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In addition, the double bonds of the aromatic group do not behave similar to alkene reactions
Aromatic Substitution
While aromatic compounds do not react through addition reactions seen earlier
Br
Br2
Br2
FeBr3
Br
Br
Initially an electrophile reacts with the aromatic compound to generate an arenium ion
(also called sigma complex)
The arenium ion has lost aromatic stabilization
(one of the carbons of the ring no longer has a conjugated p orbital)
In a second step, the arenium ion loses a proton to regenerate the aromatic stabilization
Energy Profile
Transition
states
Transition
states
Intermediate
Potential
energy
E
H
Starting
material
Products
Reaction Coordinate
The rate-limiting step is therefore the formation of the arenium ion
The properties of this arenium ion therefore control electrophilic aromatic substitutions
(just like any reaction consider the stability of the intermediate
formed in the rate limiting step)
1)
The rate will be faster for anything that stabilizes the arenium ion
2)
The regiochemistry will be controlled by the stability of the arenium ion
Bromination
Br
H
Br
With a monosubstituted aromatic ring, however, can obtain three possible products
CH3
NO2
As the aromatic ring acquires more electron density, the arenium ion will be more stable
Any substituent that increases the rate for an electrophilic aromatic substitution
is called an activating substituent
2)
Resonance
Substituents that have a lone pair of electrons adjacent to the ring
can donate electron density into the ring through resonance
O
CH3
CH3
CH3
CH3
Alkyl substituents
inductively donate,
no resonance effects,
therefore activators
Inductively withdrawing
therefore deactivating
Resonance donating,
therefore activating
when a neutral O or N is directly bonded to a benzene ring,
the resonance effect dominates and the net effect is activating
when a halogen is bonded to a benzene ring,
the inductive effect dominates and the net effect is deactivating
O
N
2)
A formal positive charge is placed directly adjacent to ring
H3C CH3
N
CH3
1)
All activating groups favor ortho/para substitution
3)
Other deactivating groups favor meta substitution
Only the meta substitution does not place a carbocation adjacent to EWG
Multiple Substituents
How to determine orientation of electrophilic aromatic substitution
if there is more than one substituent?
CH3
CN
meta director
Br2
FeBr3
CN
Br
ortho/para director
H3 C
CN
Br2
meta director
FeBr
3
H3C
CN
Br
H3C
OCH3
ortho/para director
H3 C
Br
OCH3
Often use Lewis acid with chlorine substituents to avoid cross contamination
(e.g. often use AlCl3 for chlorination but FeBr3 for bromination)
Also with strongly activated rings obtain polychlorination products with catalyst
Nitration
Nitro
Deactivating/Meta Director
Amine
Activating/Ortho-Para Director
Sulfonation
Friedel-Crafts Alkylation
With tertiary and secondary alkyl halides this generates a discrete carbocation
2)
Carbocation rearrangements occur
Because a carbocation is formed during this reaction, similar to any reaction involving
carbocations the carbocation can rearrange to a more stable carbocation
3)
Polyalkylation often occurs with Friedel-Crafts alkylation
To prevent polyreaction the starting material (benzene is this example) is used in excess
The acylium ion then reacts with aromatic ring in a typical electrophilic aromatic substitution
1)
The acyl substituent is a deactivating group
Therefore this reaction can be stopped easily at one addition
(no polyacylation occurs)
2)
No rearrangements occur
Since an isolated carbocation is not formed there is no rearrangement
Due to the steric bulk of the Friedel-Crafts acylation reagent, often see a high preference
for the para substitution with an ortho/para directing group
Clemmensen Reduction
The ability to reduce a carbonyl to a methylene
further enhances usefullness of Friedel-Crafts acylation
In a Clemmensen reduction the conversion occurs under acidic conditions
Wolf-Kishner Reduction
Benzaldehyde
Adding a formyl group requires stronger conditions than an acyl group addition
Cannot isolate formyl chloride
Birch Reduction
In addition to adding electrophiles to aromatic ring,
the aromatic ring can be reduced by adding electrons to the system
(in essence a nucleophilic addition)
This strongly basic anion will abstract a proton from alcohol solution
The radical will then undergo the same operation a second time
The final product has thus been reduced from benzene to a 1,4-cyclohexadiene
The intermediate in a Birch reduction is the radical anion formed after addition of electron
With electron withdrawing substituent:
O
NH3(l), Na
CH3OH
OCH3
OCH3
Permanganate Oxidation
Any carbon adjacent to an aromatic ring that contains at least one hydrogen
will be oxidized with permanganate to the carboxylic acid stage
Benzylic Halide
The benzylic radical is more stable due to resonance with aromatic ring
CH2
Cl
Cl
Cl2, h!
Br
Br2, h!
Mechanism
NO2
NO2
Cl
NaCN
NO2
Cl
O 2N
Cl
CN
CN
O2N
NO2
Cl
O2N
CN
O2N
NO2
Cl
CN
CN
O 2N
O2N
To regain aromatic stabilization, the chloride leaves to give the substituted product
NO2
O
H2N
R
N
H
H
N
(peptide chain)
O2N
N
H
(peptide chain)
cleave
Sanger reagent
NO2
O2N
H
N
OH
R
The Sanger reagent can react with the N-terminal amine from the peptide
The resultant nucleophilic aromatic substitution product can be cleaved
and thus the terminal amino acid structure determined
Benzyne Mechanism
A second nucleophilic aromatic substitution reaction is a benzyne mechanism
Benzyne is an extremely unstable intermediate
which will react with any nucleophile present
NH2
NH2
NaNH2, NH3
Br
benzyne
Oxidation of Phenols
Coenzyme Q
Allows a much wider diversity of products than available with Friedel-Crafts reactions
To understand these reactions one key is knowing what metal is needed to catalyze the
reaction and also what functional groups are needed for each specific reaction to occur
Organocuprates
These lithium dialkyl cuprate reagents (organocuprates) are also called Gilman reagents
Heck Reaction
Suzuki Coupling
Couples aryl or vinyl halide with boronic acid with palladium catalyst and base
Can use boronic acid [R-B(OH)2] or ester [R-B(OR)2] that is alkyl, vinyl or aryl