Chapter 16

• Electrophilic aromatic substitutionElectrophilic aromatic substitution is the most common reaction of aromatic compounds

– It replaces a protonproton (HH++) on an aromatic ring with another electrophile electrophile (EE++))

– It leads to the retention of the aromatic core

IntroductionIntroduction

Some electrophilic aromatic substitution reactionsSome electrophilic aromatic substitution reactions

11.. Bromination of Aromatic RingsBromination of Aromatic Rings

11.. Bromination of Aromatic RingsBromination of Aromatic Rings

• Benzene is a site of electron density

– Its 6 6 electrons electrons are in a cyclic conjugatedcyclic conjugated system

– Its 6 6 electrons electrons are sterically accessiblesterically accessible to other reactants because they are located above or below located above or below the plane

• Benzene acts as an electron donor (a Lewis Benzene acts as an electron donor (a Lewis base or nucleophile)base or nucleophile)

– It reacts with electron acceptors (Lewis acids or It reacts with electron acceptors (Lewis acids or electrophiles)electrophiles)

– Benzene’s electrons participate as a Lewis base in reactions with Lewis acids

• Bromination of benzene occurs in two steps:

– Step 1:Step 1: The electrons act as a nucleophile toward Br2 (in a complex with FeBr3) to form a nonaromatic carbocation intermediate

– Step 2Step 2: : The resonance-stabilized carbocation intermediate loses H+ to regenerate the aromatic ring

Electrophilic Alkene AdditionElectrophilic Alkene Addition

• Aromatic rings are less reactive toward electrophiles than alkenes

– Unlike alkenes, benzene does not react rapidly with Br2 in CH2Cl2

– For bromination, benzene requires FeBr3 as a catalyst to polarize the bromine reagent and make it more electrophilic

Electrophilic Aromatic BrominationElectrophilic Aromatic Bromination

• Step 1:Step 1: The electrons act as a nucleophile and attack the polarized Br2 (in a complex with FeBr3) to form a nonaromatic carbocation intermediate

– It is a slowslow, rate-limitingrate-limiting step (high G‡)

– The carbocationcarbocation is doubly allylic (nonaromaticnonaromatic) and has three resonance forms

– The carbocationcarbocation intermediate is not aromatic and is high in energy (less stableless stable than benzene)

– Step 1Step 1 is endergonicendergonic, has a high high GG‡‡ and is a slow slow reaction

• Step 2Step 2: : The resonance-stabilized carbocation intermediate loses H+ to regenerate the aromatic ring and yield a substitution product in which H+ is replaced by Br+

– It is similar similar to the 22ndnd step step of an E1 reaction E1 reaction

– The carbocation intermediate transfers a Htransfers a H++ to FeBr4

- (from Br- and FeBr3)

– This restores aromaticityrestores aromaticity (in contrast with addition in alkenes)

– Step 2Step 2 is exergonicexergonic, has a low low GG‡‡ and is a fast fast reaction

Electrophilic Aromatic Bromination: Electrophilic Aromatic Bromination: MechanismMechanism

– SubstitutionSubstitution reaction retainsretains the stabilitystability of the aromatic ring and is exergonicexergonic

AdditionAdditionLoss of aromaticityEndergonic

SubstitutionSubstitutionRetention of aromaticityExergonic

Why is there electrophilic aromatic substitution rather Why is there electrophilic aromatic substitution rather than addition?than addition?

Practice ProblemPractice Problem: Monobromination of toluene gives a mixture of : Monobromination of toluene gives a mixture of three bromotoluene products. Draw and name three bromotoluene products. Draw and name them. them.

22.. Other Aromatic SubstitutionsOther Aromatic Substitutions

22.. Other Aromatic SubstitutionsOther Aromatic Substitutions

• The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles

– The cationic intermediatecationic intermediate was first proposed by G. W. Wheland and is often called the Wheland Wheland intermediateintermediate

• An electrophilic aromatic substitution reaction involves two steps:

– reaction of an electrophile Ereaction of an electrophile E+ + with an aromatic ringwith an aromatic ring

– loss of Hloss of H++ from the resonance-stabilized carbocation from the resonance-stabilized carbocation intermediate to regenerate the aromatic ringintermediate to regenerate the aromatic ring

Electrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution

• The same general mechanism is used by other aromatic substitutions including:

