Chem 212Ch 16

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2011 Pearson Education, Inc.

Chem 212 Exam

4/11/2010

4:15-5:15

1PH2 102

2P1 103

3P1 102

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Organic Chemistry

6th Edition

Paula Yurkanis Bruice

Chapter 16

Reactions

ofSubstituted

Benzenes

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Chemical Modification of Substituents of Benzene

Reactions of alkyl substituents:

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The resulting halide product can undergo a nucleophilic

substitution reaction:

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Remember that halo-substituted alkyl groups can also

undergo E2 and E1 reactions (Section 9.8)

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Substitutions with double and triple bonds can undergo

catalytic hydrogenation (Sections 4.11 and 6.9)

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Oxidation of an alkyl group bonded to a benzene ring

Provided that a hydrogen is bonded to the benzylic

carbon,

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The same reagent that oxidizes alkyl substituents will

oxidize benzylic alcohols:

H ld h d k b d if

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However, aldehydes or ketones can be generated if a

milder oxidizing agent is used:

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Reducing a Nitro Substituent

It i ibl t l ti l d j t f th t

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It is possible to selectively reduce just one of the two

nitro groups:

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Examples of Substituted Benzenes

N l t f S b tit t d B

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In disubstituted benzenes, the relative positions of the

two substituents are indicated by numbers or by prefixes:

Nomenclature of Substituted Benzenes

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Common names are preferred in naming certain

substituted benzenes, e.g., toluene, aniline, phenol.

Do not deconstruct the common name; e.g., do not change

toluene to methylbenzene.

The substituent that is part of the common name is

position 1, but do not label as such in the chemical name.

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Some disubstituted benzenes have common names that

incorporate both substituents:

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Naming Polysubstituted Benzenes

The substituents are numbered in the direction that

results in the lowest possible number:

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The substituent incorporated into the common name is

the 1-position:

Always give substituents the lowest possible numbers!

Substituted benzenes undergo the five electrophilic

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Substituted benzenes undergo the five electrophilic

aromatic substitution reactions discussed in Chapter 15:

Th l t f l t hili ti b tit ti

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The slow step of an electrophilic aromatic substitution

reaction is the formation of the carbocation intermediate:

Electron-donating substituents increase the rate of

substitution reactions by stabilizing the carbocation

intermediate.

Electron-withdrawing substituents decrease the rate of

substitution reactions by destabilizing the carbocationintermediate.

Inductive Electron Withdrawal

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Inductive Electron Withdrawal

Electron Donation by Hyperconjugation

Resonance Electron Donation and Withdrawal

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Resonance Electron Donation and Withdrawal

Substituents such as NH2, OH, OR, and Cl donateelectrons by resonance, but they also withdraw electrons

inductively:

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Substituents such as C=O, CN, SO3H, and NO2

withdraw electrons by resonance:

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Electron-donating substituents

increase the reactivity of

the benzene ring towardelectrophilic aromatic substitution

Electron-withdrawing substituentsdecrease the reactivity of the

benzene ring toward electrophilic

aromatic substitution

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Electron donation into the benzene ring by resonance is

more significant than inductive electron withdrawal from

the ring:

Electron-Donating Substituents

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Resonance donation into the benzene ring competeswith resonance donation into the carbonyl

Overall, these substituents weakly release electrons

Inductive withdrawal into the benzene ring also occurs

These substituents are less effective in donating

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g

electrons into the ring because

Alkyl aryl and CH=CHR groups are weakly activating

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Alkyl, aryl, and CH=CHR groups are weakly activating

substituents because they are slightly more electron

donating than they are electron withdrawing:

These substituents donate into the ring by resonance

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g y

and withdraw electrons from the ring inductively:

They withdraw electrons inductively more strongly than

they donate electrons by resonance

These substituents withdraw electrons both inductively

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These substituents withdraw electrons both inductively

and by resonance:

These substituents are powerful electron-withdrawing

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p g

groups:

Except for the ammonium ions, these substituentswithdraw electrons both inductively and by resonance

The substituent already attached to the benzene ring

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y g

determines the location of the new substituent:

