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SSNN2 is not reasonable because the 2 is not reasonable because the aromatic ring blocks back-side aromatic ring blocks back-side approach of the nucleophile. Inversion approach of the nucleophile. Inversion is not possible.is not possible.
Chlorobenzene is quite unreactive with nucleophiles
SN1 is also unlikely:Aryl Cations are Highly Unstable
Cl
C
+ Cl
SN1
emptysp2 orbital
Aryl Cation
SN1 not reasonable because:
1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process
2) aryl cations are highly unstable
nitro-substituted aryl halides nitro-substituted aryl halides dodo undergo undergonucleophilic aromatic substitution readilynucleophilic aromatic substitution readily
But...But...
ClCl
NONO22
++ NaNaOOCHCH33
CHCH33OHOH
85°C85°C
OOCHCH33
NONO22
++ NaNaClCl
(92%)(92%)
especially when nitro group is ortho and/orespecially when nitro group is ortho and/orpara to leaving grouppara to leaving group
Effect of nitro group is cumulative Effect of nitro group is cumulative
ClCl
1.01.0
ClCl
NONO22
7 x 107 x 101010
ClCl
NONO22
NONO22OO22NN
2.4 x 102.4 x 101515
ClCl
NONO22
NONO22
too fast to measuretoo fast to measure
follows second-order rate law:follows second-order rate law:rate = rate = k k [aryl halide][nucleophile][aryl halide][nucleophile]
inference:inference:both the aryl halide and the nucleophile are both the aryl halide and the nucleophile are involved in rate-determining stepinvolved in rate-determining step
KineticsKinetics
Effect of leaving groupEffect of leaving group
unusual order: F > Cl > Br > Iunusual order: F > Cl > Br > I
XX
NONO22
XX Relative Rate*Relative Rate*
FF
ClCl
BrBr
II
312312
1.01.0
0.80.8
0.40.4
*NaOCH*NaOCH33, CH, CH33OH, 50°COH, 50°C
•bimolecular rate-determining step in whichbimolecular rate-determining step in whichnucleophile attacks aryl halidenucleophile attacks aryl halide•rate-determining step precedes carbon-halogenrate-determining step precedes carbon-halogenbond cleavagebond cleavage•rate-determining transition state is stabilized byrate-determining transition state is stabilized byelectron-withdrawing groups (such as NOelectron-withdrawing groups (such as NO22))
General Conclusions About MechanismGeneral Conclusions About Mechanism
The Addition-Elimination MechanismThe Addition-Elimination Mechanismof of
Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution
Two step mechanism:Two step mechanism:
Step 1) nucleophile attacks aryl halide andStep 1) nucleophile attacks aryl halide and bonds to the carbon that bears the halogenbonds to the carbon that bears the halogen
(slow: aromaticity of ring lost in this step)(slow: aromaticity of ring lost in this step)
Step 2) intermediate formed in first step losesStep 2) intermediate formed in first step loseshalidehalide
(fast: aromaticity of ring restored in this step)(fast: aromaticity of ring restored in this step)
Addition-Elimination MechanismAddition-Elimination Mechanism
MechanismMechanism
•••• OOCHCH33••••
••••
––
NONO22
FF••••
•••• ••••
HH
HH
HH
HH
bimolecularbimolecular
consistent with second-consistent with second-order kinetics; first order order kinetics; first order in aryl halide, first order in aryl halide, first order in nucleophilein nucleophile
