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Chapter 15

Reactions of

Aromatic Compounds

Created by

Professor William Tam & Dr. Phillis Chang

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1. Electrophilic Aromatic�Substitution Reactions

Overall reaction

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Different chemistry with alkene

2. A General Mechanism for Elec-�trophilic Aromatic Substitutions

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Benzene does not undergo electrophilic addition, but it undergoes electrophilic aromatic substitution

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Mechanism

Step 1

cyclohexadienyl cation

- not aromatic

- resonance-stabilized

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Mechanism

Step 2

A

cyclohexadienyl cation

- very acidic

- some base (A) restores aromaticity

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Benzene does not react with Br₂ or Cl₂ unless a Lewis acid is present (a catalytic amount is usually enough)

3. Halogenation of Benzene

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Examples

Reactivity: F₂ > Cl₂ > Br₂ > I₂

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Mechanism

Not a strong electrophile

Lewis acid activates Br₂

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Mechanism (Cont’d)

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Mechanism (Cont’d)

bromobenzene
HBr
catalyst (FeBr₃) regenerated

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F₂: too reactive, gives a mixture of mono-, di- and polysubstituted products

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I₂: very unreactive even in the presence of Lewis acids; usually need to add an oxidizing agent (e.g. HNO₃, Cu²⁺, H₂O₂)

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Electrophile in this case is NO₂^⊕ (nitronium ion)

4. Nitration of Benzene

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Mechanism

nitronium ion

strong electrophile

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Mechanism (Cont’d)

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Mechanism (Cont’d)

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Mechanism Step 1

5. Sulfonation of Benzene

SO₃ is protonated to form SO₃H⁺

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Step 2

SO₃H⁺ reacts as an electrophile with the benzene ring to form an arenium ion

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Step 3

Loss of a proton from the arenium ion restores aromaticity to the ring and regenerates the acid catalyst

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Sulfonation & Desulfonation

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6. Friedel–Crafts Reactions

6A. Friedel-Crafts Alkylation

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Mechanism

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Mechanism (Cont’d)

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Mechanism (Cont’d)

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The electrophile in Friedel-Crafts Alkylation

When R-X is a 2^o or 3^o alkyl halide, a carbocation is the electrophile.

When R-X is 1^o (or methyl), the electrophile is a complex of the alkyl halide and AlCl₃

(However, this “acts like” it were just a carbocation.)

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Other pairs of reagents that generate carbocations may be used in Friedel-Crafts akylations

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Acyl group:

Electrophile in this case is R–C≡O^⊕ (acylium ion)

6B. Friedel-Crafts Acylation

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Acid chlorides (or acyl chlorides)

Can be prepared by

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Mechanism

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Mechanism (Cont’d)

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Mechanism (Cont’d)

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Friedel-Crafts Acylations can also be carried out using carboxylic acid anhydrides.

Activation of carboxylic acid anhydride:

acylium ion

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When the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations that are more stable, it usually does so, and the major products obtained from the reaction are usually those from the more stable carbocations.

6C. Limitations of Friedel-Crafts

Reactions

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(How is this

formed?)

(not formed)

For example

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1^o carbocation-like

(not stable)

Reason

3^o carbocation

(more stable)

1,2-hyride shift

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Friedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH₂, –NHR, or –NR₂ group. This applies to both alkylations and acylations.

These usually give poor yields in Friedel-Crafts reactions

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The amino groups, –NH₂, –NHR, and –NR₂, are changed into powerful electron-withdrawing groups by the Lewis acids used to catalyze Friedel-Crafts reactions

Does not undergo a Friedel-Crafts reaction

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Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readily

sp²

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Polyalkylations often occur

(Polyacylations are not a problem, as the acyl group is a strong electron-withdrawing group)

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Carbon chain rearrangements do not occur in Friedel–Crafts acylations

The acylium ion, because it is stabilized by resonance, is more stable than most other carbocations. Thus, there is no driving force for a rearrangement.

7. Synthetic Applications of�Friedel-Crafts Acylations:�The Clemmensen Reduction & Wolff–Kishner Reductions

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The carbonyl group of an aryl ketone can be reduced to a CH₂ group

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Consider:

major product

(due to rearrangement)

minor product

rearrangement avoided

Alternative?

Friedel-Crafts acylation

followed by reduction

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7A. The Clemmensen Reduction

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Clemmensen reduction of ketones

A very useful reaction for making alkyl benzenes that cannot be made via Friedel-Crafts alkylations

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Clemmensen reduction of ketones

Cannot use Friedel-Crafts alkylation

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Rearrangements of carbon chains do not occur in Friedel-Crafts acylations

(no rearrangement of the R group)

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7B. The Wolff–Kishner Reduction

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When used with cyclic anhydrides, Friedel-Crafts acylations provide a means to add a new ring to an aromatic compound.

