CH. 16 - CHEMISTRY OF BENZENE: ELECTROPHILIC AROMATIC ...lightcat-files.s3.amazonaws.com/packets/organic-2-organic-chemistry... · CONCEPT: ELECTROPHILIC AROMATIC SUBSTITUTION –

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ORGANIC - MCMURRY 9E

CH. 16 - CHEMISTRY OF BENZENE: ELECTROPHILIC AROMATIC SUBSTITUTION

CONCEPT: ELECTROPHILIC AROMATIC SUBSTITUTION – GENERAL MECHANISM

Benzene reacts with very few reagents. It DOES NOT undergo typical addition reactions. Why?

If we can get benzene to react in a substitution reaction, this preserves aromaticity.

Very strong electrophiles can temporarily disrupt aromaticity of benzene to create a substitution product.

● We call this electrophilic aromatic substitution or __________. This is the most important mechanism of benzene.

EAS: General Mechanism



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CONCEPT: ELECTROPHILIC AROMATIC SUBSTITUTION – REACTIONS

EAS reactions require strong electrophiles to take place. Some of these will require catalysts.



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CONCEPT: GENERATING ELECTROPHILES – EAS HALOGENATION

EAS Bromination and Chlorination both require complexing with a Lewis Acid Catalyst before the reaction can begin.

General Reaction:

Mechanism:



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CONCEPT: GENERATING ELECTROPHILES – EAS NITRATION

EAS Nitration requires nitric acid to react with a catalytic acid to generate a strong nitronium ion electrophile.

General Reaction:

Mechanism:

Reduction of Nitro Groups:

Nitro groups can be reduced in the presence of many reducing agents to aniline. More on this in your amines chapter.



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CONCEPT: GENERATING ELECTROPHILES – FRIEDEL-CRAFTS ALKYATION

Friedel-Crafts Alkyation requires an alkyl halide to complex with a Lewis Acid Catalyst before the reaction can begin.

● Active electrophile is a carbocation

□ Watch out for ________________________________ General Reaction:

Mechanism:



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CONCEPT: GENERATING ELECTROPHILES – FRIEDEL-CRAFTS ACYLATION

Friedel-Crafts Acylation requires an acyl halide to complex with a Lewis Acid Catalyst before the reaction can begin.

● Active electrophile is an acylium ion General Reaction:

Mechanism:



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CONCEPT: GENERATING ELECTROPHILES – ANY CARBOCATION

Popular carbocations include those catalyzed by hydrofluoric acid and promoted by boron trifluoride.

● Watch out for ________________________________

General Reaction:

Mechanisms:



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CONCEPT: EAS – MONOSUBSTITUTED BENZENE

Substituents alter the electron density of benzene rings, affecting reactivity toward subsequent EAS in two ways:

1. Activity Effects

● Electron Donating Groups EDG’s ________________________ the ring toward reactions

● Electron Withdrawing Groups EWG’s _____________________ the ring toward reactions

2. Directing Effects

● Electron Donating Groups EDG’s tend to be _____________, ____________ directors

● Electron Withdrawing Groups EWG’s tend to be ____________ directors

Badass EAS Activity Chart



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PRACTICE: Predict the major products of the following EAS reaction.

O

NH Cl2

cat. FeCl3



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PRACTICE: Predict the product of the following multi-step synthesis.



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CONCEPT: EAS-O,P-MAJOR PRODUCTS

In general, we refer to the products of an EAS o,p-director as a mixture – but there are some patterns we can learn.

● The positions compete with number vs. steric hindrance

● In most cases, steric hindrance wins.

If asked to supply only one major product, assume the para-product predominates:

There is only one major exception to this assumption, and that is if the final product can _____ - _____________ with itself.

EXAMPLE: EAS Nitration of Phenol



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CONCEPT: EAS – PROTECTION OF ANILINE DERIVATIVES

Strongly activated rings like aniline can open the ring up to unwanted reactions.

To avoid this, we can reversibly acetylate (protect) the amino group to make it moderately activating.

EXAMPLE: Synthesize the target molecule from nitrobenzene and any other reagents.



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CONCEPT: LIMITATIONS OF FRIEDEL-CRAFTS ALKYLATION

Friedel-Crafts Alkylation has several limitations that render it almost useless in the lab.

