Chapter 12 Reactions of Arenes: Electrophilic and NucleophilicAromatic Substitution HE+ EY + HY ++++...

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Chapter 12Chapter 12Reactions of Arenes:Reactions of Arenes:

Electrophilic and NucleophilicAromatic Electrophilic and NucleophilicAromatic SubstitutionSubstitution

++ EE YY ++ HH YY++ ––

++ :Nu:Nu-- ++ :X:X--

12.1Representative Electrophilic Aromatic

Substitution Reactions of Benzene HH

++ EE YY ++ HH YY++ ––

+ E Y + H Y+ –

Electrophilic aromatic substitutions (EAS) include:

1. Halogenation

2. Nitration

3. Sulfonation

4. Friedel-Crafts Alkylation

5. Friedel-Crafts Acylation

Table 12.1: Halogenation of Benzene

+ + HBr

Bromobenzene(65-75%)

Note: This reaction does not go via a radical mechanism like halogenation of alkanes nor does it proceed spontaneously like halogenation of alkenes, it requires a Lewis acid catalyst and heat.

Table 12.1: Nitration of Benzene

+ + H2O

Nitrobenzene(95%)

Table 12.1: Sulfonation of Benzene

+ + H2O

heatHOSO2OH

Benzenesulfonic acid(100%)

fuming

Note: fuming H2SO4 contains dissolved SO3.

Table 12.1: Friedel-Crafts Alkylation of Benzene

+ + HCl

C(CH3)3

tert-Butylbenzene(60%)

(CH3)3CCl~00 C

Note: Once attached, the alkyl group activates the ring.

Table 12.1: Friedel-Crafts Acylation of Benzene

+ + HCl

1-Phenyl-1-propanone(88%)

CH3CH2CCl

CCH2CH3

Note: Once attached, the alkyl group deactivates the ring.

12.212.2Mechanistic PrinciplesMechanistic Principles

ofofElectrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution

Step 1: Attack of Electrophileon -electron System of Aromatic Ring H H

H HH H

E+ H H

A highly endothermic step (need to overcome the resonance energy of the ring).

The carbocation is allylic, but the ring has lost aromatic character.

Step 2: Loss of a Proton from the CarbocationIntermediate

The second step is highly exothermic; this step restores the aromatic character of the ring and the resonance energy is regained. In this step, the proton is always removed from the carbon to which the electrophile added.

H EH H

H + E+

H + H+

Energy diagram for the two step EAS reaction.

Based on this General Mechanism:

Identify the electrophile in each EAS reaction: nitration,

sulfonation,

halogenation,

Friedel-Crafts alkylation, and

Friedel-Crafts acylation.

Establish the mechanism of each specific electrophilic aromatic substitution reaction.

12.3Nitration of Benzene

Nitration of Benzene

+ + H2O

Electrophile isnitronium ion.

O N O••

•••• ••

Where does Nitronium Ion Come From ?

+•• ••

••••

•• ••••

+•• ••

••

•• ••••

O N O••

•••• •• + H

O••H

••

H2SO4 is a stronger acid than HNO3 and forces it to take a proton.

Step 1: Attack of Nitronium Cationon the -electron system of the Aromatic Ring H H

H HH H

H H NO2

Step 2: Loss of a Proton from the Carbocation Intermediate

H H NO2

12.4Sulfonation of Benzene

Sulfonation of Benzene

+ + H2O

heatHOSO2OH

The major electrophile is sulfur trioxide, SO3.

+•• ••

••••

•• ••••

Step 1: Attack of Sulfur Trioxide on the -electron system of the Aromatic Ring H H

H HH H

SO3 H H

H H SO3–

H SO3–

H H SO3–

Step 3: Protonation of the Benzenesulfonate Ion

H SO3–

H SO3HH H

This is the only EAS reaction that is reversible.

12.5Halogenation of Benzene(See the note on slide 4.)

Halogenation of Benzene

+ + HBr

Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2.

The Br2-FeBr3 Complex

+••Br Br•••• ••

•• ••

Lewis base Lewis acid

Br Br•••• ••

•• ••FeBr3

Complex

The Br2-FeBr3 complex is more electrophilic than Br2 alone.

Step 1: Attack of Br2-FeBr3 Complex on the -electron System of the Aromatic Ring

H HH H

Br Br FeBr3

–+ H H

H H Br

+ FeBr4

H H Br

H BrH H

12.6Friedel-Crafts Alkylation of Benzene

Friedel-Crafts Alkylation of Benzene

+ + HCl

C(CH3)3

(CH3)3CCl

Electrophile is tert-butyl cation. C CH3

AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide.

