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Chapter 12Chapter 12Reactions of Arenes:Reactions of Arenes:
Electrophilic and NucleophilicAromatic Electrophilic and NucleophilicAromatic SubstitutionSubstitution
HH
EE
++ EE YY ++ HH YY++ ––
XX
NuNu
++ :Nu:Nu-- ++ :X:X--
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
12.1Representative Electrophilic Aromatic
Substitution Reactions of Benzene HH
EE
++ EE YY ++ HH YY++ ––
H
E
+ E Y + H Y+ –
Electrophilic aromatic substitutions (EAS) include:
1. Halogenation
2. Nitration
3. Sulfonation
4. Friedel-Crafts Alkylation
5. Friedel-Crafts Acylation
H
Table 12.1: Halogenation of Benzene
+ + HBr
FeBr3
Br2
Br
Bromobenzene(65-75%)
heat
Note: This reaction does not go via a radical mechanism like halogenation of alkanes nor does it proceed spontaneously like halogenation of alkenes, it requires a Lewis acid catalyst and heat.
H
Table 12.1: Nitration of Benzene
+ + H2O
H2SO4
HONO2
NO2
Nitrobenzene(95%)
heat
H
Table 12.1: Sulfonation of Benzene
+ + H2O
heatHOSO2OH
SO2OH
Benzenesulfonic acid(100%)
fuming
Note: fuming H2SO4 contains dissolved SO3.
H
Table 12.1: Friedel-Crafts Alkylation of Benzene
+ + HCl
AlCl3
C(CH3)3
tert-Butylbenzene(60%)
(CH3)3CCl~00 C
Note: Once attached, the alkyl group activates the ring.
H
Table 12.1: Friedel-Crafts Acylation of Benzene
+ + HCl
AlCl3
1-Phenyl-1-propanone(88%)
O
CH3CH2CCl
CCH2CH3
O
~00 C
Note: Once attached, the alkyl group deactivates the ring.
12.212.2Mechanistic PrinciplesMechanistic Principles
ofofElectrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution
Step 1: Attack of Electrophileon -electron System of Aromatic Ring H H
H HH H
E+ H H
HH
H H E
+
A highly endothermic step (need to overcome the resonance energy of the ring).
The carbocation is allylic, but the ring has lost aromatic character.
Step 2: Loss of a Proton from the CarbocationIntermediate
H H
HH
H H E
+
The second step is highly exothermic; this step restores the aromatic character of the ring and the resonance energy is regained. In this step, the proton is always removed from the carbon to which the electrophile added.
H H
H EH H
H+
HH
H H
H + E+
H
EH
H H
H + H+
H
H H
HH
H H E
+
Energy diagram for the two step EAS reaction.
Based on this General Mechanism:
Identify the electrophile in each EAS reaction: nitration,
sulfonation,
halogenation,
Friedel-Crafts alkylation, and
Friedel-Crafts acylation.
Establish the mechanism of each specific electrophilic aromatic substitution reaction.
12.3Nitration of Benzene
H
Nitration of Benzene
+ + H2O
H2SO4
HONO2
NO2
Electrophile isnitronium ion.
O N O••
+
•••• ••
heat
Where does Nitronium Ion Come From ?
H2SO4
ON
H
O
O
+•• ••
••••
•• ••••
–O
N
H
O
O
+•• ••
••
•• ••••
–
H
+
O N O••
+
•••• •• + H
O••H
••
H2SO4 is a stronger acid than HNO3 and forces it to take a proton.
Step 1: Attack of Nitronium Cationon the -electron system of the Aromatic Ring H H
H HH H
NO2+
H H
HH
H H NO2
+
Step 2: Loss of a Proton from the Carbocation Intermediate
H H
HH
H H NO2
+
H H
H NO2
H H
H+
12.4Sulfonation of Benzene
H
Sulfonation of Benzene
+ + H2O
heatHOSO2OH
SO2OH
The major electrophile is sulfur trioxide, SO3.
