Organic Chemistry

1
Organic Chemistry

• William H. Brown Christopher S. Foote

2
Aromatics II
Chapter 21

• Chapter 20

3
Reactions of Benzene

• The most characteristic reaction of aromatic
  compounds is substitution at a ring carbon

4
Reactions of Benzene
5
Electrophilic Aromatic Sub

• Electrophilic aromatic substitution a reaction
  in which a hydrogen atom of an aromatic ring is
  replaced by an electrophile
• We study
• several common types of electrophiles
• how each is generated
• the mechanism by which each replaces hydrogen

6
Chlorination

• Step 1 formation of a chloronium ion

7
Chlorination

• Step 2 attack of the chloronium ion on the
  aromatic ring
• Step 3 proton transfer regenerates the aromatic
  character of the ring

8
EAS General Mechanism

• A general mechanism
• General question what is the electrophile and
  how is it generated?

9
Nitration

• The electrophile is NO2, generated in this way

10
Nitration

• Step 1 attack of the nitronium ion (an
  electrophile) on the aromatic ring (a
  nucleophile)
• Step 2 proton transfer regenerates the aromatic
  ring

11
Nitration

• A particular value of nitration is that the nitro
  group can be reduced to a 1 amino group

12
Sulfonation

• Carried out using concentrated sulfuric acid
  containing dissolved sulfur trioxide

13
Friedel-Crafts Alkylation

• Friedel-Crafts alkylation forms a new C-C bond
  between an aromatic ring and an alkyl group

14
Friedel-Crafts Alkylation

• Step 1 formation of an alkyl cation as an ion
  pair
• Step 2 attack of the alkyl cation on the
  aromatic ring
• Step 3 proton transfer regenerates the aromatic
  ring

15
Friedel-Crafts Alkylation

• There are two major limitations on Friedel-Crafts
  alkylations
• 1. carbocation rearrangements are common

16
Friedel-Crafts Alkylation

• the isobutyl chloride/AlCl3 complex rearranges to
  the tert-butyl cation/AlCl4- ion pair, which is
  the electrophile

17
Friedel-Crafts Alkylation

• 2. F-C alkylation fails on benzene rings bearing
  one or more of these strongly electron-withdrawing
  groups

18
Friedel-Crafts Acylation

• Friedel-Crafts acylation forms a new C-C bond
  between a benzene ring and an acyl group

19
Friedel-Crafts Acylation

• The electrophile is an acylium ion

20
Friedel-Crafts Acylation

• an acylium ion is a resonance hybrid of two major
  contributing structures
• F-C acylations are free of a major limitation of
  F-C alkylations acylium ions do not rearrange

21
Friedel-Crafts Acylation

• A special value of F-C acylations is preparation
  of unrearranged alkylbenzenes

22
Other Aromatic Alkylations

• Carbocations are generated by
• treatment of an alkene with a protic acid, most
  commonly H2SO4, H3PO4, or HF/BF3

23
Other Aromatic Alkylations

• by treating an alkene with a Lewis acid
• and by treating an alcohol with H2SO4 or H3PO4

24
Di- and Polysubstitution

• Existing groups on a benzene ring influence
  further substitution in both orientation and rate
• Orientation
• certain substituents direct preferentially to
  ortho para positions others direct
  preferentially to meta positions
• substituents are classified as either
• ortho-para directing or meta directing

25
Di- and Polysubstitution

• Rate
• certain substituents cause the rate of a second
  substitution to be greater than that for benzene
  itself others cause the rate to be lower
• substituents are classified as activating or
  deactivating toward further substitution

26
Di- and Polysubstitution

• -OCH3 is ortho-para directing

27
Di- and Polysubstitution

• -NO2 is meta directing

28
Di- and Polysubstitution
29
Di- and Polysubstitution

• From the information in Table 21.1, we can make
  these generalizations
• alkyl, phenyl, and all other groups in which the
  atom bonded to the ring has an unshared pair of
  electrons are ortho-para directing. All other
  groups are meta directing
• all ortho-para directing groups except the
  halogens are activating toward further
  substitution. The halogens are weakly deactivating

30
Di- and Polysubstitution

• the order of steps is important

31
Theory of Directing Effects

• The rate of EAS is limited by the slowest step in
  the reaction
• For almost every EAS, the rate-determining step
  is attack of E on the aromatic ring to give a
  resonance-stabilized cation intermediate
• The more stable this cation intermediate, the
  faster the rate-determining step and the faster
  the overall reaction

32
Theory of Directing Effects

• For ortho-para directors, ortho-para attack forms
  a more stable cation than meta attack
• ortho-para products are formed faster than meta
  products
• For meta directors, meta attack forms a more
  stable cation than ortho-para attack
• meta products are formed faster than ortho-para
  products