Role of AlCl3

(CH3)3C Cl ••••

••+ AlCl3

(CH3)3C Cl••

••AlCl3–

(CH3)3C+

Cl••

••AlCl3–

••+

Step 1: Attack of tert-Butyl carbocationon the -electron System of the Aromatic Ring H H

H HH H

H H C(CH3)3

C(CH3)3+

H C(CH3)3

H H C(CH3)3

Rearrangements in Friedel-Crafts Alkylation

Carbocations are intermediates in this mechanism, therefore, rearrangements can occur. Here, isobutyl chloride is the alkyl halide, but tert-butyl cation is the electrophile due to rearrangement.

(CH3)2CHCH2ClAlCl3

Isobutyl chloride tert-Butylbenzene(66%)

C(CH3)3

Rearrangements in Friedel-Crafts Alkylation

•C CH2

Cl••

AlCl3+ –

C CH2H3C

+ Cl••

••AlCl3–

••

Alkyl halide:AlCl3 complex.

Rearrangedalkyl carbocation.

Reactions Related to Friedel-Crafts Alkylation

Cyclohexylbenzene(65-68%)

Cyclohexene is protonated by sulfuric acid, to give the cyclohexyl carbocation which attacks the benzene ring.

12.7Friedel-Crafts Acylation of Benzene

Friedel-Crafts Acylation of Benzene

+ + HCl

AlCl3O

CH3CH2CCl

CCH2CH3

Electrophile is an acyl carbocation (an acylium ion).

••CH3CH2C O ••

+CH3CH2C O ••

Step 1: Attack of the acyl carbocationon the -electron System of the Aromatic Ring

H HH H

CCH2CH3+ H H

CCH2CH3

AlCl3 acts as a Lewis acid to promote ionization of the acyl halide.

CCH2CH3

Anhydrides can be used instead of acyl chlorides. H

Acid Anhydrides

Acetophenone(76-83%)

AlCl3 O

CH3COCCH3

CH3COH+

12.8Synthesis of Alkylbenzenes by

Acylation-Reduction

Reduction of aldehyde and ketonecarbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction.

Acylation-Reduction H O

Zn(Hg), HCl CH2R

Permits monosubstitution of primary alkyl groups on an aromatic ring in acid media.

Reduction of aldehyde and ketonecarbonyl groups by heating with H2NNH2

and KOH is called the Wolff-Kishner reduction.

Acylation-Reduction H O

H2NNH2, KOH,

triethylene glycol,heat

Permits monosubstitution of primary alkyl groups on an aromatic ring in basic media.

Example: Prepare Isobutylbenzene

No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement.

(CH3)2CHCH2Cl

CH2CH(CH3)3

This does not work !

Recall rearrangement !

(CH3)2CHCH2Cl

Isobutyl chloride tert-Butylbenzene(66%)

C(CH3)3

Note that although alkyl carbocations may rearrange, acylium ions do not.

So, Use Acylation-Reduction Instead

(CH3)2CHCCl

AlCl3 O

CCH(CH3)2

Zn(Hg)HCl

CH2CH(CH3)2

12.9Rate and Regioselectivity in

Electrophilic Aromatic Substitution

A substituent already present on the ring A substituent already present on the ring can affect both the can affect both the raterate and and regioselectivityregioselectivityof electrophilic aromatic substitution.of electrophilic aromatic substitution.

Activating substituents increase the rate of EAS compared to that of benzene. Activating substituents are typically electron donating groups.

Deactivating substituents decrease the rate of EAS compared to benzene. Deactivating substituents are typically electron withdrawing groups.

Effect on Rate

Toluene undergoes nitration 20-25 times faster than benzene.

A methyl group is an activating substituent.

Methyl Group CH3 CF3 (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene.

A trifluoromethyl group is adeactivating substituent.

Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Ortho-para directors are typically electron donating groups.

Meta directors direct an incoming electrophile to positions meta to themselves. Meta directors are typically electron withdrawing groups.

Effect on Regioselectivity

Nitration of Toluene CH3

aceticanhydride

34%3%63%

O- and p-nitrotoluene together comprise 97% of the product.A methyl group is an ortho-para director.

Nitration of (Trifluoromethyl)benzene CF3 CF3

3%91%6%

M-nitro(trifluoromethyl)benzene comprises 91% of the product.A trifluoromethyl group is a meta director.

the Nitration of Toluene

Carbocation Stability Controls Regioselectivity +

gives ortho gives para gives meta

more stable less stable

Which intermediate leads to product ?

ortho Nitration of Toluene

The last resonance structure is a 3o carbocation and is the rate-determining intermediate in the ortho nitration of toluene.

para Nitration of Toluene +

The center resonance structure is a 3o carbocation and is the rate-determining intermediate in the para nitration of toluene.

meta Nitration of Toluene +

All the resonance forms of the rate-determining intermediates in the meta nitration of toluene are 2o carbocations and none is adjacent to the electron donating substituent.

