Lecture № 10
Insertion to the chemistry of
heterocyclic compounds. 3-, 4-Member
heterocycles.
Fivemember heterocyclic compounds
with one heteroatom.
Ass. Medvid I.I.
Outline
Classification and nomenclature of heterocyclic
connections.
2. Three- and fourmember heterocyclic compounds
with one heteroatom:
a) oxirane and oxetan
b) aziridine and azetidine
3. 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
heterocyclic compounds
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
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 heterocycles
Names in common use of some fully saturated
heterocycles containing only one hetero atom are shown
below.
2. Three- and fourmember heterocyclic compounds with
one heteroatom
The common threemember heterocycles are ethylene oxide
(oxirane), ethyleneimine (aziridine), and ethylene sulfide
(thiirane).
The fourmember ring heterocycles are rarer, mainly
because of the greater difficulty of preparing fourmembered rings.
a)
Oxirane and oxetane
Methods of extraction:
Cyclization of halogenoalcohols.
1.
CH2 CH2
OH
+
NaOH
O
Cl
2-chlorethanol
CH2 CH2
OH
CH2
Cl
3-chlorpropanol
2.
CH2
H2C
+
NaCl
+
H2O
oxirane
+
NaOH
H2C CH2
H2C O
+
NaCl
+
H2O
oxetane
In the industry of oxirane produce mainly oxidation of
ethylene by oxygen of air at 300-400°C in the presence of
the silver catalyst. CH CH
300-400
H2C CH2
2
2
O
+ 2
Ag
O
oxirane
Physical 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.
H20, H +
H2C
CH2
OH OH
ethylenglicol
C2H5OH, H + H C CH
2
2
H2C
CH2
OH OC2H5
2-ethoxiethanol,
ethylcelozol
HO CH2 CH2
HCl
2-chlorethanol,
ethylenchlorhydrine
Cl
O
NH2-R
HO CH2
CH2
NH
CH3 MgBr
R
BrMgO CH2 CH2 CH3
propanolyat bromidmagnesium
N-alkylaminoethanol
+
HOH, H
CH3 CH2 CH2 OH
Mg(OH)Br
propanol-1
basis
HO
CH2
CH2
O
polyethylenoxide
H
n
-
H2C
O
NH3
H2C
CH2
OH
CH2 CH2 NH2
ethanolamine,
2-aminoethanol
O
OH CH2 CH2
OH CH2 CH2
OH CH2 CH2
triethanolamine
CH2
H2C
OH
CH2 CH2
diethanolamine
N
O
CH2 CH2
NH
OH
CH2
CH3OH, H +
H3CO
CH2 CH2 CH2 OH
3-meoxypropanol-1
H2C
CH2
H2C
O
HCl
HO CH2
NH3
CH3
CH2 CH2 Cl 3-chlorpropanol-1
CH2 NH2 3-aminopropanol-1
+
HOH, H
MgBr BrMgO CH CH CH
2
2
2 CH3
CH3 CH2 CH2 CH2 OH
alcoholyat bromidmagnesium Mg(OH)Br
butanol-1
HO CH2
CH2
-
The important derivatives of oxirane and oxetane
Epichlorohydrin (3-chlor-1,2CH
CH
Cl
CH2
2
epoxypropan) is an organochlorine
O
compound and an epoxide. This is a
colorless liquid with a pungent,
garlic-like odor, insoluble in water, but miscible with most
polar organic solvents. Epichlorohydrin is a highly reactive
compound and is used in the production of glycerol, plastics,
epoxy glues and resins, and elastomers. In contact with
water, epichlorohydrin hydrolyzes to 3-MCPD, a carcinogen
found in food.
