22-1 chapter 22 reaction of benzene and its derivatives
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22-22-11
Chapter 22Chapter 22
Reaction ofReaction ofBenzene and Benzene and its Derivativesits Derivatives
22-22-22
Reactions of BenzeneReactions of Benzene
Substitution at a ring carbon.
+ +
Chlorobenzene
Halogenation:
H ClCl2FeCl3 HCl
++
Nitrobenzene
Nitration:
H NO2HNO3H2 SO4
H2 O
Contrast to radical mechanism for benzylic hyrdogens
22-22-33
Reactions of BenzeneReactions of Benzene
+
Benzenesulfonic acid
Sulfonation:
H SO3HSO3H2 SO4
++
An alkylbenzene
Alkylation:
RRXAlX3 HX
++
Acylation:
An acylbenzene
H RCX AlX3 HXO
CRO
H
Friedel Crafts
Friedel Crafts
22-22-44
Electrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution
ElectrophilicElectrophilic aromatic substitution: aromatic substitution:
We study several common electrophiles• how each is generated.• the mechanism by which each replaces hydrogen.
++H E
E+
H+
22-22-55
EAS: General MechanismEAS: General Mechanism
A general mechanism
General question: What are the electrophiles and how are they generated? Look at particular reactions.
+ E+HE
H+slow, rate
determiningStep 1:
Step 2:E
H+
fast + H+E
Electro- phile
Resonance-stabilized cation intermediate
22-22-66
ChlorinationChlorination
Step 1: Generation of the electrophile: a chloronium ion.
Step 2: Attack of the chloronium ion on the ring.
+
+
+
Resonance-stabilized cation intermediate; the positivecharge is delocalized onto three atoms of the ring
+
slow, ratedetermining
Cl
HH
Cl
H
Cl
Cl
Cl Cl ClCl
ClFe
Cl
Cl
ClFeClCl Cl FeCl4+
A molecular complex with a positive charge
on chlorine
Ferric chloride(a Lewis
acid)
Chlorine(a Lewis
base)
++
An ion pair containing a
chloronium ion
22-22-77
ChlorinationChlorination
Step 3: Proton ejection regenerates the aromatic character of the ring.
Cl
HCl-FeCl3 Cl HCl FeCl3
Chlorobenzene
fast
Cation intermediate
++
+-
+
22-22-88
Addition vs SubstitutionAddition vs Substitution
Energy diagram for the bromination of benzene.
22-22-99
Nitration (Nitric and Sulfuric Acids)Nitration (Nitric and Sulfuric Acids)
Generation of the nitronium ion, NO2+
• Step 1: Proton transfer to nitric acid.
• Step 2: Loss of H2O gives the nitronium ion, a very strong electrophile. Dehydrated nitric acid.
HSO3 O H H O NO
OHSO4 O N
O
OH
H
Conjugate acidof nitric acid
+ +
Sulfuricacid
Nitricacid
The nitroniumion
O NO
OH
HO
H
H+ O N O
22-22-1010
Nitration, Nitration,
Step 1: Attack of the nitronium ion) on the aromatic ring.
Step 2: Proton transfer regenerates the aromatic ring.
OH
HO
H
H
HH NO2NO2
OH
HHO
H
HH+ ++ + ++
H NO2 NO2H H NO2
++
+
+
Resonance-stabilized cation intermediate
O N O+
Attack of electrophile as before…..
22-22-1111
Synthesis, Nitro Synthesis, Nitro AminesAmines
The nitro group can be reduced to a 1° amino group.
COOH
NO2
3H2Ni
COOH
NH2
2H2O
4-Aminobenzoic acid4-Nitrobenzoic acid
+(3 atm) +
Notice the carboxylic was untouched.
22-22-1212
SulfonationSulfonation
Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide.
Benzenesulfonic acidBenzene
+ SO3HSO3H2 SO4
22-22-1313
Friedel-Crafts AlkylationFriedel-Crafts Alkylation
Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group.
ClAlCl3
HCl+
Benzene 2-Chloropropane(Isopropyl chloride)
Cumene(Isopropylbenzene)
+
22-22-1414
Friedel-Crafts AlkylationFriedel-Crafts Alkylation
Step 1: Formation of an alkyl cation as an ion pair.
Step 2: Attack of the alkyl cation.
Step 3: Proton transfer regenerates the aromatic ring.