Nitration of Toluene: Interpretation

• The rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation and it is next to the electron donating group. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations and none are next to the electron donating group.

Nitration of Toluene: Interpretation

• Tertiary carbocations, being more stable, are formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. So, the major products are o- and p-nitrotoluene.

Nitration of Toluene: Partial Rate Factors

• The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions.

• Expressed as a numerical value, a partial rate factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene.

Nitration of Toluene: Partial Rate Factors CH3

All of the available ring positions in toluene are more reactive than a single position of benzene.A methyl group activates all of the ring positions, but the effect is greatest at the ortho and para positons.Steric hindrance by the methyl group makes each ortho position slightly less reactive than para.

Nitration of Toluene vs. tert-Butylbenzene CH3

tert-Butyl is activating and ortho-para directing.tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions.

C CH3H3C

All alkyl groups are activating, ortho-para directing and electron donating.

Note: The rate and regioselectivity effects in EAS of substituted benzenes is controlled by the substituent on the ring. The attacking electrophile has no influence on these effects.

Generalization

the Nitration of (Trifluoromethyl)benzene

A Key Point

C+H3C C+F3C

A methyl group is electron-donating and stabilizes a carbocation.

Because F is so electronegative, a CF3 group destabilizes a carbocation.

Carbocation Stability Controls Regioselectivity +

gives ortho

gives para

gives metaless stable more stable

Which intermediate leads to product ?

more destabilized less destabilized

The resonance form on the right of the rate-determining intermediate in the orthonitration of (trifluoromethyl)benzene is strongly destabilized next to the e-withdrawing group.

ortho Nitration of (Trifluoromethyl)benzene

The center of the resonance forms of the rate-determining intermediate in the paranitration of (trifluoromethyl)benzene is strongly destabilized next to the e-withdrawing group.

para Nitration of (Trifluoromethyl)benzene

None of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)-benzene have their positive charge on the carbon that bears the CF3 group. Meta is least destabilized.

meta Nitration of (Trifluoromethyl)benzene H

Nitration of (Trifluoromethyl)benzene: Interpretation

The rate-determining intermediates for ortho and para nitration each have a resonance form in which the positive charge is on a carbon that bears a CF3 group. Such a resonance structure is strongly destabilized. The intermediate in meta nitration avoids such a structure. It is the least unstable of three unstable intermediates and is the one from which most of the product is formed.

Nitration of (Trifluoromethyl)benzene:Partial Rate Factors

All of the available ring positions in (trifluoromethyl)-benzene are much less reactive than a single position of benzene.

A CF3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons.

4.5 x 10-64.5 x 10-6

67 x 10-6 67 x 10-6

4.5 x 10-6

12.12Substituent Effects in

Electrophilic Aromatic Substitution:Activating Substituents

Table 12.2

Very strongly activating VSA

Strongly activating SA

Activating A

Standard of comparison is Benzene

Deactivating D

Strongly deactivating SD

Very strongly deactivating VSD

Classification of Substituents in Electrophilic

Aromatic Substitution Reactions

Table 12.2

Classification of Substituents in Electrophilic

Aromatic Substitution Reactions

VSA SA A D SD VSD

-NH2 -OR -CH3 -Br -NO2

-C-(Any) -NHR -Ar -Cl -CF3 -NHCR-NR2 -CH=CH2 -CH2X -SO3H

-OH -OCR -CN

1. All activating substituents are ortho-para directors.

2. Halogen substituents are slightly deactivating, but ortho-para directing.

3. Strongly deactivating substituents are meta directors.

Important Generalizations

ERGs are ortho-para directing and activating. ERG

ERGs include —R (alkyl), —Ar (aryl), and —C=C.

Electron-Releasing Groups (ERGs)

Nitration of Phenol

This occurs about 1000 times faster than nitration of benzene.

ERGs such as —OH, and —OR arestrongly activating.

-OCH3 is such a strong activator that the FeBr3 catalyst not necessary. OCH3

Br 90%

aceticacid

Bromination of Anisole

OCH3••••

+ OCH3••

Oxygen Lone Pair Stabilizes Intermediate

All atomshave octets.

ERGs with a lone pair on the atom directlyattached to the ring are ortho-para directingand strongly activating.

Electron-Releasing Groups (ERGs)

••

All of these are ortho-para directingand strongly to very strongly activating.