Step 1Step 1Step 1Step 1
MechanismMechanism
slowslow
•••• OOCHCH33••••
••••
––
NONO22
FF••••
•••• ••••
HH
HH
HH
HH
NONO22
FF••••
•••• ••••
HH
HH
HH
HH
••••––
•••• OOCHCH33••••
Step 1Step 1Step 1Step 1
MechanismMechanism
NONO22
FF••••
•••• ••••
HH
HH
HH
HH
••••––
•••• OOCHCH33••••intermediate is intermediate is
negatively chargednegatively charged
formed faster when formed faster when ring bears electron-ring bears electron-withdrawing groups withdrawing groups such as NOsuch as NO22
Stabilization of Rate-Determining IntermediateStabilization of Rate-Determining Intermediateby Nitro Groupby Nitro Group
NN
FF••••
•••• ••••
HH
HH
HH
HH
••••
•••• OOCHCH33••••
OO OO••••
••••
•••••••• ••••++
––
––
Stabilization of Rate-Determining IntermediateStabilization of Rate-Determining Intermediateby Nitro Groupby Nitro Group
NN
FF••••
•••• ••••
HH
HH
HH
HH
••••
•••• OOCHCH33••••
OO OO••••
••••
•••••••• ••••++
––
––
NN
FF••••
•••• ••••
HH
HH
HH
HH
••••
•••• OOCHCH33••••
OO OO••••
••••
•••••••• ••••++
––
––
MechanismMechanism
NONO22
FF••••
•••• ••••
HH
HH
HH
HH
••••––
•••• OOCHCH33••••
Step 2Step 2Step 2Step 2
MechanismMechanism
fastfast
•••• OOCHCH33••••
NONO22
HH
HH
HH
HH
NONO22
FF••••
•••• ••••
HH
HH
HH
HH
••••––
•••• OOCHCH33••••
FF••••
•••• ••••••••
––
Step 2Step 2Step 2Step 2
carbon-halogen bond breaking does not occurcarbon-halogen bond breaking does not occuruntil after the rate-determining stepuntil after the rate-determining step
electronegative F stabilizes negatively electronegative F stabilizes negatively charged intermediatecharged intermediate
Leaving Group EffectsLeaving Group Effects
F > Cl > Br > I is unusual, but consistentF > Cl > Br > I is unusual, but consistentwith mechanismwith mechanism
The Role of Leaving Groups
FNucH
NO O
ClNucH
NO O
BrNucH
NO O
INucH
NO O
Most Stabilized Least Stabilized
Related Nucleophilic AromaticRelated Nucleophilic AromaticSubstitution ReactionsSubstitution Reactions
Example: HexafluorobenzeneExample: Hexafluorobenzene
FF
FF
FF
FF
FF
FF
NaNaOOCHCH33
CHCH33OHOH
65°C65°CFF
OOCHCH33
FF
FF
FF
FF
(72%)(72%)
Six fluorine substituents stabilize negatively Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic step and increase rate of nucleophilic aromatic substitution.substitution.
Example: 2-ChloropyridineExample: 2-Chloropyridine
NaNaOOCHCH33
CHCH33OHOH
2-Chloropyridine reacts 230,000,000 times 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these faster than chlorobenzene under these conditions.conditions.
ClClNN
OOCHCH33NN50°C50°C
Example: 2-ChloropyridineExample: 2-Chloropyridine
Nitrogen is more electronegative than carbon, Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and stabilizes the anionic intermediate, and increases the rate at which it is formed.increases the rate at which it is formed.
ClClNN
•••• OOCHCH33••••
••••
––
••••
Example: 2-ChloropyridineExample: 2-Chloropyridine
Nitrogen is more electronegative than carbon, Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and stabilizes the anionic intermediate, and increases the rate at which it is formed.increases the rate at which it is formed.