ChlorinationChlorination

IodinationIodination

NitrationNitration

SulfonationSulfonation

F is too reactive for monofluorination

• Benzene ring reacts with Cl2 in the presence of FeCl3 catalyst to yield chlorobenzene

– It requires FeCl3 to polarize Cl2 (make it more electrophilic)

Aromatic ChlorinationAromatic Chlorination

• Benzene ring reacts with I2 in the presence of an oxidizing agent (H2O2 or CuCl2) to yield iodobenzene

– Iodine must be oxidized to form a more powerful electrophilic I+ species (with Cu2+ or peroxide)

Aromatic IodinationAromatic Iodination

• Benzene ring reacts with a mixture of concentrated nitric and sulfuric acids (HNO3 and H2SO4) to yield nitrobenzene

– The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion), an

electrophile

Aromatic NitrationAromatic Nitration

– The electrophile NO2+ is produced when HNO3 is

protonated by H2SO4 and loses H2O

– NO2+ reacts with benzene to give a carbocation

intermediate which loses H+ to yield nitrobenzene

– Aromatic nitration is useful in the pharmaceutical industry because the nitro-substituted product can be reduced by Fe or SnCl2 to yield arylamine

• Benzene ring reacts with fuming sulfuric acid (a mixture of H2SO4 and SO3) to yield benzenesulfonic acid

– The reactive electrophile is either HSO3+ or neutral SO3 depending on reaction

conditions

Aromatic SulfonationAromatic Sulfonation

– The reactive electrophile is either sulfur trioxide SO3

or its conjugate acid HSO3+

– The reaction occurs via the Wheland intermediate (carbocation)

– The reaction is reversible (Sulfonation is favored in strong acid; desulfonation, in hot, dilute aqueous acid)

– Aromatic sulfonic acids are useful as intermediates in the synthesis of dyes and pharmaceuticals.

• ExampleExample: Sulfadrugs

A sulfadrug

– Aromatic sulfonic acids undergo alkali fusion reaction

• Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO3H group with an OH

• ExampleExample: Synthesis of p-cresol

Practice ProblemPractice Problem: How many products might be formed on : How many products might be formed on chlorination of o-xylene (o-dimethylbenzene), chlorination of o-xylene (o-dimethylbenzene), m-xylene, and p-xylene? m-xylene, and p-xylene?

Practice ProblemPractice Problem: When benzene reacts with D: When benzene reacts with D22SOSO44, deuterium , deuterium

slowly replaces all six hydrogens in the slowly replaces all six hydrogens in the aromatic ring. Explain. aromatic ring. Explain.

33.. Alkylation of Aromatic Rings: The Alkylation of Aromatic Rings: The

Friedel-Crafts ReactionFriedel-Crafts Reaction

33.. Alkylation of Aromatic Rings: The Alkylation of Aromatic Rings: The

Friedel-Crafts ReactionFriedel-Crafts Reaction

• Benzene ring reacts with an alkyl chloride in the presence of AlCl3 catalyst to yield an arene

– Alkylation was first reported by Charles Friedel and James Crafts in 1877

• Friedel-Crafts alkylationFriedel-Crafts alkylation – is an electrophilic aromatic substitution in which the electrophile is a carbocation, R+.

– AlCl3 catalyst promotes the formation of the alkyl carbocation, R+, from the alkyl halide, RX

– The Wheland (carbocation) intermediate forms

– Alkylation is the attachment of an alkyl group to benzene; R+ substitutes for H+

Friedel-Crafts Alkylation Reaction: Friedel-Crafts Alkylation Reaction: MechanismMechanism

1.1. Only Only alkylalkyl halides can be used (F, Cl, Br, I) halides can be used (F, Cl, Br, I)

– Aryl halides and vinylic halides do not react (their carbocations are too high in energy to form)

Limitations of the Friedel-Crafts AlkylationLimitations of the Friedel-Crafts Alkylation

2.2. No reaction occurs if the aromatic ringNo reaction occurs if the aromatic ring has an amino has an amino group or a strongly electron-withdrawing group group or a strongly electron-withdrawing group substituentsubstituent

– Amino groups react with AlCl3 catalyst in an acid-base reaction

3.3. It is difficult to control the reaction. Multiple alkylations It is difficult to control the reaction. Multiple alkylations can occur because the first alkylation is activatingcan occur because the first alkylation is activating

