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

Br Br
Br2 Br2
FeBr3 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

Transition
states
Transition
states

Intermediate

Potential E
energy
H

Starting
material
E
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

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

Br2
FeBr3 Br Br
H
 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 O O O
CH3 CH3 CH3 CH3
 Many substituents will have both inductive and resonance effects

Need to balance the effects

Electronegative atoms with lone pair

of electrons have opposing effects

R
Z Z

Alkyl substituents
Inductively withdrawing
Resonance donating,

inductively donate,
therefore deactivating
therefore activating

no resonance effects,

therefore activators

•
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

Z O O
N
Y N
O

Whenever Z is more electronegative than Y as seen in structure

2)
A formal positive charge is placed directly adjacent to ring

H3C CH3
N
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 CH3
CN Br2 CN
meta director
FeBr3

Br
ortho/para director

H3 C CN Br2 H3C CN
meta director
FeBr
3

Br
Stronger director wins

ortho/para director

H3C Br2 H3 C Br
FeBr3
OCH3 OCH3
ortho/para director

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

Nitro
Amine

Deactivating/Meta Director
Activating/Ortho-Para Director

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

 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

 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:

O NH3(l), Na O O O
CH3OH

Placing negative charge adjacent to carbonyl allows resonance

With electron donating substituent:

NH3(l), Na
OCH3 CH3OH OCH3 OCH3

Want negative charge as far removed from donating group as possible

 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

Cl
Cl2, h! Cl

Br
Br2, h!

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

NO2 NO2 NO2 NO2

Cl Cl Cl
Cl
NaCN CN CN CN
O2N O 2N O2N O2N

The anion is stabilized by electron withdrawing groups ortho/para to leaving group

NO2 NO2
Cl
CN
CN
O 2N O2N

To regain aromatic stabilization, the chloride leaves to give the substituted product

 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

NO2 NO2 O
O H
F N (peptide chain)
H2N (peptide chain) N
N H
H R
O2N R O2N

cleave
Sanger reagent

NO2 O
H
N
OH
R
O2N

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
H NH2
Br 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