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ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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CONCEPT: ELECTROPHILIC AROMATIC SUBSTITUTION – REACTIONS
EAS reactions require strong electrophiles to take place. Some of these will require catalysts.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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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CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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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CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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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CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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:
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Predict the major products of the following EAS reaction.
O
NH Cl2
cat. FeCl3
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CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Predict the product of the following multi-step synthesis.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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CONCEPT: WOLFF-KISCHNER REDUCTION
This reaction sequence is used to completely remove carbonyls from alkane chains, much like:
a. _______________________________
b. _______________________________
Mechanism:
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CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Beginning from Benzene, synthesize the following compound.
Cl
(the only isomer)
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Predict the major products of the following EAS reaction.
O Br2
cat. FeBr3
PRACTICE: Predict the major products of the following EAS reaction.
O
O
conc. H2SO4
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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:
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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?
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Predict the major product from the Birch Reduction
CF32 Eq. Na, 2 Eq. t-buOH
Liq. NH3
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Predict the major product from the Birch Reduction
CH32 Eq. Na, 2 Eq. t-buOH
Liq. NH3
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Provide the product for each of the following reaction steps
Br
OH
OH
O
Br
OH
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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PRACTICE: Beginning from Benzene, synthesize the following compound.
Br
PRACTICE: Beginning from Benzene, synthesize the following compound.
1-Phenylethanol
PRACTICE: Beginning from Benzene, synthesize the following compound.
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CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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EXAMPLE: Which of the following compounds will most readily undergo nucleophilic aromatic substitution in the addition-
elimination pathway?
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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
ORGANIC - CAREY 10E
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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.
ORGANIC - CAREY 10E
CH. 13 - REACTIONS OF AROMATIC COMPOUNDS
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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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