+ R+
R
H
R
H
R
H
A resonance-stabilized cation
+
+
+
H
RCl AlCl3 R AlCl3 HCl+ ++
R Cl ClAlCl
Cl
R Cl
Cl
ClAl Cl R+ AlCl4
-
An ion pair containing a carbocation
+-
+
A molecular complex
22-22-1515
Friedel-Crafts AlkylationFriedel-Crafts Alkylation
There are four major limitations on Friedel-Crafts alkylations:1. Carbocation rearrangements are common
+
Isobutylchloride
tert-ButylbenzeneBenzene
AlCl3+ HClCl
CH3CHCH2-Cl
CH3
AlCl3 CH3C-CH2-Cl-AlCl3
CH3
H
CH3C+ AlCl4-
CH3
CH3
Isobutyl chloride
+-
+
a molecularcomplex
an ion pair
22-22-1616
Friedel-Crafts AlkylationFriedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron-withdrawing groups.
Y
RXAlCl3
SO3H NO2 NR3+
CF3 CCl3
C N
CHO
CRO
COHO
CORO
CNH2
O
+ No reaction
When Y Equals Any of These Groups, the BenzeneRing Does Not Undergo Friedel-Crafts Alkylation
22-22-1717
Friedel-Crafts AlkylationFriedel-Crafts Alkylation
3. F-C multiple alkylation can occur more rapidly than monoalkylation. The first alkyl group activates the ring to the second substitution.
CH3Cl
AlCl3
4. The steps in the Friedel Crafts Alkylation are reversible and rearrangments may occur.
CH3Cl
AlCl3
AlCl3
22-22-1818
Friedel-Crafts Friedel-Crafts AcylationAcylation
Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group.
OCl
CH3CClO
AlCl3
AlCl3
O
O
HCl
HCl+
Benzene AcetophenoneAcetylchloride
4-Phenylbutanoylchloride
-Tetralone
+
+
22-22-1919
Friedel-Crafts AcylationFriedel-Crafts Acylation
The electrophile is an acylium ion.
R-C ClO
Cl
ClAl-Cl
OR-C Cl Al Cl
Cl
Cl
O
R-C+ AlCl4-
Aluminumchloride
An acyl chloride
A molecular complexwith a positive charge
charge on chlorine
An ion pair containing an acylium ion
+ -
••
•• •• +(1)
(2)
••••
22-22-2020
Friedel-Crafts AcylationFriedel-Crafts Acylation
• An acylium ion is represented as a resonance hybrid of two major contributing structures.
Friedel-Crafts acylations are free of major limitation of Friedel-Crafts alkylations; acylium ions do not rearrange, do not polyacylate (why?), do not rearrange.
:+ +
complete valence shells
The more importantcontributing structure
O OR-C R-C::
22-22-2121
Synthesis, Synthesis, Friedel-Crafts AcylationFriedel-Crafts Acylation
preparation of unrearranged alkylbenzenes.
+AlCl3
N2H4, KOHdiethylene glycol Isobutylbenzene2-Methyl-1-
phenyl-1-propanone
2-Methylpropanoyl chloride
Cl
O
O
What else could be used here?
22-22-2222
Other Aromatic AlkylationsOther Aromatic Alkylations
Carbocations are generated by • treatment of an alkene with a proton acid, most
commonly H2SO4, H3PO4, or HF/BF3.
• treating an alkene with a Lewis acid.
CH3CH=CH2H3PO4
Benzene Propene Cumene
+
+
Benzene Cyclohexene Phenylcyclohexane
AlCl3
22-22-2323
Other Aromatic AlkylationsOther Aromatic Alkylations
• and by treating an alcohol with H2SO4 or H3PO4.
+
Benzene
H3PO4+ H2O
2-Methyl-2-propanol(tert-Butyl alcohol)
HO
2-Methyl-2-phenylpropane
(tert-Butylbenzene)
22-22-2424
Di- and PolysubstitutionDi- and Polysubstitution
Orientation on nitration of monosubstituted benzenes.
OCH3
Cl
Br
COOH
CN
NO2
ortho meta paraortho +para meta
44 - 55 99 trace
70 - 30 100 trace
37 1 62 99 1
18 80 2 20 80
19 80 1 20 80
6.4 93.2 0.3 6.7 93.2
Substituent
CH3 58 4 38 96 4Favor ortho/para substitution
Favor ortho/para substitution
Favor ortho/para substitution
Favor meta substitution
22-22-2525
Directivity of substituentsDirectivity of substituents
XXX X
E
E
E
E
+ +
ortho and para, appear together X is o,p director
metaX is m director
22-22-2626
Di- and PolysubstitutionDi- and Polysubstitution
Two ways to characterize the substituent • Orientation:
• Some substituents direct preferentially to ortho & para positions; others to meta positions.
