Vollhardt  Capítulo 15 (Benzenos e Aromaticidade)

Vollhardt Capítulo 15 (Benzenos e Aromaticidade)


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infections)
H2N SO2NH
Sulfadiazine
N
N
(Antimalarial)
H2N SO2NH
N O
CH3
ANIM
ATION ANIMATED MECHANISM: 
Electrophilic aromatic 
sulfonation of benzene
1 5 - 1 0 N i t r a t i o n a n d S u l f o n a t i o n o f B e n z e n e
708 C h a p t e r 1 5 B e n z e n e a n d A r o m a t i c i t y
About 15,000 sulfa derivatives have been synthesized and screened for antibacterial activity; 
some have become new drugs. With the advent of newer generations of antibiotics, the 
medicinal use of sulfa drugs has greatly diminished, but their discovery was a milestone in 
the systematic development of medicinal chemistry.
Exercise 15-25
Formulate mechanisms for (a) the reverse of sulfonation; (b) the hydration of SO3.
In Summary Nitration of benzene requires the generation of the nitronium ion, NO21, 
which functions as the active electrophile. The nitronium ion is formed by the loss of water 
from protonated nitric acid. Sulfonation is achieved with fuming sulfuric acid, in which 
sulfur trioxide, SO3, is the electrophile. Sulfonation is reversed by hot aqueous acid. 
 Benzenesulfonic acids are used in the preparation of detergents, dyes, compounds contain-
ing leaving groups, and sulfa drugs.
15-11 Friedel-Crafts Alkylation
None of the electrophilic substitutions mentioned so far has led to carbon \u2013 carbon bond 
formation, one of the primary challenges in organic chemistry. In principle, such reactions 
could be carried out with benzene in the presence of a suffi ciently electrophilic carbon-based 
electrophile. This section introduces the fi rst of two such transformations, the Friedel-Crafts* 
reactions. The secret to the success of both processes is the use of a Lewis acid, usually 
aluminum chloride. In the presence of this reagent, haloalkanes attack benzene to form 
alkylbenzenes.
In 1877, Friedel and Crafts discovered that a haloalkane reacts with benzene in the 
presence of an aluminum halide. The resulting products are the alkylbenzene and hydrogen 
halide. This reaction, which can be carried out in the presence of other Lewis acid catalysts, 
is called the Friedel-Crafts alkylation of benzene.
Friedel-Crafts Alkylation
\ufffd
H
AlX
R
RX \ufffd HX
3
The reactivity of the haloalkane increases with the polarity of the C \u2013 X bond in the order 
RI , RBr , RCl , RF. Typical Lewis acids are BF3, SbCl5, FeCl3, AlCl3, and AlBr3.
H
Friedel-Crafts Alkylation of Benzene with Chloroethane
AlCl , 25°C
CH2CH3
\ufffd HCl \ufffdCH3CH2Cl
28%
Ethylbenzene
3
*Professor Charles Friedel (1832 \u2013 1899), Sorbonne, Paris; Professor James M. Crafts (1839 \u2013 1917), 
Massachusetts Institute of Technology, Cambridge, MA.
REACTION
 C h a p t e r 1 5 709
With primary halides, the reaction begins with coordination of the Lewis acid to the 
halogen of the haloalkane, much as in the activation of halogens in electrophilic halogena-
tion. This coordination places a partial positive charge on the carbon bearing the halogen, 
rendering it more electrophilic. Attack on the benzene ring is followed by proton loss in 
the usual manner, giving the observed product.
Mechanism of Friedel-Crafts Alkylation with Primary Haloalkanes
Step 1. Haloalkane activation
\ufffd AlX3)Xp
p
RCH2 )Xp
p
) AlX3
+
_
RCH2
\ufffd\ufffd
Step 2. Electrophilic attack
CH2R \ufffd AlX4
\ufffd\ufffd
HAlX3
f
i
H2C
>XpO
R
+
+
\ufffd\ufffd
\ufffd
Step 3. Proton loss
XHðXp
\ufffd
CH2R
\ufffd\ufffd AlX3AlX3O\ufffd
\ufffd
CH2R
H
With secondary and tertiary halides, free carbocations are usually formed as intermediates; 
these species attack the benzene ring in the same way as the cation NO2
1.
1 5 - 1 1 F r i e d e l - C r a f t s A l k y l a t i o n
MECHANISM
Exercise 15-26
Write a mechanism for the formation of (1,1-dimethylethyl)benzene (tert-butylbenzene) from 
2-chloro-2-methylpropane (tert-butyl chloride), benzene, and catalytic AlCl3.
Intramolecular Friedel-Crafts alkylations can be used to fuse a new ring onto the ben-
zene nucleus.
