Transcript Carey Chapter 23 Aryl Halides

Nucleophilic Aromatic Substitution
Aryl Halides
Chlorobenzene is quite unreactive with
nucleophiles
SN2 is not reasonable because the
aromatic
ring
blocks
back-side
approach of the nucleophile. Inversion
is not possible.
SN1 is also unlikely:
Aryl Cations are Highly Unstable
Cl
empty
sp2 orbital
SN1
C
 Cl
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
But...
nitro-substituted aryl halides do undergo
nucleophilic aromatic substitution readily
Cl
OCH3
+ NaOCH3
NO2
CH3OH
+ NaCl
85°C
NO2
(92%)
Effect of nitro group is cumulative
especially when nitro group is ortho and/or
para to leaving group
Cl
Cl
Cl
Cl
NO2
NO2 O2N
NO2
1.0
7 x 1010
NO2
2.4 x 1015
NO2
too fast to measure
Kinetics
follows second-order rate law:
rate = k [aryl halide][nucleophile]
inference:
both the aryl halide and the nucleophile are
involved in rate-determining step
Effect of leaving group
unusual order: F > Cl > Br > I
X
X
F
NO2
Relative Rate*
312
Cl
1.0
Br
0.8
I
0.4
*NaOCH3, CH3OH, 50°C
General Conclusions About Mechanism
•bimolecular rate-determining step in which
nucleophile attacks aryl halide
•rate-determining step precedes carbon-halogen
bond cleavage
•rate-determining transition state is stabilized by
electron-withdrawing groups (such as NO2)
The Addition-Elimination Mechanism
of
Nucleophilic Aromatic Substitution
Addition-Elimination Mechanism
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)
Reaction
F
OCH3
+ NaOCH3
NO2
CH3OH
+ NaF
85°C
NO2
(93%)
Mechanism
Step 1
••
•• F ••
– ••
•• OCH3
••
H
H
H
H
NO2
bimolecular
consistent with secondorder kinetics; first order
in aryl halide, first order
in nucleophile
Mechanism
Step 1
••
•• F ••
H
– ••
•• OCH3
••
•• F ••
••
H
H
slow
H
H
NO2
••
••
•• OCH3
H
–
H
H
NO2
Mechanism
intermediate is
negatively charged
formed faster when
ring bears electronwithdrawing groups
such as NO2
••
•• F ••
H
••
•• OCH3
H
– ••
H
H
NO2
Stabilization of Rate-Determining Intermediate
by Nitro Group
••
••
• F•
• •
H
•• OCH3
H
– ••
H
•• O
••
H
N
+
••
O ••
•• –
Stabilization of Rate-Determining Intermediate
by Nitro Group
••
••
• F•
• •
H
H
•• O
••
• F•
• •
•• OCH3
– ••
N
+
••
••
•• OCH3
H
H
H
H
H
H
••
O ••
•• –
••
•• O
– ••
N
+
••
O ••
•• –
Mechanism
Step 2
••
•• F ••
H
••
•• OCH3
H
– ••
H
H
NO2
Mechanism
Step 2
– ••
•• F ••
••
••
••
•• OCH3
H
•• F ••
H
H
fast
H
H
NO2
••
•• OCH3
H
– ••
H
H
NO2
Leaving Group Effects
F > Cl > Br > I is unusual, but consistent
with mechanism
carbon-halogen bond breaking does not occur
until after the rate-determining step
electronegative F stabilizes negatively
charged intermediate
The Role of Leaving Groups
Nuc
F
Nuc
Cl
H
Most Stabilized
O
H
N
N
O
I
H
N
O
Nuc
Br
H
N
O
Nuc
O
O
O
O
Least Stabilized
Related Nucleophilic Aromatic
Substitution Reactions
Example: Hexafluorobenzene
F
F
OCH3
F
F
F
F
F
NaOCH3
F
F
F
CH3OH
65°C
F
(72%)
Six fluorine substituents stabilize negatively
charged intermediate formed in rate-determining
step and increase rate of nucleophilic aromatic
substitution.