– Polyalkylation is often observed

4.4. Carbocation rearrangements occur during alkylation, Carbocation rearrangements occur during alkylation, particularly when a 1particularly when a 1oo alkyl halide is used alkyl halide is used

– Catalyst, temperature and solvent affect the amount of rearrangement

Rearranged Unrearranged

Carbocation rearrangements of Friedel-Crafts alkylationCarbocation rearrangements of Friedel-Crafts alkylation

– are similar to those that occur during electrophilic additions to alkenes

– can involve hydridehydride (H:-) or alkylalkyl shifts

More Stable

1.1. Only Only alkylalkyl halides can be used (F, Cl, Br, I) halides can be used (F, Cl, Br, I)

2.2. No reaction occurs if the aromatic ringNo reaction occurs if the aromatic ring has an amino has an amino group or a strongly electron-withdrawing group group or a strongly electron-withdrawing group substituentsubstituent

3.3. It is difficult to control the reaction. Multiple alkylations It is difficult to control the reaction. Multiple alkylations can occur because the first alkylation is activatingcan occur because the first alkylation is activating

4.4. Carbocation rearrangements occur during alkylation, Carbocation rearrangements occur during alkylation, particularly when a 1particularly when a 1oo alkyl halide is used alkyl halide is used

Limitations of the Friedel-Crafts AlkylationLimitations of the Friedel-Crafts Alkylation

Practice ProblemPractice Problem: The Friedel-Crafts reaction of benzene with 2-: The Friedel-Crafts reaction of benzene with 2- chloro-3-methylbutane in the presence of AlCl chloro-3-methylbutane in the presence of AlCl3 3

occurs with carbocation rearrangement. What occurs with carbocation rearrangement. What

is the structure of the product? is the structure of the product?

Practice ProblemPractice Problem: Which of the following alkyl halides undergo : Which of the following alkyl halides undergo Friedel-Crafts reaction Friedel-Crafts reaction withoutwithout

rearrangement? rearrangement? Explain. Explain.

a. CH3CH2Cl

b. CH3CH2CH(Cl)CH3

c. CH3CH2CH2Cl

d. (CH3)3CCH2Cl

e. Chlorocyclohexane

Practice ProblemPractice Problem: What is the major monosubstitution product : What is the major monosubstitution product from Friedel-Crafts reaction of benzene with 1- from Friedel-Crafts reaction of benzene with 1- chloro-2-methylpropane in the presence of chloro-2-methylpropane in the presence of AlCl AlCl33??

44.. Acylation of Aromatic Rings: The Acylation of Aromatic Rings: The

Friedel-Crafts ReactionFriedel-Crafts Reaction

44.. Acylation of Aromatic Rings: The Acylation of Aromatic Rings: The

Friedel-Crafts ReactionFriedel-Crafts Reaction

• Benzene ring reacts with a carboxylic acid chloride, RCOCl, in the presence of AlCl3 catalyst to yield an acylbenzene

– Acylation is the attachment of an acyl group,-COR, to benzene; RCO+ substitutes for H+

• Friedel-Crafts acylationFriedel-Crafts acylation – is an electrophilic aromatic substitution in which the reactive electrophile is a resonance-stabilized acyl cation, RCO+.

– AlCl3 catalyst promotes the formation of the acyl cation, RCO+, from the acyl chloride, RCOCl

– The acyl cation, RCO+, does not rearrange; it is resonance-stabilized

– The Wheland (carbocation) intermediate forms

Friedel-Crafts Acylation Reaction: Friedel-Crafts Acylation Reaction: MechanismMechanism

– The mechanism of Friedel-Crafts acylation is similar to Friedel-Crafts alkylation

• In Friedel-Crafts acylation, there is no carbocation rearrangement nor multiple substitution

– No carbocation rearrangement: The acyl cation, RCO+, does not

rearrange because it is resonance-stabilized by interaction of the vacant orbital on C with lone pair of electrons on O

– No multiple substitution: Acylated benzene is less reactive than nonacylated benzene

Practice ProblemPractice Problem: Identify the carboxylic acid chloride that might : Identify the carboxylic acid chloride that might be used in a Friedel-Crafts acylation reaction be used in a Friedel-Crafts acylation reaction to prepare each of the following acylbenzenes to prepare each of the following acylbenzenes