β-Propiolactone (lactone βhydroxypropionic acid) is an
C
O
organic compound of the lactone
O
family, with a four-membered ring. It is a
clear, colorless liquid with a slightly sweet odor, highly
soluble in water and miscible with ethanol, acetone, diethyl
ether and chloroform. The word propiolactone usually
refers to this compound, although it may also refer to αpropiolactone. β-Propiolactone is a disinfectant and has
been used to sterilize blood plasma, vaccines, tissue grafts,
surgical instruments, and enzymes
CH2
CH2
O
CH2
OH
CH2
C
OCH3
methyl ester 3-hydroxy
propanoic acid
CH3OH
CH2
O
CH2
O
CH3NH2
CH2
C
O
OH
CH2
C
NHCH3
methylamide 3-hydroxypropanoic acid
b) Aziridine and azetidine
Methods of extraction:
1.
Cyclization of halogenoamines.
CH2 CH2
+
H2C
NaOH
CH2
+
H2O
+
NaCl
+
H2O
H2C CH2
NaOH
H2C NH
Cl
+
azetidine,
trimethylenimine
3-chlorpropylamine
2.
NaCl
aziridine,
ethylenimine
2-chlorethylamine
NH2
+
NH
NH2 Cl
CH2 CH2
CH2
In the industry of aziridine is produced by react of 1,2dichlorethane with an ammonia in the presence of CaO.
CH2 CH2
Cl
+
Cl
1, 2-dichlorethane
CaO
NH3
H2C CH2
NH
+
aziridine,
ethylenimine
CaCl2
+
H2O
Physical and chemical properties of aziridine and
azetidine
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.
Azetidine is a colorless liquid with the ammonia`s smell. The
well soluble in a water and alcohols.
RNH2
R HN CH2 CH2 NH2
diamine
H2C
CH2
HCl
Cl
NH
CH2
CH2
NH2
2-chlorethane amine
NH3
HOH
H2N
CH2
CH2
NH2 etane diamide-1,2
HO CH2 CH2 NH2
2-aminoethanol
The important derivatives of aziridine and azetidine
CH2
N
CH2
C
O
H
A beta-lactam ring (β-lactam or azetidinon2) is a lactam with a heteroatomic ring
structure, consisting of three carbon atoms and one
nitrogen atom. A lactam is a cyclic amide. The beta-
lactam ring is part of the structure of several antibiotic families,
principally the penicillins, cephalosporins, carbapenems and
monobactams, which are therefore also called beta-lactam
antibiotics. These antibiotics work by inhibiting the bacterial
cell wall synthesis.
O
CH2
NH2
CH2
NH3
CH2
C
N
NH2
amide of 2-aminopropanoic
acid
H
CH2
HOH, H
+
O
CH2
C
O
NH2
CH2
C
OH
2-aminopropanoic acid
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 
molecular system in which the three lowest molecular orbitals are
bonding. The six  electrons (one for each carbon and two for
nitrogen) fill the three bonding orbitals and give the molecule its
aromatic character. Pyrrole is isoelectronic with cyclopentadienyl
anion, an unusually stable carbanion that also has а cyclic 
electronic system with six electrons.
Furan and thiophene have similar structures. In these cases, the
second lone pair on the heteroatom may be considered to occupy
an sp² orbital that is perpendicular to the  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
because the nitrogen lone pair is involved in the aromatic sextet
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
conjugate acid in which protonation has occurred predominantly
on carbon rather than on nitrogen.
a) Methods of extraction of fivemember heterocyclic
compounds with one heteroatom.
1. Cyclization of 1,4-dicarbones compounds (Paale-Knorr
synthesis )
H H
C C
H 2C CH 2
R C
C R
R C
C R
OH HO
H
SO
c.
2
4
O O
P 2S 5
NH3
R
O
R
R
R
N
H
R
S
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 PaalКлоrr 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.
2. Reciprocal transformation of furan, pyrrole, thiophene
(Yurie`s cycle reactions)
NH3
H2O
O
H2S
Al2O3
H2O
NH3
S
N
H
H2S
Extraction of pyrrole :
H H
НО С С ОН
t°
H С
С H _ -2СO2, -4H2O, -NH3
_
+
+
H 4NOOC ОН HO СОО NН 4
pyrrole
Diammonia salt of mucic acid
H2C
O
CH2
C
C
NH
succimide
2Zn
O
N
H
+
NH
pyrrole
2ZnO
Extraction of furan:
In laboratory conditions furan is produce by dry distillation of
mucic acid.
