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Dr. Wolf's CHM 201 & 202

12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents. Dr. Wolf's CHM 201 & 202. 12-104. •. •. ERG. ERG. •. •. X. H. H. H. +. +. H. H. H. H. H. X. H. H. ERGs Stabilize Intermediates for ortho and para Substitution.

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Dr. Wolf's CHM 201 & 202

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  1. 12.13Substituent Effects in ElectrophilicAromatic Substitution:Strongly Deactivating Substituents Dr. Wolf's CHM 201 & 202 12-104

  2. • • ERG ERG • • X H H H + + H H H H H X H H ERGs Stabilize Intermediates forortho and para Substitution Dr. Wolf's CHM 201 & 202 12-105

  3. Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution —CF3 is a powerful EWG. It is strongly deactivating and meta directing EWG EWG X H H H + + H H H H H X H H Dr. Wolf's CHM 201 & 202 12-106

  4. O O —CH —CR O O —COH —COR O —CCl Many EWGs Have a Carbonyl GroupAttached Directly to the Ring All of these are meta directing and strongly deactivating —EWG = Dr. Wolf's CHM 201 & 202 12-107

  5. —C N Other EWGs Include: All of these are meta directing and strongly deactivating —EWG = —NO2 —SO3H Dr. Wolf's CHM 201 & 202 12-108

  6. O2N O O CH CH Nitration of Benzaldehyde HNO3 H2SO4 75-84% Dr. Wolf's CHM 201 & 202 12-109

  7. O O CCl CCl Problem 12.14(a); page 468 Cl Cl2 FeCl3 62% Dr. Wolf's CHM 201 & 202 12-110

  8. Disulfonation of Benzene HO3S SO3 SO3H H2SO4 90% Dr. Wolf's CHM 201 & 202 12-111

  9. Bromination of Nitrobenzene Br Br2 NO2 NO2 Fe 60-75% Dr. Wolf's CHM 201 & 202 12-112

  10. 12.14Substituent Effects in ElectrophilicAromatic Substitution:Halogens F, Cl, Br, and I are ortho-para directing,but deactivating Dr. Wolf's CHM 201 & 202 12-113

  11. Cl Cl Cl Cl NO2 NO2 NO2 Nitration of Chlorobenzene The rate of nitration of chlorobenzene is about 30 times slower than that of benzene. HNO3 + + H2SO4 30% 1% 69% Dr. Wolf's CHM 201 & 202 12-114

  12. CH3 42 42 2.5 2.5 58 Nitration of Toluene vs. Chlorobenzene Cl 0.029 0.029 0.009 0.009 0.137 Dr. Wolf's CHM 201 & 202 12-115

  13. Halogens • thus, for the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger • the net effect is that halogens are deactivating but ortho-para directing

  14. 12.15Multiple Substituent Effects Dr. Wolf's CHM 201 & 202 12-116

  15. O CH3 O O CH3COCCH3 CH3 The Simplest Case all possible EAS sites may be equivalent CH3 CCH3 AlCl3 + CH3 99% Dr. Wolf's CHM 201 & 202 12-117

  16. CH3 Br2 Fe NO2 Another Straightforward Case CH3 Br directing effects of substituents reinforceeach other; substitution takes place orthoto the methyl group and meta to the nitro group NO2 86-90% Dr. Wolf's CHM 201 & 202 12-118

  17. Generalization regioselectivity is controlled by themost activating substituent Dr. Wolf's CHM 201 & 202 12-119

  18. NHCH3 NHCH3 Br Cl Cl The Simplest Case all possible EAS sites may be equivalent strongly activating Br2 aceticacid 87% Dr. Wolf's CHM 201 & 202 12-120

  19. CH3 HNO3 H2SO4 C(CH3)3 When activating effects are similar... CH3 substitution occurs ortho to the smaller group NO2 C(CH3)3 88% Dr. Wolf's CHM 201 & 202 12-121

  20. CH3 CH3 HNO3 H2SO4 CH3 CH3 NO2 Steric effects control regioselectivity whenelectronic effects are similar position between two substituents is lastposition to be substituted 98% Dr. Wolf's CHM 201 & 202 12-122

  21. 12.16Regioselective Synthesis of Disubstituted Aromatic Compounds Dr. Wolf's CHM 201 & 202 12-123