55.. Substituent Effects in Substituted Substituent Effects in Substituted

Aromatic RingsAromatic Rings

55.. Substituent Effects in Substituted Substituent Effects in Substituted

Aromatic RingsAromatic Rings

A substituent present on an aromatic ring affects:

• the reactivity of the aromatic ringthe reactivity of the aromatic ring

• the orientation of the reactionthe orientation of the reaction

Substituents may

• activateactivate the ring, make it (much) more reactive than benzene or

• deactivatedeactivate the ring, make it (much) less reactive than benzene

Substituents affect the Substituents affect the reactivityreactivity of the aromatic ring of the aromatic ring

Substituents present on the ring determine the position of the 2nd substitution: orthoortho, metameta, and parapara

Substituents affect the Substituents affect the orientationorientation of the reaction of the reaction

Substituents can be classified as:

• ortho- and para-directing activators, • ortho- and para-directing deactivators, and • meta-directing deactivators

Classification of Substituent EffectClassification of Substituent Effect

The directing effects of the groups correlate with their reactivities:

• All meta-directing groups are strongly deactivating • Most ortho- and para-directing groups are activating • Halogens are unique being ortho- and para-directing but

weakly deactivating

Reactivity and orientation in electrophilic aromatic substitutions are controlled by an interplay of inductive effectsinductive effects and resonance effectsresonance effects:

– Inductive effectInductive effect - withdrawal or donation of electrons through a bondbond

– Resonance effectResonance effect - withdrawal or donation of electrons through a bondbond

Origins of Substituent EffectsOrigins of Substituent Effects

Inductive effectsInductive effects - withdrawal or donation of electrons through a bond due to electronegativity and polarity of bonds in functional groups

• Halogens, C=O, CN, and NO2 groups inductively withdraw electrons through bond connected to ring

• Alkyl groups inductively donate electrons

Inductive EffectsInductive Effects

• Halogens, C=O, CN, and NO2 inductively withdraw electrons through bond connected to ring

• Alkyl groups inductively donate electrons

Resonance effectResonance effect - withdrawal or donation of electrons through a bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring

• C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance

• Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic ring by resonance

Resonance EffectsResonance Effects

• C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance

electrons flow from the ring to the substituents, placing a positive charge in the ring

• C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance placing a positive charge in the ring

– Effect is greatest at ortho and para

– Z is more electronegative than Y

• Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic ring by resonance

electrons flow from the substituents to the rings placing a negative charge in the ring

• Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic ring by resonance placing a negative charge in the ring

– Effect is greatest at ortho and para

– Y has a lone pair of electrons

• When the two effects act in opposite direction, the strongest effects dominate.

– Halogens have electron-withdrawing inductive effects due to electronegativity

– Halogens have electron-donating resonance effects due to lone-pair electrons

– Resonance interactions are generally weaker, affecting orientation. Thus, halogens deactivate the ring

Contrasting Effects: Inductive vs ResonanceContrasting Effects: Inductive vs Resonance

Practice ProblemPractice Problem: Predict the major product of the monosulfonation : Predict the major product of the monosulfonation of toluene. of toluene.

Practice ProblemPractice Problem: Write resonance structures for nitrobenzene to : Write resonance structures for nitrobenzene to show the electron-withdrawing resonance show the electron-withdrawing resonance effect of the nitro group. effect of the nitro group.

Practice ProblemPractice Problem: Write resonance structures for chlorobenzene : Write resonance structures for chlorobenzene to show the electron-donating resonance to show the electron-donating resonance effect of the chloro group. effect of the chloro group.

Practice ProblemPractice Problem: Predict the major products of the following : Predict the major products of the following reactions reactions

a. Mononitration of bromobenzene

b. Monobromination of nitrobenzene

c. Monochlorination of phenol

d. Monobromination of aniline

66.. An Explanation of SubstituentAn Explanation of Substituent

EffectsEffects

66.. An Explanation of SubstituentAn Explanation of Substituent

EffectsEffects

• Activating groups donate electrons to the ringActivating groups donate electrons to the ring, , stabilizing the Wheland intermediate (carbocation)stabilizing the Wheland intermediate (carbocation)

– OH, OR, NH2 and R

• Deactivating groups withdraw electrons from the Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediatering, destabilizing the Wheland intermediate

– CN, C=O, NO2 and X

• An electron-withdrawing group makes the ring more electron-poor (eg. CN and Cl)