ClClNN
•••• OOCHCH33••••
••••
––
••••
ClClNN
OOCHCH33••••
••••––
••••
••••
Nucleophilic AromaticNucleophilic AromaticSubstitution ReactionsSubstitution Reactions
ininSynthesisSynthesis
Triketones
Herbicides that inhibit HPPD
Hydroxyphenylpyruvate dioxygenase
NTBC- orphan drug for tyrosine anemia
O
O
O
N
O
2
C
F
3
O
O
O
N
O
2
S
O
2
C
H
3
O
O
O
Cl
S
O
2
C
H
3
NTBC - Pharmaceutical
Callisto (mesotrione)
MIkado (sulfotrione)
Triketones Continued
Inhibition of HPPD
Hydroxyphenylpyruvate dioxygenase
Third Generation
O
O
O
Cl
S
O
2
C
H
3
O
C
H
2
C
H
3
Synthetic IntermediateSynthetic Intermediate
O
H
O
Cl
S
O
2
C
H
3
O
C
H
2
C
H
3
Triketones: Synthetic IntermediateSynthetic Intermediate
O
H
O
Cl
S
O
2
C
H
3
O
C
H
2
C
H
3
Starting from 2,3-dichlorothiophenol Starting from 2,3-dichlorothiophenol which is commercially availablewhich is commercially available
1)1) S- methylateS- methylate
2)2) EAS acylationEAS acylation
3)3) oxidationoxidation
Cl
Cl
S
O
2
C
H
3
H
O
2
C
Ofloxacin
http://www.ofloxacin.com/
Ofloxacin (trade name Floxin) is a broad-spectrum quinolone antibiotic
Ofloxacin
N
O
O O
OEt
Me
H
N
F
NMe
H
N
O
O O
OH
Me
H
N
F
NMe
H
Synthesis of Ofloxacin, Part 1
F
F
O O
OEt
F
F
OMe
H
F
F
O O
OEt
F
F
OMe
H
HN
MeOH
F
F
O O
OEt
F
F
H
NH
MeOH
NH2
MeOH -MeO
1,4-Addition
Elimination
Synthesis of Ofloxacin, Part 2
N
O O
OEt
F
F
H
FMe
OH
N
O O
OEt
F
F
H
FMe
OHF
F
F
O O
OEt
F
F
H
NH
MeOH
Elimination
Addition
NucleophilicAromatic Substition
Synthesis of Ofloxacin, Part 3
N
O
O O
OEt
Me
H
F
F
H
N
O
O O
OEt
Me
H
F
F
H
N
O O
OEt
F
F
H
FMe F
H
HO
Addition
EliminationNucleophilicAromatic Substition
-F
Synthesis of Ofloxacin, Part 4
N
O
O O
OEt
Me
H
N
F
NMe
H
N
O
O O
OEt
Me
H
F
F
H
N
N
Me
N
O
O O
OEt
Me
H
F
F
H
NH
NMe
NucleophilicAromatic Substition
Addition
Elimination
Synthesis of Ofloxacin, Part 5
Ofloxacin
N
O
O O
OH
Me
H
N
F
NMe
H
N
O
O O
OEt
Me
H
N
F
NMe
H
NaOHH2O
The Elimination-Addition MechanismThe Elimination-Addition Mechanism
of Nucleophilic Aromatic of Nucleophilic Aromatic
Substitution:Substitution:
BenzyneBenzyne
Aryl Halides Undergo Substitution WhenAryl Halides Undergo Substitution WhenTreated With Very Strong BasesTreated With Very Strong Bases
ClCl
NHNH22
KNHKNH22, NH, NH33
––33°C33°C
(52%)(52%)
CHCH33
NHNH22
new substituent becomes attached to eithernew substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon that bore the leaving group orthe carbon adjacent to itthe carbon adjacent to it
RegiochemistryRegiochemistry
++
NaNHNaNH22,,
NHNH33
––33°C33°C
CHCH33
BrBr
CHCH33
NHNH22
new substituent becomes attached to eithernew substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon that bore the leaving group orthe carbon adjacent to itthe carbon adjacent to it
RegiochemistryRegiochemistry
CHCH33
BrBr
++NaNHNaNH22, NH, NH33
––33°C33°C
CHCH33
NHNH22
CHCH33
NHNH22
RegiochemistryRegiochemistry
++
NaNHNaNH22, NH, NH33 ––33°C33°C
CHCH33
NHNH22
CHCH33
NHNH22
CHCH33
ClCl
++
CHCH33
NHNH22
Same result using Same result using 1414C labelC label
ClCl**
KNHKNH22, NH, NH33 ––33°C33°C
NHNH22**++
NHNH22
**
(48%)(48%)(52%)(52%)
MechanismMechanism
•••• NNHH22••••
––
Step 1Step 1Step 1Step 1
HH
HH
•••• ••••
HH
HH
ClCl
HH
••••
HH
HH
HH
HHNNHH22••••
HH
••••••••ClCl••••
••••––
compound formed in this step is called compound formed in this step is called benzynebenzyne
BenzyneBenzyne
HH
HH
HH
HH
Benzyne has a strained triple bond.Benzyne has a strained triple bond.
