QUIMICA PARA FARMACIA
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QUIMICA PARA FARMACIA


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NO2
BrCl
Br
Br
Br
3-Bromo-5-chloronitrobenzene 1,2,4-Tribromobenzene
1 2
3 45
1
4.6.8 Electrophilic substitution of benzene
Benzene is susceptible to electrophilic attack, and unlike any alkene it
undergoes substitution reactions rather than addition reactions. Before we go
into any details of such reactions, let us try to understand the following
terms.
Arenes. Aromatic hydrocarbons, as a class, are called arenes.
Aryl group. An aromatic hydrocarbon with a hydrogen atom removed is
called an aryl group, designated by Ar\ufffd\ufffd.
Phenyl group. The benzene ring with one hydrogen atom removed
(C6H5\ufffd\ufffd) is called the phenyl group, designated by Ph\ufffd\ufffd.
Electrophile. Electron loving. Cations, Eþ, or electron-deficient species.
For example, Clþ or Brþ (halonium ion) and þNO2 (nitronium ion).
An electrophile (Eþ) reacts with the benzene ring and substitutes for one of
its six hydrogen atoms. A cloud of p electrons exists above and below the
plane of the benzene ring. These p electrons are available to electrophiles.
Benzene\u2019s closed shell of six p electrons gives it a special stability.
4.6 AROMATIC COMPOUNDS AND THEIR DERIVATIVES 121
H
H
H
H
H
H
H
H
H
H
H
E
E+ + H+
Electrophile
+
Substitution reactions allow the aromatic sextet of p electrons to be
regenerated after attack by the electrophile has occurred. Electrophiles
attack the p system of benzene to form a delocalized nonaromatic carboca-
tion (arenium ion or s complex). Some specific examples of electrophilic
substitution reactions of benzene are summarized below (see Chapter 5).
X
NO2
SO3H
R
COR
X2, FeX3
 (X = Cl, Br)
Halogenation
HNO3, H2SO4
Nitration
SO3, H2SO4
Sulphonation
RCl, AlCl3
FC alkylation
RCOCl, AlCl3
FC acylation
+ HX
+ H2O
+ H2O
+ HCl
+ HCl
Reactivity and orientation in electrophilic substitution of substitued
benzene
When substituted benzene undergoes electrophilic attack, groups already on the
ring affect the reactivity of the benzene ring as well as the orientation of the
reaction. A summary of these effects of substituents on reactivity and orienta-
tion of electrophilic substitution of substituted benzene is presented below.
Substituent Reactivity Orientation Inductive effect Resonance effect
\ufffd\ufffdCH3 Activating ortho, para Weak electron None
donating
\ufffd\ufffdOH, \ufffd\ufffdNH2 Activating ortho, para Weak electron Strong electron
withdrawing donating
\ufffd\ufffdF, \ufffd\ufffdCl, Deactivating ortho, para Strong electron Weak electron
\ufffd\ufffdBr, \ufffd\ufffdI withdrawing donating
\ufffd\ufffdNþ(CH3)3 Deactivating meta Strong electron None
withdrawing
\ufffd\ufffdNO2, \ufffd\ufffdCN, \ufffd\ufffdCHO, Deactivating meta Strong electron Strong electron
\ufffd\ufffdCOOCH3, withdrawing withdrawing
COCH3, \ufffd\ufffdCOOH
122 CH4 ORGANIC FUNCTIONAL GROUPS
Reactivity Groups already present on the benzene ring may activate the
ring (activating groups), making it more reactive towards electrophilic
substitution than benzene, e.g. the \ufffd\ufffdOH substituent makes the ring 1000
times more reactive than benzene, or may deactivate the ring (deactivating
groups), making it less reactive than benzene, e.g. the \ufffd\ufffdNO2 substituent
makes the ring more than 10 million times less reactive. The relative rate of
reaction depends on whether the substituent group (\ufffd\ufffdS) withdraws or
releases electrons relative to hydrogen. When \ufffd\ufffdS is an electron-releasing
group the reaction is faster, whereas when this group is an electron-with-
drawing group a slower rate of reaction is observed.