OS
O
O
+•• ••
••••
•• ••••
–
Step 1: Attack of Sulfur Trioxide on the -electron system of the Aromatic Ring H H
H HH H
SO3 H H
HH
H H SO3–
+
Step 2: Loss of a Proton from the Carbocation Intermediate
H H
H SO3–
H H
H+
H H
HH
H H SO3–
+
Step 3: Protonation of the Benzenesulfonate Ion
H H
H SO3–
H H
H2SO4
H H
H SO3HH H
This is the only EAS reaction that is reversible.
12.5Halogenation of Benzene(See the note on slide 4.)
H
Halogenation of Benzene
+ + HBr
FeBr3
Br2
Br
Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2.
heat
The Br2-FeBr3 Complex
+••Br Br•••• ••
•• ••
Lewis base Lewis acid
FeBr3
Br Br•••• ••
•• ••FeBr3
–+
Complex
The Br2-FeBr3 complex is more electrophilic than Br2 alone.
Step 1: Attack of Br2-FeBr3 Complex on the -electron System of the Aromatic Ring
H H
H HH H
Br Br FeBr3
–+ H H
HH
H H Br
+
+ FeBr4
–
Step 2: Loss of a Proton from the Carbocation Intermediate
H H
HH
H H Br
+
H H
H BrH H
H+
12.6Friedel-Crafts Alkylation of Benzene
H
Friedel-Crafts Alkylation of Benzene
+ + HCl
AlCl3
C(CH3)3
(CH3)3CCl
Electrophile is tert-butyl cation. C CH3
H3C
H3C+
AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide.
Role of AlCl3
(CH3)3C Cl ••••
••+ AlCl3
+
(CH3)3C Cl••
••AlCl3–
(CH3)3C+
Cl••
••AlCl3–
••+
Step 1: Attack of tert-Butyl carbocationon the -electron System of the Aromatic Ring H H
H HH H
H H
HH
H H C(CH3)3
+
C(CH3)3+
Step 2: Loss of a Proton from the Carbocation Intermediate
H H
H C(CH3)3
H H
H+
H H
HH
H H C(CH3)3
+
Rearrangements in Friedel-Crafts Alkylation
Carbocations are intermediates in this mechanism, therefore, rearrangements can occur. Here, isobutyl chloride is the alkyl halide, but tert-butyl cation is the electrophile due to rearrangement.
H
(CH3)2CHCH2ClAlCl3
Isobutyl chloride tert-Butylbenzene(66%)
C(CH3)3
+
Rearrangements in Friedel-Crafts Alkylation
•
•C CH2
H3C
CH3
H
Cl••
AlCl3+ –
C CH2H3C
CH3
H+
+ Cl••
••AlCl3–
••
Alkyl halide:AlCl3 complex.
Rearrangedalkyl carbocation.
H
Reactions Related to Friedel-Crafts Alkylation
H2SO4
+
Cyclohexylbenzene(65-68%)
Cyclohexene is protonated by sulfuric acid, to give the cyclohexyl carbocation which attacks the benzene ring.
12.7Friedel-Crafts Acylation of Benzene
H
Friedel-Crafts Acylation of Benzene
+ + HCl
AlCl3O
CH3CH2CCl
CCH2CH3
O
Electrophile is an acyl carbocation (an acylium ion).
••CH3CH2C O ••
+CH3CH2C O ••
+
Step 1: Attack of the acyl carbocationon the -electron System of the Aromatic Ring
H H
H HH H
O
CCH2CH3+ H H
HH
H H
+
O
CCH2CH3
AlCl3 acts as a Lewis acid to promote ionization of the acyl halide.
H H
HH H
H+
O
CCH2CH3
H H
HH
H H
+
O
CCH2CH3
Step 2: Loss of a Proton from the Carbocation Intermediate
Anhydrides can be used instead of acyl chlorides. H
Acid Anhydrides
Acetophenone(76-83%)
AlCl3 O
CCH3
O
CH3COCCH3
O
+
O
CH3COH+
12.8Synthesis of Alkylbenzenes by
Acylation-Reduction
Reduction of aldehyde and ketonecarbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction.
Acylation-Reduction H O
CR
AlCl3
RCCl
O
Zn(Hg), HCl CH2R
Permits monosubstitution of primary alkyl groups on an aromatic ring in acid media.
