chapter 16- chemistry of benzene: electrophilic aromatic ... · 2/1/16 1 chapter 16- chemistry of...
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Chapter 16- Chemistry of Benzene: Electrophilic Aromatic Substitution
Ashley Piekarski, Ph.D.
Substitution Reactions of Benzene and Its Derivatives
• Benzene is aroma%c • What does aromatic mean?
• Reac9ons of benzene lead to the reten9on of the aroma9c core
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Why do I care, Dr. P?
• In the last chapter, we learned about the structure and stability of aroma9c compounds
• We established a structure-‐property rela%onship! • This valuable information will help us
understand the reactions these molecules undergo and the products that are made
• Rela9onship cri9cal to understanding of how biological molecules/pharmaceu9cal agents are synthesizedà real-‐world applica%ons!
Electrophilic Aromatic Substitution Reactions: Bromination
• Benzene’s π electrons par9cipate as a Lewis base in reac9ons with Lewis acids
• The product is formed by loss of a proton, which is replaced by bromine
• FeBr3 is added as a catalyst to polarize the bromine reagent
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Bromination of alkenes
• What was the product of the bromina9on of propene?
• This doesn’t happen with benzene… • Why do you think that is?
Addition Intermediate in Bromination
• The addi9on of bromine occurs in two steps • In the first step the π electrons act as a nucleophile toward
Br2 (in a complex with FeBr3) • This forms a ca9onic addi9on intermediate from benzene and
a bromine ca9on • The intermediate is not aroma(c and therefore high in energy
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Formation of Product from Intermediate
• The ca9onic addi9on intermediate transfers a proton to FeBr4-‐ (from Br-‐ and FeBr3)
• This restores aroma%city! (in contrast with addi9on in alkenes)
Other Aromatic Substitutions
• Chlorine and iodine (but not fluorine, which is too reac9ve) can produce aroma9c subs9tu9on with the addi9on of other reagents to promote the reac9on
• Chlorina9on requires FeCl3 (acts as a catalyst to make chlorine a beXer electrophile)
AKA Valium (an9-‐anxiety drug)
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Other Aromatic Substitutions
• Chlorine and iodine (but not fluorine, which is too reac9ve) can produce aroma9c subs9tu9on with the addi9on of other reagents to promote the reac9on
• Chlorina9on requires FeCl3 (acts as a catalyst) • Iodine must be oxidized to form a more powerful I+ species
(with Cu+ or peroxide)
Aromatic Nitration
• The combina9on of nitric acid and sulfuric acid produces NO2+
(nitronium ion) • The reac9on with benzene produces nitrobenzene
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Aromatic Sulfonation
• Subs9tu9on of H by SO3 (sulfona9on) • Reac9on with a mixture of sulfuric acid and SO3 • Reac9ve species is sulfur trioxide or its conjugate acid
Aromatic Hydroxylation
• Not performed in the laboratory • Does occur in biological pathways!
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Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
• Alkyla9on among most useful electrophilic aroma9c subs9tu9on reac9ons! Very powerful rxn. to put in your organic toolbox!
• Aroma9c subs9tu9on of R+ for H+
• Aluminum chloride promotes the forma9on of the carboca9on
Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
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Limitations of the Friedel-Crafts Alkylation
• Only alkyl halides can be used (F, Cl, I, Br) • Aryl halides and vinylic halides do not react (their
carboca9ons are not stable enough to form) • Will not work with rings containing an amino group
subs9tuent or a strongly electron-‐withdrawing group
Control Problems
• Mul9ple alkyla9ons can occur because the first alkyla9on is ac9va9ng
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Carbocation Rearrangements During Alkylation
• Similar to those that occur during electrophilic addi9ons to alkenes
• What are the two types of carboca9on rearrangements and why do they occur?
Carbocation Rearrangements During Alkylation
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Learning check
• Predict the product and write the complete stepwise mechanism for the reac9on below:
CH3CH2Cl
AlCl3
AlCl3
Cl
Cl
O
AlCl3
CH3SO3
H2SO4
a)
OCH3
Br2
FeBr3
b)
NO2
1. HNO3, H2SO4
2. H2/Pd
c)CH3
O
Learning check
• Predict the product and write the complete stepwise mechanism for the reac9on below:
CH3CH2Cl
AlCl3
AlCl3
Cl
Cl
O
AlCl3
CH3SO3
H2SO4
a)
OCH3
Br2
FeBr3
b)
NO2
1. HNO3, H2SO4
2. H2/Pd
c)CH3
O
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Acylation of Aromatic Rings
• Reac9on of an acid chloride (RCOCl) and an aroma9c ring in the presence of AlCl3 introduces acyl group, ⎯COR • Benzene with acetyl chloride yields acetophenone
Mechanism of Friedel-Crafts Acylation
• Similar to alkyla9on • Reac9ve electrophile: resonance-‐stabilized acyl ca9on • An acyl ca9on does not rearrange
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Learning check
• Predict the product and write the complete stepwise mechanism for the reac9on below:
CH3CH2Cl
AlCl3
AlCl3
Cl
Cl
O
AlCl3
CH3SO3
H2SO4
a)
OCH3
Br2
FeBr3
b)
NO2
1. HNO3, H2SO4
2. H2/Pd
c)CH3
O
Substituent Effects in Aromatic Rings
• Subs9tuents can cause a compound to be more or less reac9ve than benzene
• Subs9tuents affect the orienta9on of the reac9on – the posi9onal rela9onship is controlled • ortho- and para-directing activators, ortho- and para-
directing deactivators, and meta-directing deactivators
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Origins of Substituent Effects
• An interplay of induc(ve effects and resonance effects
• Induc%ve effect -‐ withdrawal or dona9on of electrons through a σ bond
• Resonance effect -‐ withdrawal or dona9on of electrons through a π bond due to the overlap of a p orbital on the subs9tuent with a p orbital on the aroma9c ring
• It is cri9cal you know the difference between these two defini9ons!