1. It does not react with vinyl or aryl halides. Their carbocations are far too unstable.

● Solution: Avoid vinyl or aryl halides

2. Aniline derivatives ruin the Lewis Acid Catalyst

● Solution: Avoid aniline derivatives or protect (reversibly acetylate) the amino group.

3. Alkylation reactions _________________ the ring further reactions

● Solution: Excess benzene or acylate instead

4. Alkylation reactions are susceptible to carbocation rearrangements

● Solution: Acylate instead

EXAMPLE: FC Alkylation vs. FC Acylation of benzene



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PRACTICE: Provide the major product and the correct mechanism for the following reaction.

PRACTICE: Provide the major product and the correct mechanism for the following reaction.



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CONCEPT: ADVANTAGES OF FRIEDEL-CRAFTS ACYLATION

Friedel-Crafts Acylation has several advantages that make it much more synthetically useful than alkylation.

1. Acylation reactions ______________________ the ring further reactions, promoting monosubstitution.

2. Acylation reactions are not susceptible to carbocation rearrangements.

3. Acylation products can be converted to alkylbenzenes with a zinc amalgam using Clemmenson Reduction.

● The mechanism for this reduction is still unknown, but you need to memorize the reagents.

EXAMPLE: Sample preparation of n-propylbenzene



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CONCEPT: BLOCKING GROUPS – SULFONIC ACID

As the only reversible EAS reaction, sulfonation is used to __________ the para position and _________ o-substitution.

● Sometimes called a blocking group because it is not found in the final product.

EXAMPLE: Predict the product of the following multistep synthesis.



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PRACTICE: Beginning from Benzene, synthesize the following compound.

Cl

(the only isomer)



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CONCEPT: EAS – POLYSUBSTITUTED BENZENE

When two or more substituents are already on benzene, there are multiple new factors we must take into account.

1. Steric Effects

● Crowded sites will not be reactive towards subsequent EAS reactions

2. Synergistic Groups

● When multiple directing groups direct toward the same position, yields of that product will be high

3. Competitive Groups

● When multiple directing groups disagree on where to substitute, mixed products will result

□ The strongest ______________________ will determine the major product of the reaction



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O Br2

cat. FeBr3


O

O

conc. H2SO4



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CONCEPT: SIDE-CHAIN HALOGENATION

The alkyl group directly attached to benzene is known as an alkyl side-chain.

● The benzylic position of a side-chain is one of the most stable locations for radicals due to conjugation.

● Recall that benzylic radicals are some of the most stable radical intermediates possible

Benzylic Resonance Structures:

Specific Side-Chain Halogenations:



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CONCEPT: SIDE-CHAIN OXIDATION

The alkyl group directly attached to benzene is known as an alkyl side-chain.

Regardless of the length of an alkylbenzene side-chain, it can be oxidized to benzoic acid using hot KMnO4.

● However, there must be at least one benzylic hydrogen present for oxidation to occur.

EXAMPLE: Which of the following alkylbenzenes would not yield benzoic acid when treated with hot KMnO4?



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CONCEPT: EAS – SEQUENCE GROUPS

Sequence groups are groups that have the ability to alter the sequence of an aromatic synthesis.

● These are groups that can be easily transformed into another type of director

1. Reduction of Nitro Groups

2. Clemmenson Reduction

3. Side-Chain Oxidation



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CONCEPT: EAS — PROPOSING AROMATIC SYNTHESIS

You may be asked to propose an aromatic synthesis starting only from benzene or other benzene derivatives.

● We must use our knowledge sequence groups to plan synthetic steps in the correct order

EXAMPLE: Synthesize the target molecule from acetophenone and any other reagents.

EXAMPLE: Synthesize the target molecule from ethylbenzene and any other reagents.



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PRACTICE: Provide the product for each of the following reaction steps

Br

OH

OH

O

Br

OH



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Br


1-Phenylethanol




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CONCEPT: EAS — PROPOSING AROMATIC SYNTHESIS

You may be asked to propose an aromatic synthesis starting only from benzene or other benzene derivatives.

● We must use our knowledge sequence groups to plan synthetic steps in the correct order

EXAMPLE: Synthesize the target molecule from acetophenone and any other reagents.

EXAMPLE: Synthesize the target molecule from ethylbenzene and any other reagents.



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PRACTICE: Provide the product for each of the following reaction steps

Br

OH

OH

O

Br

OH



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Br


1-Phenylethanol




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CONCEPT: BIRCH REDUCTION

The birch reduction is a dissolving metal reduction, except reacting with benzenes instead of alkynes.