Reduction of aldehyde and ketonecarbonyl groups by heating with H2NNH2
and KOH is called the Wolff-Kishner reduction.
Acylation-Reduction H O
CR
H2NNH2, KOH,
triethylene glycol,heat
CH2R
Permits monosubstitution of primary alkyl groups on an aromatic ring in basic media.
AlCl3
RCCl
O
Example: Prepare Isobutylbenzene
No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement.
(CH3)2CHCH2Cl
AlCl3
CH2CH(CH3)3
This does not work !
AlCl3
Recall rearrangement !
(CH3)2CHCH2Cl
Isobutyl chloride tert-Butylbenzene(66%)
C(CH3)3
+
Note that although alkyl carbocations may rearrange, acylium ions do not.
So, Use Acylation-Reduction Instead
+
(CH3)2CHCCl
O
AlCl3 O
CCH(CH3)2
Zn(Hg)HCl
CH2CH(CH3)2
12.9Rate and Regioselectivity in
Electrophilic Aromatic Substitution
A substituent already present on the ring A substituent already present on the ring can affect both the can affect both the raterate and and regioselectivityregioselectivityof electrophilic aromatic substitution.of electrophilic aromatic substitution.
Activating substituents increase the rate of EAS compared to that of benzene. Activating substituents are typically electron donating groups.
Deactivating substituents decrease the rate of EAS compared to benzene. Deactivating substituents are typically electron withdrawing groups.
Effect on Rate
Toluene undergoes nitration 20-25 times faster than benzene.
A methyl group is an activating substituent.
Methyl Group CH3 CF3 (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene.
A trifluoromethyl group is adeactivating substituent.
Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Ortho-para directors are typically electron donating groups.
Meta directors direct an incoming electrophile to positions meta to themselves. Meta directors are typically electron withdrawing groups.
Effect on Regioselectivity
Nitration of Toluene CH3
aceticanhydride
HNO3
CH3
NO2
CH3
NO2
CH3
NO2
+ +
34%3%63%
O- and p-nitrotoluene together comprise 97% of the product.A methyl group is an ortho-para director.
Nitration of (Trifluoromethyl)benzene CF3 CF3
NO2
CF3
NO2
CF3
NO2
+ +
3%91%6%
M-nitro(trifluoromethyl)benzene comprises 91% of the product.A trifluoromethyl group is a meta director.
HNO3
H2SO4
12.10Rate and Regioselectivity in
the Nitration of Toluene
Carbocation Stability Controls Regioselectivity +
H
H
H
CH3
H
H
NO2
+
H
H
H
H
H
NO2
CH3 +
H
H
H
H
H
NO2
CH3
gives ortho gives para gives meta
more stable less stable
Which intermediate leads to product ?
ortho Nitration of Toluene
The last resonance structure is a 3o carbocation and is the rate-determining intermediate in the ortho nitration of toluene.
+
H
H
H
CH3
H
H
NO2
H
H
H
CH3
H
H
NO2
+
H
H
H
CH3
H
H
NO2
+
para Nitration of Toluene +
H
H
H
H
H
NO2
CH3 H
H
H
H
H
NO2
CH3
H
H
H
H
H
NO2
CH3
+
+
The center resonance structure is a 3o carbocation and is the rate-determining intermediate in the para nitration of toluene.
meta Nitration of Toluene +
H
H
H
H
H
NO2
CH3 H
H
H
H
H
NO2
CH3
+
All the resonance forms of the rate-determining intermediates in the meta nitration of toluene are 2o carbocations and none is adjacent to the electron donating substituent.
H
H
H
H
H
NO2
CH3
+
Nitration of Toluene: Interpretation
• The rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation and it is next to the electron donating group. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations and none are next to the electron donating group.
Nitration of Toluene: Interpretation
• Tertiary carbocations, being more stable, are formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. So, the major products are o- and p-nitrotoluene.
Nitration of Toluene: Partial Rate Factors
• The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions.
• Expressed as a numerical value, a partial rate factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene.