• An electron-donating group makes the ring more electron-rich (eg. CH3 and NH2)

Practice ProblemPractice Problem: Rank the compounds in each group in order of : Rank the compounds in each group in order of their reactivity to electrophilic substitution their reactivity to electrophilic substitution

a. Nitrobenzene, phenol, toluene, benzene

b. Phenol, benzene, chlorobenzene, benzoic acid

c. Benzene, bromobenzene, benzaldehyde, aniline

Practice ProblemPractice Problem: Explain why Friedel-Crafts alkylations often : Explain why Friedel-Crafts alkylations often give polysubstitution but Friedel-Crafts give polysubstitution but Friedel-Crafts acylations do not acylations do not

Practice ProblemPractice Problem: Would you expect trifluoromethylbenzene to be : Would you expect trifluoromethylbenzene to be more reactive or less reactive than toluene more reactive or less reactive than toluene toward electrophilic substitution? Explain. toward electrophilic substitution? Explain.

• Alkyl groups are activatingAlkyl groups are activating

– They have an electron-donating inductiveelectron-donating inductive effect

• Alkyl groups are ortho and para directorsAlkyl groups are ortho and para directors

– The orthoortho and para intermediatespara intermediates are the most stabilizedstabilized (lower in energy)

– The positive charge is directly on the alkyl-substituted carbon (33oo carbon carbon) and is stabilized by the inductive electron-donatingstabilized by the inductive electron-donating effect of the alkyl group

Ortho- and Para-Directing Activators: Alkyl GroupsOrtho- and Para-Directing Activators: Alkyl Groups

• The positive charge is directly on the alkyl-substituted carbon (33oo carbon carbon) and is stabilized by the inductive stabilized by the inductive electron-donating effect ofelectron-donating effect of the alkyl group

• OH, OR and NHOH, OR and NH22 groups are activating groups are activating

– They have a strong electron-donating resonance strong electron-donating resonance and a weak electron-withdrawing inductive effect

• OH, OR and NHOH, OR and NH22 groups are ortho and para directors groups are ortho and para directors

– The orthoortho and para intermediatespara intermediates are the most stabilizedstabilized (lower in energy)

– The positive charge is stabilized by resonance donation of an electron pairstabilized by resonance donation of an electron pair from O or N

Ortho- and Para-Directing Activators: OH and NHOrtho- and Para-Directing Activators: OH and NH22

• The ortho and para intermediates are more stable more stable because of resonance donation of an electron pairresonance donation of an electron pair from O or N

Practice ProblemPractice Problem: Acetanilide is less reactive than aniline toward : Acetanilide is less reactive than aniline toward electrophilic substitution. Explain. electrophilic substitution. Explain.

• Halogens are deactivatingHalogens are deactivating

– They have a strong electron-withdrawing inductivestrong electron-withdrawing inductive and a weak electron-donating resonance effect

• Halogens are ortho and para directorsHalogens are ortho and para directors

– The orthoortho and para intermediatespara intermediates are the most stabilizedstabilized (lower in energy)

– Halogens stabilize stabilize the positive charge by resonance donation of a lone pair of electronsby resonance donation of a lone pair of electrons

Ortho- and Para-Directing Deactivators: HalogensOrtho- and Para-Directing Deactivators: Halogens

• The ortho and para intermediates are more stable more stable because of resonance donation of an electron pairresonance donation of an electron pair from X

• All meta-directing groups are strongly deactivatingAll meta-directing groups are strongly deactivating

– They have electron-withdrawing inductive and resonance effects that reinforce each other

– The orthoortho and para intermediatespara intermediates are destabilizeddestabilized

– The positive charge of the carbocation intermediate in ortho and para attack is directly on the carbon that bears the deactivating group and resonance cannot produce stabilization

Meta-Directing DeactivatorsMeta-Directing Deactivators

• The meta intermediate is more stable more stable because resonance does not place the positive charge directly on the carbon that bears the deactivating group

Summary of Substituent Effects in Aromatic SubstitutionSummary of Substituent Effects in Aromatic Substitution

Practice ProblemPractice Problem: Draw resonance structures for the intermediates : Draw resonance structures for the intermediates from reaction of an electrophile at the ortho, meta, from reaction of an electrophile at the ortho, meta, and para positions of nitrobenzene. Which and para positions of nitrobenzene. Which intermediates are most stable? intermediates are most stable?

