17 lecture
TRANSCRIPT
© 2013 Pearson Education, Inc. Chapter 17 1
Chapter 17Lecture
Organic Chemistry, 8th Edition
L. G. Wade, Jr.
Reactions of Aromatic Compounds
© 2013 Pearson Education, Inc.
Rizalia KlausmeyerBaylor UniversityWaco, TX
© 2013 Pearson Education, Inc. Chapter 17 2
Electrophilic Aromatic Substitution
Although benzene’s pi electrons are in a stable aromatic system, they are available to attack a strong electrophile to give a carbocation.
This resonance-stabilized carbocation is called a sigma complex because the electrophile is joined to the benzene ring by a new sigma bond.
Aromaticity is regained by loss of a proton.
© 2013 Pearson Education, Inc. Chapter 17 3
Mechanism of Electrophilic Aromatic Substitution
Step 1: Attack on the electrophile forms the sigma complex.
Step 2: Loss of a proton gives the substitution product.
© 2013 Pearson Education, Inc. Chapter 17 5
Mechanism for the Bromination of Benzene:
Preliminary Step
Before the electrophilic aromatic substitution can take place, the electrophile must be activated.
A strong Lewis acid catalyst, such as FeBr3, should be used.
© 2013 Pearson Education, Inc. Chapter 17 6
Step 1: Electrophilic attack and formation of the sigma complex.
Step 2: Loss of a proton to give the products.
Mechanism for the Bromination of Benzene: Steps
1 and 2
© 2013 Pearson Education, Inc. Chapter 17 7
Note that the three resonance forms of the sigma complex show the
positive charge on the three carbon atoms ortho and para to the site of
substitution.
© 2013 Pearson Education, Inc. Chapter 17 9
Chlorination of Benzene
Chlorination is similar to bromination. AlCl3 is most often used as catalyst, but FeCl3 will also work.
© 2013 Pearson Education, Inc. Chapter 17 10
Iodination of Benzene
Iodination requires an acidic oxidizing agent, like nitric acid, to produce iodide cation.
H+ + HNO3 + ½ I2 I+ + NO2 + H2O
© 2013 Pearson Education, Inc. Chapter 17 11
Nitration of Benzene
Sulfuric acid acts as a catalyst, allowing the reaction to be faster and at lower temperatures.
HNO3 and H2SO4 react together to form the electrophile of the reaction: nitronium ion (NO2
+).
© 2013 Pearson Education, Inc. Chapter 17 12
Mechanism for the Nitration of Benzene: Preliminary Step
Formation of the nitronium ion is the preliminary step of the reaction.
© 2013 Pearson Education, Inc. Chapter 17 13
Mechanism for the EAS Nitration of Benzene
Step 1: Formation of the sigma complex.
Step 2: Loss of a proton gives nitrobenzene.
© 2013 Pearson Education, Inc. Chapter 17 14
Reduction of the Nitro Group
Treatment with zinc, tin, or iron in dilute acid will reduce the nitro to an amino group.
This is the best method for adding an amino group to the ring.
© 2013 Pearson Education, Inc. Chapter 17 15
Sulfonation of Benzene
Sulfur trioxide (SO3) is the electrophile in the reaction. A 7% mixture of SO3 and H2SO4 is commonly referred
to as “fuming sulfuric acid.” The —SO3H group is called a sulfonic acid.
© 2013 Pearson Education, Inc. Chapter 17 16
Sulfur Trioxide
Sulfur trioxide is a strong electrophile, with three sulfonyl bonds drawing electron density away from the sulfur atom.
© 2013 Pearson Education, Inc. Chapter 17 17
Mechanism of Sulfonation
Benzene attacks sulfur trioxide, forming a sigma complex.
Loss of a proton on the tetrahedral carbon and reprotonation of oxygen gives benzenesulfonic acid.
© 2013 Pearson Education, Inc. Chapter 17 18
Desulfonation Reaction
Sulfonation is reversible. The sulfonic acid group may be removed
from an aromatic ring by heating in dilute sulfuric acid.
© 2013 Pearson Education, Inc. Chapter 17 19
Mechanism of Desulfonation
In the desulfonation reaction, a proton adds to the ring (the electrophile) and loss of sulfur trioxide gives back benzene.
© 2013 Pearson Education, Inc. Chapter 17 20
Nitration of Toluene
Toluene reacts 25 times faster than benzene. The methyl group is an activator. The product mix contains mostly ortho and
para substituted molecules.