α-tetralone

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8. Existing Substituents Direct the Position of Electrophilic Aromatic Substitution

Statistical mixture of o-, m-, p- products, or any preference?

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Ortho-para directors predominantly direct the incoming group to an ortho or para position.

Meta directors predominantly direct the incoming group to the meta position.

ortho

para

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The unshared electron pair on an existing substituent causes ortho-para substitution.

Para substitution usually dominates over ortho substitution due to steric effects.

We can account for the predominance of ortho-para substitution over meta substitution if we consider the different arenium ions formed by each pathway.

90%

10%

8A. Ortho-Para Directors

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ortho addition

4 resonance structures

Relatively stable contributor

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para addition

4 resonance structures

Relatively stable contributor

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meta addition

3 resonance structures

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Four reasonable resonance structures can be drawn for ortho-para addition, versus only three for meta addition.

That alone suggests the arenium formed by the ortho-para addition mechanism should be more stable.

Additionally, the “extra” resonance structure in both cases is relatively stable for a cation.

These resonance structures make a large and stabilizing impact on the stability of the arenium intermediate.

Additional covalent bond compared to other resonance structures
Every atom has full octet

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Electron donation to the ring by resonance is reduced when there is an alternative resonance pathway from the ring.

Thus, the amide group is less activating than an amine group.

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Halogen atoms (X = F, Cl, Br, I) are also ortho-para directors, because they can donate electron density by resonance.

However, halogens’ electronegativity means they withdraw electrons from the ring, destabilizing the areneium ion overall. (See Section 15.9)

ortho

para

The p orbital overlap in X=C is poor, except for F.

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Alkyl groups are ortho-para directors, even though they lack a lone pair of electrons.

ortho

para

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An existing substituent that is an electron withdrawing group (EWG) causes meta substitution.

We can account for the predominance of meta substitution over ortho-para substitution if we consider the different arenium ions formed by each pathway.

8B. Meta Directors

6%

93%

1%

Nitro group has positive formal charge on N, withdrawing electron density from atoms bonded to it.

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ortho addition

1 highly unstable

resonance structure

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para addition

1 highly unstable

resonance structure

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meta addition

0 highly unstable

resonance structures

(comparatively)

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The arenium ion arising from ortho-para addition has one resonance structure that is highly unstable.

The arenium ion arising from meta addition has no such highly unstable resonance structure.

Thus, the pathway leading to the meta-substituted arenium ion is favored because it is the least unfavorable of three unfavorable pathways.

Electron-withdrawing group located on the carbon bearing a positive charge

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Classification of different substituents

Y (Electron Donating Group)
–NH₂, –NR₂ –OH, –O⁻	Strongly activating	o-, p-directing
–NHCOR –OR	Moderately activating	o-, p-directing
–R (alkyl) –Ph	Weakly activating	o-, p-directing
–H	NA	NA

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Classification of different substituents

Y (Electron Withdrawing Groups)
–Halide (F, Cl, Br, I)	Weakly deactivating	o-, p-directing
–COOR, –COR, –CHO, –COOH, –SO₃H, –CN	Moderately deactivating	m-directing
–CF₃, –CCl₃, –NO₂, –^⊕NR₃	Strongly deactivating	m-directing

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9. Activating and Deactivating Effects: How Electron-Donating and Electron-Withdrawing Groups Affect the Rate of an EAS Reaction

The RDS for an EAS reaction is formation of the arenium ion.
Any substituent that reduces the energy of the transition state lowers the free energy of activation and increases the relative rate of reaction.
Any substituent that raises the energy of the transition state raises the free energy of activation and decreases the relative rate of reaction.

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If G is an electron-releasing group (relative to hydrogen), the reaction occurs faster than the corresponding reaction of benzene

When G is electron donating,

the reaction is faster

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If G is an electron-withdrawing group, the reaction is slower than that of benzene

When G is electron withdrawing, the reaction is slower

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When two different groups are present on a benzene ring, the more powerful activating group determines the outcome of the reaction.

10. Directing Effect in Disubstituted Benzenes

Ortho-director

Major Product

?

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Examples [only major product(s) shown]

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Substitution does not occur to an appreciable extent between meta- substituents if another position is open

X

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11. Reactions of Benzene Ring Side Chains

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Benzylic radicals are stabilized by resonance

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11A. Benzylic Halogenation of the Side Chain

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Mechanism

Chain initiation

Chain propagation

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Chain propagation

Chain termination

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e.g.