• Substituents are classified as either ortho-para directingortho-para directing or meta directing meta directing toward further substitution.
• Rate• Some substituents cause the rate of a second substitution to
be greater than that for benzene itself; others cause the rate to be lower.
• Substituents are classified as activatingactivating or deactivatingdeactivating toward further substitution.
22-22-2727
Di- and PolysubstitutionDi- and Polysubstitution
• -OCH3 is ortho-para directing.
• -COOH is meta directing.
OCH3
HNO3 CH3COOH
OCH3NO2
OCH3
NO2
H2O
p-Nitroanisole (55%)
o-Nitroanisole (44%)
Anisole
+++
COOH
HNO3H2SO4
NO2
COOH COOH
NO2NO2
COOH
100°C
m-Nitro-benzoic
acid(80%)
Benzoicacid
+ ++
o-Nitro-benzoic
acid(18%)
p-Nitro-benzoic
acid(2%)
22-22-2828
Di- and PolysubstitutionDi- and Polysubstitution
Weakly activating
Ort
ho-p
ara
Dir
ect
ing
Weakly deactivating
Moderately activating
Strongly activating NH2 NHR NR2 OH
NHCR NHCAr
OR
OCArOCR
R
F Cl Br I
: : : : :::
: : ::
::
::
::
::
:: ::::
Strongly deactivating
Moderately deactivating
CH
O O
CR COH
SO3H
CORO
CNH2
NO2 NH3+ CF3 CCl3M
eta
Dir
ect
ing
C N
O O O O
OO
Recall the polysubstitution in FC alkylation.
22-22-2929
Di- and PolysubstitutionDi- and Polysubstitution
Generalizations:• Directivity: Alkyl, phenyl, and all substituents in which
the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other substituents are meta directing.
• Activation: All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating.
22-22-3030
Di- and PolysubstitutionDi- and Polysubstitution
• The order of steps is important.
CH3
K2Cr2O7
H2SO4
HNO3
H2SO4
CH3
NO2
COOH
H2SO4
HNO3
K2Cr2O7
H2SO4
COOH
NO2
COOH
NO2
m-Nitrobenzoicacid
p-Nitrobenzoic acid
22-22-3131
Theory of Directing EffectsTheory of Directing Effects
The rate of EAS is limited by the slowest step in the reaction.
For almost every EAS, the rate-determining step is attack of E+ on the aromatic ring to give a resonance-stabilized cation intermediate.
The more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction.
22-22-3232
Theory of Directing EffectsTheory of Directing Effects
The orientation is controlled by the stability of the carbocation being formed by attack of the electrophile.
Products are formed under kinetic control.
22-22-3333
Theory of Directing Effects, ortho-para director.Theory of Directing Effects, ortho-para director.
• -OCH3: assume ortho-para attack. Here only para attack is shown.
OCH3
NO2+
fast
+
(d) (e) (f)
OCH3
H NO2
OCH3
H NO2
OCH3
H NO2
OCH3
H NO2
OCH3
NO2
-H+
+
slow
+
+
+
(g)
::::
: : :
Very stable resonance structure. Why?
o,p director
22-22-3434
Theory of Directing Effects , ortho-para director.Theory of Directing Effects , ortho-para director.
• -OCH3; look at meta attack.OCH3
NO2+
OCH3
NO2
H
OCH3
NO2
H
OCH3
NO2
H
slow
fast-H+
+
OCH3
NO2+
++
(a) (b) (c)
No corresponding resonance structure putting positive charge on oxygen.
o,p director
22-22-3535
Theory of Directing Effects, meta director.Theory of Directing Effects, meta director.
• -CO2H : assume ortho-para attack.
COOH
NO2+
COOH
H NO2
COOH
H NO2
COOH
H NO2
-H+
COOH
NO2
+ slow
fast
(d) (e) (f)The most disfavoredcontributing structure
Meta director
Disfavored because CO2H is electron withdrawing
22-22-3636
Theory of Directing Effects, meta director.Theory of Directing Effects, meta director.
• -CO2H; assume meta attack.
COOH
NO2+
COOH
H
NO2
COOH
H
NO2
COOH
H
NO2
-H+
COOH
NO2
+ slow
fast
(a) (b) (c)
Meta director
22-22-3737
Activating-DeactivatingActivating-Deactivating ResonanceResonance Effects Effects
Any resonance effectAny resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation by has an activating effect toward further EAS.
Any resonance effectAny resonance effect, such as that of -NO2, -CN, -C=O, and -SO3H, that decreases electron density on the ring deactivates the ring toward further EAS.