© 2013 Pearson Education, Inc. Chapter 17 21
Ortho and Para Substitution
Ortho and para attacks are preferred because their resonance structures include one tertiary carbocation.
© 2013 Pearson Education, Inc. Chapter 17 23
Meta Substitution
When substitution occurs at the meta position, the positive charge is not delocalized onto the tertiary carbon, and the methyl group has a smaller effect on the stability of the sigma complex.
© 2013 Pearson Education, Inc. Chapter 17 24
Alkyl Group Stabilization
Alkyl groups are activating substituents and ortho, para-directors.
This effect is called the inductive effect because alkyl groups can donate electron density to the ring through the sigma bond, making them more active.
© 2013 Pearson Education, Inc. Chapter 17 25
Anisole
Anisole undergoes nitration about 10,000 times faster than benzene and about 400 times faster than toluene.
This result seems curious because oxygen is a strongly electronegative group, yet it donates electron density to stabilize the transition state and the sigma complex.
© 2013 Pearson Education, Inc. Chapter 17 26
Substituents with Nonbonding Electrons
Resonance stabilization is provided by a pi bond between the —OCH3 substituent and the ring.
© 2013 Pearson Education, Inc. Chapter 17 27
Meta Attack on Anisole
Resonance forms show that the methoxy group cannot stabilize the sigma complex in the meta substitution.
© 2013 Pearson Education, Inc. Chapter 17 28
Bromination of Anisole
A methoxy group is so strongly activating that anisole is quickly tribrominated without a catalyst.
© 2013 Pearson Education, Inc. Chapter 17 29
The Amino Group
Aniline reacts with bromine water (without a catalyst) to yield the tribromoaniline.
Sodium bicarbonate is added to neutralize the HBr that is also formed.
© 2013 Pearson Education, Inc. Chapter 17 31
Activators and Deactivators
If the substituent on the ring is electron donating, the ortho and para positions will be activated.
If the group is electron withdrawing, the ortho and para positions will be deactivated.
© 2013 Pearson Education, Inc. Chapter 17 32
Nitration of Nitrobenzene
Electrophilic substitution reactions for nitrobenzene are 100,000 times slower than for benzene.
The product mix contains mostly the meta isomer, and only small amounts of the ortho and para isomers.
© 2013 Pearson Education, Inc. Chapter 17 33
Ortho Substitution of Nitrobenzene
The nitro group is a strongly deactivating group when considering its resonance forms. The nitrogen always has a formal positive charge.
Ortho or para addition will create an especially unstable intermediate.
© 2013 Pearson Education, Inc. Chapter 17 34
Meta Substitution on Nitrobenzene
Meta substitution will not put the positive charge on the same carbon that bears the nitro group.
© 2013 Pearson Education, Inc. Chapter 17 36
Deactivators and Meta-Directors
Most electron-withdrawing groups are deactivators and meta-directors.
The atom attached to the aromatic ring has a positive or partial positive charge.
Electron density is withdrawn inductively along the sigma bond, so the ring has less electron density than benzene, and thus it will be slower to react.
© 2013 Pearson Education, Inc. Chapter 17 37
Ortho Attack of Acetophenone
In ortho and para substitution of acetophenone, one of the carbon atoms bearing the positive charge is the carbon attached to the partial positive carbonyl carbon.
Since like charges repel, this close proximity of the two positive charges is especially unstable.
© 2013 Pearson Education, Inc. Chapter 17 38
Meta Attack on Acetophenone
The meta attack on acetophenone avoids bearing the positive charge on the carbon attached to the partial positive carbonyl.
© 2013 Pearson Education, Inc. Chapter 17 40
Halogens
Halogens are deactivators since they react slower than benzene.
Halogens are ortho, para-directors because the halogen can stabilize the sigma complex.
© 2013 Pearson Education, Inc. Chapter 17 41
Halogens Are Deactivators
Inductive effect: Halogens are deactivating because they are electronegative and can withdraw electron density from the ring along the sigma bond.
© 2013 Pearson Education, Inc. Chapter 17 42
Halogens Are Ortho, Para-Directors
Resonance effect: The lone pairs on the halogen can be used to stabilize the sigma complex by resonance.
© 2013 Pearson Education, Inc. Chapter 17 45
Remember which substituents are activating and which are deactivating. Activators are ortho, para-directing, and deactivators are meta-directing, except for the halogens.