31%
Tetralin
(Common name)
Cl
, CS2AlCl3 and CH
\ufffdHCl
(solvents), 25\ufffdC, 72 hNO3 2
An Intramolecular Friedel-Crafts Alkylation
H
Friedel-Crafts alkylations can be carried out with any starting material that functions as 
a precursor to a carbocation, such as an alcohol or alkene (Sections 9-2 and 12-3).
710 C h a p t e r 1 5 B e n z e n e a n d A r o m a t i c i t y
Friedel-Crafts Alkylations Using Other Carbocation Precursors
CH2
H
CH CH3 CH3\ufffd
\ufffd 36%
(1-Methylpropyl)benzene
BF3
\ufffdHOH
, 60\ufffdC, 9 h
\ufffd
\ufffd
62%
Cyclohexylbenzene
HF, 0\ufffdC
OH
H
H
CH2CH CH3 CH3
H
Forms CH3CH2CHCH3
Forms
Friedel-Crafts vinylations or arylations employing haloalkenes or haloarenes do not work 
(margin). The reason is that the corresponding cations are energetically inaccessible 
(Sections 13-9 and 22-10).
Unreactive Halides
in the Friedel-
Crafts Alkylation
Cl
Br Exercise 15-27
In 2007, more than 3.7 million tons of (1-methylethyl)benzene (isopropylbenzene or cumene), an 
important industrial intermediate in the manufacture of phenol (Section 22-4), was synthesized in 
the United States from propene and benzene in the presence of phosphoric acid. Write a mechanism 
for its formation in this reaction.
Exercise 15-28
Working with the Concepts: Reversible Friedel-Crafts Alkylations
Heating any of the three isomeric dimethylbenzenes with HF in the presence of BF3 to 80
oC leads 
to the equilibrium mixture shown below. Formulate a mechanism for these isomerizations, starting 
with 1,2-dimethylbenzene and simply using H1 to represent the acid. Why is the equilibrium 
concentration of the 1,2-isomer the lowest?
CH3
18%
1,2-Dimethylbenzene
(o-Xylene)
CH3
CH3
58%
1,3-Dimethylbenzene
(m-Xylene)
CH3
CH3
CH3
24%
1,4-Dimethylbenzene
(p-Xylene)
Strategy
Topologically, these isomerizations are reminiscent of alkyl shifts, which we studied earlier in 
connection with carbocation rearrangements (Section 9-3). To generate a carbocation from a ben-
zene derivative, we protonate with acid (Section 15-8, Exercises 15-23 and 15-24). Protonation 
can occur anywhere on the ring and is reversible.
 C h a p t e r 1 5 711
In Summary The Friedel-Crafts alkylation produces carbocations (or their equivalents) capa-
ble of electrophilic aromatic substitution by formation of aryl \u2013 carbon bonds. Haloalkanes, 
alkenes, and alcohols can be used to achieve aromatic alkylation in the presence of a Lewis 
or mineral acid.
Solution
\u2022 There are three possible distinct delocalized carbocations (write them), but the one of interest 
results from protonation at the methyl-bearing carbon, shown below as its resonance forms.
CH3
CH3
CH3
A
H\ufffd
\ufffd
CH3
\ufffd
CH3
\ufffd
CH3
H/
\u2211 CH3
H/
\u2211 CH3
H/
\u2211
\u2022 Inspection of the resonance contributors reveals that one of them, form A, looks exactly like the 
type of carbocation drawn in Section 9-3 for H and alkyl shifts.
\u2022 Execution of a methyl shift from A gives a new carbocation, which can deprotonate to give 
1,3-dimethylbenzene.
CH3 CH3
CBA
\ufffd H\ufffd
H H H
HH
H H H
\ufffd
\ufffd
CH3
\ufffd
CH3
CH3H
\ufffd
1,3-Dimethylbenzene
\ufffd H\ufffd
1,4-Dimethylbenzene
CH3
H/
\u2211
CH3
H
/
\u2211 CH3
H
/
\u2211
/\u2211
Alternatively, another methyl shift (best visualized from resonance form B) gives C, which then 
loses a proton to give the 1,4-isomer. Therefore, the mechanism is indeed a sequence of simple 
alkyl shifts occurring in protonated benzene.
\u2022 Why is 1,2-dimethylbenzene the minor component of the mixture? You have probably guessed 
the answer: steric hindrance, like that seen in cis alkenes (Figure 11-13).
1 5 - 1 1 F r i e d e l - C r a f t s A l k y l a t i o n
Exercise 15-29
Try It Yourself
Intramolecular Friedel-Crafts alkylation of A provided