33
Theory of Directing Effects

• -OCH3 assume meta attack

34
Theory of Directing Effects

• -OCH3 assume ortho-para attack

35
Theory of Directing Effects

• -NO2 assume meta attack

36
Theory of Directing Effects

• -NO2 assume ortho-para attack

37
Activating-Deactivating

• Any resonance effect, such as that of -NH2, -OH,
  and -OR, that delocalizes the positive charge on
  the cation intermediate lowers the activation
  energy for its formation, and has an activating
  effect toward further EAS
• Any resonance or inductive effect, such as that
  of -NO2, -CN, -CO, or -SO3H, that decreases
  electron density on the ring deactivates the ring
  toward further EAS

38
Activating-Deactivating

• Any inductive effect, such as that of -CH3 or
  other alkyl group, that releases electron density
  toward the ring activates the ring toward further
  EAS
• Any inductive effect, such as that of -halogen,
  -NR3, -CCl3, or -CF3, that decreases electron
  density on the ring deactivates the ring toward
  further EAS

39
Halogens

• 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

40
Nucleophilic Aromatic Sub.

• Aryl halides do not undergo nucleophilic
  substitution by either SN1 or SN2 pathways
• They do undergo nucleophilic substitutions, but
  by mechanisms quite different from those of
  nucleophilic aliphatic substitution
• Nucleophilic aromatic substitutions are far less
  common than electrophilic aromatic substitutions

41
Benzyne Intermediates

• When heated under pressure with aqueous NaOH,
  chlorobenzene is converted to sodium phenoxide.
  Neutralization with HCl gives phenol.

42
Benzyne Intermediates

• the same reaction with 2-chlorotoluene gives a
  mixture of ortho- and meta-cresol
• the same type of reaction can be brought about
  using of sodium amide in liquid ammonia

43
Benzyne Intermediates

• ?-elimination of HX gives a benzyne intermediate,
  that then adds the nucleophile to give products

44
Nu Addition-Elimination

• when an aryl halide contains electron-withdrawing
  NO2 groups ortho and/or para to X, nucleophilic
  aromatic substitution takes place readily
• neutralization with HCl gives the phenol

45
Meisenheimer Complex

• reaction involves a Meisenheimer complex
  intermediate

46
Prob 21.7

• Write a mechanism for each reaction.

47
Prob 21.8

• Offer an explanation for the preferential
  nitration of pyridine in the 3 position rather
  than the 2 position.

48
Prob 21.9

• Offer an explanation for the preferential
  nitration of pyrrole in the 2 position rather
  than in the 3 position.

49
Prob 21.15

• Predict the major product(s) from treatment of
  each compound with HNO3/H2SO4.

50
Prob 21.16

• Account for the fact that N-phenylacetamide is
  less reactive toward electrophilic aromatic
  substitution than aniline.

51
Prob 21.17

• Propose an explanation for the fact that the
  trifluoromethyl group is meta directing.

52
Prob 21.19

• Arrange the compounds in each set in order of
  decreasing reactivity toward electrophilic
  aromatic substitution.

53
Prob 21.19 (contd)

• Arrange the compounds in each set in order of
  decreasing reactivity toward electrophilic
  aromatic substitution.

54
Prob 21.20

• Draw a structural formula for the major product
  of nitration of each compound.

55
Prob 21.21

• Which ring in each compound undergoes
  electrophilic aromatic substitution more readily?
  Draw the product of nitration of each compound.

56
Prob 21.22

• Propose a mechanism for the formation of
  bisphenol A.

57
Prob 21.23

• Propose a mechanism for the formation of BHT.

58
Prob 21.24

• Propose a mechanism for the formation of DDT.

59
Prob 21.27

• Propose a mechanism for this reaction.

60
Prob 21.28

• Account for the regioselectivity of the
  nitration in Step 1, and propose a mechanism for
  Step 2.

61
Prob 21.29

• Propose a mechanism for the displacement of
  chlorine by (1) the NH2 group of the dye and (2)
  an -OH group of cotton.

62
Prob 21.31

• Show how to prepare (a) and (b) from
  1-phenyl-1-propanone.

63
Prob 21.33

• Show how to bring about each conversion.

64
Prob 21.35

• Propose a synthesis for each compound from
  benzene.

65
Prob 21.36

• Propose a synthesis of 2,4-D from chloroacetic
  acid and phenol.

66
Prob 21.41

• Propose a synthesis of this compound from
  benzene.

67
Prob 21.42

• Propose a synthesis of this compound from
  3-methylphenol.

68
Prob 21.43

• Propose a synthesis of this compound from
  toluene and phenol.

69
Prob 21.44

• Propose a mechanism for this example of
  chloromethylation (introduction of a CH2Cl group
  on an aromatic ring). Show how to convert the
  product of chloromethylation to piperonal.

70
Prob 21.45

• Given this retrosynthetic analysis, propose a
  synthesis for Dinocap from phenol and 1-octene.

71
Prob 21.46

• Show how to synthesize this trichloro derivative
  of toluene from toluene.

72
Prob 21.47

• Given this retrosynthetic analysis, propose a
  synthesis for bupropion.

73
Aromatics II
End Chapter 21