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Created by Professor William Tam & Dr. Phillis Chang Ch. 15 - 1 Chapter 15 Reactions of Aromatic Compounds.

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Presentation on theme: "Created by Professor William Tam & Dr. Phillis Chang Ch. 15 - 1 Chapter 15 Reactions of Aromatic Compounds."— Presentation transcript:

1 Created by Professor William Tam & Dr. Phillis Chang Ch Chapter 15 Reactions of Aromatic Compounds

2 Ch About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3 Ch Electrophilic Aromatic Substitution Reactions  Overall reaction

4 Ch

5 Ch A General Mechanism for Electro- philic Aromatic Substitution  Different chemistry with alkene

6 Ch  Benzene does not undergo electrophilic addition, but it undergoes electrophilic aromatic substitution

7 Ch  Mechanism ●Step 1

8 Ch  Mechanism ●Step 2

9 Ch

10 Ch Halogenation of Benzene  Benzene does not react with Br 2 or Cl 2 unless a Lewis acid is present (catalytic amount is usually enough)

11 Ch  Examples ●Reactivity:F 2 > Cl 2 > Br 2 > I 2

12 Ch  Mechanism

13 Ch  Mechanism (Cont’d)

14 Ch  Mechanism (Cont’d)

15 Ch  F 2 : too reactive, give mixture of mono-, di- and highly substituted products

16 Ch  I 2 : very unreactive even in the presence of Lewis acid, usually need to add an oxidizing agent (e.g. HNO 3, Cu 2+, H 2 O 2 )

17 Ch Nitration of Benzene  Electrophile in this case is NO 2  (nitronium ion)

18 Ch  Mechanism

19 Ch  Mechanism (Cont’d)

20 Ch  Mechanism (Cont’d)

21 Ch Sulfonation of Benzene  Mechanism ●Step 1 ●Step 2

22 Ch ●Step 3 ●Step 4

23 Ch  Sulfonation & Desulfonation

24 Ch Friedel–Crafts Alkylation  Electrophile in this case is R  ●R = 2 o or 3 o ●Or (R = 1 o )

25 Ch  Mechanism

26 Ch  Mechanism (Cont’d)

27 Ch  Mechanism (Cont’d)

28 Ch  Note: Not necessary to start with alkyl halide, other possible functional groups can be used to generate a reactive carbocation

29 Ch

30 Ch Friedel–Crafts Acylation  Acyl group:  Electrophile in this case is R–C ≡ O  (acylium ion)

31 Ch  Mechanism

32 Ch  Mechanism (Cont’d)

33 Ch  Mechanism (Cont’d)

34 Ch  Acid chlorides (or acyl chlorides) ●Can be prepared by

35 Ch Limitations of Friedel–Crafts Reactions  When the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations that are more stable, it usually does so, and the major products obtained from the reaction are usually those from the more stable carbocations

36 Ch (How is this Formed?) (not formed)  For example

37 Ch o cation (not stable)  Reason 3 o cation (more stable)

38 Ch  Friedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH 2, –NHR, or –NR 2 group. This applies to both alkylations and acylations These usually give poor yields in Friedel-Crafts reactions

39 Ch  The amino groups, –NH 2, –NHR, and –NR 2, are changed into powerful electron- withdrawing groups by the Lewis acids used to catalyze Friedel-Crafts reactions Does not undergo a Friedel-Crafts reaction

40 Ch  Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readily sp 2

41 Ch  Polyalkylations often occur

42 Ch Synthetic Applications of Friedel-Crafts Acylations: The Clemmensen Reduction  Clemmensen ketone reduction

43 Ch  Clemmensen ketone reduction ●A very useful reaction for making alkyl benzene that cannot be made via Friedel-Crafts alkylations

44 Ch  Clemmensen ketone reduction ●Cannot use Friedel-Crafts alkylation

45 Ch  Rearrangements of carbon chain do not occur in Friedel-Crafts acylations (no rearrangement of the R group)

46 Ch

47 Ch Substituents Can Affect Both the Reactivity of the Ring and the Orientation of the Incoming Group  Two questions we would like to address here ●Reactivity ●Regiochemistry

48 Ch ●Reactivity faster or slower than Y = EDG (electron-donating group) or EWG (electron-withdrawing group)

49 Ch ●Regiochemistry Statistical mixture of o-, m-, p- products or any preference?

50 Ch   A substituted benzene Electrophilic reagent Arenium ion

51 Ch Y withdraws electrons Z donates electrons The ring is electron poor and reacts more slowly with an electrophile The ring is more electron rich and reacts faster with an electrophile

