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Reactions of Aromatic Compounds
Aromatic compounds are stabilized by this “aromatic stabilization” energy
Due to this stabilization, normal SN2 reactions observed with alkanes do not occur with aromatic compounds
(SN2 reactions never occur on sp2 hybridized carbons!)
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
Br2
Br
BrBr2FeBr3
Br
With an appropriate catalyst, benzene will react with bromine
The product is a substitution, not an addition (the bromine has substituted for a hydrogen)
The product is still aromatic
Electrophilic Aromatic Substitution
Aromatic compounds react through a unique substitution type reaction
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)
Electrophilic Aromatic Substitution
In a second step, the arenium ion loses a proton to regenerate the aromatic stabilization
The product is thus a substitution (the electrophile has substituted for a hydrogen)
and is called an Electrophilic Aromatic Substitution
Energy Profile
Potential energy
Reaction Coordinate
Starting material
Transition states Transition
states
Intermediate
Products
EH
E
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
The properties of the arenium ion will predict the outcome of electrophilic aromatic substitution chemistry
Bromination
To brominate an aromatic ring need to generate an electrophilic source of bromine
In practice typically add a Lewis acid (e.g. FeBr3) to bromine
In presence of aromatic ring this electrophilic bromine source will react
Br2FeBr3 Br
HBr
With unsubstituted benzene the position of reaction is arbitrary
With a monosubstituted aromatic ring, however, can obtain three possible products
How to predict which is favored?
Controlled by stability of arenium ion intermediate
The stability is different depending upon placement of carbocation
Alkyl groups are electron donating
Therefore toluene will favor electrophilic substitution at ortho/para positions (only ortho/para substitution places carbocation adjacent to alkyl group on ring)
Often obtain more para than ortho due to sterics
In addition to orientational control, substituents affect reactivity
CH3 NO2
As the aromatic ring acquires more electron density, the arenium ion will be more stable
Toluene therefore reacts faster in an electrophilic aromatic substitution than benzene
The alkyl group is called an activating group (it activates the ring for a faster rate)
Any substituent that increases the rate for an electrophilic aromatic substitution is called an “activating” substituent
Substituents that lower the rate for an electrophilic aromatic substitution are called “deactivating” subsituents
(nitro is one example of a deactivating group) These are groups that lower the electron density of the aromatic ring
Factors that affect Activators/Deactivators
There are in general two mechanisms that can affect a substituent
1) Inductive
Substituents that are more electronegative than carbon will inductively pull electron density out of the ring
2) Resonance
Substituents that have a lone pair of electrons adjacent to the ring can donate electron density into the ring through resonance
O CH3O CH3
O CH3O CH3
Many substituents will have both inductive and resonance effects
Need to balance the effects
R
Alkyl substituents inductively donate,
no resonance effects, therefore activators
Electronegative atoms with lone pair of electrons have opposing effects
Inductively withdrawing therefore deactivating
Resonance donating, therefore activating
Z Z
• 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
Other Deactivating Groups
There are two other main classes of deactivating groups
1) A conjugated system where both inductive and resonance effects pull electron density from the ring
YZ
Whenever Z is more electronegative than Y as seen in structure
NO
O
ON
2) A formal positive charge is placed directly adjacent to ring
NCH3
H3C CH3
Activating vs. Deactivating Ability can be compared
The substituents can be compared relatively
Orientational Control Can Be Predicted
1) All activating groups favor ortho/para substitution
2) Deactivating groups with a lone pair of electrons adjacent to the ring favor ortho/para substitution (halogens are in this category)
3) Other deactivating groups favor meta substitution
With deactivating groups besides halogens, the favored substitution is meta
Can be predicted by stability of arenium ion
Only the meta substitution does not place a carbocation adjacent to EWG
All positions with a deactivating group are slower than benzene
* The meta position is the LEAST disfavored
Consider reaction coordinate for the first, rate-determining step
Multiple Substituents
How to determine orientation of electrophilic aromatic substitution if there is more than one substituent?