Nitration of Toluene: Partial Rate Factors CH3
42
2.5
58
42
2.5
1
1
1
1
1
1
All of the available ring positions in toluene are more reactive than a single position of benzene.A methyl group activates all of the ring positions, but the effect is greatest at the ortho and para positons.Steric hindrance by the methyl group makes each ortho position slightly less reactive than para.
Nitration of Toluene vs. tert-Butylbenzene CH3
42
2.5
58
42
2.5
tert-Butyl is activating and ortho-para directing.tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions.
CH3
75
3
4.5
3
4.5
C CH3H3C
All alkyl groups are activating, ortho-para directing and electron donating.
Note: The rate and regioselectivity effects in EAS of substituted benzenes is controlled by the substituent on the ring. The attacking electrophile has no influence on these effects.
Generalization
12.11Rate and Regioselectivity in
the Nitration of (Trifluoromethyl)benzene
A Key Point
C+H3C C+F3C
A methyl group is electron-donating and stabilizes a carbocation.
Because F is so electronegative, a CF3 group destabilizes a carbocation.
Carbocation Stability Controls Regioselectivity +
H
H
H
CF3
H
H
NO2
gives ortho
+
H
H
H
H
H
NO2
CF3
gives para
+
H
H
H
H
H
NO2
CF3
gives metaless stable more stable
Which intermediate leads to product ?
more destabilized less destabilized
+
H
H
H
CF3
H
H
NO2
The resonance form on the right of the rate-determining intermediate in the orthonitration of (trifluoromethyl)benzene is strongly destabilized next to the e-withdrawing group.
H
H
H
CF3
H
H
NO2
H
H
H
CF3
H
H
NO2
+
+
ortho Nitration of (Trifluoromethyl)benzene
+
H
H
H
H
H
NO2
CF3 H
H
H
H
H
NO2
CF3
H
H
H
H
H
NO2
CF
+
+
The center of the resonance forms of the rate-determining intermediate in the paranitration of (trifluoromethyl)benzene is strongly destabilized next to the e-withdrawing group.
para Nitration of (Trifluoromethyl)benzene
+
H
H
H
H
H
NO2
CF3 H
H
H
H
H
NO2
CF3
+
None of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)-benzene have their positive charge on the carbon that bears the CF3 group. Meta is least destabilized.
meta Nitration of (Trifluoromethyl)benzene H
H
H
H
H
NO2
CF3
+
Nitration of (Trifluoromethyl)benzene: Interpretation
The rate-determining intermediates for ortho and para nitration each have a resonance form in which the positive charge is on a carbon that bears a CF3 group. Such a resonance structure is strongly destabilized. The intermediate in meta nitration avoids such a structure. It is the least unstable of three unstable intermediates and is the one from which most of the product is formed.
Nitration of (Trifluoromethyl)benzene:Partial Rate Factors
All of the available ring positions in (trifluoromethyl)-benzene are much less reactive than a single position of benzene.
A CF3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons.
CF3
4.5 x 10-64.5 x 10-6
67 x 10-6 67 x 10-6
4.5 x 10-6
12.12Substituent Effects in
Electrophilic Aromatic Substitution:Activating Substituents
Table 12.2
Very strongly activating VSA
Strongly activating SA
Activating A
Standard of comparison is Benzene
Deactivating D
Strongly deactivating SD
Very strongly deactivating VSD
Classification of Substituents in Electrophilic
Aromatic Substitution Reactions
Table 12.2
Classification of Substituents in Electrophilic
Aromatic Substitution Reactions
VSA SA A D SD VSD
-NH2 -OR -CH3 -Br -NO2
-C-(Any) -NHR -Ar -Cl -CF3 -NHCR-NR2 -CH=CH2 -CH2X -SO3H
-OH -OCR -CN
O
O
O
1. All activating substituents are ortho-para directors.
2. Halogen substituents are slightly deactivating, but ortho-para directing.
3. Strongly deactivating substituents are meta directors.
Important Generalizations
ERGs are ortho-para directing and activating. ERG
ERGs include —R (alkyl), —Ar (aryl), and —C=C.
Electron-Releasing Groups (ERGs)
OH
HNO3
OH
NO2
OH
NO2
+
44%
56%
Nitration of Phenol
This occurs about 1000 times faster than nitration of benzene.