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11B. Conjugation is Favored When Alkenylbenzenes are Formed by Elimination Reactions

Alkenylbenzenes that have their side-chain double bond conjugated with the benzene ring are more stable than those that do not

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Example

(not observed)

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11C. Additions to the Double Bond of� Alkenylbenzenes

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Mechanism (top reaction)

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Mechanism (bottom reaction)

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11D. Oxidation of the Side Chain

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Using hot alkaline KMnO₄, alkyl, alkenyl, alkynyl and acyl groups all oxidized to –COOH group
For alkyl benzene, 3^o alkyl groups resist oxidation

Need benzylic hydrogen for alkyl group oxidation

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11E. Oxidation of the Benzene Ring

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12. Synthetic Strategies

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CH₃ group: ortho-, para-directing
NO₂ group: meta-directing

12A. Choosing the Order of Reactions

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If the order is reversed, the wrong regioisomer is produced

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We do not know how to substitute a hydrogen on a benzene ring with a –COOH group. However, side chain oxidation of alkylbenzene could provide the –COOH group
Both the –COOH group and the NO₂ group are meta-directing

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Route 1

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Route 2

COOH

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Which synthetic route is better?
Recall “Limitations of Friedel-Crafts Reactions, Section 15.6C”

Friedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH₂, –NHR, or –NR₂ group. This applies to both alkylations and acylations
Route 2 is a better route

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Both Br and Et groups are ortho-, para-directing
How do you place them meta to each other?
Recall: an acyl group is meta-directing and can be reduced to an alkyl group by Clemmensen reduction

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12B. Use of Protecting and Blocking� Groups

Problem: Very powerful activating groups (like NH₂) cause the benzene ring to be too reactive

Multiple substitutions
Oxidation of the benzene ring

Considerable destruction of benzene ring

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Solution: Temporarily convert NH₂ into a less-activating group

Converts amine into amide

Only moderately activating

(o-p director)

+ ortho product (minor)

Removes CH₃CO; replaces with H

90%

The steric bulk of the acetamido group decreases ortho substitution.

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So, we can prepare p-nitroaniline from aniline.

�

Problem: How do we prepare o-nitroaniline from aniline?

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Solution: Place an easily-removable blocking group in the para position.

Place SO₃H in para position

NO₂ can only go to ortho position

Dilute, aqueous H₂SO₄ both removes acetamido group and desulfonates

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13. The S_NAr Mechanism: Nucleophilic Aromatic Substitution by Addition-Elimination

no substitution

The standard S_N1 or S_N2 mechanism are not possible because of the sp²-hybridization of benzene carbons.

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Electron-withdrawing groups allow substitution to occur.

The more ortho or para electron withdrawing groups, the temperature required for the reaction decreases.

Meta groups do not produce a similar effect.

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Mechanism: S_NAr (Nucleophilic Aromatic Substitution)

(Additional Step: Under the basic conditions of this reaction, the phenol is deprotonated.)

Resonance-stabilized carbanion

“Meisenheimer Intermediate”

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14. Benzyne: Nucleophilic Aromatic Substitution by Elimination-Addition

Under forcing conditions, the substitution by ^–OH can take place.

With a very powerful base (^–NH₂), less-forcing conditions are required.

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These reactions take place via an elimination-addition mechanism that involves the intermediate benzyne.

The solvent for this reaction is liquid ammonia (NH₃).

Elimination

Addition

Benzyne (unstable)

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Instability of benzyne

Extra π bond lines in plane of molecule

Two π bonds are perpendicular to each other

Poor overlap of carbon p-orbitals to form extra π bond

Much angle strain present

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Experimental Evidence for Benzyne

Chlorobenzene labeled with ¹⁴C (*) at chlorine carbon

Elimination

Addition

Equal mixture of both products. Nucleophile can attack at either carbon of benzyne.

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Experimental Evidence for Benzyne

m-(trifluoromethyl)aniline from o-chlorotrifluoromethyl benzene

Elimination

Nucleophilic Attack

The more stable carbanion has the formal negative charge closer to the electron-withdrawing group (CF₃).

more stable

less stable

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Benzyne in Diels-Alder Reactions

Benzyne can be prepared in situ by diazotization of anthranilic acid.

Benzyne thus prepared can be “trapped” by furan in a Diels-Alder Reaction.

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15. Reduction of Aromatic�Compounds

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16A. The Birch Reduction

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Mechanism

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Synthesis of 2-cyclohexenones