77.. Trisubstituted Benzenes: Additivity Trisubstituted Benzenes: Additivity

of Effectsof Effects

77.. Trisubstituted Benzenes: Additivity Trisubstituted Benzenes: Additivity

of Effectsof Effects

Three rules for the additive effects of two different groups:

1.1. If the directing effects of the two groups are the If the directing effects of the two groups are the same, the result is additivesame, the result is additive

2.2. If the directing effects of two groups oppose If the directing effects of two groups oppose each other, the more powerful activating group each other, the more powerful activating group determines the principal outcomedetermines the principal outcome

3.3. The position between the two groups in meta-The position between the two groups in meta-disubstituted compounds is unreactivedisubstituted compounds is unreactive

1.1. If the directing effects of the two groups are the same, the result is If the directing effects of the two groups are the same, the result is additiveadditive

– It gives a single product

2.2. If the directing effects of two groups oppose each other, the more powerful If the directing effects of two groups oppose each other, the more powerful activating group determines the principal outcomeactivating group determines the principal outcome

– It usually gives mixtures of products

3.3. The position between the two groups in meta-disubstituted compounds is unreactiveThe position between the two groups in meta-disubstituted compounds is unreactive

– The reaction site is too hindered

– To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound

Practice ProblemPractice Problem: What product would you expect from bromination : What product would you expect from bromination of p-methylbenzoic acid? of p-methylbenzoic acid?

Practice ProblemPractice Problem: At what positions would you expect electrophilic : At what positions would you expect electrophilic substitution to occur in the following substances? substitution to occur in the following substances?

Practice ProblemPractice Problem: Show the major product(s) from reaction of the : Show the major product(s) from reaction of the following substances with (i) CH following substances with (i) CH33CHCH22Cl, AlClCl, AlCl33

and (ii) HNO and (ii) HNO33, H, H22SOSO44

88.. Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution

88.. Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution

• Nucleophilic aromatic substitutionNucleophilic aromatic substitution is a reaction that aryl halides with electron-withdrawing substituents undergo

– It replaces a halide ionhalide ion (XX--) on an aromatic ring with another nucleophilenucleophile (NuNu--)

• A nucleophilic aromatic substitution reaction occurs in two steps by the addition/elimination mechanism:

– Step 1Step 1:: Addition of the nucleophile (Nu-) to the electron-deficient aryl halide, forming a resonance stabilized carbanion intermediate (Meisenheimer complex)

– Step 2Step 2: : Elimination of a halide ion (X-) from the carbanion intermediate to regenerate the aromatic ring

Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution

Nucleophilic Aromatic Substitution: Nucleophilic Aromatic Substitution: MechanismMechanism

• Nucleophilic aromatic substitution occurs ONLY if the aryl halide has an electron-withdrawing substituent in ortho and/or para position

– The more such substituents, the faster the reaction

– Only ortho and para electron-withdrawing substituents can stabilize the anion intermediate through resonance

• Only ortho and para intermediate carbanions (Meisenheimer complex) are resonance stabilized by electron-withdrawal

• A nucleophilic aromatic substitution reaction is neither an Sn1 nor an Sn2 reaction:

– Not SnNot Sn11:: Aryl cations are unstable for dissociation to occur

– Not SnNot Sn22: : Backside displacement is sterically blocked

Electrophilic vs Nucleophilic Aromatic SubstitutionElectrophilic vs Nucleophilic Aromatic Substitution

• Electrophilic Aromatic Electrophilic Aromatic SubstitutionSubstitution

– is favored by electron-electron-donatingdonating groups

– involves a carbocationcarbocation intermediate

– replaces a HH with an electrophileelectrophile

• Nucleophilic Aromatic Nucleophilic Aromatic SubstitutionSubstitution

– is favored by electron-electron-withdrawingwithdrawing groups

– involves a carbanion carbanion intermediate

– replaces a leaving leaving groupgroup with a nucleophilenucleophile

• Electron-donating Electron-donating groupsgroups

– favor electrophilic electrophilic aromatic substitution

– stabilize carbocationcarbocation intermediate

– are ortho-para ortho-para directors directors in electrophilic reaction

• Electron-withdrawing Electron-withdrawing groupsgroups

– favor nucleophilic nucleophilic aromatic substitution

– stabilize carbanion carbanion intermediate

– are ortho-para directorsortho-para directors in nucleophilicnucleophilic reaction but meta-directors in electrophilic substitution

Practice ProblemPractice Problem: Propose a mechanism for the reaction of 1-: Propose a mechanism for the reaction of 1- chloroanthraquinone with methoxide ion to give chloroanthraquinone with methoxide ion to give the substitution product 1-methoxyanthraquinone. the substitution product 1-methoxyanthraquinone.

