2-1 Reactions of Aromatic Compounds 15.1 2-2 lectrophilic Aromatic Substitution Reactions Aromatic hydrocarbons (= arenes) undergo a substitution reaction with electrophiles: + catalyst + xample: omination of benzene + e 3 Review: Alkenes undergo addition reactions: + CM 2312 all 2017 otes: C.J. ahrni
15.1 2-3 X 2, ex 3 X =, X + X 3 2 S 4 2 + 2 S 3 S 3 2 S 4 R Al 3 R Al 3 R R + + 15.2 2-4 General Mechanism for AS: Arenium Ions Step 1: The electrophile attacks the -system of benzene to form a non-aromatic cyclohexadienyl carbocation: + A + A Step 2: The proton is removed to reform the aromatic delocalized -system: + A + A CM 2312 all 2017 otes: C.J. ahrni
15.2 2-5 + A + A + A 15.3 2-6 alogenation of Benzene + e 3 25 C + e 3 heat Mechanism: CM 2312 all 2017 otes: C.J. ahrni
15.4 2-7 itration of Benzene 3, 2 S 4 2 50 C Mechanism: 15.5 2-8 Sulfonation of Benzene S 3, 2 S 4 S 3 Mechanism: CM 2312 all 2017 otes: C.J. ahrni
15.6A 2-9 riedel-crafts Alkylation + R X Al 3 R Mechanism: 2-10 The carbocation intermediate can be also generated through protonation of an alkene, + 0 C or starting from an alcohol in the presence of a Lewis acid (B 3 ): + B 3 60 C Limitation: rearrangement reactions of carbocation intermediate: CM 2312 all 2017 otes: C.J. ahrni
15.6B 2-11 riedel-crafts Acylation + Al 3 Mechanism: acetophenone 15.6B 2-12 riedel-crafts acylations can be also carried using carboxylic acid anydrides: + 1. Al 3 2. 2 + acetic anhydride Mechanism: CM 2312 all 2017 otes: C.J. ahrni
15.6C 2-13 Limitations of riedel-crafts Reactions 1. Rearrangement to more stable carbocation intermediate: Al 3 + + 36% 64% 2. Vinyl or aryl halide do not form stable carbocations: + Al 3 + Al 3 15.6C 2-14 3. Aldehydes are not accessible through riedel-crafts reactions: Al 3 4. Poor yields with electronwithdrawing substituents: 2 (C 3 ) 3 R C 3 S 3 2 CM 2312 all 2017 otes: C.J. ahrni
15.6C 2-15 5. Polyalkylation often occur: + Al 3 15.7 2-16 emmensen Reduction Problem (slide 2-13): Al 3 + + 36% 64% Solution: riedel-crafts acylation followed by emmensen reduction: + Al 3 Zn(g)/ reflux ote: only arylketones (or aldehydes) are reduced (e.g. carboxylic acids remain unaffected) CM 2312 all 2017 otes: C.J. ahrni
2-17 Problem: Starting from benzene, outline a synthesis for a) tert-butyl benzene: b) 1-phenyl-2-methylbutane: 1-18 Designing Multistep Syntheses: Retrosynthesis Challenge: starting material reaction A reaction B reaction C product inexpensive, commercially available Solution(s): Retrosynthetic Analysis product intermediate B-1 intermediate B-2 intermediate A-1 intermediate A-3 intermediate A-4 intermediate A-5 intermediate A-2 starting starting starting material material material S-1 S-2 S-3 CM 2312 all 2017 otes: C.J. ahrni
2-19 Problem: Propose a synthesis of -tetralone starting from benzene and succinic anhydride: + 15.8 2-20 ffect of Substituents on Reactivity and rientation Substituents affect both the rate of reaction (kinetics) and the site of attack (regioselectivity) C 3 C 3 2 1000 25 1 0.03 0.001 activation deactivation CM 2312 all 2017 otes: C.J. ahrni
15.8A 2-21 1. Activating Groups: rtho/para Directors Alkyl substituents: C 3 C 3 C 3 C 3 toluene 3 2 S 4 2 + + 2 2 59% 4% 37% -donors (e.g. -, -R, 2, R 2 ): 2 2 2 2 aniline >99% 15.8A 2-22 The rate determining step in electrophilic aromatic substitution of substituted benzenes is the step that results in the formation of the arenium ion. Because this step is endothermic, there is a strong resemblance between the arenium cation and the transition state leading to it (ammond-leffler postulate) CM 2312 all 2017 otes: C.J. ahrni
15.8A 2-23 Q + A Q + A ffect of electronwithdrawing (left) and electrondonating substituents (right) on the free energy profiles for the formation of the arenium ion: 15.8A 2-24 C 3 C 3 C 3 C 3 C 3 C 3 CM 2312 all 2017 otes: C.J. ahrni
