

SR R

OR R

NH

R R

Substituted furans, pyrroles, and thiophenes may be prepared by electrophilic substitution on one of the available materials discussed or by а variety of cyclization reactions. The most general is the 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

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

С

ОН OHС

ССHH

ОННО

H

СОО NН4

H

H4NOOC+ +__

t°

NH

Extraction of pyrrole :Extraction of pyrrole :

Diammonia salt of mucic acid

-2СO2, -4H2O, -NH3

pyrrole

H2C CH2

C CNH

OO

2Zn

NH

+ 2ZnO

succimidepyrrole

Extraction of furan:Extraction 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

Extraction 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

b) Physical properties of b) Physical properties of furan, pyrrole, thiophene

At room temperature, At room temperature, thiophenethiophene is a colorless liquid with a mildly is a colorless liquid with a mildly pleasant odor reminiscent of benzene, with which thiophene shares some pleasant odor reminiscent of benzene, with which thiophene shares some similarities. The high reactivity of thiophene towardsimilarities. The high reactivity of thiophene towardss sulfonation is the sulfonation is the basis for the separation of thiophene from benzene, which are difficult to basis for the separation of thiophene from benzene, which are difficult to separate by distillation due to their similar boiling points (4 °C difference separate by distillation due to their similar boiling points (4 °C difference at ambient pressure). Like benzene, thiophene forms an azeotrope with at ambient pressure). Like benzene, thiophene forms an azeotrope with water.water.

FuranFuran is typically derived by the thermal decomposition of pentose-is typically derived by the thermal decomposition of pentose-containing materials, cellulosic solids especially pine-wood. Furan is a containing materials, cellulosic solids especially pine-wood. Furan is a colorless, flammable, highly volatile liquid with a boiling point close to colorless, flammable, highly volatile liquid with a boiling point close to room temperature. It is toxic and may be carcinogenic. Catalytic room temperature. It is toxic and may be carcinogenic. Catalytic hydrogenation (see redox) of furan with a palladium catalyst gives hydrogenation (see redox) of furan with a palladium catalyst gives tetrahydrofuran. tetrahydrofuran.

PyrrolePyrrole is a heterocyclic aromatic organic compound is a heterocyclic aromatic organic compound. . Substituted Substituted derivatives are also called pyrroles. For example, C4H4NCH3 is derivatives are also called pyrroles. For example, C4H4NCH3 is NN--methylpyrrole. Porphobilinogen is a trisubstituted pyrrole, which is the methylpyrrole. Porphobilinogen is a trisubstituted pyrrole, which is the

biosynthetic precursor to many natural productsbiosynthetic precursor to many natural products

c) c) Chemical properties of Chemical properties of furan, pyrrole, thiophene

The most typical reaction of furan, pyrrole, and The most typical reaction of furan, pyrrole, and thiophene is electrophilic substitution. All three thiophene is electrophilic substitution. All three heterocycles are much more reactive than benzene, heterocycles are much more reactive than benzene, the reactivity order beingthe reactivity order being

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 mineral with mineral acidsPyrroles are polymerized by even mineral 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.

When the 3-substituent is electron donating (ortho, раrа directing), substitution occurs at the adjacent а-position (that is, ortho to the group present).

b) Sulfonationb) Sulfonation

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

c) Acylationc) Acylation

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, eyen 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.

d) Halogenation

The position of second substitution in а monosubstituted furan, pyrrole, or lhiophene is governed by а combination оf the directing effect of the group present and the inherent -directing effect of the heteroatom. Substitution on 3-substituted compounds occurs exclusively at an -position. When the substituent present is electron attracting (meta directing), reaction occurs at the nonadjacent -position (that is, meta to the group present).

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:

3. Reactions of reconstruction

O

+ 2 H2

Ni

O

+ 2 H2

Pd

SS

furantetrahydrofuran

thiophene tetrahydrothiophene

4. 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

N

CH3I

K+-

N CH3to

H 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..

Thank you for attention!