It cannot be isolated in this reaction, but is It cannot be isolated in this reaction, but is formed as a reactive intermediate.formed as a reactive intermediate.
Benzyne - A Reactive MoleculeWith an Abnormal -Bond
Benzyne has a reactive triple bond.
It cannot be isolated in this reaction, but is formed as a reactive intermediate.
H
H
H
H
Benzyne
H
H
H
H
2pZ-2pZ Bond
H
H
H
H
sp2-sp2
Bond
Benzyne - A Reactive Aromatic MoleculeWith An Abnormal, In-Plane -Bond
C
C
R
R
'Normal' C-C Triple Bond
CC
C
CCCH
H H
H
Benzyne C-C Triple Bond
overlapping sp2 orbitalspoor overap resultsin a weak, reactive bond
MechanismMechanism
•••• NNHH22••••
––
Step 2Step 2Step 2Step 2
HH
HH
HH
HH
HH
HH
HH
HH
NNHH22
––••••
••••
Angle strain is relieved. The two Angle strain is relieved. The two spsp-hybridized -hybridized ring carbons in benzyne become ring carbons in benzyne become spsp22 hybridized hybridized in the resulting anion.in the resulting anion.
MechanismMechanism
•••• NNHH22••••
––
Step 3Step 3Step 3Step 3
HH
HH
HH
HH
NNHH22
––••••
••••
NNHH22••••
HH
HH
HH
HH
HH
HH NNHH22••••
Hydrolysis of ChlorobenzeneHydrolysis of Chlorobenzene
ClCl**
NaOH, HNaOH, H22OO 395°C395°C
OOHH**++
OOHH
**
(54%)(54%)(43%)(43%)
1414C labeling C labeling indicates that indicates that the high-the high-temperature temperature reaction of reaction of chlorobenzene chlorobenzene with NaOH with NaOH goes via goes via benzyne.benzyne.
Other Routes to BenzyneOther Routes to Benzyne
Benzyne can be prepared as a reactive Benzyne can be prepared as a reactive intermediate by methods other than treatment of intermediate by methods other than treatment of chlorobenzene with strong bases.chlorobenzene with strong bases.
Another method involves loss of fluoride ion Another method involves loss of fluoride ion from the Grignard reagent of 1-bromo-2-from the Grignard reagent of 1-bromo-2-fluorobenzene.fluorobenzene.
Other Routes to BenzyneOther Routes to Benzyne
••••
BrBr
FF••••
••••
Mg, THFMg, THF
heatheat ••••
MgMgBrBr
FF••••
••••
FFMgMgBrBr++
Benzyne as a DienophileBenzyne as a Dienophile
Benzyne is a fairly reactive dienophile, and Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in gives Diels-Alder adducts when generated in the presence of conjugated dienes.the presence of conjugated dienes.
The Diels-Alder Reaction Revisited
BA
X Y
A
X
B
Y
cycloaddition
diene dienophile cycloadduct
H
H
H
H
isoprene maleic anhydride cycloadduct
O
O
O
H3C H3C
O
O
O
100°C
Electron-Deficient AlkynesBehave as Dienophiles
butadiene but-3-yn-2-one cycloadduct
120°C
CH3O
HH
CH3
O
Benzyne Behaves as a Dienophile
Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.
CH3O
H
H
H
O
O
O
H
H
H
H
Benzyne