Examples

ERG = •• ••OH ••

OR ••••

OCR ••••

••NH2 NHCR ••

••NHR ••NR2

Lone Pair Stabilizes Intermediates forortho and para Substitution

Comparable stabilization not possible for intermediate leading to meta substitution.

+ ERG H

Electrophilic Aromatic Substitution:Strongly Deactivating Substituents

Remember: ERGs Stabilize Intermediates forortho and para Substitution

ERG•• H

ERG••

Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution

—CF3 is a powerful EWG. It is strongly deactivating and meta directing.

All of these are meta directing and strongly deactivating.

Many EWGs Have a Carbonyl GroupAttached Directly to the Ring

—EWG =

—COH

—COR

—CCl

All of these are meta directing and strongly deactivating.

Other EWGs Include:

—EWG = —NO2

—SO3H

—C N

75-84%

Nitration of Benzaldehyde CH

Problem 12.17(a)Chlorination of benzoylchloride

Disulfonation of Benzene

60-75%

Bromination of Nitrobenzene Fe

NO2 NO2

Electrophilic Aromatic Substitution:Halogens

F, Cl, Br, and I are ortho-para directing,F, Cl, Br, and I are ortho-para directing,but deactivating.but deactivating.

Nitration of Chlorobenzene Cl

69%1%30%

The rate of nitration of chlorobenzene is about 30 times slower than that of benzene but directs ortho/para.

Nitration of Toluene vs. Chlorobenzene CH3

Rate factors (compared to benzene) for the nitration of various positions in these two compounds.

Halogen Substituents X

Electron withdrawing via induction.

Electron releasing via resonance.

For the halogens, the inductive effect outweighs the resonance effect. The weak releasing effect stabilizes the carbocations from o- and p-attack.

12.15Multiple Substituent Effects

Here, all possible EAS sites are equivalent.

The Simplest Case CH3

AlCl3O

CH3COCCH3

Directing effects of these substituents reinforceeach other: substitution takes place orthoto the methyl group and meta to the nitro group.

Another Straightforward Case CH3

86-90%

Example NHCH3

aceticacid

strongly

activating

Regioselectivity is controlled by thestronger activating substituent.

Substitution occurs ortho to the smaller group.

When activating effects are similar... CH3

C(CH3)3

The position between two substituents is lastposition to be substituted for steric reasons.

Steric effects control regioselectivity whenelectronic effects are similar

CH3 CH3

12.16Regioselective Synthesis of

Disubstituted Aromatic Compounds

Synthesis of m-Bromoacetophenone Br CCH3

Which substituent should be introduced first ?

Introduce substituents in the order that ensures the correct orientation in the product.

Synthesis of m-Bromoacetophenone Br CCH3

If bromine is introduced first, p-bromoacetophenone is major product.

Synthesis of m-Bromoacetophenone CCH3

CH3COCCH3

OBr If the acetyl group is first, then

m-bromoacetophenone is the major product.

Synthesis of m-Nitroacetophenone CCH3

Which substituent should be introduced first ?

Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics.

NO2 CCH3

If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails.

Synthesis of m-Nitroacetophenone

If the acetyl group is first, then m-nitroacetophenone is the major product.

CH3COCCH3

Synthesis of p-Nitrobenzoic Acid from Toluene

Which first ? (oxidation of methyl group or nitration of ring)

CO2H NO2

Sometimes electrophilic aromatic substitution must be combined with a functional group transformation.

Synthesis of p-Nitrobenzoic Acid from Toluene CH3

CO2H NO2

nitration givesm-nitrobenzoicacid

oxidation givesp-nitrobenzoicacid

Synthesis of p-Nitrobenzoic Acid from Toluene CH3 NO2

Na2Cr2O7, H2OH2SO4, heat

So, one would elect to nitrate first and then oxidize.

12.17Substitution in Naphthalene

Two sites are possible for electrophilicaromatic substitution.

All other sites at which substitution can occurare equivalent to 1 and 2.

Naphthalene

EAS in Naphthalene

CH3CCl

O Reaction is faster at C-1 than at C-2.

EAS in Naphthalene

When attack is at C-1 the carbocation is stabilized by allylic resonance and benzenoid character of other ring is maintained.

E H E H

EAS in Naphthalene

When attack is at C-2, in order for the carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is lost.

Sulfonation of Naphthalene

SO3H Kinetic vs. thermodynamic control!

At 0°C

At 160°C

12.18Substitution in

Heterocyclic Aromatic Compounds

There is none.

There are so many different kinds of heterocyclicaromatic compounds that no generalizationis possible.

Some heterocyclic aromatic compoundsare very reactive toward electrophilicaromatic substitution, others are very unreactive...