Use curved arrows to show the electron flow in Use curved arrows to show the electron flow in each step. each step.

99.. BenzyneBenzyne

99.. BenzyneBenzyne

• Aryl halides without electron-withdrawing substituents undergo substitution with a benzyne intermediate

– Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure

• The synthesis of phenol occurs in two steps by the elimination/addition mechanism rather than addition/elimination:

– Step 1Step 1: : Elimination of a HX from halobenzene in an E2 reaction catalyzed by a strong base, forming a highly reactive benzyne intermediate

– Step 2Step 2:: Addition of a nucleophile (Nu-) to the benzyne intemediate

Evidence for Benzyne as an IntermediateEvidence for Benzyne as an Intermediate

• Bromobenzene with 14C only at C1 gives substitution product with label scrambled between C1 and C2

– The reaction proceeds through a symmetrical intermediate in which C1 and C2 are equivalent

– The intermediate must be benzyne

• Trapping experiments further demonstrate that benzyne was the intermediate

– Benzyne is too reactive to be isolated and thus can be intercepted in a Diels-Alder reaction

Structure of BenzyneStructure of Benzyne

• Benzyne is a highly distorted alkyne

– The triple bond uses sp2-hybridized carbons, not the usual sp

– The triple bond has one bond formed by p–p overlap and one bond formed by weak sp2–sp2 overlap

Practice ProblemPractice Problem: Treatment of p-bromotoluene with NaOH at 300: Treatment of p-bromotoluene with NaOH at 300ooC C yields a mixture of yields a mixture of twotwo products, but treatment of products, but treatment of m-bromotoluene with NaOH yields a mixture of m-bromotoluene with NaOH yields a mixture of threethree products. Explain products. Explain

1010.. Oxidation of Aromatic CompoundsOxidation of Aromatic Compounds

1010.. Oxidation of Aromatic CompoundsOxidation of Aromatic Compounds

There are two reactions of alkylbenzene side chains:

• Oxidation of Alkylbenzene Side ChainsOxidation of Alkylbenzene Side Chains

• Bromination of Alkylbenzene Side ChainsBromination of Alkylbenzene Side Chains

Aromatic ring activates neighboring benzylic (C-H) position toward oxidation

• Alkyl side chains can be oxidized to carboxyl groups, -Alkyl side chains can be oxidized to carboxyl groups, -COCO22H, by strong oxidizing agents such as KMnOH, by strong oxidizing agents such as KMnO44 and and NaNa22CrCr22OO77

– The alkyl side chains must have a C-H next to the ring

– This converts an alkylbenzene into a benzoic acid, Ar-R Ar-CO2H

Oxidation of Alkylbenzene Side ChainsOxidation of Alkylbenzene Side Chains

• The mechanism of side-chain oxidation involves reaction of C-H next to the ring to form intermediate benzylic radicals

– t-butylbenzene is inert (no benzylic H’s)

Practice ProblemPractice Problem: What aromatic products would you obtain from : What aromatic products would you obtain from the the KMnO KMnO44 oxidation of the following substances? oxidation of the following substances?

• Reaction of an alkylbenzene with Reaction of an alkylbenzene with NN-bromo-succinimide -bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chainintroduces Br into the side chain

– Bromination occurs exclusively in the benzylic position

Bromination of Alkylbenzene Side ChainsBromination of Alkylbenzene Side Chains

• Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical

– This reacts with Br2 to yield product and Br·

– Br· radical cycles back into reaction to carry on chain

– Br2 is produced from reaction of HBr with NBS

Mechanism of NBS (Radical) ReactionMechanism of NBS (Radical) Reaction

• Bromination occurs exclusively in the benzylic position because the benzylic radical intermediate is resonance-stabilized

– The benzylic radical is stabilized by overlap of its p orbital with the ring p electron system