Example: 2-Chloropyridine
NaOCH3
N
Cl
CH3OH
N
OCH3
50°C
2-Chloropyridine reacts 230,000,000 times
faster than chlorobenzene under these
conditions.
Example: 2-Chloropyridine
– ••
•• OCH3
••
N
••
Cl
Nitrogen is more electronegative than carbon,
stabilizes the anionic intermediate, and
increases the rate at which it is formed.
Example: 2-Chloropyridine
– ••
•• OCH3
••
••
N
••
Cl
••
–N
••
OCH3
••
Cl
Nitrogen is more electronegative than carbon,
stabilizes the anionic intermediate, and
increases the rate at which it is formed.
Nucleophilic Aromatic
Substitution Reactions
in
Synthesis
Triketones
O
Herbicides that
inhibit HPPD
Hydroxyphenyl
pyruvate
dioxygenase
NTBCorphan drug
for tyrosine
anemia
O
NO2
O
CF 3
NTBC - Phar m ace utical
O
O
NO2
O
Callis to (m e s otr ione )
O
O
SO2CH3
Cl
O
MIk ado (sulfotr ione )
SO2CH3
Triketones Continued
Inhibition of
HPPD
O
O
OCH2CH3
Hydroxyphenyl
pyruvate
dioxygenase
O
Third
Generation
Synthetic Intermediate
Cl
O
HO
SO2CH3
Cl
OCH2CH3
SO2CH3
Triketones: Synthetic Intermediate
O
HO
Cl
OCH2CH3
SO2CH3
Starting from 2,3-dichlorothiophenol
which is commercially available
Cl
1) S- methylate
HO2 C
2) EAS acylation
3) oxidation
Cl
SO2 CH3
Ofloxacin
H
Ofloxacin
(trade name
Floxin) is a
broadspectrum
quinolone
antibiotic
O
O
F
OH
OEt
N
Me
N
N
Me
O
H
Ofloxacin
http://www.ofloxacin.com/
Synthesis of Ofloxacin, Part 1
H
O
O
F
F
F
F
H
1,4-Addition
F
OEt
OMe
O
OEt
F
F
HN
F
NH2
OH
Elimination
H
O
O
F
OEt
F
F
F
NH
OH
Me
OMe
OH
Me
-MeO
Me
O
Synthesis of Ofloxacin, Part 2
H
O
H
O
O
O
Addition F
F
OEt
OEt
F
F
F
N
F
NH
F
F
OH
Me
OH
Me
Elimination
Nucleophilic
Aromatic
Substition
H
O
O
F
OEt
F
N
F
OH
Me
Synthesis of Ofloxacin, Part 3
H
O
O
F
F
H
Nucleophilic
Aromatic
Substition
N
F
Me
HO
O
Me
O
-F
H
H
Elimination
O
F
OEt
F
O
OEt
N
F
O
F
OEt
F
H
Addition
N
Me
O
H
Synthesis of Ofloxacin, Part 4
H
O
O
H
Addition
F
O
O
F
OEt
OEt
F
F
N
N
Me
O
NH
N
H
H
N
N
Elimination
Me
Me
Nucleophilic
Aromatic
Substition
Me
O
H
O
O
F
OEt
N
N
Me
N
Me
O
H
Synthesis of Ofloxacin, Part 5
H
O
O
F
OEt
N
N
Me
N
NaOH
H2O
Me
O
H
H
O
O
F
OH
N
N
Me
N
Me
O
H
Ofloxacin
The Elimination-Addition Mechanism
of Nucleophilic Aromatic Substitution:
Benzyne
Aryl Halides Undergo Substitution When
Treated With Very Strong Bases
Cl
KNH2, NH3
NH2
–33°C
(52%)
Regiochemistry
new substituent becomes attached to either
the carbon that bore the leaving group or
the carbon adjacent to it
CH3
CH3
Br
NaNH2,
NH3
–33°C
CH3
NH2
+
NH2
Regiochemistry
new substituent becomes attached to either
the carbon that bore the leaving group or
the carbon adjacent to it
CH3
NaNH2, NH3
–33°C
Br
CH3
CH3
+
NH2
NH2
Regiochemistry
CH3
Cl
NaNH2, NH3
CH3
–33°C
CH3
CH3
NH2
+
+
NH2
NH2
Same result using 14C label
*
Cl
–33°C
KNH2, NH3
NH2
*
(52%)
+
*
(48%)
NH2
Mechanism
Step 1
H
••
Cl ••
H
••
H
H
H
–
•• NH2
••
Mechanism
Step 1
H
H
••
Cl ••
H
H
••
H
H
H
•• –
•• Cl •
•
••
–
•• NH2
••
H
H
NH2
H
compound formed in this step is called benzyne
••
Benzyne
H
H
H
H
Benzyne has a strained triple bond.
