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Chapter 16. Chemistry of Benzene: Electrophilic Aromatic Substitution. Introduction. Electrophilic aromatic substitution is the most common reaction of aromatic compounds It replaces a proton ( H + ) on an aromatic ring with another electrophile ( E + )

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Chapter 16

Chemistry of Benzene:

Electrophilic Aromatic Substitution


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Introduction

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

    • It replaces a proton (H+) on an aromatic ring with another electrophile (E+)

    • It leads to the retention of the aromatic core



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1.Bromination of Aromatic Rings

  • Benzene is a site of electron density

    • Its 6  electrons are in a cyclic conjugated system

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


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

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

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


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  • Bromination of benzene occurs in two steps:

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

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



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Electrophilic Aromatic Bromination

  • 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


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  • 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 slow, rate-limiting step (high DG‡)

    • The carbocation is doubly allylic (nonaromatic) and has three resonance forms


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  • The carbocation intermediate is not aromatic and is high in energy (less stablethan benzene)


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  • Step 1 is endergonic, has a high DG‡ and is a slow reaction


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  • Step 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 to the 2nd step of an E1 reaction

    • The carbocation intermediate transfers a H+ to FeBr4- (from Br- and FeBr3)

    • This restores aromaticity (in contrast with addition in alkenes)


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  • Step 2 is exergonic, has a low DG‡ and is a fast reaction



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Why is there electrophilic aromatic substitution rather than addition?

  • Substitution reaction retains the stability of the aromatic ring and is exergonic

Addition

Loss of aromaticity

Endergonic

Substitution

Retention of aromaticity

Exergonic


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


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2 addition?.Other Aromatic Substitutions

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

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


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Electrophilic Aromatic Substitution addition?

  • An electrophilic aromatic substitution reaction involves two steps:

    • reaction of an electrophile E+ with an aromatic ring

    • loss of H+ from the resonance-stabilized carbocation intermediate to regenerate the aromatic ring


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Aromatic Chlorination substitutions including:

  • Benzene ring reacts with Cl2 in the presence of FeCl3catalyst to yield chlorobenzene

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


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Aromatic Iodination substitutions including:

  • Benzene ring reacts with I2 in the presence of anoxidizing agent (H2O2or CuCl2) to yield iodobenzene

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


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Aromatic Nitration substitutions including:

  • 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


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  • The substitutions including:electrophileNO2+ is produced when HNO3 is protonated by H2SO4 and loses H2O


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  • NO substitutions including:2+ reactswith benzene to give a carbocation intermediate which loses H+ to yield nitrobenzene


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Aromatic Sulfonation because the nitro-substituted product can be reduced by Fe or SnCl

  • Benzene ring reacts with fuming sulfuric acid (a mixture of H2SO4and SO3) to yield benzenesulfonic acid

    • The reactive electrophile is either HSO3+ or neutral SO3depending on reaction conditions


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  • The reactive because the nitro-substituted product can be reduced by Fe or SnClelectrophile is either sulfur trioxide SO3 or its conjugate acid HSO3+


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  • The reaction is because the nitro-substituted product can be reduced by Fe or SnClreversible (Sulfonation is favored in strong acid; desulfonation, in hot, dilute aqueous acid)


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A sulfadrug


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  • Aromatic sulfonic acids undergo synthesis of dyes and pharmaceuticals.alkali fusion reaction

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

    • Example: Synthesis of p-cresol


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


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Practice Problem synthesis of dyes and pharmaceuticals.: When benzene reacts with D2SO4, deuterium slowly replaces all six hydrogens in the aromatic ring. Explain.


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3 synthesis of dyes and pharmaceuticals..Alkylation of Aromatic Rings: The Friedel-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


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  • Friedel-Crafts alkylation synthesis of dyes and pharmaceuticals. – is an electrophilic aromatic substitution in which the electrophile is a carbocation, R+.

    • AlCl3catalyst 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+


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Friedel-Crafts Alkylation Reaction: synthesis of dyes and pharmaceuticals.Mechanism


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Limitations of the Friedel-Crafts Alkylation synthesis of dyes and pharmaceuticals.

  • Only alkyl 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)


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  • No reaction occurs if the aromatic ring synthesis of dyes and pharmaceuticals. has an amino group or a strongly electron-withdrawing group substituent

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


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Rearranged Unrearranged


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Carbocation rearrangements of Friedel-Crafts alkylation particularly when a 1

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

  • can involve hydride (H:-) or alkyl shifts

More Stable


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Limitations of the Friedel-Crafts Alkylation particularly when a 1

  • Only alkyl halides can be used (F, Cl, Br, I)

  • No reaction occurs if the aromatic ring has an amino group or a strongly electron-withdrawing group substituent

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

  • Carbocation rearrangements occur during alkylation, particularly when a 1o alkyl halide is used


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Practice Problem particularly when a 1: The Friedel-Crafts reaction of benzene with 2- chloro-3-methylbutane in the presence of AlCl3 occurs with carbocation rearrangement. What is the structure of the product?