ERGs such as —OH, and —OR arestrongly activating.
-OCH3 is such a strong activator that the FeBr3 catalyst not necessary. OCH3
Br2
OCH3
Br 90%
aceticacid
Bromination of Anisole
+
H
H
H
H
H
Br
OCH3••••
H
H
H
H
H
Br
+
OCH3••••
H
H
H
H
H
Br
+ OCH3••
Oxygen Lone Pair Stabilizes Intermediate
All atomshave octets.
ERGs with a lone pair on the atom directlyattached to the ring are ortho-para directingand strongly activating.
ERG
Electron-Releasing Groups (ERGs)
••
All of these are ortho-para directingand strongly to very strongly activating.
Examples
ERG = •• ••OH ••
OR ••••
OCR ••••
O
••NH2 NHCR ••
O
••NHR ••NR2
Lone Pair Stabilizes Intermediates forortho and para Substitution
Comparable stabilization not possible for intermediate leading to meta substitution.
H
H
H
H
H
X
+ ERG H
H
H
H
H
X
+ ERG
12.13Substituent Effects in
Electrophilic Aromatic Substitution:Strongly Deactivating Substituents
Remember: ERGs Stabilize Intermediates forortho and para Substitution
H
H
H
H
H
X
+
ERG•• H
H
H
H
H
X
+
ERG••
Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution
H
H
H
H
H
X
+
EWG H
H
H
H
H
X
+
EWG
—CF3 is a powerful EWG. It is strongly deactivating and meta directing.
All of these are meta directing and strongly deactivating.
Many EWGs Have a Carbonyl GroupAttached Directly to the Ring
—EWG =
O
—CH
O
—CR
O
—COH
O
—COR
O
—CH
+
O
—CH
-O
—CCl
All of these are meta directing and strongly deactivating.
Other EWGs Include:
—EWG = —NO2
—SO3H
—C N
HNO3
75-84%
Nitration of Benzaldehyde CH
O
H2SO4
CH
OO2N
Cl2
62%
Problem 12.17(a)Chlorination of benzoylchloride
CCl
O
FeCl3
CCl
OCl
SO3
90%
Disulfonation of Benzene
H2SO4
SO3H
HO3S
Br2
60-75%
Bromination of Nitrobenzene Fe
Br
NO2 NO2
12.14Substituent Effects in
Electrophilic Aromatic Substitution:Halogens
F, Cl, Br, and I are ortho-para directing,F, Cl, Br, and I are ortho-para directing,but deactivating.but deactivating.
Nitration of Chlorobenzene Cl
HNO3
Cl
NO2
Cl
NO2
Cl
NO2
+ +
69%1%30%
The rate of nitration of chlorobenzene is about 30 times slower than that of benzene but directs ortho/para.
H2SO4
Nitration of Toluene vs. Chlorobenzene CH3
42
2.5
58
42
2.5
0.137
0.009
0.029
Cl
0.029
0.009
Rate factors (compared to benzene) for the nitration of various positions in these two compounds.
Halogen Substituents X
Electron withdrawing via induction.
X
Electron releasing via resonance.
For the halogens, the inductive effect outweighs the resonance effect. The weak releasing effect stabilizes the carbocations from o- and p-attack.
12.15Multiple Substituent Effects
Here, all possible EAS sites are equivalent.
The Simplest Case CH3
CH3
O
AlCl3O
CH3COCCH3
O
+
CH3
CH3
CCH3
99%
Directing effects of these substituents reinforceeach other: substitution takes place orthoto the methyl group and meta to the nitro group.
Another Straightforward Case CH3
NO2
CH3
NO2
Br
86-90%
Br2
Fe
Example NHCH3
Cl
aceticacid
Br2
87%
NHCH3
Cl
Br
strongly
activating
Regioselectivity is controlled by thestronger activating substituent.
Substitution occurs ortho to the smaller group.
When activating effects are similar... CH3
C(CH3)3
CH3
C(CH3)3
NO2
HNO3
H2SO4
88%
The position between two substituents is lastposition to be substituted for steric reasons.
