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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5852_Библиотеки_им_академика_М_И_Перельмана.pdf
C H A P T e r 10 u Arenes
Toluene
o-Nitrotoluene
p-Nitrotoluene
Further nitration
Trinitrotoluene (TNT)
conc. HNO
3
conc. H2SO
3
Arenium cation stabalizes itself by resonance
Slow
conc. H2SO
4
371
Mechanism: mixture of conc. nitric acid and
sulphuric acid generates the nitronium ion
+
(nO
), which acts as electrophile. Following
2
sequence of reaction is observed in that nitra-
& Learning Plus
Strong sulphuric acid protonates nitric acid and causes it to split into NO
O+. Water is absorbed by H2SO4 to form NO
and H
3
tion action:
3. Sulphonation: With hot concentrated sulphuric acid, arenes give arenesulphonic acid.
+
and H3O+.
2
+
2
PHArmACeuT i CAl OrgAniC CH emiSTry
372
o- and p-toluene
sulphonic acid
2
Mechanism: In rst step, SO3 is formed, which acts as electrophile.
SO3 molecule is a neutral molecule but it has a powerful electron-decient sulphur atom:
Toluene gives a mixture of o- and p-toluenesulphonic acid.
& Learning Plus
Sulphonation is a reversible
reaction whereas nitration
is essentially irreversible.
4. Halogenation: Arenes show two types of halogenation reaction.
a. Nuclear-substituted halogenated product: Halogenations, when carried out in the presence of
halogen carriers in dark, nuclear-substituted product are obtained. For example, in toluene, one or
more hydrogen atoms is replaced by chlorine or bromine during halogenations.
C H A P T e r 10 u Arenes
Cl2, FeCl
3
dark, –HCl
Toluene
o- and p-Chlorotoluene
i.
ii.
iii.
–
(Slow step)
(Fast step)
373
Di- or trichlorotoluenes are obtained on prolonged
treatment with chorine or bromine.
Mechanism: Chlorination involves following steps:
Metallic iron commonly used catalyst in the commercial
method is converted into FeCl
Other Lewis acids can also be used as halogen carriers.
REMEMBER
by chlorine in the reaction.
3
b. Side chain substituted products: Side chain substitution is favoured at high temperature, in the
presence of light and in the absence of halogen carriers. When chlorine is passed through boiling
toluene in presence of sunlight, substitution takes place at side chain.
374
(Free radical)
Free radical
Benzyl radical
Benzyl chloride
(O)
o-, m- and p-Xylene o-, m- and p-To luic acid
Oxidation
dil. HNO
3
PHArmACeuTiCAl OrgAniC CHemiSTry
Mechanism: The reaction proceeds by free-radical mechanism just like halogenations of methane.
The ease of formation of free radicals is in the following order:
Allyl or Benzyl > 3° (Tertiary) > 2° (Secondary) > 1° (Primary) > CH3 > Vinyl
This is because benzyl and allyl radicals are stabilized by resonance.
5. Oxidation: in arenes, side chains (irrespective of its length) are oxidized to carboxyl group by strong
oxidizing agents like chromic acid and potassium permanganate. With mild oxidizing agents like chromyl
chloride, only the end methyl group is oxidized to aldehyde group. For example, butylbenzene gives benzoic
acid with KmnO4 and phenylbutyraldehyde with chromyl chloride.
Similarly, toluene gives benzoic acid with KmnO4 or chromic acid while with chromyl chloride, it gives
benzaldehyde.
Xylene on oxidation with hot dil. HnO3 gives toluic acid.
C H A P T e r 10 u Arenes
KMnO4 /OH/∆
KMnO4 /OH/∆
No oxidation
K2Cr2O7/H2SO
4
High temperature
(ii) H2O/H
(i) KMnO
4
/OH/∆
⊕
X = any functional group
Toluene Methyl hexahydrocyclohexane
& Learning Plus
Alkyl benzene can only be oxidized when benzyl carbon atom has at least one hydrogen, i.e. benzyl carbon should not be quaternary:1.
If side chain has no 2. α-hydrogen, then benzene ring is cleaved at higher temperature:
375
3. Side chain oxidation is not restricted to alkyl group. Alkenyl, alkynyl, acyl and alkyl substituted groups are oxidized to benzoic acid.
6. Reduction: On reduction with hydroiodic acid at 520 K or hydrogen under pressure in the presence of
nely divided nickel at 470 K, arenes form cycloalkanes. For example, toluene on reduction gives methylhexahydrocyclohexane.
376
Arene
Arene triozonide
–
–
o- and p-Acyl-substituted arenes
o- and p-Acyl-substituted arenes
7. Ozonolysis: Arenes, due to presence of three double bonds, add three ozone molecules to form triozonide.
8. Friedel–Crafts reaction: introduction of an alkyl or acyl group into the benzene ring in presence of a
PHArmACeuTiCAl OrgAniC CHemiSTry
catalyst is known as Friedel–Crafts reaction. The alkylating agents used are alkyl halides, alcohols and olens
while acylating agents used are acids, acid chloride, acid anhydrides and esters. Various catalyst used are
anhydrous AlCl
, FeCl3, ZnCl2, SnCl4 and BCl3 (lewis acids). The general order of reactivity of such catalyst
3
is:
Alkylation
Acylation
AlCl3 > BF3 > SbCl5 > FeCl3 > SnCl4 > ZnCl
2
C H A P T e r 10 u Arenes
Mechanism: Alkyl or acyl halides in presence of AlCl3 generate cations (electrophile) as shown below:
+
CH3Cl + AlCl3
CH3 + AlC–l
4
377
RCOCl + AlCl3
(CH3CO)2O + AlCl3
R–CO+ + AlC–l
CH3CO+ + (CH3COO)Al–Cl
4
3
This cation reacts with arenes to give arenium ion, which is stabilized by resonance and thus available in
reasonable concentration. The reaction is completed by a rapid loss of a proton to yield alkyl or acyl arenes
or aromatic ketones.
