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Home , Acyl group, Alkylation, Aryl, Birch reduction, Electrophilic addition

Reactions of Aromatic Compounds

Aromatic compounds are stabilized by this “aromatic stabilization” energy

Due to this stabilization, normal SN2 reactions observed with do not occur with aromatic compounds 2 (SN2 reactions never occur on sp hybridized !)

In addition, the double bonds of the aromatic group do not behave similar to reactions Aromatic Substitution

While aromatic compounds do not react through addition reactions seen earlier

Br Br Br2 Br2

FeBr3 Br

With an appropriate catalyst, will react with bromine

The product is a substitution, not an addition (the bromine has substituted for a )

The product is still aromatic Electrophilic Aromatic Substitution

Aromatic compounds react through a unique substitution type reaction

Initially an reacts with the to generate an arenium (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 Products E

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 (e.g. FeBr3) to bromine

In presence of aromatic ring this electrophilic bromine source will react

Br2 Br FeBr3 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 groups are electron donating

Therefore 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 will inductively pull electron density out of the ring

2)

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 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 CH CH3 3 CN Br2 CN meta director FeBr3

Br ortho/para director

H C CN Br2 H C CN 3 meta director 3 FeBr3 Br Stronger director wins ortho/para director

H3C Br2 H3C 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 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 Beside Bromine

Chlorination reaction is similar to bromination

Often use Lewis acid with 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

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

Often use HF as acid source since fluoride is weak , therefore higher lifetime of carbocation to react

2) From 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 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

Instead of adding an alkyl group this reaction adds an acyl substituent

First need to generate an acid chloride

Thus any 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 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 )

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

e

Addition of one electron thus generates a anion

This strongly basic anion will abstract a proton from 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 formed after addition of electron

With electron withdrawing substituent:

O O O NH3(l), Na 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 Cl Cl2, h!

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

This is NOT a SN2 reaction

Initially a is formed which subsequently loses the leaving group,

unlike a SN2 reaction which is a one step

NO2 NO2 NO2 NO2 Cl Cl Cl Cl NaCN CN CN CN

O2N O2N O2N O2N

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

NO2 NO2 Cl CN CN

O2N 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 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

NO NO O 2 2 H F O N (peptide chain) H N (peptide chain) N 2 N H H R O2N R O2N cleave Sanger reagent

NO O 2 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 structure determined Benzyne Mechanism

A second nucleophilic aromatic 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 at moderate temperatures, but do not need EWG’s on ring Oxidation of

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 -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 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 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 with palladium catalyst and base

Can use boronic acid [R-B(OH)2] or [R-B(OR)2] that is alkyl, vinyl or aryl