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All activating substituents are orthopara directors:

The weakly deactivating halogens are orthopara

di t

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directors:

All substituents that are more deactivating than halogens

t di t

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are meta directors:

An ortho,para-directing substituent:

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An ortho,para-directing substituent:

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An meta-directing substituent:

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The Effect of Substituents on pKa

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Electron-withdrawing groups stabilize a base andtherefore increase the strength of its conjugate acid

Electron-donating groups destabilize a base and thusdecrease the strength of its conjugate acid

The more electronic deficient a substituent on phenol,

the stronger the acid:

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the stronger the acid:

To understand the relative pK

a values, consider the delocalizationof the phenolate anion (stars show anion distribution):

Unstable

Stable: through resonanceof anion into nitro

More stable anion =

lower pKa

The more electronic deficient a substituent on benzoic

acid the stronger the acid:

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acid, the stronger the acid:

Substituent effect on pKa is minimal in benzoic acidsbecause only inductive electronic effects are present:

Why?

Because the benzene ring is

cross conjugated with the

carboxylate anion

The orthopara product ratio decreases with an increase

in the size of the substituents:

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in the size of the substituents:

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Methoxy and hydroxy substituents are so strongly

activating that halogenation is carried out without a

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activating that halogenation is carried out without a

Lewis acid:

The presence of Lewis acid and excess brominegenerates the tribromo derivative:

A benzene ring with a meta director cannot undergo a

FriedelCrafts reaction:

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Friedel Crafts reaction:

Aniline and N-substituted anilines do not undergo


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Phenol and anisole undergo FriedelCrafts reactions at

the ortho and para positions

Aniline cannot be nitrated, because it is oxidized by nitric

acid

In designing a disubstituted benzene, consider

h d f b i i

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the order of substitution:

The FriedelCrafts acylation must be carried out first,

b th it i t l d ti ti

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because the nitro group is strongly deactivating:

In the synthesis ofpara-chlorobenzoic acid from toluene,the methyl group is oxidized after chlorination:

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y g p

In the synthesis ofmeta-chlorobenzoic acid, the methylgroup is oxidized before chlorination:

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What is the best method for carrying out the

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following reaction?

Provide the major organic product(s) of the reactions

below.

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Synthesis of Trisubstituted Benzenes

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Steric hindrance makes the position between the

substituents less accessible

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A strongly activating substituent will win out over a

weakly activating substituent or a deactivating

substituent

If the two substituents have similar activating properties,

neither will dominate:

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neither will dominate:

Synthesis of Substituted Benzenes

Using Arenediazonium Salts

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Using Arenediazonium Salts

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The reaction stops because a secondary amine lacks asecond proton:

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The bulky dialkyl amino group blocks the approach of thenitrosonium ion to the ortho position:

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[unnumbered fig, pg 690]

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Consider the synthesis ofpara-chloroethylbenzene:

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Fluorination and Iodination of Benzene

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Hydroxylation of Benzene

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y y

Summary of Diazonium Reactions

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Synthesis Example

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y p

Synthetic target:Propose a

synthesis from a

monosubstitutedbenzene

Answer:

The Arenediazonium Ion as anElectrophile

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p

Only highly activated benzene rings can undergo thisreaction

Substitution takes place preferentially at the para

position

However, if the para position is blocked

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Mechanism:

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Diazo Dyes and Sulfa Drugs

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Gerhard Domagk studied the antibiotic properties of diazodyes. He was awarded the Nobel Prize for medicine in 1939

for his work.

Domagk cured his

daughter of strep

with sulfanilamide

Sulfanilamide looks like PABA, a bacterial nutrient:

The dye prontosil is

reduced to the sulfa

drug sulfanilamide

Nucleophilic Aromatic SubstitutionReactions

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Nucleophilic aromatic substitution reactions require at least one

strongly electron-withdrawing substituent to occur:

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Electron-withdrawing substituents increase the reactivity

of the benzene ring toward nucleophilic substitution and

decrease the reactivity of the benzene ring toward

electrophilic substitution

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The incoming group has to be a stronger base than thegroup that is being replaced:

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Chem 212Ch 16