ORGANIC - KLEIN 3E CH. 18 - AROMATIC SUBSTITUTION...

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ORGANIC - KLEIN 3E

CH. 18 - AROMATIC SUBSTITUTION REACTIONS

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: 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: 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: 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

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ORGANIC - KLEIN 3E CH. 18 - AROMATIC SUBSTITUTION...

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