Vollhardt  Capítulo 16 (Ataque Eletrofílico + Benzeno)

Vollhardt Capítulo 16 (Ataque Eletrofílico + Benzeno)


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bonds between carbon and oxygen atoms, which occur in 
the important classes of compounds that contain the carbonyl group. We shall see that 
some of the electronic effects that occur in carbon\u2013carbon double bonds also occur in 
carbon\u2013oxygen double bonds, but other effects are unique to the polar carbonyl group. 
As a result, carbonyl chemistry is a rich and very important area of organic chemistry. 
Understanding reactions involving the carbonyl group is essential to understanding 
many areas of biochemistry, from the action of pharmaceuticals to the details of molecular 
genetics. We start in Chapter 17 with a discussion of the carbonyl group in aldehydes 
and ketones.
CHAPTER INTEGRATION PROBLEMS
16-28. Specifi cally substituted, functionalized benzenamines (anilines) are important synthetic inter-
mediates in medicinal chemistry and the dye industry. Propose a selective synthesis of 5-chloro-2-
methoxy-1,3-benzenediamine, B, from methoxybenzene, A.
Carcinogenic
Alkylating Agents and
Sites of Reactivity
CH2CH2Br Br
1,2-Dibromoethane
O
Oxacyclopropane
CH2OCH3Cl
Chloro(methoxy)methane
(Chloromethyl methyl ether)
 C h a p t e r 1 6 761
A B
OCH3 OCH
Cl
3
NH2H N2
SOLUTION
What are the feasible bond disconnections that lead to a simpler precursor to B directly\u2013a, b, or c? 
Our retrosynthetic analysis below (Section 8-9) answers the question: None. Retrosynthetic step a 
proposes a transformation that is impossible to achieve with our present repertory of reactions and, 
in fact, is very diffi cult even with special reagents (requiring a source of \u201cCH3O
1\u201d). Quite apart from 
this problem, step a appears unwise because it cleaves a bond that is given in the starting material. 
Step c is a reverse electrophilic chlorination (Section 15-9), feasible in principle but not in practice 
because no selectivity for the desired position at C5 can be expected. Thus, while CH3O directs para 
(and hence to C5) as wanted, the amino groups activate the other positions ortho, para (and hence to 
C4 and C6) even more (Section 16-3), ruling out step c as a good option, at least as such.
OCH
Cl
3
NH2H N2
Cl
NH2H N2
OCH3
NH2H N2
OCH3
Cl
a
b
c
a
c
b b
What about disconnection b? While direct electrophilic amination of arenes is (like alkoxylation 
or hydroxylation) not viable, we know that we can achieve it indirectly through a nitration\u2013reduction 
sequence (Section 16-5). Thus, the problem reduces to a nitration of 1-chloro-4-methoxybenzene. Will 
it proceed with the desired regioselectivity? Guideline 2 in Section 16-4 answers in the affi rmative. 
This analysis provides 1-chloro-4-methoxybenzene as a new relay point, available, in addition to its 
ortho isomer, by chlorination of methoxybenzene.
OCH
Cl
3 OCH
Cl
3 OCH3
NO2O N2
B
1-Chloro-4-
methoxybenzene
Therefore, a reasonable solution to our synthetic problem is that shown below as a proper syn-
thetic scheme, with reagents, synthetic intermediates, and forward arrows in place.
Solution Synthetic Scheme 1
OCH3 OCH
Cl
(\ufffd ortho
isomer)
3
Cl2, FeCl3 HNO3, H2SO4 H2, Ni
OCH3
Cl
NO2O N2
OCH3
Cl
NH2H N2
BA
C h a p t e r I n t e g r a t i o n P r o b l e m s
762 C h a p t e r 1 6 E l e c t r o p h i l i c A t t a c k o n D e r i v a t i v e s o f B e n z e n e
As a purist, you might not be satisfi ed with the lack of regiochemical control of the fi rst step, 
which not only cuts down on yields but also requires a cumbersome separation. Consideration of a 
blocking strategy employing a sulfonation may help (Section 16-5). SO3 is more bulky than chlorine 
and will furnish exclusively the para substitution product of electrophilic attack on methoxybenzene. 
Blocking the para position allows selective dinitration ortho to methoxy. After deblocking, the chlo-
rine can be introduced, as shown below.
Solution Synthetic Scheme 2
SO H3 SO H3
SO3, H2SO4
Cl2, FeCl3
HNO3, H2SO4
H2, Ni
H\ufffd, H2O, \ufffd
OCH3
NO2ON2
OCH3
NO2O N2
OCH
Cl
3
NO2O N2
OCH
Cl
3
NH2H N2
OCH3 OCH3
A
B
This sequence requires two additional steps and, in practice, overall yields, ease of experimentation, 
including work-up, disposal cost of waste, and the value and availability of starting materials will 
determine which route to take, Scheme 1 or Scheme 2.