15.8A 2-25 3 C + A 3 C + A Alkyl groups: stabilization through inductive effect (hyperconjugation): C 3 C 3 C 3 para attack: C 3 C 3 C 3 ortho attack: C 3 C 3 C 3 meta attack: Stabilization of the arenium ion intermediate yields a lower activation barrier and thus the fastest reaction pathway for ortho and para substitution. 15.8A 2-26 -donors: resonance stabilization of arenium ion para attack: ortho attack: meta attack: lectron donating resonance stabilization applies with decreasing strength in the following order: R 2 2 > R > X CM 2312 all 2017 otes: C.J. ahrni
15.8B 2-27 2. Deactivating Groups: Meta Directors 2 2 2 2 nitrobenzene 3 2 S 4 2 + + 2 2 6% 93% 1% lectronwithdrawing substituents (- 2, -C, -C, -C, -CR, -CR 2, -S 3 ) destabilize the arenium ion intermediate. 15.8B 2-28 C 3 C 3 C 3 para attack: C 3 C 3 C 3 ortho attack: C 3 C 3 C 3 meta attack: Meta substitution yields the least destabilized intermediate and therefore the fastest reaction pathway. CM 2312 all 2017 otes: C.J. ahrni
15.8A 2-29 3. alo Substituents: Deactivating rtho/para Directors chlorobenzene 2 e 3 + + 39% 6% 55% 3 2 + + 2 S 4 2 2 chlorobenzene 30% 0% 70% 15.8A 2-30 para attack: ortho attack: meta attack: alo substituents stabilize the arenium ion intermediate through resonance (π-donation): CM 2312 all 2017 otes: C.J. ahrni
Table 15.1 2-31 ffect of Substituents: verview rtho/para Directors Meta Directors Strongly activating: 2, R, R 2, Moderately activating: CC 3, CR C 3, R Weakly activating: C 3, C 2 5, R C 6 5 Strongly deactivating: 2 R 3 + C 3, C 3 Moderately deactivating: C S 3 C 2, C 2 R C, CR Weakly deactivating:,,, I 2-32 xamples: C 3 2 Al 3 C 3 3 2 S 4 2 e 3 C 3 C Al 3 C 3 I Al 3 CM 2312 all 2017 otes: C.J. ahrni
15.19 2-33 Directing ffects on Disubstituted Rings C 3 C 3 C 3 C Al 3 C 3 C 3 C 3 2 2 e 3 C 3 2 C 3 C(C 3 ) 3 3 2 S 4 C 3 C(C 3 ) 3 15.19 2-34 C 3 C 3 3 2 S C 4 3 C 3 C 3 C 3 2 Ac C 3 C 3 C C 3 2 S 4 C 3 C 3 CM 2312 all 2017 otes: C.J. ahrni
15.12B 2-35 2 3 2 S 4 Solution: 2 C 3 C pyridine 15.11 2-36 Reactions of the Side Chain of Alkylbenzenes 1. alogenation of the side chain: BS, light C 4 2. Addition to the double bond of alkenyl benzenes: peroxides (no peroxides) CM 2312 all 2017 otes: C.J. ahrni
15.11 2-37 3. xidation of the side chain: C 3 1. KMn 4, a, heat 2. 3 + Alkyl, alkynyl, and acyl benzenes are also degraded to benzoic acid: C 2 R C 3 1. KMn 4, a, heat 2. 3 + 15.12 2-38 Problem (15.36): xplain why the following syntheses will fail: 1. 3 / 2 S 4 2. C 3 C/Al 3 2 3. Zn(g)/ 1. BS, C 4, light 2. at, t, heat 3. 2, e 3 CM 2312 all 2017 otes: C.J. ahrni
15.12 2-39 Synthetic Strategies 1. Introducing substituent through electrophilic aromatic substitution: R R =,, I, S 3, 2, CR, alkyl 2. Modifying existing substituents: R 1 R 2 C 2 from alkyl C 2 R from CR C 2 from C 3 C 2 from C 2 15.12 2-40 3. Using protective groups ighly activating substituents such as 2, R 2, and render the aromatic ring so reactive that undesirable reactions may take place. => Reduce reactivity through a protective group: 2 C 3 C 1. 2, 2 S 4 heat 2 base R 2. a R 4. rientation in disubstituted benzenes: => Consider directing effects of other substituents and effect of reagents/conditions on existing substituents CM 2312 all 2017 otes: C.J. ahrni
2-41 Problem: Starting from benzene, outline a synthesis for p-bromonitrobenzene 2-42 Problem: Starting from benzene, outline a synthesis for m-chloroethylbenzene. CM 2312 all 2017 otes: C.J. ahrni
2-43 Problem: Starting from benzene, outline a synthesis for p-nitrobenzoic acid. 2-44 Problem : Starting from toluene, outline a synthesis for 1-chloro-3-trichloromethyl-benzene. CM 2312 all 2017 otes: C.J. ahrni
20.4B 2-45 Anilines: Synthesis and Reactivity Anilines can be prepared through reduction of nitro compounds: 3 2 reducing reagent 2 2 S 4 reducing reagents a) (1) e, ; (2) a b) (1) Zn, ; (2) a c) Sn 2 d) 2 /Pt (catalyst) e) 2 S, 3, t 20.6-7 Anilines react with nitrous acid to form diazonium salts, which can be converted to a wide range of derivatives: B 4, heat 2-46 Cu Cu 2 a 2 KI I CuC C 3 P 2 Cu 2, Cu 2+ CM 2312 all 2017 otes: C.J. ahrni