  22. Factors to Consider order of introduction of substituents to ensure correct orientation Dr. Wolf's CHM 201 & 202 12-124

  23. Br O CCH3 Synthesis of m-Bromoacetophenone Which substituent should be introduced first? Dr. Wolf's CHM 201 & 202 12-125

  24. Br O CCH3 Synthesis of m-Bromoacetophenone If bromine is introduced first, p-bromoacetophenone is major product. para meta Dr. Wolf's CHM 201 & 202 12-126

  25. Br O CCH3 O O CH3COCCH3 O CCH3 Synthesis of m-Bromoacetophenone Br2 AlCl3 AlCl3 Dr. Wolf's CHM 201 & 202 12-127

  26. Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics Dr. Wolf's CHM 201 & 202 12-128

  27. NO2 O CCH3 Synthesis of m-Nitroacetophenone Which substituent should be introduced first? Dr. Wolf's CHM 201 & 202 12-129

  28. NO2 O CCH3 Synthesis of m-Nitroacetophenone If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails. Dr. Wolf's CHM 201 & 202 12-130

  29. O CCH3 O O CH3COCCH3 O CCH3 Synthesis of m-Nitroacetophenone O2N HNO3 H2SO4 AlCl3 Dr. Wolf's CHM 201 & 202 12-131

  30. Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Craftsreactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics sometimes electrophilic aromatic substitution must be combined with a functional group transformation Dr. Wolf's CHM 201 & 202 12-132

  31. CO2H CH3 CH3 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene Which first? (oxidation of methyl group or nitration of ring) Dr. Wolf's CHM 201 & 202 12-133

  32. CO2H CH3 CH3 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene nitration givesm-nitrobenzoicacid oxidation givesp-nitrobenzoicacid Dr. Wolf's CHM 201 & 202 12-134

  33. CO2H CH3 CH3 NO2 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene HNO3 Na2Cr2O7, H2O H2SO4, heat H2SO4 Dr. Wolf's CHM 201 & 202 12-135

  34. 12.17Substitution in Naphthalene Dr. Wolf's CHM 201 & 202 12-136

  35. Naphthalene H H 1 two sites possible for electrophilicaromatic substitution all other sites at which substitution can occurare equivalent to 1 and 2 H H 2 H H H H Dr. Wolf's CHM 201 & 202 12-137

  36. O CCH3 O CH3CCl EAS in Naphthalene is faster at C-1 than at C-2 AlCl3 90% Dr. Wolf's CHM 201 & 202 12-138

  37. EAS in Naphthalene E E H H when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained + + Dr. Wolf's CHM 201 & 202 12-139

  38. E + H EAS in Naphthalene when attack is at C-2 in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed E H + Dr. Wolf's CHM 201 & 202 12-140

  39. 12.18Substitution inHeterocyclic Aromatic Compounds Dr. Wolf's CHM 201 & 202 12-141

  40. Generalization There is none. There are so many different kinds of heterocyclicaromatic compounds that no generalizationis possible. Some heterocyclic aromatic compoundsare very reactive toward electrophilicaromatic substitution, others are very unreactive.. Dr. Wolf's CHM 201 & 202 12-142

  41. N Pyridine Pyridine is very unreactive; it resemblesnitrobenzene in its reactivity. Presence of electronegative atom (N) in ringcauses p electrons to be held more strongly thanin benzene. Dr. Wolf's CHM 201 & 202 12-143

  42. SO3H N N Pyridine SO3, H2SO4 Pyridine can be sulfonated at high temperature. EAS takes place at C-3. HgSO4, 230°C 71% Dr. Wolf's CHM 201 & 202 12-144

  43. •• •• •• O S N •• •• H Pyrrole, Furan, and Thiophene Have 1 less ring atom than benzene or pyridine to hold same number of p electrons (6). p electrons are held less strongly. These compounds are relatively reactive toward EAS.. Dr. Wolf's CHM 201 & 202 12-145

  44. O O O CH3COCCH3 Example: Furan undergoes EAS readilyC-2 is most reactive position BF3 + CCH3 O O 75-92% Dr. Wolf's CHM 201 & 202 12-146

  45. End of Chapter 12

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