52 Ch ●Reactivity  Since electrophilic aromatic substitution is electrophilic in nature, and the r.d.s. is the attack of an electrophile (E  ) with the benzene  -electrons, an increase in e ⊖ density in the benzene ring will increase the reactivity of the aromatic ring towards attack of an electrophile, and result in a faster reaction

53 Ch ●Reactivity  On the other hand, decrease in e ⊖ density in the benzene ring will decrease the reactivity of the aromatic ring towards the attack of an electrophile, and result in a slower reaction

54 Ch Y EDG –H EWG Increasing activity ●Reactivity

55 Ch ●Reactivity  EDG (electron-donating group) on benzene ring  Increases electron density in the benzene ring  More reactive towards electrophilic aromatic substitution

56 Ch ●Reactivity  EWG (electron-withdrawing group) on benzene ring  Decreases electron density in the benzene ring  Less reactive towards electrophilic aromatic substitution

57 Ch ●Reactivity towards electrophilic aromatic substitution

58 Ch  Regiochemistry: directing effect ●General aspects  Either o-, p- directing or m- directing  Rate-determining-step is  - electrons on the benzene ring attacking an electrophile (E  )

59 Ch

60 Ch

61 Ch

62 Ch  If you look at these resonance structures closely, you will notice that for ortho- or para- substitution, each has one resonance form with the positive charge attached to the carbon that directly attached to the substituent Y (o-I and p-II)

63 Ch  When Y = EWG, these resonance forms (o-I and p-II) are highly unstable and unfavorable to form, thus not favoring the formation of o- and p- regioisomers, and m- product will form preferentially

64 Ch  On the other hand, if Y = EDG, these resonance forms (o-I and p-II) are extra-stable (due to positive mesomeric effect or positive inductive effect of Y) and favorable to form, thus favoring the formation of o- and p- regioisomers

65 Ch  Classification of different substituents Y (EDG) –NH 2, –NR 2 –OH, –O  Strongly activating o-, p- directing –NHCOR –OR Moderately activating o-, p- directing –R (alkyl) –Ph Weakly activating o-, p- directing –H–HNA

66 Ch  Classification of different substituents Y (EWG) –Halide (F, Cl, Br, I) Weakly deactivating o-, p- directing –COOR, –COR, –CHO, –COOH, –SO 3 H, –CN Moderately deactivating m- directing –CF 3, –CCl 3, –NO 2, – ⊕ NR 3 Strongly deactivating m- directing

67 Ch How Substituents Affect Electrophilic Aromatic Substitution: A Closer Look

68 Ch  If G is an electron-releasing group (relative to hydrogen), the reaction occurs faster than the corresponding reaction of benzene 11A. Reactivity: The Effect of Electron-Releasing and Electron-Withdrawing Groups When G is electron donating, the reaction is faster

69 Ch  If G is an electron-withdrawing group, the reaction is slower than that of benzene When G is electron withdrawing, the reaction is slower

70 Ch

71 Ch  Two types of EDG (i) 11B. Inductive and Resonance Effects: Theory of Orientation by positive mesomeric effect (donates electron towards the benzene ring through resonance effect) (ii) by positive inductive effect (donates electron towards the benzene ring through  bond)

72 Ch  Two types of EDG ●Positive mesomeric effect is usually stronger than positive inductive effect if the atoms directly attacked to the benzene ring is in the same row as carbon in the periodic table

73 Ch  Similar to EDG, EWG can withdraw electrons from the benzene ring by resonance effect (negative mesomeric effect) or by negative inductive effect Deactivate the ring by resonance effect Deactivate the ring by negative inductive effect

74 Ch  EWG = –COOR, –COR, –CHO, –CF 3, –NO 2, etc. 11C. Meta-Directing Groups (EWG ≠ halogen)

75 Ch  For example (highly unstable due to negative inductive effect of – CF 3 )

76 Ch (highly unstable due to negative inductive effect of – CF 3 )

77 Ch (positive charge never attaches to the carbon directly attached to the EWG: – CF 3 )  relatively more favorable

78 Ch  EDG = –NR 2, –OR, –OH, etc. 11D. Ortho – Para-Directing Groups

79 Ch  For example (extra resonance structure due to positive mesomeric effect of –OCH 3 )

80 Ch (extra resonance structure due to positive mesomeric effect of –OCH 3 )

81 Ch (3 resonance structures only, no extra stabilization by positive mesomeric effect of –OCH 3 )  less favorable

82 Ch  For halogens, two opposing effects negative inductive effect withdrawing electron density from the benzene ring positive mesomeric effect donating electron density to the benzene ring

83 Ch  Overall ●Halogens are weak deactivating groups  Negative inductive effect > positive mesomeric effect in this case)