20.6 2-47 Mechanism of diazotization: 2 a 2 2-48 Problem: Starting from benzene, outline a synthesis for 3-chlorophenol. CM 2312 all 2017 otes: C.J. ahrni
2-49 Problem: Suggest a synthesis for 1,3,5-tribromobenzene. 20.8 Diazo coupling: reaction of diazonium salts with electron-rich arenes: 2-50 G G + G = R 2 or CM 2312 all 2017 otes: C.J. ahrni
20.8 2-51 Azo compounds have found a wide range of applications: S 3 a 2 2 2 Ca S Alizarine Yellow R (p Indicator) Methyl orange (p Indicator) 2 Prontosil (antibiotic ) Ct S 3 a S 3 a 2 S 3 a a 3 S range B (food dye) S 3 a range G (histological stain) riochrome Black T (complexometric Indicator) a 3 S 2 S 3 a a 3 S 2 S 3 a Trypan Blue (vital stain to selectively color dead cells) The Trypan Blue exclusion assay identifies dead cells 2-52 Phenols omenclature: phenol m-chlorophenol 1-naphthol 2-naphthol C 3 C 3 C 3 p-cresol m-cresol o-cresol hydroquinone resorcinol catechol CM 2312 all 2017 otes: C.J. ahrni
3.10 2-53 Phenols: Acidity + 2 + 3 pk a = 9.89 phenol phenolate anion 2 2 2 C 3 2 2 2 pk a = 18 10.17 8.11 7.15 3.96 0.38 2-54 free energy transition state ΔG, A + 2 ΔG G = RT ln K a K a = [ 3 + ][A ] [A][ 2 ] A + 3 + reaction coordinate lectron withdrawing substituents stabilize the negatively charged phenolate anion lectron donating substituents destabilize the negatively charged phenolate anion CM 2312 all 2017 otes: C.J. ahrni
3.10 2-55 The degree of resonance stabilization depends on the substituent position: pk a = 7.15 pk a = 8.28 2-56 Problem: rder the following compounds with increasing pk a : CM 2312 all 2017 otes: C.J. ahrni
2-57 Phenols: Synthesis 1. ydrolysis of aryldiazonium salts (slide 2-45) 2 a 2 Cu 2, Cu 2+ 2 2. Industrial syntheses: 2 a a + e 350 C high pressure 2 2 S 4 3 P 4 250 C 95-135 C 50-90 C 21.6 2-58 Phenols: Reactions 1. Phenol oxygen as nucleophile: pyridine pyridine 1. a, 2 conc. 2. R CM 2312 all 2017 otes: C.J. ahrni
2-59 2. Aromatic -system as nucleophile: excess 2 3 2 S 4 conc. 2 S 4 2-60 Kolbe Reaction: 1. a 2. C 2 3. 3 + Mechanism: CM 2312 all 2017 otes: C.J. ahrni
2-61 Problem: Starting from phenol, suggest a synthesis for Aspirin Aspirin 2-62 Problem: Starting from phenol, suggest a synthesis for acetaminophen (Tylenol) Acetaminophen CM 2312 all 2017 otes: C.J. ahrni
2-63 The aisen Rearrangement heat a 15.14 2-64 Aryl alides: ucleophilic Aromatic Substitution ydrolysis reaction of halides: 2 r.t. 2 r.t. Aryl halides undergo substitution only under more drastic reaction conditions: a 350 C K 2 2 CM 2312 all 2017 otes: C.J. ahrni
15.14 2-65 Labeling experiment: 14 C K + 2 3 (l) 14 C 2 + 14 C 2 The Benzyne limination-addition Mechanism: phenyl anion benzyne 15.13 2-66 lectronwithdrawing substituents greatly facilitate the hydrolysis of aryl halides: 2 a 2 130 C 2 a 100 C 2 2 2 2 2 a 2 2 35 C 2 2 ote: a meta-nitro group does not produce a similar activating effect => underlying mechanism is different from hydrolysis of unsubstituted halides ffect of alide: Reaction rate decreasing with >> CM 2312 all 2017 otes: C.J. ahrni
15.13 2-67 Addition-limination Mechanism: + Problem: Rank the following compounds in descending order of reactivity toward hydroxide ion: 2-68 2 2 2 2 2 2 2 I II III IV V CM 2312 all 2017 otes: C.J. ahrni
2-69 Problem: Propose a mechanism for the following conversion: ac 3 2 3 C S 2 3 C S 2 a 2-70 Problem: Predict the main product(s) of the following reactions: 2 2 2 2 2 2 ac 3 C 3 Lit 2 C 3 t 2 CM 2312 all 2017 otes: C.J. ahrni
2-71 Problem The following scheme outlines the synthesis of the -blocker toliprolol. Give the structures of the intermediates and the final product. C 10 13 2 C 10 12 2 2 C 13 21 2 toliprolol C 3 CM 2312 all 2017 otes: C.J. ahrni