HE
HE
+ E+
S
\u3b4+
S
\u3b4+
+
+
+
\u2212S releases electron Transition state
is stabilized
Reaction is faster Arenium ion is stabilized
S
HE HE
+ E+
S
\u3b4+
S
\u3b4+
+
+
+
\u2212S withdraws electron Transition state
is destabilized
Reaction is slower Arenium ion is destabilized
S
Orientation Similarly, groups already present on the benzene ring direct
the orientation of the new substituent to ortho, para or meta positions. For
example, nitration of chlorobenzene yields ortho-nitrochlorobenzene (30%)
and para-nitrochlorobenzene (70%).
Cl Cl
NO2
Cl
NO2
+
ortho-Nitrochlorobenzene
(30%)
para-Nitrochlorobenzene
(70%)
All activating groups are ortho and para directing, and all deactivating
groups other than halogens are meta directing. The halogens are unique in
being deactivating but ortho and para directing. A summary of various
4.6 AROMATIC COMPOUNDS AND THEIR DERIVATIVES 123
groups and their effects on the benzene ring in relation to reactivity and
orientation is presented below.
Ortho- and para-
directing activators
Ortho- and para-
directing deactivators
Meta-directing
deactivators
Reactivity
Y=
Y
C6H5
NR3
NO2
OH
NHCOCH3
H
Cl
I
COOCH3COCH3
CN
NH2
OCH3
CH3
F
Br
CHO
COOH
SO3H
+
Inductive effect of substituent present on the benzene ring
An inductive effect is the withdrawal or donation of electrons through a s
bond due to electronegativity and the polarity of bonds in functional groups
(electrostatic interaction). When the substituent (\ufffd\ufffdS) bonded to a benzene
ring is a more electronegative atom (or group) than carbon; e.g. F, Cl or Br,
the benzene ring will be at the positive end of the dipole. These substituents
will withdraw electron from the ring. As a consequence, an electrophilic
attack will be less favoured because of an additional full positive charge on
the ring.
S \u3b4\u2212
\u3b4+
S = F, Cl or Br
\u3b4\u2212
\u3b4+S
S = CH3
If a substituent (\ufffd\ufffdS) bonded to a benzene ring is less electron withdrawing
than a hydrogen, the electrons in the s bond that attaches the substituent to
the benzene ring will move toward the ring more readily than will those in
the s bond that attaches a hydrogen to the ring. Such a substituent (e.g.
CH3), compared with a hydrogen atom, donates electrons inductively into
the ring. Inductive electron donation makes the ring more reactive towards
electrophilic substitution because of the increased availability of electrons.
Resonance effect of substituent present on the benzene ring
A resonance effect is the withdrawal (e.g. by \ufffd\ufffdCO, \ufffd\ufffdCN or \ufffd\ufffdNO2) or
donation (e.g. by \ufffd\ufffdX, \ufffd\ufffdOH or \ufffd\ufffdOR) of electrons through a p bond due to
124 CH4 ORGANIC FUNCTIONAL GROUPS
the overlap of a p orbital on the substituent with a p orbital on the aromatic
ring. The presence of a substituent may increase or decrease the resonance
stabilization of the intermediate arenium ion complex.
H
O
H
O
H
O O
H
: :
..
+
:
..
+
+
Electron withdrawing effect by an aldehyde (CHO) group
:
..
..
O H
O H O H
O H
..
..
..
_
_
_
+
Electron donating phenolic hydroxyl group (OH)
..
..
..
+
..
+
..
The electron-donating resonance effect applies with decreasing strength in
the following order:
NH2 NR2 OH OR X
..
.. ..
....
..
..
..
:> > Least 
electron
donating
Most 
electron
donating
Why the \ufffd\ufffdCF3 group is meta directing
All meta-directing groups have either a partial positive charge or a full positive
charge on the atom directly linked to the benzene ring. In the trifluoromethyl
group (CF3), there are three electronegative fluorine atoms, which make this
group strongly electron withdrawing. As a result \ufffd\ufffdCF3 deactivates the benzene
CF3
E
H
CF3
E
H
CF3
E
H
CF3
E
H
CF3
E
H
CF3
E
H
CF3
CF3
E H E H
CF3
E H
CF3
+ E+
Trifluoromethylbenzene
\u2212CF3 is an electron-withdrawing group
ortho attack
meta attack
para attack
+ +
+
Highly unstable
contributor
+ +
+
Highly unstable contributor
+
+
+
4.6 AROMATIC COMPOUNDS AND THEIR DERIVATIVES 125
ring, and directs further substitutions to meta positions. The ortho