Practice ProblemPractice Problem: Refer to Table 5.3 for a quantitative idea of the : Refer to Table 5.3 for a quantitative idea of the stability of a benzyl radical. How much stable (in stability of a benzyl radical. How much stable (in kJ/mol) is the benzyl radical than a primary alkyl kJ/mol) is the benzyl radical than a primary alkyl radical? How does a benzyl radical compare in radical? How does a benzyl radical compare in stability to an allyl radical stability to an allyl radical

Practice ProblemPractice Problem: Styrene, the simplest alkenylbenzene, is prepared : Styrene, the simplest alkenylbenzene, is prepared commercially for use in plastics manufacture by commercially for use in plastics manufacture by catalytic dehydrogenation of ethylbenzene. How catalytic dehydrogenation of ethylbenzene. How might you prepare styrene from benzene? might you prepare styrene from benzene?

1111.. Reduction of Aromatic CompoundsReduction of Aromatic Compounds

1111.. Reduction of Aromatic CompoundsReduction of Aromatic Compounds

There are two reduction reactions:

• Catalytic hydrogenation of Aromatic RingsCatalytic hydrogenation of Aromatic Rings

• Reduction of Aryl Alkyl KetonesReduction of Aryl Alkyl Ketones

• Reduction of an aromatic ring requires more powerful Reduction of an aromatic ring requires more powerful reducing conditions (Hreducing conditions (H22/Pt at high pressure or /Pt at high pressure or rhodium catalysts)rhodium catalysts)

Catalytic hydrogenation of Aromatic RingsCatalytic hydrogenation of Aromatic Rings

• Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds

– It is possible to selectively reduce an alkene double bond in the presence of an aromatic ring

• Aromatic ring activates neighboring carbonyl group toward reduction

• Aryl alkyl ketone is converted into an alkylbenzene by catalytic Aryl alkyl ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalysthydrogenation over Pd catalyst

Reduction of Aryl Alkyl KetonesReduction of Aryl Alkyl Ketones

• Conversion of a carbonyl group to a methylene group by catalytic hydrogenation (C=O CH2)

– is limited to aryl alkyl ketones– is not compatible with the presence of a nitro group

Practice ProblemPractice Problem: Show how you would prepare diphenylmethane : Show how you would prepare diphenylmethane (Ph) (Ph)22CHCH22, from benzene and an appropriate acid , from benzene and an appropriate acid

chloride chloride

1212.. Synthesis of Trisubstituted BenzenesSynthesis of Trisubstituted Benzenes

1212.. Synthesis of Trisubstituted BenzenesSynthesis of Trisubstituted Benzenes

• These syntheses require planning and consideration of alternative routes

1. Compare the target and the starting material

1. Consider reactions that efficiently produce the outcome.

1. Look at the product and think of what can lead to it

• A synthesis combines a series of proposed steps to go from a defined set of reactants to a specified product

Synthesis as a Tool for Learning Organic ChemistrySynthesis as a Tool for Learning Organic Chemistry

• In order to propose a synthesis, one must be familiar with reactions:

– What they begin with– What they lead to– How they are accomplished– What the limitations are

• The order in which reactions are carried is critical in the The order in which reactions are carried is critical in the synthesis of substituted aromatic ringssynthesis of substituted aromatic rings

– The introduction of a new substituent is strongly affected by the directing effects of other substituents

Practice ProblemPractice Problem: Synthesize p-bromobenzoic acid from benzene: Synthesize p-bromobenzoic acid from benzene

Br – Bromination using Br2/FeBr3

CO2H – Friedel-Crafts alkylation or acylation followed by oxidation

Practice ProblemPractice Problem: Propose a synthesis of 4-chloro-1-nitro-2-: Propose a synthesis of 4-chloro-1-nitro-2- propylbenzene from benzene propylbenzene from benzene

Cl – Chlorination using Cl2/FeCl3

NO2 – Nitration using HNO3/H2SO4

CH2CH2CH3 – Friedel-Crafts acylation followed by reduction

Practice ProblemPractice Problem: Propose syntheses of the following substances : Propose syntheses of the following substances from benzene: from benzene:

a. m-Chloronitrobenzene

b. m-Chloroethylbenzene

c. p-Chloropropylbenzene

Practice ProblemPractice Problem: In planning a synthesis, it is important to know : In planning a synthesis, it is important to know what NOT to do as to know what do. As written, what NOT to do as to know what do. As written, the following reaction schemes have flaws in the following reaction schemes have flaws in them. What is wrong with each? them. What is wrong with each?

Chapter 16