16-29. Acid-catalyzed cascade reactions are employed by nature and also by synthetic chemists in 
the construction of complex polycyclic molecules, including steroids (Section 4-7). Provide a mechanism 
for the following multiple cyclization.
OH
A
BF3
CH3OCH3O
B
SOLUTION
This is a mechanistic and not a synthetic problem, and therefore we can use only what is given above. 
Let us look at the general features of this transformation. A starting material with only two rings is 
converted into a product with four rings by the making of two new C\u2013C bonds, and somewhere along 
the sequence, the hydroxy function is lost. The reagent BF3 is a Lewis acid (Section 2-2), \u201chungry\u201d 
for an electron pair, and the hydroxy oxygen is an obvious source for such. What are the exact changes 
in composition during the reaction? This question is answered by assessing the change in the 
respective molecular formulas: C19H26O2 turns into C19H24O. Thus, overall, the process constitutes a 
dehydration (2H2O).
After this general analysis, we can go about addressing the details of the mechanism. What 
do we anticipate to happen when a secondary (and allylic) alcohol is treated with a Lewis acid? 
Answer: (Allylic) carbocation (C) formation (Sections 9-2, 9-3, and 14-3):
 C h a p t e r 1 6 763
\ufffdOH
\ufffdBF3
BF3
CH3O
\ufffdA
CH3O
CH3O
\ufffd
\ufffd
C
What do we expect from a carbocation in the presence of a nearby double bond? Answer: electrophilic 
addition (Section 12-14) to form a new carbocation (D):
C
CH3OCH3O
D
\ufffd
\ufffd
While this answer satisfi es the structural requirements for proceeding on to the eventual fi nal 
product, we can ponder several questions regarding the selectivity of the formation of D. First, 
C contains two electrophilic sites. Why is only one picked? Answer: The less hindered carbon should 
react faster. Second, conversion to D makes a six-membered ring. Why not attack the other end of 
the double bond to give a fi ve-membered ring? Answer: The observed six-membered ring should be 
less strained (Section 4-3). And third, when going from C to D, a resonance-stabilized allylic carbo-
cation is converted into an \u201cordinary\u201d secondary cation. What is the driving force? Answer: A new 
carbon\u2013carbon bond is formed. Having arrived at D, we can recognize the last step as a Friedel-Crafts 
alkylation of an activated benzene, para to the directing methoxy group.
\ufffd
CH3O
D
CH3O
CH3O
\ufffd
\ufffd
B etc.
\ufffd\u161
\u161
H
H
\ufffdH\ufffd
C h a p t e r I n t e g r a t i o n P r o b l e m s
764 C h a p t e r 1 6 E l e c t r o p h i l i c A t t a c k o n D e r i v a t i v e s o f B e n z e n e
New Reactions
Electrophilic Substitution of Substituted Benzenes
1. Ortho- and Para-Directing Groups (Sections 16-1 through 16-3)
\ufffd
E\ufffd
E
Ortho isomer Para isomer
G G
E
G
(Usually predominates)
G \ufffd NH2, OH; strongly activating
 \ufffd NHCOR, OR; moderately activating
 \ufffd alkyl, aryl; weakly activating
 \ufffd halogen; weakly deactivating
2. Meta-Directing Groups (Sections 16-1 through 16-3)
E\ufffd
E
Meta isomer
G G
G \ufffd N(CH3)3, NO2, CF3, CqN, SO3H; very strongly deactivating
 \ufffd CHO, COR, COOH, COOR, CONH2; strongly deactivating
\ufffd
Synthetic Planning: Switching and Blocking of Directing Power
3. Interconversion of Nitro and Amino Groups (Section 16-5)
NO2 NH2
HCl, Zn(Hg) or H2, Ni or Fe, HCl 
CF3CO3H
Meta directing Ortho, para directing
4. Interconversion of Acyl and Alkyl (Section 16-5)
PRC O RCH2
H2, Pd, CH3CH2OH or
Zn(Hg), HCl, \ufffd 
CrO3, H2SO4, H2O 
Meta directing Ortho, para directing
 C h a p t e r 1 6 765
5. Blocking by Sulfonation (Section 16-5)
SO3, 
H2SO4
\ufffdH2SO4
Deblock
SO H3
Block
R R
SO H3
R
E
R
E
E\ufffd H2O, \ufffd
6. Moderation of Strong Activators by Protection (Section 16-5)