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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 Page 2
CONCEPT: ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS EAS reactions require strong electrophiles to take place. Some of these will require catalysts. Page 3
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: Page 4
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. Page 5
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: Page 6
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: Page 7
CONCEPT: GENERATING ELECTROPHILES ANY CARBOCATION Popular carbocations include those catalyzed by hydrofluoric acid and promoted by boron trifluoride. Watch out for General Reaction: Mechanisms: Page 8
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 Page 9
PRACTICE: Predict the major products of the following EAS reaction. O NH Cl 2 cat. FeCl 3 Page 10
PRACTICE: Predict the product of the following multi-step synthesis. Page 11
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 Page 12
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 Page 13
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. Page 14
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 Page 15
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. Page 16
PRACTICE: Beginning from Benzene, synthesize the following compound. Cl (the only isomer) Page 17
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 Page 18
PRACTICE: Predict the major products of the following EAS reaction. O Br 2 cat. FeBr 3 PRACTICE: Predict the major products of the following EAS reaction. O conc. H 2 SO 4 O Page 19
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 Page 20
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. Page 21
PRACTICE: Provide the product for each of the following reaction steps Br O OH OH Br OH Page 22
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. Page 23
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 SN 2 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.. Page 24
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. Page 25
EXAMPLE: Which of the following compounds will most readily undergo nucleophilic aromatic substitution in the additionelimination pathway? Page 26
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. Page 27
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? O N + O- O Cl N + O - N Cl N N Cl N N Cl N Page 28
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: Page 29
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. Page 30
PRACTICE: Provide the major product(s) from the following reaction. H 3 C O NaNH 2 NH 3 Br PRACTICE: Provide the major product(s) from the following reaction. CH 3 Cl NaNH 2 NH 3 Page 31
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. Page 32
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 EXAMPLE: Predict which of the following would be the most acidic phenol. Page 33
EXAMPLE: Predict which of the following would be the most acidic phenol. EXAMPLE: Predict which of the following would be the most acidic phenol. Page 34
PRACTICE: Rank the following phenols in order of increasing acidity. Page 35
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 Page 36
PRACTICE: Predict the major product from the Birch Reduction CF 3 2 Eq. Na, 2 Eq. t-buoh Liq. NH 3 Page 37
PRACTICE: Predict the major product from the Birch Reduction CH 3 2 Eq. Na, 2 Eq. t-buoh Liq. NH 3 Page 38