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Practice Problem particularly when a 1: Which of the following alkyl halides undergo Friedel-Crafts reaction without rearrangement? Explain.

  • CH3CH2Cl

  • CH3CH2CH(Cl)CH3

  • CH3CH2CH2Cl

  • (CH3)3CCH2Cl

  • Chlorocyclohexane


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Practice Problem particularly when a 1: What is the major monosubstitution product from Friedel-Crafts reaction of benzene with 1- chloro-2-methylpropane in the presence of AlCl3?


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4 particularly when a 1.Acylation of Aromatic Rings: The Friedel-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+


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  • Friedel-Crafts acylation particularly when a 1 – is an electrophilic aromatic substitution in which the reactive electrophile is a resonance-stabilized acyl cation, RCO+.

    • AlCl3catalyst 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


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Friedel-Crafts Acylation Reaction: particularly when a 1Mechanism

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


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  • 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


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Practice Problem rearrangement nor multiple substitution: Identify the carboxylic acid chloride that might be used in a Friedel-Crafts acylation reaction to prepare each of the following acylbenzenes


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5 rearrangement nor multiple substitution.Substituent Effects in Substituted Aromatic Rings

A substituent present on an aromatic ring affects:

  • the reactivity of the aromatic ring

  • the orientation of the reaction


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Substituents affect the rearrangement nor multiple substitutionreactivity of the aromatic ring

Substituents may

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

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


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Substituents affect the rearrangement nor multiple substitutionorientation of the reaction

Substituents present on the ring determine the position of the 2nd substitution: ortho, meta, and para


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Classification of Substituent Effect rearrangement nor multiple substitution

Substituents can be classified as:

  • ortho- and para-directing activators,

  • ortho- and para-directing deactivators, and

  • meta-directing deactivators


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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


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Origins of Substituent Effects reactivities:

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

  • Inductive effect - withdrawal or donation of electrons through a s bond

  • Resonance effect - withdrawal or donation of electrons through a  bond


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Inductive Effects reactivities:

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

  • Halogens, C=O, CN, and NO2 groups inductively withdrawelectrons through s bond connected to ring

  • Alkylgroups inductively donate electrons


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  • Halogens reactivities:, C=O, CN, and NO2 inductively withdrawelectrons through s bond connected to ring


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  • Alkyl reactivities:groups inductively donate electrons


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Resonance Effects reactivities:

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

  • C=O, CN, and NO2 groups withdrawelectrons from the aromatic ring by resonance

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


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  • C=O reactivities:, CN, and NO2 groups withdrawelectrons from the aromatic ring by resonance

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


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  • C=O reactivities:, CN, and NO2 groups withdrawelectrons 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


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  • Halogen reactivities:, 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


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  • Halogen reactivities:, 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


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Contrasting Effects: Inductive vs Resonance reactivities:

  • 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


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


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


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


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

  • Mononitration of bromobenzene

  • Monobromination of nitrobenzene

  • Monochlorination of phenol

  • Monobromination of aniline


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6 reactivities:.An Explanation of SubstituentEffects

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

    • OH, OR, NH2and R

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

    • CN, C=O, NO2 and X


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    • An reactivities:electron-withdrawing group makes the ring more electron-poor (eg. CN and Cl)

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


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

    • Nitrobenzene, phenol, toluene, benzene

    • Phenol, benzene, chlorobenzene, benzoic acid

    • Benzene, bromobenzene, benzaldehyde, aniline


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


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


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

    • Alkyl groups are activating

      • They have an electron-donating inductive effect

  • Alkyl groups are ortho and para directors

    • The orthoand para intermediates are the most stabilized(lower in energy)

    • The positive charge is directly on the alkyl-substituted carbon (3o carbon) and is stabilized by the inductive electron-donating effect of the alkyl group


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    Ortho- and Para-Directing Activators: OH and NH carbon (2

    • OH, OR and NH2 groups are activating

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

  • OH, OR and NH2 groups are ortho and para directors

    • The orthoand para intermediates are the most stabilized(lower in energy)

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


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


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    Ortho- and Para-Directing Deactivators: Halogens carbon (

    • Halogens are deactivating

      • They have a strong electron-withdrawing inductive and a weak electron-donating resonanceeffect

  • Halogens are ortho and para directors

    • The orthoand para intermediates are the most stabilized(lower in energy)

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


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    Meta-Directing Deactivators carbon (

    • All meta-directing groups are strongly deactivating

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

      • The orthoand para intermediates are destabilized

      • 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


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



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


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    7 carbon (.Trisubstituted Benzenes: Additivity of Effects

    Three rules for the additive effects of two different groups:

    • If the directing effects of the two groups are the same, the result is additive

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

    • The position between the two groups in meta-disubstituted compounds is unreactive


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


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


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    Practice Problem compounds is unreactive: Show the major product(s) from reaction of the following substances with (i) CH3CH2Cl, AlCl3 and (ii) HNO3, H2SO4