● The product of an unsubstituted benzene is a simple isolated cyclohexadiene.

Mechanism:

Regiochemistry:

Substituents affect the course of the mechanism, yielding regiospecific products.

● ______________________ groups isolate themselves from the diene

● ______________________ groups attach themselves to the diene



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PRACTICE: Predict the major product from the Birch Reduction

CF32 Eq. Na, 2 Eq. t-buOH

Liq. NH3



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PRACTICE: Predict the major product from the Birch Reduction

CH32 Eq. Na, 2 Eq. t-buOH

Liq. NH3



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CONCEPT: SNAr ADDITION-ELIMINATION MECHANISM

Unlike EAS, where addition is initiated by the presence of a strong electrophile, addition-elimination can also be initiated by

a strong nucleophile in the presence of a good aryl leaving group.

● Reaction has similarities to SN2 but it is not _____________________

● Known as Addition-Elimination Nucleophilic Aromatic Substitution, SNAr or ipso-substitution.

An early method of preparing phenol called the Dow Process used chlorobenzene, NaOH and high heat to force SNAr.

.



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CONCEPT: THE MEISENHEIMER COMPLEX

The Dow Process, a typical SNAr reaction, requires tons of heat and pressure to proceed forward.

● This is due to the instability of the anionic sigma-complex

● Withdrawing groups or Heteroatoms to the Ortho or Para positions (WHOP) stabilize the intermediate

□ A classical trinitrobenzene Meisenheimer Complex can proceed in room temperature

EXAMPLE: Use resonance structures to determine which of the following ipso-substitutions is more favored.



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EXAMPLE: Which of the following compounds will most readily undergo nucleophilic aromatic substitution in the addition-

elimination pathway?



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PRACTICE: Provide the structure and name of the intermediate formed from the reaction of 1-bromo-2,4,6-

trinitrobenzene with one equivalent of sodium methoxide.

PRACTICE: Provide the major organic product for the following reaction.

PRACTICE: Provide the major organic product for the following reaction.



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PRACTICE: Which of the following compounds is most likely to undergo nucleophilic aromatic substitution via the

addition-elimination Pathway?

PRACTICE: Which of the following compounds is most likely to undergo nucleophilic aromatic substitution via the

addition-elimination Pathway?

N

Cl

N

Cl

NN

N+ O

-O

Cl

NN

Cl

N+

O-

O



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CONCEPT: BENZYNE PATHWAY – GENERAL MECHANISM

Benzene can also undergo Nucleophilic Aromatic Substitution via an Elimination-Addition pathway to make aniline.

● This mechanism requires the formation of a highly unstable aryne (C6H4) intermediate.

Benzyne Amination Mechanism:



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CONCEPT: BENZYNE PATHWAY – REGIOSPECIFIC PRODUCTS

MIT chemist John D. Roberts proposed that we could use donating and withdrawing groups to favor ortho vs. meta products

● Donating Groups favor the _____________ position

● Withdrawing Groups favor the _____________ position

EXAMPLE: Predict the product of the reaction. Use your knowledge of activating and deactivating groups to determine what

the final product is. Show the full mechanism for the benzyne pathway.



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PRACTICE: Provide the major product(s) from the following reaction.

OCH3

Br

NaNH2 NH3

PRACTICE: Provide the major product(s) from the following reaction.

NaNH2 NH3

CH3

Cl



Page 40

CONCEPT: ACIDITY OF PHENOLS

Phenols are substantially more acidic than typical alcohols due to the _________________ effect.

● Recall, the more we can stabilize the conjugate base, the more acidic a compound will be.

Donating and Withdrawing Groups:

EXAMPLE: Predict which of the following would be the most acidic phenol.



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O,P-Directors vs. Meta-Directors

The __________ position has a much lessor effect on acidity than the _________ and __________ positions.

● This is due to the resonance structures that are able to be produced by different positions




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PRACTICE: Rank the following phenols in order of increasing acidity.



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CH. 16 - CHEMISTRY OF BENZENE: ELECTROPHILIC AROMATIC ...lightcat-files.s3.amazonaws.com/packets/organic-2-organic-chemistry... · CONCEPT: ELECTROPHILIC AROMATIC SUBSTITUTION –

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