© 2013 Pearson Education, Inc. Chapter 17 46
Effect of Multiple Substituents
The directing effect of the two (or more) groups may reinforce each other.
© 2013 Pearson Education, Inc. Chapter 17 47
Effect of Multiple Substituents (Continued)
The position in between two groups in positions 1 and 3 is hindered for substitution, and it is less reactive.
© 2013 Pearson Education, Inc. Chapter 17 48
Effect of Multiple Substituents (Continued)
If directing effects oppose each other, the most powerful activating group has the dominant influence.
© 2013 Pearson Education, Inc. Chapter 17 49
Predict the major product(s) of bromination of p-chloroacetanilide.
The amide group (–NHCOCH3) is a strong activating and directing group because the nitrogen atom with its nonbonding pair of electrons is bonded to the aromatic ring. The amide group is a stronger director than the chlorine atom, and substitution occurs mostly at the positions ortho to the amide. Like an alkoxyl group, the amide is a particularly strong activating group, and the reaction gives some of the dibrominated product.
Solved Problem 1
Solution
© 2013 Pearson Education, Inc. Chapter 17 50
Friedel–Crafts Alkylation
Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl3.
Reactions of alkyl halide with Lewis acid produces a carbocation, which is the electrophile.
© 2013 Pearson Education, Inc. Chapter 17 51
Mechanism of the Friedel–Crafts Reaction
Step 1
Step 2
Step 3
© 2013 Pearson Education, Inc. Chapter 17 52
Protonation of Alkenes
An alkene can be protonated by HF. This weak acid is preferred because the
fluoride ion is a weak nucleophile and will not attack the carbocation.
© 2013 Pearson Education, Inc. Chapter 17 53
Alcohols and Lewis Acids
Alcohols can be treated with BF3 to form the carbocation.
© 2013 Pearson Education, Inc. Chapter 17 54
Limitations of Friedel–Crafts
Reaction fails if benzene has a substituent that is more deactivating than halogens.
Rearrangements are possible. The alkylbenzene product is more reactive
than benzene, so polyalkylation occurs.
© 2013 Pearson Education, Inc. Chapter 17 56
Devise a synthesis of p-nitro-t-butylbenzene from benzene.
To make p-nitro-t-butylbenzene, we would first use a Friedel–Crafts reaction to make t-butylbenzene. Nitration gives the correct product. If we were to make nitrobenzene first, the Friedel–Crafts reaction to add the t-butyl group would fail.
Solved Problem 2
Solution
© 2013 Pearson Education, Inc. Chapter 17 57
Friedel–Crafts Acylation
Acyl chloride is used in place of alkyl chloride. The product is a phenyl ketone that is less
reactive than benzene.
© 2013 Pearson Education, Inc. Chapter 17 58
Mechanism of Acylation
Step 1: Formation of the acylium ion.
Step 2: Electrophilic attack to form the sigma complex.
© 2013 Pearson Education, Inc. Chapter 17 59
Mechanism of Acylation (Continued)
Step 3: Loss of a proton to form the product.
© 2013 Pearson Education, Inc. Chapter 17 60
Friedel–Crafts acylations are generally free from rearrangements
and multiple substitution. They do not go on strongly deactivated rings,
however.
© 2013 Pearson Education, Inc. Chapter 17 61
Clemmensen Reduction
The Clemmensen reduction is a way to convert acylbenzenes to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc.
© 2013 Pearson Education, Inc. Chapter 17 62
Nucleophilic Aromatic Substitution
A nucleophile replaces a leaving group on the aromatic ring.
This is an addition–elimination reaction. Electron-withdrawing substituents activate the
ring for nucleophilic substitution.
© 2013 Pearson Education, Inc. Chapter 17 63
Mechanism of Nucleophilic Aromatic Substitution
Step 1: Attack by hydroxide gives a resonance-stabilized complex.
Step 2: Loss of chloride gives the product. Step 3: Excess base deprotonates the product.
© 2013 Pearson Education, Inc. Chapter 17 64
Activated Positions
Nitro groups ortho and para to the halogen stabilize the intermediate (and the transition state leading to it).
Electron-withdrawing groups are essential for the reaction to occur.
© 2013 Pearson Education, Inc. Chapter 17 65
Benzyne Reaction: Elimination–Addition
Reactant is halobenzene with no electron-withdrawing groups on the ring.
Use a very strong base like NaNH2.