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    8 compounds is unreactive.Nucleophilic Aromatic Substitution

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

      • It replaces a halide ion (X-) on an aromatic ring with another nucleophile(Nu-)


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    Nucleophilic Aromatic Substitution compounds is unreactive

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

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

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


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    Nucleophilic Aromatic Substitution: compounds is unreactiveMechanism


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    • Nucleophilic aromatic substitution occurs compounds is unreactiveONLY 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


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    Electrophilic vs Nucleophilic Aromatic Substitution Sn

    • Nucleophilic Aromatic Substitution

      • is favored by electron-withdrawing groups

      • involves a carbanion intermediate

      • replaces a leaving group with a nucleophile

    • Electrophilic Aromatic Substitution

      • is favored by electron-donating groups

      • involves a carbocation intermediate

      • replaces a H with an electrophile


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    • Electron-withdrawing groups Sn

      • favor nucleophilic aromatic substitution

      • stabilize carbanion intermediate

      • are ortho-para directors in nucleophilic reaction but meta-directors in electrophilic substitution

    • Electron-donating groups

      • favor electrophilic aromatic substitution

      • stabilize carbocation intermediate

      • are ortho-para directors in electrophilic reaction


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    Practice Problem Sn: Propose a mechanism for the reaction of 1- chloroanthraquinone with methoxide ion to give the substitution product 1-methoxyanthraquinone. Use curved arrows to show the electron flow in each step.


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    9 Sn.Benzyne

    • 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


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

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

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


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    Evidence for Benzyne as an Intermediate Sn

    • 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


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    Structure of Benzyne the intermediate

    • 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


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    Practice Problem the intermediate: Treatment of p-bromotoluene with NaOH at 300oC yields a mixture of two products, but treatment of m-bromotoluene with NaOH yields a mixture of three products. Explain


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    10 the intermediate.Oxidation of Aromatic Compounds

    There are two reactions of alkylbenzene side chains:

    • Oxidation of Alkylbenzene Side Chains

    • Bromination of Alkylbenzene Side Chains

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


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    Oxidation of Alkylbenzene Side Chains the intermediate

    • Alkyl side chains can be oxidized to carboxyl groups, -CO2H, by strong oxidizing agents such as KMnO4 and Na2Cr2O7

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

      • Thisconverts an alkylbenzene into a benzoic acid, Ar-R  Ar-CO2H


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    Practice Problem the intermediate: What aromatic products would you obtain from the KMnO4 oxidation of the following substances?


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    Bromination of Alkylbenzene Side Chains the intermediate

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

      • Bromination occurs exclusively in the benzylic position


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    Mechanism of NBS (Radical) Reaction the intermediate

    • 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


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


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    Practice Problem because the benzylic radical intermediate is resonance-stabilized: Styrene, the simplest alkenylbenzene, is prepared commercially for use in plastics manufacture by catalytic dehydrogenation of ethylbenzene. How might you prepare styrene from benzene?


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    11 because the benzylic radical intermediate is resonance-stabilized.Reduction of Aromatic Compounds

    There are two reduction reactions:

    • Catalytic hydrogenation of Aromatic Rings

    • Reduction of Aryl Alkyl Ketones


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    Catalytic hydrogenation of Aromatic Rings because the benzylic radical intermediate is resonance-stabilized

    • Reduction of an aromatic ring requires more powerful reducing conditions (H2/Pt at high pressure or rhodium catalysts)


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    Reduction of Aryl Alkyl Ketones conditions that reduce alkene double bonds

    • Aromatic ring activates neighboring carbonyl group toward reduction

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


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    Practice Problem catalytic hydrogenation (C=O : Show how you would prepare diphenylmethane (Ph)2CH2, from benzene and an appropriate acid chloride


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    12 catalytic hydrogenation (C=O .Synthesis of Trisubstituted Benzenes

    • These syntheses require planning and consideration of alternative routes

      • Compare the target and the starting material

      • Consider reactions that efficiently produce the outcome.

      • 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


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    Synthesis as a Tool for Learning Organic Chemistry catalytic hydrogenation (C=O

    • 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 synthesis of substituted aromatic rings

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


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    Practice Problem catalytic hydrogenation (C=O : Synthesize p-bromobenzoic acid from benzene

    Br – Bromination using Br2/FeBr3

    CO2H – Friedel-Crafts alkylation or acylation followed by oxidation


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    Practice Problem catalytic hydrogenation (C=O : Propose a synthesis of 4-chloro-1-nitro-2- propylbenzene from benzene

    Cl – Chlorination using Cl2/FeCl3

    NO2– Nitration using HNO3/H2SO4

    CH2CH2CH3– Friedel-Crafts acylation followed by reduction


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    Practice Problem catalytic hydrogenation (C=O : Propose syntheses of the following substances from benzene:

    • m-Chloronitrobenzene

    • m-Chloroethylbenzene

    • p-Chloropropylbenzene


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


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    Chapter 16 catalytic hydrogenation (C=O

    The End


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