Steric effects control regioselectivity whenelectronic effects are similar
CH3 CH3
HNO3
H2SO4
98%
NO2
CH3
CH3
12.16Regioselective Synthesis of
Disubstituted Aromatic Compounds
Synthesis of m-Bromoacetophenone Br CCH3
O
Which substituent should be introduced first ?
Introduce substituents in the order that ensures the correct orientation in the product.
Synthesis of m-Bromoacetophenone Br CCH3
O
Introduce substituents in the order that ensures the correct orientation in the product.
If bromine is introduced first, p-bromoacetophenone is major product.
para
meta
Synthesis of m-Bromoacetophenone CCH3
O
O
CH3COCCH3
O
AlCl3
Br2
AlCl3
CCH3
OBr If the acetyl group is first, then
m-bromoacetophenone is the major product.
Synthesis of m-Nitroacetophenone CCH3
O
Which substituent should be introduced first ?
Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics.
NO2
NO2 CCH3
O
Introduce substituents in the order that ensures the correct orientation in the product.
If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails.
Synthesis of m-Nitroacetophenone
Synthesis of m-Nitroacetophenone
If the acetyl group is first, then m-nitroacetophenone is the major product.
CCH3
O
O
CH3COCCH3
O
AlCl3
HNO3
H2SO4
CCH3
OHNO3
Synthesis of p-Nitrobenzoic Acid from Toluene
Which first ? (oxidation of methyl group or nitration of ring)
CH3
CO2H NO2
CH3
Sometimes electrophilic aromatic substitution must be combined with a functional group transformation.
Synthesis of p-Nitrobenzoic Acid from Toluene CH3
CO2H NO2
CH3
nitration givesm-nitrobenzoicacid
oxidation givesp-nitrobenzoicacid
Synthesis of p-Nitrobenzoic Acid from Toluene CH3 NO2
CH3
HNO3
H2SO4
NO2
CO2H
Na2Cr2O7, H2OH2SO4, heat
So, one would elect to nitrate first and then oxidize.
12.17Substitution in Naphthalene
Two sites are possible for electrophilicaromatic substitution.
All other sites at which substitution can occurare equivalent to 1 and 2.
Naphthalene
1
2
HH
H H
HH
H H
EAS in Naphthalene
AlCl3
O
CH3CCl
90%
CCH3
O Reaction is faster at C-1 than at C-2.
EAS in Naphthalene
When attack is at C-1 the carbocation is stabilized by allylic resonance and benzenoid character of other ring is maintained.
E H E H
+
+
EAS in Naphthalene
When attack is at C-2, in order for the carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is lost.
E
H+
E
H+
Sulfonation of Naphthalene
SO3H Kinetic vs. thermodynamic control!
H2SO4
SO3
SO3H
At 0°C
At 160°C
12.18Substitution in
Heterocyclic Aromatic Compounds
There is none.
There are so many different kinds of heterocyclicaromatic compounds that no generalizationis possible.
Some heterocyclic aromatic compoundsare very reactive toward electrophilicaromatic substitution, others are very unreactive...
Generalization
Pyridine is very unreactive; it resemblesnitrobenzene in its reactivity.
Presence of electronegative atom (N) in ringcauses electrons to be held more strongly thanin benzene.
Pyridine N
Pyridine can be sulfonated at high temperature.
EAS takes place at C-3.
N
SO3, H2SO4
HgSO4, 230°C
SO3H
N
71%
Pyridine
Pyrrole, Furan, and Thiophene O••
••
S••
••
N
H
••
Have 1 less ring atom than benzene or pyridine to hold same number of electrons (6).
The electrons are held less strongly.
These compounds are relatively reactive toward EAS.
Furan undergoes EAS readily andC-2 is most reactive position.
Example: Furan
BF3
O
CH3COCCH3
O
+ CCH3
O
75-92%
O
O
12.19Nucleophilic Aromatic Substitution
Nucleophilic Aromatic Substitution
•Because the carbon-halogen bond is stronger (where LG = halide), aryl halides react more slowly than alkyl halides when carbon-halogen bond breaking is rate determining.