© 2013 Pearson Education, Inc. Chapter 17 66
Benzyne Mechanism
Sodium amide abstracts a proton. The benzyne intermediate forms when the bromide is
expelled and the electrons on the sp2 orbital adjacent to it overlap with the empty sp2 orbital of the carbon that lost the bromide.
Benzynes are very reactive species due to the high strain of the triple bond.
© 2013 Pearson Education, Inc. Chapter 17 68
With strong electron-withdrawinggroups ortho or para, the addition–
elimination mechanism is more likely. Without these activating groups,
stronger conditions are required, and the benzyne mechanism is likely.
© 2013 Pearson Education, Inc. Chapter 17 69
Aromatic Substitutions Using Organometallic Reagents
Friedel–Craft reactions have limitations. Rearrangements. Multiple alkylations. Cannot occur on deactivated rings. Need strong electrophiles.
Organometallic reagents can add alkyl groups to the benzene without these limitations.
© 2013 Pearson Education, Inc. Chapter 17 70
Organocuprate Reagents
Lithium dialkylcuprate reagents (Gilman reagents) can be prepared by reaction of two equivalents of an organolithium reagent with cuprous iodide.
R—X + 2 Li R—Li + LiX
2 R—Li + CuX R2CuX + LiX
© 2013 Pearson Education, Inc. Chapter 17 71
Coupling Using Organocuprate Reagents
Mechanisms vary depending on the alkyl halide and organocuprate used.
Cannot be SN2 because vinyl and aryl halides work well in this reaction.
© 2013 Pearson Education, Inc. Chapter 17 72
The Heck Reaction
Palladium-catalyzed coupling of an aryl or vinyl halide with an alkene.
Produces C–C bond at the less substituted end of the alkene.
Triethylamine or sodium acetate is added to neutralize the HX produced.
© 2013 Pearson Education, Inc. Chapter 17 74
The Suzuki Reaction
Also called the Suzuki coupling. Palladium-catalyzed substitution that couples
an aryl or vinyl halide with an alkyl, alkenyl, or aryl boronic acid or boronate ester.
© 2013 Pearson Education, Inc. Chapter 17 75
Synthesis of Boronate Esters
The boronate esters can be synthesized from alkyl-, vinyl-, and arylboronic acids.
Can also be made by the hydroboration of double and triple bonds.
© 2013 Pearson Education, Inc. Chapter 17 77
Chlorination of Benzene
Addition to the benzene ring may occur with excess of chlorine under heat and pressure.
The first Cl2 addition is difficult, but the next two moles add rapidly.
© 2013 Pearson Education, Inc. Chapter 17 78
Catalytic Hydrogenation
Elevated heat and pressure are required. Possible catalysts: Pt, Pd, Ni, Ru, Rh. Reduction cannot be stopped at an
intermediate stage.
© 2013 Pearson Education, Inc. Chapter 17 79
Birch Reduction
This reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene.
The reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol.
© 2013 Pearson Education, Inc. Chapter 17 82
Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic acid by heating in basic KMnO4 or heating in Na2Cr2O7/H2SO4.
The benzylic carbon will be oxidized to the carboxylic acid.
© 2013 Pearson Education, Inc. Chapter 17 83
Side-Chain Halogenation
The benzylic position is the most reactive.
Br2 reacts only at the benzylic position.
Cl2 is not as selective as bromination, so results in mixtures.
© 2013 Pearson Education, Inc. Chapter 17 85
In predicting reactions on side chains of aromatic rings,
consider resonance forms that delocalize a charge or a radical
electron onto the ring.
© 2013 Pearson Education, Inc. Chapter 17 86
SN1 Reactions
Benzylic carbocations are resonance-stabilized, easily formed.
Benzyl halides undergo SN1 reactions.
© 2013 Pearson Education, Inc. Chapter 17 87
SN2 Reactions
Benzylic halides are 100 times more reactive than primary halides via SN2.
The transition state is stabilized by a ring.
© 2013 Pearson Education, Inc. Chapter 17 89
Oxidation of Phenols to Quinones
Phenol will react with oxidizing agents to produce quinones.
Quinones are conjugated 1,4-diketones. This can also happen (slowly) in the presence of air.
© 2013 Pearson Education, Inc. Chapter 17 90
Electrophilic Aromatic Substitution of Phenols
Phenols are highly reactive because the hydroxyl group stabilizes the sigma complex formed.
Usually alkylated or acylated using relatively weak Friedel–Crafts catalysts (such as HF) to avoid overalkylation or overacylation.