Generalization

Pyridine is very unreactive; it resemblesnitrobenzene in its reactivity.

Presence of electronegative atom (N) in ringcauses electrons to be held more strongly thanin benzene.

Pyridine N

Pyridine can be sulfonated at high temperature.

EAS takes place at C-3.

SO3, H2SO4

HgSO4, 230°C

Pyridine

Pyrrole, Furan, and Thiophene O••

••

S••

••

Have 1 less ring atom than benzene or pyridine to hold same number of electrons (6).

The electrons are held less strongly.

These compounds are relatively reactive toward EAS.

Furan undergoes EAS readily andC-2 is most reactive position.

Example: Furan

CH3COCCH3

+ CCH3

75-92%

12.19Nucleophilic Aromatic Substitution

Nucleophilic Aromatic Substitution

•Because the carbon-halogen bond is stronger (where LG = halide), aryl halides react more slowly than alkyl halides when carbon-halogen bond breaking is rate determining.

+ :Nu- + :LG-

1. NaOH, H2O370°C

2. H+/HOH

We have not yet seen any nucleophilic substitution reactions of aryl halides. Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required. This goes by the benzyne mechanism (elimination-addition).

Reactions of Aryl Halides

NaNH2, NH3(l)-33°C

In this mechanism, the base causes elimination of HCl to form benzyne. Here, addition of NH3 to either carbon of the benzyne yields product.

Reactions of Aryl Halides

Reasons for Low Reactivity

•SN1 not reasonable because:

• 1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process

• 2) aryl cations are less stable than alkyl cations

+ + Cl

Reasons for Low Reactivity

•SN2 not reasonable because ring blocks attack of nucleophile from side opposite bond to the leaving group.

12.20Nucleophilic Substitution in

Nitro-Substituted Aryl Halides

Nitro-substituted aryl halides undergonucleophilic aromatic substitution more readily.

But... Cl

+ NaOCH3

+ NaCl

•especially when nitro group is ortho and/orpara to leaving group

Effect of nitro group is cumulative Cl Cl

NO2O2N

1.0 7 x 1010 2.4 x 1015 too fast to measure

•follows second-order rate law:rate = k[aryl halide][nucleophile]

•inference:both the aryl halide and the nucleophile are involved in rate-determining step.

Kinetics

Effect of leaving group

unusual order: F > Cl > Br > I Based on electronegativity rather than basicity. XNO2

X Relative Rate*

*NaOCH3, CH3OH, 50°C

•bimolecular rate-determining step in whichnucleophile attacks aryl halide•rate-determining step precedes carbon-halogenbond cleavage•rate-determining transition state is stabilized byelectron-withdrawing groups (such as NO2)

General Conclusions About Mechanism

12.21The Addition-Elimination Mechanism

of Nucleophilic Aromatic Substitution

•Two step mechanism:• Step 1) nucleophile attacks aryl halide and bonds to the carbon that bears the halogen

(slow: aromaticity of ring lost in this step)• Step 2) intermediate formed in first step loses

halide(fast: aromaticity of ring restored in this step)

Addition-Elimination Mechanism

Reaction FNO2

+ NaOCH3

•• ••F••

Step 1

••

•••• OCH3

Mechanism

•Bimolecular; consistent with second-order kinetics; first order in aryl halide, first order in nucleophile,•intermediate is negatively charged,•formed faster when ring bears electron-withdrawing groups such as NO2.

••F•• ••

••–

•••• OCH3

Stabilization of Rate-Determining Intermediate

by Nitro Group

••••

F ••

••

•••• OCH3

O O••

••

•••• ••+

••••

F ••

••

•••• OCH3

O O••

••

•••• ••+

•• OCH3••

F••

•• ••••

–Step 2

F••

•• ••

•• OCH3••

••

Mechanism

Regeneration of aromatic character in the ring.

•Carbon-halogen bond breaking does not occur until after the rate-determining step.

•Electronegative F stabilizes negatively charged intermediate.

Leaving Group Effects

F > Cl > Br > I is unusual, but consistentwith mechanism

12.22Related Nucleophilic Substitution

Reactions

Example: 2-Chloropyridine

NaOCH3

•2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions.

Example: 2-Chloropyridine

•Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed.

•••• OCH3••

••

••OCH3••

–••

End of Chapter 12End of Chapter 12Reactions of Arenes:Reactions of Arenes:

Electrophilic and NucleophilicAromatic Electrophilic and NucleophilicAromatic SubstitutionSubstitution

Chapter 12 Reactions of Arenes: Electrophilic and NucleophilicAromatic Substitution HE+ EY + HY ++++...

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