Limitations of Friedel–Crafts reaction
1. Aryl and vinyl halides do not form carbocation easily.
2. Quite often, polyalkylation takes place during the reaction. After introduction of an alkyl group, the
ring gets activated for further substitution.
3. Carbocation formed during the reaction may rearrange into most stable carbocation, thus giving
different products.
4. The presence of an electron-withdrawing group in the ring hinders the Friedel–Crafts reaction.
9. Mercuration: When heated (360–430 K) with mercuric acetate for one or more hour, hydrogen atom is
replaced by acetoxy-mercuric group:
CH3C6H5 + (CH3COO)2Hg
Toluene Acetoxymercuritoluene
CH3 — C6H4– HgOOCCH3 + CH3COOH
Aromatic mercurated compounds are important in medicine and in preparation of other compounds.
378
PHArmACeuTiCAl OrgAniC CHemiSTry
MEMORY FOCUS
1. Arenes can be prepared by
a. Heating sodium salt of aromatic acid with soda lime (NaOH + CaO).
b. Passing vapours of phenol over heated zinc dust (removal of –OH group).
c. Hydrolysing sulphonic acid with super-heated steam or by boiling with dilute hydrochloric
acid under pressure at 400–470 K (removal of –SO
d. The action of hypophosphorous acid, H3PO2 (reducing agent) on arene diazonium salt (removal of
–N
Cl group).
2
e. By the action of alkyl halide on benzene in presence of anhydrous aluminium chloride as catalyst
(Friedel–Crafts reaction).
f. Treating Grignard reagent with alkyl halide in dry ether.
g. Cyclization of long chain alkanes obtained from petroleum.
h. Heating halobenzene or its homologous and an alkyl halide with sodium metal in dry ether
(Wurtz–Fittig reaction).
i. Reduction of ketones with zinc amalgam and hydrochloride (Clemmensen reduction).
2. Chemical properties: Arenes show the following reactions:
a. Reaction due to benzene ring: It undergoes electrophilic substitution reactions like nitration,
chloromethylation, halogenation, sulphonation, alkylation, acylation
b. Reaction due to side chain: Arenes shows reaction on their side chain like chlorination, bromination,
oxidation, etc.
c. Reduction
d. Ozonolysis
e. Mercuration
H group).
3
10.8 ORTHO–PARA RATIO IN THE FORMATION OF DISUBSTITUTION DERIVATIVES
Certain substituents are mainly ortho–para directing while others are primarily meta directing. When the
ortho and para isomers are the chief products, they may be expected to be formed in the ratio 2:1 since there
are two ortho and one para positions with respect to the group already present. But in actual practice the ratio
is found to be different in different cases. The observed ratio in a given reaction is largely determined by the
size of the group already present. The larger the size of the groups the smaller the amount of ortho isomer and
vice versa.
Benzene is a symmetrical molecule and electrophilic substitution gives a monosubstituted product.
monosubstituted benzene derivatives are not symmetrical and more than one substitution isomers are
usually possible. For example:
C H A P T e r 10 u Arenes
Conc. H2SO4 + HNO
3
379
The above examples show that group already present on benzene ring directs the incoming group either
to ortho/para positions or to the meta position. This is called as orientation effects. The list of ortho–para
directors and meta directors are given in the table below .
Ortho–para directors and meta directors
Ortho–para director Meta director
C
– O– , Phenoxide ion
6H5
:
–NH2 Amino
:
–NR2 Dialkyl amino
:
–NHR Alkyl amino
Quaternary ammonium salt
Nitro
–
–
–C
N; Cyano
–
Sulphonic acid
380
:
–OH Phenolic hydroxyl
:
:
–OCH3 Methoxy
:
:
–OR Alkoxy
:
:
–NHCOCH3 N-acetyl
:
–Cl: Chloro
:
:
–Br: Bromo
:
:
–X: Halo
:
PHArmACeuTiCAl OrgAniC CHemiSTry
Aldehyde
Keto
Carboxylic acid
NH2;
Amide
–CX3; Trihalomethyl
An atom or group already present on a benzene ring not only directs the orientation of substitution of an
incoming group but also inuences the rate of substitution. If substituted benzene derivative is more reactive
than benzene itself then the substituent group is known as activating group and the benzene derivatives
that react more slowly than benzene itself then the substituent group is said to be deactivating group.
For example, anisole is 3,00,000 times more reactive than benzene for Friedel–Crafts alkylation reaction.
Thus, methoxy group is an activating group. Bromination of nitrobenzene is 1,00,000 times slower than
bromination of benzene; thus nitro group is deactivating group.
10.9 ORIENTATION IN DISUBSTITUTED BENZENE (INTRODUCTION OF A THIRD GROUP IN
BENZENE RING)
When a benzene ring undergoes trisubstitution (i.e. when benzene ring undergoes substitution in presence
of two groups), the position of the third incoming group depends upon the nature of the two groups already
present in the ring. The most powerful activating group generally determines the position of attacking group.
Following cases can arise:
1. Both the groups already present belong to category of o- and p-directing groups, i.e. when both
groups are activating groups, position of third group is governed by the group with higher activating
power. For example: