Substitution Reactions of Benzene and Its Derivatives Benzene does not undergo electrophilic addition It undergoes electrophilic aromatic substitution maintaining the aromatic core Electrophilic aromatic substitution replaces a proton on benzene with another electrophile 1
electrophilic aromatic substitution 2
Electrophilic Aromatic Substitution 3
Halogenation of Benzene Benzene s electrons participate as a Lewis base in reactions with Lewis acids Lewis acid: electron pair acceptor Lewis base: electron pair donor The product is formed by loss of a proton, which is replaced by a halogen 4
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 FeBr 3 is added as a catalyst to polarize the bromine reagent Br FeBr + Br 3 2 + HBr 5
Bromine Polarization 6
Mechanism 1 Diagram the mechanism for the bromination of benzene and note the formation of the carbocation: 7
Example 1 Draw and name the three possible products of the bromination of toluene (not including HBr). 8
Chlorination of Aromatic Rings Cl FeCl + Cl 3 2 + HCl Same mechanism as Br 2 with FeBr 3 9
Iodination of Aromatic Rings I 2 + I CuCl 2 HI Iodine is unreactive towards aromatic rings Oxidizing agents must be added to make reaction go (H 2 O 2 or CuCl 2 ) Oxidizing agents oxidize I 2 to a usable form (electrohphillic) that reacts as if it were I + 10
Mechanism 2: Iodination of Aromatic Rings I 2 + 2 Cu 2+ 2 I + + 2 Cu + + I+ I 2 + I H I CuCl 2 I + HI 11
Nitration of Aromatic Rings HNO 3 H 2 SO 4 NO 2 H2O Electrophile is the nitronium ion (NO 2+ ) Generated from HNO 3 by protonation and loss of water 12
Mechanism 3: Nitration of Aromatic Rings An electrophile must first be generated by treating concentrated nitric acid with concentrated sulfuric acid H O NO 2 + H 2 SO 4 H O H NO 2 + HSO 4 NO 2 H 2 O nitronium ion 13
Mechanism 3: Nitration of Aromatic Rings The nitronium electrophile is attacked by the benzene ring (nucleophile) NO2 + NO2 NO2 H2SO4 14
Sulfonation of Aromatic Rings SO 3 H 2 SO 4 SO 2 OH + H 2 O Fuming sulfuric acid combination of SO 3 and H 2 SO 4 Electrophile is HSO 3+ or SO 3 Reaction is reversible Favored in forward direction with strong acid Favored in reverse direction with hot dilute aqueous acid 15
Mechanism 4: Sulfonation of Aromatic Rings O O S + O H O O + H O S OH S + + O O O O O S O OH + O O H S + O O O S OH + H O O S OH O SO 3 H + H 2 SO 4 16
Conversion of sulfonic acids Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO 3 H group with an OH SO 3 H 1. NaOH, 300 o 2.H 3 O OH No mechanism 17
Friedel-Crafts Reaction Cl + CH3 CHCH 3 CH 3 AlCl 3 CHCH 3 + HCl benzene 2-chloropropane isopropylbenzene 18
Mechanism 5: Friedel-Crafts Reaction Cl AlCl 3 HCl + + Cl + AlCl 3 + + Cl--AlCl3 - + + + H Cl--AlCl3 - + HCl + AlCl 3 19
Friedel-Crafts Reaction (Alkylation of Aromatic Rings) the electrophile is a carbocation, R + only alkyl halides can be used aryl halides and vinylic halides do not react. will not occur on aromatic rings substituted by electron withdrawing substituents can t eat just one! It s hard to stop after one substitution skeletal rearrangements of the alkyl group often occur when using primary alkyl halides 20
Non-reactive 21
Ring Deactivators 22
Example 2: Friedel-Crafts Reaction Diagram the mechanism for the electrophilic substitution of benzene by 2-chloropentane: 23
Friedel-Crafts Reaction Multiple substitutions: Reaction of benzene with 2-chloro- 2methylpropane. Polyalkylation Cl + CH3 CCH 3 C(CH 3 ) 3 AlCl 3 + C(CH 3 ) 3 HCl CH 3 C(CH 3 ) 3 Major product 24
Friedel-Crafts Reaction Skeletal rearrangements in Friedel-Crafts reactions (hydride shift): Will rearrange to form more stable carbocation intermediates CH 3 CH 2 CH 2 CH 2 Cl Major product CH 3 CHCH 2 CH 3 AlCl 3 sec-butylbenzene + CH 2 CH 2 CH 2 CH 3 HCl Butylbenzene 25
Friedel-Crafts Reaction Skeletal rearrangements in Friedel-Crafts reactions (alkyl shift): Will rearrange to form more stable carbocation intermediates + Cl AlCl 3 HCl 1-Chloro-2,2- dimethylpropane (1,1-Dimethylpropyl)- benzene 26
Example 3: Which of the following alkyl halides would you expect to undergo Friedel-Crafts reaction without rearrangement? Chloroethane 2-chlorobutane 1-chloropropane 1-chloro-2,2-dimethylpropane Chlorocyclohexane 27
Only alkyl halides can be used!! Friedel-Crafts Alkylation Summary Will not occur on aromatic rings substituted by electron withdrawing substituents Carbonyl and amino groups Will have polyalkylation Will have rearrangement to form more stable carbocation intermediate Hydride shift or methyl shift You need to know the mechanism!!! 28
Friedel-Crafts Acylation Reaction of benzene with a carboxylic acid chloride, RCOCl in the presence of AlCl 3 Note: the acyl cation does not undergo rearrangement. It also is not prone to multiple substitutions. O O + AlCl 3 CH 3 CH 2 CCl C CH 2 CH 3 HCl 29
Friedel-Crafts Acylation After acylation we can do a hydrogenation to get desired alkylated product AlCl3 HCl H2 Pd 30
Mechanism 6: Friedel-Crafts Acylation Cl O + AlCl 3 Acyl cation H 3 C C + O CH O + 3 C + Cl--AlCl3 - O + H 3 C C + O + H Cl--AlCl3 - O + HCl + AlCl 3 31
Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or (much) less reactive than benzene Substituents affect the orientation of the reaction the positional relationship is controlled ortho- and para-directing activators, orthoand para-directing deactivators, and metadirecting deactivators 32
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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 bond (comparative electronegativity) 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 35
Inductive Effects Controlled by electronegativity and the polarity of bonds in functional groups Halogens, C=O, CN, and NO 2 withdraw electrons through bond connected to ring Alkyl groups donate electrons 36
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Resonance Effects Electron Withdrawal C=O, CN, NO 2 substituents withdraw electrons from the aromatic ring by resonance electrons flow from the rings to the substituents 38
Resonance Effects Electron Donation Halogen, OH, alkoxyl (OR), and amino substituents donate electrons electrons flow from the substituents to the ring Effect is greatest at ortho and para 39
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 40
Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation) An Explanation of Substituent Effects Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate 41
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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 43
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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 45
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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 47
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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 49
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Summary Table: Effect of Substituents in Aromatic Substitution 51
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Is it ortho/para or meta directing????? All ortho- and para- directors have a lone pair of electrons on the atom directly attached to the ring (with the exception of alkyl, aryl, and CH=CHR groups). All meta- directors have a positive charge or a partial positive charge on the atom attached to the ring. 53
In Summary: All activating substituents are ortho/para directors The weakly deactivating halogens are ortho/para directors All other deactivating substituents are meta directors 54
CH 3 Example 4: + Br 2 FeCl 3 NO 2 Cl 2 toluene FeCl 3 nitrobenzene Br + Cl 2 FeCl 3 O C CH 3 HNO 3 bromobenzene H 2 SO 4 benzaldehyde 55
Example 5: What product(s) would result from the nitration of each of the following compounds? propylbenzene benzenesulfonic acid iodobenzene benzaldehyde cyclohexylbenzene benzonitrile 56
Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive 57
Substituents with Opposite Effects If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome Usually gives mixtures of products 58
Meta-Disubstituted Compounds Are Unreactive The reaction site is too hindered To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound 59
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OCH 3 Example 6: Br 2 Br FeBr 3 NH 2 Br Br 2 FeBr 3 Cl NO 2 Br 2 FeBr 3 61
Nucleophilic Aromatic Substitution Aryl halides with electron-withdrawing substituents ortho and para react with nucleophiles Form addition intermediate (Meisenheimer complex) that is stabilized by electron-withdrawal Halide ion is lost O 2 N Cl NO 2 1. - OH O 2 N OH NO 2 2. H 3 O + NO 2 2,4,6-trinitrochlorobenzene NO 2 2,4,6-trinitrophenol 62
Mechanism 7: Nucleophilic Aromatic Substitution Cl NO 2 130 C OH + - OH + NO 2 Cl Cl Cl - OH OH +.. C NO 2 NO 2 OH NO 2 + Cl 63
Cl + - OH 130 C OH + Cl NO 2 NO 2 o-chloronitrobenzene Cl NO 2 + - OH 130 C HO NO 2 + Cl p-chloronitrobenzene Cl NO 2 + - OH 130 C NR m-chloronitrobenzene 64
Nucleophilic Aromatic Substitution Br Na + - NH2 NH 2 NaBr NH 3 + No Mechanism 65
Electrophilic and Nucleophilic Substitution Electrophilic Sub Favored by electron donating substituents Stabilize carbocation intermediate Nucleophilic Sub Favored by electron withdrawing substituents Stabilize carbanion intermediate 66
Bromination of Alkylbenzene Side Chains Reaction of an alkylbenzene with N-bromosuccinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain 67
Bromination of Alkylbenzene Side Chains 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 No Mechanism 68
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, Ar R Ar CO 2 H 69
Example 7: KMnO 4 H 2 O O 2 N KMnO 4 H 2 O KMnO 4 H 2 O 70
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) 71
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 72
Reduction of Aryl Nitro Compounds NO 2 Fe, H3O + - OH NH 2 NO 2 SnCl2, H3O + - OH NH 2 NO 2 H2, Pd/C EtOH NH 2 73
Reduction of Aromatic Ring or H 2 /Pt in ethanol 2000 psi, 25 o C H 2 /(Rh/C) in ethanol 1 atm, 25 o C 74
Synthesis Strategies These syntheses require planning and consideration of alternative routes It s important to pay attention to the order in which substituents are placed on the ring meta or or ortho/para directing When should an added substituent be modified? 75
Example 8: Synthesize the following 1. m-bromobenzenesulfonic acid from benzene 2. p-bromobenzenesulfonic acid from benzene 3. p-propylbenzenesulfonic acid from benzene 4. 2-bromo-4-ethylphenol from benzene 76