Organic Chemistry M. R. Naimi-Jamal Faculty of Chemistry Iran University of Science & Technology
Chapter 5-2. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry s Organic Chemistry, 6 th edition, Chapter 16
Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6 electrons Reactions of benzene lead to the retention of the aromatic -system Electrophilic aromatic substitution replaces a proton on benzene with another electrophile 3
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Bromination of Aromatic Rings Benzene s electrons participate as a Lewis base in reactions with Lewis acids The product is formed by loss of a proton, which is replaced by bromine 5
Bromination of Aromatic Rings FeBr 3 is added as a catalyst to polarize the bromine reagent 6
Cationic Intermediate in Bromination The addition of bromine occurs in two steps In the first step the electrons act as a nucleophile toward Br 2 (in a complex with FeBr 3 ) 7
This forms a cationic addition intermediate The intermediate is not aromatic and therefore high in energy 8
Formation of Product from Intermediate The cationic addition intermediate transfers a proton to FeBr 4 - (from Br - and FeBr 3 ) This restores aromaticity (in contrast with addition in alkenes) 9
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Other Aromatic Substitutions The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles The cationic intermediate was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate 11
Aromatic Chlorination and Iodination Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution in the presence of Lewis acids. Chlorination requires FeCl 3 12
Aromatic Chlorination and Iodination Iodine must be oxidized to form a more powerful I + species (with Cu + or peroxide) 13
Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO 2 + (nitronium ion), which is isoelectronic with CO 2 14
Aromatic Nitration The reaction with benzene produces nitrobenzene 15
Reduction of nitro compounds to amines 16
Aromatic Sulfonation Substitution of H by SO 3 (sulfonation) Reaction with a mixture of sulfuric acid and SO 3 (fuming sulfuric acid) Reactive species is sulfur trioxide or its conjugate acid 17
Aromatic Sulfonation Sulfur trioxide, or its conjugate acid, react by the usual mechanism: 18
Useful reactions of sulfonic acids Sulfonic acids are useful as intermediates in the synthesis of sulfa drugs and phenols: 19
Alkylation of Aromatic Rings: The Friedel Crafts Reaction Aromatic substitution of R + for H, alkylating the ring 20
Alkylation of Aromatic Rings: The Friedel Crafts Reaction Aromatic substitution of a R + for H Aluminum chloride promotes the formation of the carbocation Wheland intermediate forms 21
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 carbocations are too hard to form) 22
Limitations of the Friedel-Crafts Alkylation Will not work with rings containing an amino group substituent or a strongly electronwithdrawing group 23
Control Problems Multiple alkylations can occur because the first alkylation is activating 24
Carbocation Rearrangements During Alkylation Similar to those that occur during electrophilic additions to alkenes 25
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Similar reactions: Mechanism? 27
Solution: 28
Another variation: 29
Acylation of Aromatic Rings Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl 3 introduces acyl group, COR 30
Mechanism of Friedel-Crafts Acylation Similar to alkylation; reactive electrophile is a resonance-stabilized acyl cation, which does not rearrange 31
Problem: acid chloride reactant? 32
Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or (much) less reactive than benzene 33
Substituent Effects in Aromatic Rings Substituents affect the orientation of the reaction the positional relationship is controlled ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators 34
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Origins of Substituent Effects An interplay of inductive effects and resonance effects Inductive effect - withdrawal or donation of electrons through a s bond Resonance effect - withdrawal or donation of electrons through a bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring 36
Inductive Effects Controlled by electronegativity and the polarity of bonds in functional groups Halogens, C=O, CN, and NO 2 withdraw electrons through s bond connected to ring Alkyl groups donate electrons 37
Resonance Effects Electron Withdrawal C=O, CN, NO 2 substituents withdraw electrons from the aromatic ring by resonance 38
Resonance Effects Electron Withdrawal 39
Resonance Effects Electron Donation Halogen, OH, alkoxyl (OR), and amino substituents donate electrons Effect is greatest at ortho and para 40
Resonance Effects Electron Donation 41
Contrasting Effects Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring Resonance interactions are generally weaker, affecting orientation The strongest effects dominate 42
An Explanation of Substituent Effects Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation) Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate 43
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Electron Donation & Withdrawal from Benzene Rings 45
Ortho- and Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions ortho and para to themselves Alkyl group is most effective in the ortho and para positions 46
Ortho- and Para-Directing Activators: OH and NH 2 Alkoxyl, and amino groups have a strong, electron-donating resonance effect Most pronounced at the ortho and para positions 48
Ortho- and Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate 50
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Meta-Directing Deactivators Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by deactivation from carbocation intermediate Resonance cannot produce stabilization 52
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Summary Table: Effect of Substituents in Aromatic Substitution 54
Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive 55
Substituents with Opposite Effects If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome 56
Meta-Disubstituted Compounds Are Unreactive between the two groups The reaction site is too hindered 57
Prob.: Substitution at which positions? 58
Prob.: Major substitution product(s)? 59
Oxidation of Aromatic Compounds Alkyl side chains can be oxidized to CO 2 H by strong reagents such as KMnO 4 and Na 2 Cr 2 O 7 if they have a C-H next to the ring Converts an alkylbenzene into a benzoic acid 60
Prob.: Oxidation products? 61
Bromination of Alkylbenzene Side Chains Reaction of an alkylbenzene with N-bromosuccinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain 62
Mechanism of NBS (Radical) Reaction Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical Reacts with Br 2 to yield product Br radical cycles back into reaction to carry chain Br 2 produced from reaction of HBr with NBS 63
Mechanism of NBS (Radical) Reaction 64
Benzylic Radical: 65
Reduction of Aromatic Compounds Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the presence of an aromatic ring Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium catalysts) 66
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Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group toward reduction Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst 68
Synthesis Strategies These syntheses require planning and consideration of alternative routes Work through the practice problems in this section following the general guidelines for synthesis and retrosynthetic analysis. 69
Practice Problem: Synthesize From Benzene: 70
Solutions: 71
Practice Problem: Synthesize From Benzene: 72
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How can we make m-chloropropylbenzene? 74
Putting it all together: 75
Prob.: What s wrong with these syntheses? 76
Prob.: What s wrong with these syntheses? 77
Prob.: Synthesize from benzene 78
Prob.: Identify the reagents 79
Chapter 5-2, Questions 27, 33, 35, 41, 42 45, 51 80