LG
Nu
+ :Nu- + :LG-
Cl
OH
1. NaOH, H2O370°C
2. H+/HOH
(97%)
We have not yet seen any nucleophilic substitution reactions of aryl halides. Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required. This goes by the benzyne mechanism (elimination-addition).
Reactions of Aryl Halides
Cl
NH2
NaNH2, NH3(l)-33°C
In this mechanism, the base causes elimination of HCl to form benzyne. Here, addition of NH3 to either carbon of the benzyne yields product.
Reactions of Aryl Halides
Reasons for Low Reactivity
•SN1 not reasonable because:
• 1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process
• 2) aryl cations are less stable than alkyl cations
Cl
+ + Cl
–
Reasons for Low Reactivity
•SN2 not reasonable because ring blocks attack of nucleophile from side opposite bond to the leaving group.
12.20Nucleophilic Substitution in
Nitro-Substituted Aryl Halides
Nitro-substituted aryl halides undergonucleophilic aromatic substitution more readily.
But... Cl
NO2
+ NaOCH3
CH3OH
85°C
OCH3
NO2
+ NaCl
(92%)
•especially when nitro group is ortho and/orpara to leaving group
Effect of nitro group is cumulative Cl Cl
NO2
Cl
NO2
NO2O2N
Cl
NO2
NO2
1.0 7 x 1010 2.4 x 1015 too fast to measure
•follows second-order rate law:rate = k[aryl halide][nucleophile]
•inference:both the aryl halide and the nucleophile are involved in rate-determining step.
Kinetics
Effect of leaving group
unusual order: F > Cl > Br > I Based on electronegativity rather than basicity. XNO2
X Relative Rate*
F
Cl
Br
I
312
1.0
0.8
0.4
*NaOCH3, CH3OH, 50°C
•bimolecular rate-determining step in whichnucleophile attacks aryl halide•rate-determining step precedes carbon-halogenbond cleavage•rate-determining transition state is stabilized byelectron-withdrawing groups (such as NO2)
General Conclusions About Mechanism
12.21The Addition-Elimination Mechanism
of Nucleophilic Aromatic Substitution
•Two step mechanism:• Step 1) nucleophile attacks aryl halide and bonds to the carbon that bears the halogen
(slow: aromaticity of ring lost in this step)• Step 2) intermediate formed in first step loses
halide(fast: aromaticity of ring restored in this step)
Addition-Elimination Mechanism
Reaction FNO2
+ NaOCH3
CH3OH
85°C
OCH3
NO2
+ NaF
(93%)
slow
NO2
•• ••F••
H
H
H
H
Step 1
••
•••• OCH3
–
Mechanism
•Bimolecular; consistent with second-order kinetics; first order in aryl halide, first order in nucleophile,•intermediate is negatively charged,•formed faster when ring bears electron-withdrawing groups such as NO2.
NO2
••F•• ••
H
H
H
H
••–
•••• OCH3
Stabilization of Rate-Determining Intermediate
by Nitro Group
••••
N
F ••
H
H
H
H
••
•••• OCH3
O O••
••
•••• ••+
–
–
••••
N
F ••
H
H
H
H
••
•••• OCH3
O O••
••
•••• ••+
–
–
fast
•• OCH3••
NO2
H
H
H
H
F••
•• ••••
–Step 2
NO2
F••
•• ••
H
H
H
H
–
•• OCH3••
••
Mechanism
Regeneration of aromatic character in the ring.
•Carbon-halogen bond breaking does not occur until after the rate-determining step.
•Electronegative F stabilizes negatively charged intermediate.
Leaving Group Effects
F > Cl > Br > I is unusual, but consistentwith mechanism
12.22Related Nucleophilic Substitution
Reactions
Example: 2-Chloropyridine
NaOCH3
CH3OH
•2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions.
ClN
OCH3N
50°C
Example: 2-Chloropyridine
•Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed.
ClN
•••• OCH3••
–
••
••
ClN
••OCH3••
–••
End of Chapter 12End of Chapter 12Reactions of Arenes:Reactions of Arenes:
Electrophilic and NucleophilicAromatic Electrophilic and NucleophilicAromatic SubstitutionSubstitution
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