A few rules to consider:
1) The effects are cumulative
2) The stronger substituent according to the relative effects will be correspondingly more important for directing effects
3) When given a choice, a new substituent typically will not go ortho to two other substituents
Consider some examples:
ortho/para director CH3
CN Br2FeBr3meta director
CH3CN
Br
H3C CN Br2FeBr3
ortho/para director
meta director H3C CN
Br
Br2FeBr3
H3C
OCH3
ortho/para director
ortho/para director
H3C
OCH3
Br
Stronger director wins
Stronger director wins
Reactivity of aromatic ring can affect amount of reaction
In reactions with strongly activated rings, polyhalogenation occurs
With either phenol or aniline, the reaction will proceed until all ortho/para positions are reacted when catalyst is used
With these highly activated ring systems, catalyst is not necessary
Reaction will only proceed with strongly activated ring systems, still need catalyst for less activated aromatic rings,
but with phenol or aniline reaction of one halogen can occur with no catalyst present
Other Electrophiles Beside Bromine
Chlorination reaction is similar to bromination
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
Iodination requires a stronger oxidizing reagent
The reagents are a method to generate iodonium ion in situ
The iodonium can then react as the electrophile
Fluorine is much harder to add in an electrophilic addition
There is not an easy method to generate F+
Typically to add fluorine to an aromatic ring a diazonium route is used
This chemistry will be dealt in more detail in chapter 19
Other Common Electrophiles Besides Halogens
Nitration
Adding a nitro group to an aromatic ring is a convenient and useful reaction
Need to generate a source of nitronium ion
An advantage of nitration is the nitro group can be reduced to an amine
Allows the introduction of an amine group to the aromatic ring (almost all compounds that contain a nitrogen attached to aromatic ring
occurred through a nitration)
This conversion changes the electronic properties of the ring
Nitro Deactivating/Meta Director
Amine Activating/Ortho-Para Director
Sulfonation
Allows the introduction of a sulfur group (many biological/medicinal uses)
The reverse step can also occur
The desulfonation step allows introduction of isotopes
Occurs through arenium ion where compound is sulfonated, then add D+ and desulfonate to eliminate sulfur and add deuterium
Friedel-Crafts Alkylation
In general carbon-carbon bonds can be made by reacting an aromatic ring with a carbocation
This reaction is called a Friedel-Crafts alkylation
The key is formation of electrophilic carbon
The alkyl halide reacts with the Lewis acid
With tertiary and secondary alkyl halides this generates a discrete carbocation
With primary alkyl halides the full carbocation is not formed
Any method that generates a carbocation can be used in a Friedel-Crafts alkylation
Two other common methods:
1) From alkenes
Often use HF as acid source since fluoride is weak nucleophile, therefore higher lifetime of carbocation to react
2) From alcohols
Limtations of Friedel-Crafts Alkylation
1) Reaction does not work with strongly deactivated aromatic rings
Friedel-Crafts alkylations do not work with nitro, sulfonic, or acyl substituents
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
Can therefore never obtain n-alkyl substituents longer than 2 carbons
3) Polyalkylation often occurs with Friedel-Crafts alkylation
Because an alkyl group is an activating group, the product is more reactive than the starting material
Causes the product to react further
To prevent polyreaction the starting material (benzene is this example) is used in excess
Another Option: Friedel-Crafts Acylation
Instead of adding an alkyl group this reaction adds an acyl substituent
First need to generate an acid chloride
Thus any carboxylic acid can be converted into an acid chloride
The acid chloride can then be reacted in a Friedel-Crafts acylation
First form an acylium ion by reacting with Lewis acid
The acylium ion then reacts with aromatic ring in a typical electrophilic aromatic substitution
Advantages of Friedel-Crafts Acylation
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 these two advantages, the Friedel-Crafts acylation is a much more convenient reaction than the Friedel-Crafts alkylation
-still will not react with strongly deactivated aromatic rings
High para substitution preference
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
*often see para preference with bulky electrophiles
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
Overall these two steps, Friedel-Crafts acylation followed by Clemmensen, allows the introduction of an n-alkyl substituent
which would not be possible with a Friedel-Crafts alkylation
Wolf-Kishner Reduction
Another method to reduce a carbonyl to methylene is a Wolf-Kishner reduction
Main difference is that the Wolf-Kishner occurs under basic conditions
Both Clemmensen and Wolf-Kishner require strong conditions, Clemmensen uses acidic while Wolf-Kishner uses basic conditions
Benzaldehyde
Adding a formyl group requires stronger conditions than an acyl group addition
Cannot isolate formyl chloride
Therefore normal Friedel-Crafts acylation conditions cannot be used
Need to generate in situ
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)
The electrons need to be generated in situ
This electron is called a “solvated” electron
In the presence of an aromatic ring this electron will react
Addition of one electron thus generates a radical anion
This strongly basic anion will abstract a proton from alcohol solution
e
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 aromatic stabilization has been lost
Orientation of Birch Reduction
What happens if there is a substituent on the aromatic ring before reduction?