22-22-3838
Activating-DeactivatingActivating-Deactivating InductiveInductive Effects Effects
Any inductive effectAny inductive effect, such as that of -CH3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS.
Any inductive effectAny inductive effect, such as that of halogen, -NR3
+, -CCl3, or -CF3, that decreases electron density on the ring deactivates the ring toward further EAS.
22-22-3939
Activating-Deactivating: Activating-Deactivating: HalogensHalogens
• For the halogens, the inductive and resonance effects oppose each other. Inductive is somewhat stronger.
• Result: halogens are deactivating but ortho-para directing.
++
+E
HClCl Cl
H
EE
+
::
:: :: ::
22-22-4040
Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution
Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 pathways.
They do undergo nucleophilic substitutions, but
by two mechanisms.• Benzyne using strong base.• Addition/elimination typically with nitro activating
groups.
22-22-4141
BenzyneBenzyne Intermediates Intermediates
When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide.• Neutralization with HCl gives phenol.
Cl
2NaOHH2O
O-Na
+
NaCl H2O
Sodium phenoxide
Chloro-benzene
++pressure, 300oC
+
22-22-4242
Benzyne Intermediates (strong base) Benzyne Intermediates (strong base)
• The same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol.
• The same type of reaction can be brought about using sodium amide in liquid ammonia.
3-Methylphenol(m-Cresol)
2-Methylphenol(o-Cresol)
+
CH3Cl OH
CH3 CH3
OH
1. NaOH, heat, pressure
2. HCl, H2O
CH3
Cl
NaNH2NH3(l)
CH3
NH2
CH3
NH2
NaCl
3-Methylaniline (m-Toluidine)
4-Methylaniline (p-Toluidine)
++(-33oC)
+
22-22-4343
Benzyne IntermediatesBenzyne Intermediates
• -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products.
H
CH3
Cl
NaNH2
CH3
A benzyneintermediate
-elimin-ation
CH3
+
CH3
NH2
NH2
NH2-
CH3
+
CH3
NH2
NH2
NH2-
22-22-4444
Benzyne IntermediatesBenzyne Intermediates
But wait, do we believe this crazy idea? We need some evidence….
Cl
* NaNH2
NH2
*
NH2
*+
47% 53%
Cl
CH3H3CO
NaNH2NR
A
B
22-22-4545
Benzyne IntermediatesBenzyne Intermediates
D
F
H
F
NaNH2
NH3
but
D
Br
D
NH2
NaNH2
NH3
NH2rapid
slow
+
H
NH2NH2
D
+
C
next
The deuterated fluoride below exchanges the D with solvent ammonia although the deuterated bromide does not. This indicates a relatively rapid exchange process for the fluoro compound.
22-22-4646
Benzyne IntermediatesBenzyne Intermediates
X
+ NH2-
H
X
k1
k-1
X
k2
+ NH3
X = F k-1 >> k2
X = Br k-1 << k2
explanation
22-22-4747
OrientationOrientation
The methyl group is essentially just a marker to allow the observation of the mixture of products.
Consider the methoxy group, -OCH3, stabilizing of positive charge via resonance but also inductively withdrawing.
The methoxy group is not in resonance with the negative charge of the anion, Inductive Effect dominates. Next slide.
22-22-4848
Benzyne IntermediatesBenzyne Intermediates
D
OCH3
Br
OCH3
NH2
and
OCH3OCH3
NH2
Br
NaNH2
NaNH2
Get same product Explation
next
22-22-4949
Benzyne IntermediatesBenzyne Intermediates
OCH3
Br
OCH3
Br
NaNH2
NaNH2
H
OCH3
Br
only H to remove
preferred due to inductive effect
OCH3
Br
H
OCH3
NH2-
OCH3
NH2-
OCH3
NH2
preferred due to inductive effect
explanation
22-22-5050
Addition-Elimination (nitro groups)Addition-Elimination (nitro groups)
• When an aryl halide contains electron-withdrawing NO2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily.
• Neutralization with HCl gives the phenol.
ClNO2
NO2
Na2CO3, H2O
O- Na
+
NO2
NO2
100oC
Sodium 2,4-dinitro- phenoxide
1-Chloro-2,4-dinitrobenzene
22-22-5151
Meisenheimer ComplexMeisenheimer Complex
• Reaction involves formation of reactive intermediate called a Meisenheimer complex.
N Cl
NO2
O
O
Nu-
Cl
NuN
O
ONO2
N
O
O
NO2
Nu :Cl -fast
slow, ratedetermining
++
+ + +
A Meisenheimer complex
(1)
(2)
Similar to nucleophilic subsititution on carboxylic acid derivatives.
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