It cannot be isolated in this reaction, but is
formed as a reactive intermediate.
Benzyne - A Reactive Molecule
With an Abnormal p-Bond
H
H
H
H
H
H
H
H
H
H
H
H
Benzyne
2pZ-2pZ
p Bond
sp2-sp2
p Bond
Benzyne has a reactive triple bond.
It cannot be isolated in this reaction, but is
formed as a reactive intermediate.
Benzyne - A Reactive Aromatic Molecule
With An Abnormal, In-Plane p-Bond
overlapping sp2 orbitals
poor overap results
in a weak, reactive bond
R
C
C
'Normal' C-C Triple Bond
C
H C
C
C
C
R
H
H
C
H
Benzyne C-C Triple Bond
Mechanism
Step 2
H
H
–
•• NH2
••
H
H
Mechanism
Step 2
H
H
H
–
•• NH2
–
H
••
••
H
NH2
H
H
••
H
Angle strain is relieved. The two sp-hybridized
ring carbons in benzyne become sp2 hybridized
in the resulting anion.
Mechanism
Step 3
NH2
H
H
••
–
H
••
NH2
H
••
H
Mechanism
Step 3
–
•• NH2
H
••
H
H
H
H
NH2
H
••
H
NH2
H
H
••
–
••
NH2
••
H
Hydrolysis of Chlorobenzene
*
14C
labeling
indicates that
the hightemperature
reaction of
chlorobenzene
with NaOH
goes via
benzyne.
NaOH, H2O
Cl
395°C
OH
*
(43%)
+
*
(54%)
OH
Diels-Alder Reactions of Benzyne
Other Routes to Benzyne
Benzyne can be prepared as a reactive
intermediate by methods other than treatment of
chlorobenzene with strong bases.
Another method involves loss of fluoride ion
from the Grignard reagent of 1-bromo-2fluorobenzene.
Other Routes to Benzyne
Br
••
F ••
••
Mg, THF
heat
MgBr
••
F ••
••
+
FMgBr
Benzyne as a Dienophile
Benzyne is a fairly reactive dienophile, and
gives Diels-Alder adducts when generated in
the presence of conjugated dienes.
The Diels-Alder Reaction Revisited
A
A
B
B
cycloaddition
X
diene
Y
Y
X
cycloadduct
dienophile
O
H3C
H
H
100°C
O
H3C
O
O
H
O
isoprene
maleic anhydride
H
O
cycloadduct
Electron-Deficient Alkynes
Behave as Dienophiles
O
CH3
O
120°C
H
butadiene
but-3-yn-2-one
CH3
H
cycloadduct
Benzyne Behaves as a Dienophile
O
O
H
CH3
H
H
O
H
H
O
H
H
Benzyne
Benzyne is a fairly reactive dienophile, and gives
Diels-Alder adducts when generated in the
presence of conjugated dienes.
Benzyne as a Dienophile
Br
+
F
Mg, THF
heat
(46%)