OH
OH
CH
CH
CH
CH
CO
OH OH
OH
t
COOH
t
- 3 H2O
O
COOH
O
furan
furoic acid
dehydromucic acid
mucic acid
- CO2
- CO2
COOH
COOH O
t
In the industry furan derived from aldopentozes
H
H
HO
nH2O
(C5H8O4)n
t0
polypentoze
H
nC5H10O5
pentoza
H
- CO2
O
furoic acid
COOH
C
O
furan
H
C
C
t
O
C
OH
OH HO
C
t0
C
O
H
O
furfural
O
H
+ 3H2O
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 furan, pyrrole, thiophene
At room temperature, thiophene is a colorless liquid with a mildly
pleasant odor reminiscent of benzene, with which thiophene shares some
similarities. The high reactivity of thiophene towards sulfonation is the
basis for the separation of thiophene from benzene, which are difficult to
separate by distillation due to their similar boiling points (4 °C difference at
ambient pressure). Like benzene, thiophene forms an azeotrope with
water.
Furan is typically derived by the thermal decomposition of pentosecontaining materials, cellulosic solids especially pine-wood. Furan is a
colorless, flammable, highly volatile liquid with a boiling point close to
room temperature. It is toxic and may be carcinogenic. Catalytic
hydrogenation (see redox) of furan with a palladium catalyst gives
tetrahydrofuran.
Pyrrole is a heterocyclic aromatic organic compound. Substituted
derivatives are also called pyrroles. For example, C4H4NCH3 is Nmethylpyrrole. Porphobilinogen is a trisubstituted pyrrole, which is the
biosynthetic precursor to many natural products
c) Chemical properties of furan, pyrrole, thiophene
The most typical reaction of furan, pyrrole, and
thiophene is electrophilic substitution. All three
heterocycles are much more reactive than benzene,
the 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. Interaction with mineral acids
Pyrroles 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)
Nitration
(CH3CO)2O + р.HNO3
N
N
H
H
NO2
2-nitropyrrole
Further substitution on 2-substituted furans tends to осcur at the other
-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) Sulfonation
+
X
X=O, NH
+
N
SO3
pyridine
sulfotrioxide
X
SO3H
furan-2-sulfoacid
pyrrole-2-sulfoacid
N
pyridine
c) Acylation
(CH3CO)2O
N
H
SnCl4
N
H
C
CH3
O
2-acetylpyrrole
Because of this high reactivity, even mild electrophiles to
cause reaction. Substitution occurs predominantly at the αposition (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.
d) Halogenation
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.
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).
Cl
Cl
SO2Cl2
SO2Cl2
NH
pyrrole
NH
Cl
2-chlorpyrrole
SO2Cl2
Cl
NH
Cl
2, 5- chlorpyrrole
Cl
NH
Cl
tetrachlorpyrrole
3. Reactions of reconstruction
Thiophen are more stable and do not undergo hydrolysis.
Reduction of pyrrole:
Ni
+
2 H2
O
O
tetrahydrofuran
furan
Pd
+
S
thiophene
2 H2
S
tetrahydrothiophene
4. Reactions of oxidation
O
O
V2O5
O
O
O
maleinic anhydride
furan
O
NH
pyrrole
H2Cr2O4 O
NH
O
maleinmide
O
NaNH2
N
N
H
;t
H3C C
Cl
+
Na
N
-NaCl
H
sodium pyrrolide
C CH3
O
2-acetylpyrrole
pyrrole
- +
NK
+ H3C C
O
t 0C
N
Cl
COCH3
Potassium pyrrolide
N-acethylpyrrole
- +
NK
CH 3I
-KI,to
N
H
CH3
2-methyllpyrrole
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
the method coloring of a pine chip.
Couples of pyrrole painted a pine chip
soaked in hydrochloric acid in the red
colour and furan - in the green colour.
Qualitative reaction on thiophene is
indophenin`s reaction: a mixture of
izathine with concentrated sulfuric acid
painted in the blue colour.
Thank you for attention!