Vollhardt  Capítulo 16 (Ataque Eletrofílico + Benzeno)

Vollhardt Capítulo 16 (Ataque Eletrofílico + Benzeno)


DisciplinaQuímica Orgânica II1.666 materiais36.176 seguidores
Pré-visualização11 páginas
A t some time in your life you have probably ingested at least one of the painkillers aspirin, acetaminophen, naproxen, or ibuprofen, perhaps better known under one of their respective brand names, aspirin, Tylenol, 
Naprosyn, and Advil. Aspirin, acetaminophen, and ibuprofen are ortho- or para-
disubstituted benzenes; naproxen is a disubstituted naphthalene. How are such 
compounds synthesized? The answer is by electrophilic aromatic substitution.
Electrophilic Attack on 
Derivatives of Benzene
Substituents Control Regioselectivity
[ ]
Aspirin, prepared industrially 
by selective electrophilic 
aromatic substitution of phenol, 
is arguably the blockbuster drug 
of all times. Its active metabolite, 
2-hydroxybenzoic acid (salicylic 
acid), obtained from the bark of 
the white willow tree, has been 
used for four millennia for the 
treatment of infl ammation and 
to relieve pain or discomfort 
caused by arthritis, soft-tissue 
injuries, and fever. Aspirin was 
discovered by the German 
company Bayer in the late 19th 
century and ironically marketed 
together with another drug, heroin, 
whose addictive side effects 
were not recognized then.
O
O
O
O
COOH
2-Acetyloxybenzoic acid
(Aspirin)
OCCH3
O
B
OH
HNCCH3
N-(4-Hydroxyphenyl)acetamide
(Acetaminophen)
O
B
CH3O
OH
O
CH3
2-[2-(6-Methoxynaphthyl)]-
propanoic acid
(Naproxen)
OH
H3C
O
2-[4-(2-Methylpropyl)-
phenyl]propanoic acid
(Ibuprofen)
C H A P T E R S I X T E E N
732 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
 Chapter 15 described the use of this transformation in the preparation of monosubstituted 
benzenes. In this chapter we analyze the effect of such a fi rst substituent on the reactivity 
and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifi -
cally, we shall see that substituents on benzene can be grouped into (1) activators (electron 
donors), which generally direct a second electrophilic attack to the ortho and para positions, 
and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta 
positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such 
as the analgesics depicted on the previous page.
para
meta meta
orthoortho
Donor Acceptor
Activated ring Deactivated ring
16-1 Activation or Deactivation by Substituents on a 
Benzene Ring
In Section 14-8 we discussed the effect that substituents have on the effi ciency of the Diels-
Alder reaction: Electron donors on the diene and acceptors on the dienophile are benefi cial 
to the outcome of the cycloaddition. Chapter 15 revealed another manifestation of these 
effects: Introduction of electron-withdrawing substituents into the benzene ring (e.g., as in 
nitration) caused further electrophilic aromatic substitution (EAS) to slow down, whereas the 
incorporation of donors, as in the Friedel-Crafts alkylation, caused substitution to accelerate. 
What are the factors that contribute to the activating or deactivating nature of substituents 
in these processes? How do they make a monosubstituted benzene more or less susceptible 
to further electrophilic attack?
NO2 CH3
\ufffd \ufffd
Increasing rate of EAS
The electronic infl uence of any substituent is determined by an interplay of two effects 
that, depending on the structure of the substituent, may operate simultaneously: induction 
and resonance. Induction occurs through the s framework, tapers off rapidly with distance, 
and is mostly governed by the relative electronegativity of atoms and the resulting polariza-
tion of bonds (Tables 1-2 and 8-2). Resonance takes place through p bonds, is therefore 
longer range, and is particularly strong in charged systems (Section 1-5, Chapter 14).
Let us look at both of these effects of typical groups introduced by electrophilic aromatic 
substitution, starting with inductive donors and acceptors. Thus, simple alkyl groups, such 
as methyl, are donating by virtue of their hyperconjugating s frame, a phenomenon that we 
encountered earlier (Sections 7-5 and 11-5). On the other hand, trifl uoromethyl (by virtue 
