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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 Electrophilic Aromatic Substitution Reactions  Overall reaction:

3 Ch

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

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

6 Ch  Mechanism ●Step 1:

7 Ch  Mechanism ●Step 2:

8 Ch  Energy Profile for EAS:

9 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) and the reaction typically requires heat.

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

11 Ch  Mechanism:

12 Ch  Mechanism (Cont’d):

13 Ch  Mechanism (Cont’d):

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

15 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 ).

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

17 Ch  Mechanism:

18 Ch  Mechanism (Cont’d):

19 Ch  Mechanism (Cont’d):

20 Ch Sulfonation of Benzene  Mechanism ●Step 1: ●Step 2:

21 Ch ●Step 3: ●Step 4:

22 Ch  Sulfonation & Desulfonation: This is the only reversible EAS reaction.

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

24 Ch  Mechanism:

25 Ch  Mechanism (Cont’d):

26 Ch  Mechanism (Cont’d):

27 Ch  Note: It is not necessary to start with an alkyl halide, other possible functional groups can be used to generate a reactive carbocation.

28 Ch  Examples:

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

30 Ch  Mechanism:

31 Ch  Mechanism (Cont’d):

32 Ch  Mechanism (Cont’d):

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

34 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.

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

36 Ch o cation (not stable)  Reason: 3 o cation (more stable)

37 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, i.e. these do not work. These usually give poor yields in Friedel-Crafts reactions

38 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

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

40 Ch  Polyalkylations often occur:

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

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

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

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

45 Ch  FC Acylation followed by Clemmenson.

46 Ch Substituents Can Affect Both the Reactivity of the Ring and the Orientation of the Incoming Group  Two questions need to be addressed when the ring already has a substituent: ●Reactivity toward EAS ●Regiochemistry of products

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

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

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

50 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

51 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.

52 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.

53 Ch Y EDG –H EWG Increasing activity ●Reactivity:

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

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

56 Ch ●Reactivity towards electrophilic aromatic substitution.

57 Ch  Regiochemistry: the directing effect ●General aspects:  Substituents are either o-, p- directing or m-directing.  The rate-determining-step is due to  -electrons of the benzene ring attacking an electrophile (E  ).

58 Ch

59 Ch

60 Ch

61 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).

62 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.

63 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.

64 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

65 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

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

67 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.

68 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.

69 Ch  Energy Profiles for these Cases: EWGEDGNo Substituent

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

71 Ch  Two types of EDG ●The resonance 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

72 Ch  Similar to EDG, EWG can withdraw electrons from the benzene ring by resonance effect or by negative inductive effect. Deactivate the ring by resonance effect Deactivate the ring by negative inductive effect

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

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

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

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

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

78 Ch  For example: (extra resonance structure due to –OCH 3 ).

79 Ch (extra resonance structure due to –OCH 3 )

80 Ch (3 resonance structures only, no extra stabilization by resonance with –OCH 3 )  less favorable.

81 Ch  For halogens, two opposing effects: negative inductive effect withdrawing electron density from the benzene ring resonance effect from – Cl donating electron density to the benzene ring

82 Ch  Overall: ●Halogens are weak deactivating groups.  Negative inductive effect > resonance effect in this case)

83 Ch  Regiochemistry: (extra resonance structure due to resonance of –Cl).

84 Ch (extra resonance structure due to resonance of –Cl).

85 Ch (3 resonance structures only, no extra stabilization by resonance effect of – Cl)  less favorable.

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

87 Ch  Ortho attack: Relatively stable contributor

88 Ch  Meta attack:

89 Ch  Para attack: Relatively stable contributor

90 Ch Reactions of the Side Chain of Alkylbenzenes

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

92 Ch Benzylic cations are stabilized by resonance.

93 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.

94 Ch  Mechanism ●Chain initiation: ●Chain propagation:

95 Ch ●Chain propagation: ●Chain termination:

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

97 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.

98 Ch  Example: (not observed)

99 Ch B. Additions to the Double Bond of Alkenylbenzenes

100 Ch  Mechanism (top reaction):

101 Ch  Mechanism (bottom reaction):

102 Ch C. Oxidation of the Side Chain

103 Ch

104 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.

105 Ch D. Oxidation of the Benzene Ring

106 Ch Synthetic Applications

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

108 Ch  If the order is reversed  the wrong regioisomer is given. This gives very poor yields anyway. F.C. is not effective on a deactivated ring.

109 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.

110 Ch  Route 1: (Poor yield)

111 Ch  Route 2: (Better method)

112 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.

113 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.

114 Ch

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

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

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

118 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.

119 Ch

120 Ch Problem  Difficult to get o-product without getting p-product.  Due to excessive bromination.

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

122 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.

123 Ch Examples (only major product(s) shown):

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

125 Ch

126 Ch

127 Ch

128 Ch Allylic and Benzylic Halides in Nucleophilic Substitution Reactions

129 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.

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

131 Ch Reduction of Aromatic Compounds

132 Ch A. The Birch Reduction

133 Ch  Mechanism:

134 Ch  Synthesis of 2-cyclohexenones:

135 Ch  END OF CHAPTER 15 


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