Which regioisomer will be obtained?
Similar to every other reaction studied need to ask yourself, “What is the stability of the intermediate structure?”
The preferred product is a result of the more stable intermediate
The intermediate in a Birch reduction is the radical anion formed after addition of electron
With electron withdrawing substituent:
With electron donating substituent:
O NH3(l), NaCH3OH
O
Placing negative charge adjacent to carbonyl allows resonance
O O
NH3(l), NaCH3OHOCH3
Want negative charge as far removed from donating group as possible
OCH3 OCH3
Reactions of Alkyl Substituents to Aromatic Ring
Once alkyl groups are attached to aromatic rings they can undergo subsequent reactions
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
As seen in chapter 4, halogenation reactions can occur with either chlorine or bromine under photolytic conditions
Reaction proceeds through a radical intermediate
The benzylic radical is more stable due to resonance with aromatic ring
CH2
Remember that chlorination was more reactive, bromination though occurred selectively
Cl2, h! ClCl
Br2, h!
Br
Realize reaction does not occur on aromatic ring, do not obatin radical from sp2 hybridized carbon
Nucleophilic Aromatic Substitution
Another type of reaction with aromatic rings is a nucleophilic addition
Instead of adding an electrophile to form an arenium ion, a nucleophile replaces a leaving group
This is NOT a SN2 reaction
Initially a carbanion is formed which subsequently loses the leaving group, unlike a SN2 reaction which is a one step reaction
Mechanism
Cl
O2N
NO2
NaCN
NO2
O2N
ClCN
NO2
O2N
ClCN
NO2
O2N
ClCN
The anion is stabilized by electron withdrawing groups ortho/para to leaving group
To regain aromatic stabilization, the chloride leaves to give the substituted product
NO2
O2N
ClCN
NO2
O2N
CN
Unique factors for Nucleophilic Aromatic Substitution
1) Must have EWG’s ortho/para to leaving group -the more EWG’s present the faster the reaction rate
(intermediate is stabilized)
2) The leaving group ability does not parallel SN2 reactions -bond to leaving group is not broken in rate-determining step
(fluorine for example is a good leaving group for nucleophilic aromatic substitution but is a horrible leaving group for SN2 reaction)
More electronegative atom has a faster rate F > Cl > Br > I
(polarizability is not a factor)
Using Nucleophilic Aromatic Substitution for Peptide Determination
React 2,4-dinitrobenzene with peptide
F
O2N
NO2
H2NO
NH
(peptide chain)
R
HN
O2N
NO2 O
NH
(peptide chain)
R
Sanger reagent
HN
O2N
NO2 O
ROH
cleave
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
HBr
NH2NH2
NaNH2, NH3
benzyne
Need strong base at moderate temperatures, but do not need EWG’s on ring
Oxidation of Phenols
Many reactions of phenols follow the same reactivity seen earlier -they are highly activating groups (ortho/para directors)
for electrophilic aromatic substitution
Phenols can also be oxidized to create quinones
Coenzyme Q
All oxygen-consuming organisms use this process
Aromatic Substitution using Organometallic Reagents
Extremely useful in forming carbon-carbon bonds with aromatic rings
Allows a much wider diversity of products than available with Friedel-Crafts reactions
Tremendous progress has been made using transition metal compounds to catalyze 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
Formed by reacting organolithium compounds with cuprous iodide (CuI)
These lithium dialkyl cuprate reagents (organocuprates) are also called Gilman reagents
These Gilman reagents can react with alkyl halides to form new carbon-carbon bonds similar to SN2 reactions
Reactions at sp2 Hybridized Carbons
Unlike SN2 reactions, however, these organocuprates can react with sp2 hybridized aryl or vinyl halides
Heck Reaction
Can also accomplish reaction at alkene using a palladium catalyzed reaction (called Heck reaction)
-the halide can be either aryl or vinyl -the halogen can be either bromine or iodine
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