of its electronegative fl uorines) is electron withdrawing. Similarly, directly bound hetero-
atoms, such as N, O, and the halogens (by virtue of their relative electronegativity), as well 
as positively polarized atoms, such as those in carbonyl, cyano, nitro, and sulfonyl functions, 
are inductively electron withdrawing.
 C h a p t e r 1 6 733
D
Donors D
D \ufffd \u2013CH3, other alkyl groups
A
Acceptors A
Inductive Effects of Some Substituents on the Benzene Ring
A \ufffd \u2013CF3, \u2013NR2, \u2013OR, \u2013X (\u2013F, \u2013Cl, \u2013Br, \u2013I),
CR,\ufffd\ufffd
\ufffd\ufffd \ufffd
\ufffd
\ufffd\ufffd
\ufffd\ufffd
\ufffd\ufffd
\ufffd\ufffd\ufffd
C NOO S
O
OHO ON
O
O
Oq ð, ,
ð ð
Oð ð
B
\ufffd\ufffdO
B
BH
K
\u161
ð
\ufffd
\u161\ufffd
Now we turn to substituents that resonate with the aromatic p system. Resonance donors 
bear at least one electron pair capable of delocalization into the benzene ring. Therefore, 
such groups as \u2013NR2, \u2013OR, and the halogens belong in that category. You will note that, 
inductively, these groups are electron withdrawing; in other words, here the two phenomena, 
induction and resonance, are opposing each other. Which one wins out? The answer depends 
on the relative electronegativity of the heteroatoms (Table 1-2) and on the ability of their 
respective p orbitals to overlap with the aromatic p system. For amino and alkoxy groups, 
resonance overrides induction. For the halogens, induction outcompetes resonance, making 
them weak electron acceptors.
Dð
ð
D\ufffd
Resonance Donation to Benzene
D \ufffd \u2013NR2, \u2013OR, \u2013F , \u2013Cl , \u2013Br , \u2013I
\ufffd
D\ufffd
\ufffd
D\ufffd
\ufffd
\ufffd
\ufffd
\ufffd
\ufffd \ufffd
\ufffd
\ufffd
\ufffd ð
\ufffd
\ufffd ð
\ufffd
\ufffd ð
\ufffd
\ufffd
Finally, groups bearing a polarized double or triple bond, whose positive (d1) end is 
attached to the benzene nucleus, such as carbonyl, cyano, nitro, and sulfonyl, are electron 
withdrawing through resonance.
B
B
\ufffd
A
A \ufffd
\ufffd
\ufffd \ufffd
\ufffd
)
))
Resonance Acceptance from Benzene
B CR,
O
B \ufffd
\ufffd
\ufffd\ufffd
\ufffd\ufffd
\ufffd\ufffd\ufffd
C NOO S
O
OHO ON
O
O
Oq , ,
) )
O) )
B
BH
K
>
)
p
>p
>p
EK B
A \ufffd)EB
A \ufffd)EB
A \ufffd)EB
A
)
Note that, here, resonance reinforces induction.
Electrostatic potential maps indicate the presence of electron-donating substituents by 
depicting the benzene ring as shaded relatively red; electron-withdrawing groups make the 
benzene ring appear shaded relatively blue (green).
1 6 - 1 A c t i v a t i o n o r D e a c t i v a t i o n b y S u b s t i t u e n t s
734 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
Benzene Methylbenzene
(Toluene)
Benzenamine
(Aniline)
Nitrobenzene
How do we know whether a substituent functions as a donor or acceptor? In electrophilic 
aromatic substitution, the answer is simple. Because the attacking species is an electrophile, 
the more electron rich the arene, the faster the reaction. Conversely, the more electron poor 
the arene, the slower the reaction. Hence, electron donors activate the ring, whereas electron 
acceptors deactivate.
Exercise 16-3
Specify whether the benzene rings in the compounds below are activated or deactivated.
(a) 
CH2CH3
CH2CH3
 
(b) 
NO2
CH3
 
(c) 
CF3
CO2H
 
(d) 
N(CH3)2
OCH3
Exercise 16-2
The 13C NMR spectrum of phenol, C6H5OH, shows four lines at d 5 116.1 (C2), 120.8 (C4), 
130.5 (C3), and 155.6 (C1) ppm. Explain these assignments. (Hint: The 13C chemical shift for 
benzene is d 5 128.7 ppm.)
Exercise 16-1
Explain the 1H NMR spectral assignments in Figures 15-11 and 15-12. (Hint: Draw resonance 
structures involving the substituents on the benzene ring.)
In Summary When considering the effect of substituents on the reactivity of the benzene 
nucleus, we have to analyze the contributions that occur by induction and resonance. We can 
group these substituents into two classes: (1) electron donors, which accelerate electrophilic 
aromatic substitutions relative to benzene, and (2) electron acceptors, which retard them.
16-2 Directing Inductive Effects of Alkyl Groups