84 Ch  Regiochemistry (extra resonance structure due to positive mesomeric effect of –Cl)

85 Ch (extra resonance structure due to positive mesomeric effect of –Cl)

86 Ch (3 resonance structures only, no extra stabilization by positive mesomeric effect of –Cl)  less favorable

87 Ch E. Ortho – Para Direction and Reactivity of Alkylbenzenes

88 Ch  Ortho attack Relatively stable contributor

89 Ch  Meta attack

90 Ch  Para attack Relatively stable contributor

91 Ch Reactions of the Side Chain of Alkylbenzenes

92 Ch A. Benzylic Radicals and Cations Benzylic radicals are stabilized by resonance

93 Ch Benzylic cations are stabilized by resonance

94 Ch B. Halogenation of the Side Chain: Benzylic Radicals  N-Bromosuccinimide (NBS) furnishes a low concentration of Br 2, and the reaction is analogous to that for allylic bromination

95 Ch  Mechanism ●Chain initiation ●Chain propagation

96 Ch ●Chain propagation ●Chain termination

97 Ch  e.g. (more stable benzylic radicals) (less stable 1 o radicals) (major)(very little)

98 Ch Alkenylbenzenes 13A. Stability of Conjugated Alkenyl- benzenes  Alkenylbenzenes that have their side-chain double bond conjugated with the benzene ring are more stable than those that do not

99 Ch  Example (not observed)

100 Ch B. Additions to the Double Bond of Alkenylbenzenes

101 Ch  Mechanism (top reaction)

102 Ch  Mechanism (bottom reaction)

103 Ch C. Oxidation of the Side Chain

104 Ch

105 Ch  Using hot alkaline KMnO 4, alkyl, alkenyl, alkynyl and acyl groups all oxidized to –COOH group  For alkyl benzene, 3 o alkyl groups resist oxidation ●Need benzylic hydrogen for alkyl group oxidation

106 Ch D. Oxidation of the Benzene Ring

107 Ch Synthetic Applications

108 Ch  CH 3 group: ortho-, para-directing  NO 2 group: meta-directing

109 Ch  If the order is reversed  the wrong regioisomer is given

110 Ch  We do not know how to substitute a hydrogen on a benzene ring with a –COOH group. However, side chain oxidation of alkylbenzene could provide the –COOH group  Both the –COOH group and the NO 2 group are meta-directing

111 Ch  Route 1

112 Ch  Route 2

113 Ch  Which synthetic route is better? ●Recall “Limitations of Friedel-Crafts Reactions, Section 15.8”  Friedel–Crafts reactions usually give poor yields when powerful electron- withdrawing groups are present on the aromatic ring or when the ring bears an –NH 2, –NHR, or –NR 2 group. This applies to both alkylations and acylations  Route 2 is a better route

114 Ch  Both Br and Et groups are ortho-, para- directing  How to make them meta to each other?  Recall: an acyl group is meta-directing and can be reduced to an alkyl group by Clemmensen ketone reduction

115 Ch

116 Ch A. Use of Protecting and Blocking Groups  Protected amino groups ●Example

117 Ch Problem  Not a selective synthesis, o- and p- products + dibromo and tribromo products

118 Ch Solution  Introduction of a deactivated group on –NH 2

119 Ch  The amide group is less activating than –NH 2 group ●No problem for over bromination  The steric bulkiness of this group also decreases the formation of o-product

120 Ch

121 Ch Problem  Difficult to get o-product without getting p-product  Over nitration

122 Ch Solution  Use of a –SO 3 H blocking group at the p-position which can be removed later

123 Ch B. Orientation in Disubstituted Benzenes  Directing effect of EDG usually outweighs that of EWG  With two EDGs, the directing effect is usually controlled by the stronger EDG

124 Ch Examples (only major product(s) shown)

125 Ch  Substitution does not occur to an appreciable extent between meta- substituents if another position is open X

126 Ch

127 Ch

128 Ch

129 Ch Allylic and Benzylic Halides in Nucleophilic Substitution Reactions

130 Ch  A Summary of Alkyl, Allylic, & Benzylic Halides in S N Reactions ●These halides give mainly S N 2 reactions: ●These halides may give either S N 1 or S N 2 reactions:

131 Ch  A Summary of Alkyl, Allylic, & Benzylic Halides in S N Reactions ●These halides give mainly S N 1 reactions:

132 Ch Reduction of Aromatic Compounds

133 Ch A. The Birch Reduction

134 Ch  Mechanism

135 Ch  Synthesis of 2-cyclohexenones

136 Ch  END OF CHAPTER 15 


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