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Inductive Effects
• Controlled by electronega9vity and the polarity of bonds in func9onal groups
• Halogens, C=O, CN, and NO2 withdraw electrons through σ bond connected to ring
• Alkyl groups donate electrons
Resonance Effects – Electron Withdrawal
• C=O, CN, NO2 subs9tuents withdraw electrons from the aroma9c ring by resonance
• π electrons flow from the rings to the subs9tuents
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Resonance Effects – Electron Donation
• Halogen, OH, alkoxyl (OR), and amino subs9tuents donate electrons
• π electrons flow from the subs9tuents to the ring • Effect is greatest at ortho and para
An Explanation of Substituent Effects
• Ac%va%ng groups donate electrons to the ring, stabilizing the carboca9on intermediate
• Deac%va%ng groups withdraw electrons from the ring, destabilizing the carboca9on intermediate
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Ortho- and Para-Directing Activators: Alkyl Groups
• Alkyl groups ac9vate: direct further subs9tu9on to posi9ons ortho and para to themselves
• Alkyl group is most effec9ve in the ortho and para posi9ons because they form the most stable intermediates!
Ortho- and Para-Directing Activators: OH and NH2
• Alkoxyl, and amino groups have a strong, electron-‐dona9ng resonance effect
• Most pronounced at the ortho and para posi9ons
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Ortho- and Para-Directing Deactivators: Halogens
• Electron-‐withdrawing induc9ve effect outweighs weaker electron-‐dona9ng resonance effect
• Resonance effect is only at the ortho and para posi9ons, stabilizing carboca9on intermediate
Meta-Directing Deactivators
• Induc9ve and resonance effects reinforce each other • Ortho and para intermediates destabilized by deac9va9on of
carboca9on intermediate • Resonance cannot produce stabiliza9on
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Summary Table: Effect of Substituents in Aromatic Substitution
Trisubstituted Benzenes
• If the direc9ng effects of the two groups are the same, the result is addi9ve
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Substituents with Opposite Effects
• If the direc9ng effects of two groups oppose each other, the more powerful ac9va9ng group decides the principal outcome
• Usually gives mixtures of products
Meta-Disubstituted Compounds
• The reac9on site is too hindered • To make aroma9c rings with three adjacent subs9tuents, it is
best to start with an ortho-‐disubs9tuted compound
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Learning check
• Predict the products of the reac9ons below:
CH3CH2Cl
AlCl3
AlCl3
Cl
Cl
O
AlCl3
CH3SO3
H2SO4
a)
OCH3
Br2
FeBr3
b)
NO2
1. HNO3, H2SO4
2. H2/Pd
c)CH3
O
Nucleophilic Aromatic Substitution • Aryl halides with electron-‐withdrawing subs9tuents ortho and
para react with nucleophiles • Form addi9on intermediate that is stabilized by electron-‐
withdrawal • Halide ion is lost to give aroma9c ring
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Benzyne
• Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure
• The reac9on involves an elimina9on reac9on that gives a triple bond
• The intermediate is called benzyne
Evidence for Benzyne as an Intermediate
• Bromobenzene with 14C only at C1 gives subs9tu9on product with label scrambled between C1 and C2
• Reac9on proceeds through a symmetrical intermediate in which C1 and C2 are equivalent— must be benzyne
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Structure of Benzyne
• Benzyne is a highly distorted alkyne • The triple bond uses sp2-‐hybridized carbons, not the usual sp • The triple bond has one π bond formed by p–p overlap and
another by weak sp2–sp2 overlap
Oxidation of Aromatic Compounds
• Alkyl side chains can be oxidized to ⎯CO2H by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C-‐H next to the ring
• Converts an alkylbenzene into a benzoic acid, Ar⎯R → Ar⎯CO2H
• Benzene ring cannot be oxidized!
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Bromination of Alkylbenzene Side Chains
• Reac9on of an alkylbenzene with N-‐bromo-‐succinimide (NBS) and benzoyl peroxide (radical ini9ator) introduces Br into the side chain
Mechanism of NBS (Radical) Reaction
• Abstrac9on of a benzylic hydrogen atom generates an intermediate benzylic radical
• Reacts with Br2 to yield product • Br· radical cycles back into reac9on to carry chain • Br2 produced from reac9on of HBr with NBS
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Reduction of Aromatic Compounds
• Aroma9c rings are inert to cataly9c hydrogena9on under condi9ons that reduce alkene double bonds
• Can selec9vely reduce an alkene double bond in the presence of an aroma9c ring
• Reduc9on of an aroma9c ring requires more powerful reducing condi9ons (high pressure or rhodium catalysts)
Reduction of Aryl Alkyl Ketones
• Aroma9c ring ac9vates neighboring carbonyl group toward reduc9on
• Ketone is converted into an alkylbenzene by cataly9c hydrogena9on over Pd catalyst
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Synthesis of Trisubstituted Benzenes
• These syntheses require planning and considera9on of alterna9ve routes
• Ability to plan a sequence of reac9ons in right order is valuable to synthesis of subs9tuted aroma9c rings
Learning check
• Propose a synthesis for 3-‐bromo-‐2methylbenzenesulfonic acid.
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Learning check
• Propose a synthesis for 4-‐chloro-‐1-‐nitro-‐2-‐propylbenzene.