1. William H. Brown & Christopher S. Foote
Organic Chemistry
William H. Brown & Christopher S. Foote

2. Nucleophilic Substitution and -Elimination
Chapter 8
Chapter 8

3. Nucleophilic Substitution
Nucleophilic substitution: any reaction in which one nucleophile is substituted for another at a tetravalent carbon
Nucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond; a Lewis base

4. Nucleophilic Substitution
An important reaction of alkyl halides

5. Solvents Protic solvent: a solvent that is a hydrogen bond donor
the most common protic solvents contain -OH groups
Aprotic solvent: a solvent that cannot serve as a hydrogen bond donor
nowhere in the molecule is there a hydrogen bonded to an atom of high electronegativity

6. Dielectric Constant Solvents are classified as polar and nonpolar
the most common measure of solvent polarity is dielectric constant
Dielectric constant: a measure of a solvent’s ability to insulate opposite charges from one another
the greater the value of the dielectric constant of a solvent, the smaller the interaction between ions of opposite charge dissolved in that solvent
polar solvent: dielectric constant > 15
nonpolar solvent: dielectric constant < 15

7. Protic Solvents

8. Aprotic Solvents

9. Mechanisms
Chemists propose two limiting mechanisms for nucleophilic displacement
a fundamental difference between them is the timing of bond breaking and bond forming steps
At one extreme, the two processes take place simultaneously; designated SN2
S = substitution
N = nucleophilic
2 = bimolecular (two species are involved in the rate-determining step)

10. Mechanism - SN2
both reactants are involved in the transition state of the rate-determining step

11. Mechanism - SN2

12. Mechanism - SN1
Bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins
This mechanism is designated SN1 where
S = substitution
N = nucleophilic
1 = unimolecular (only one species is involved in the rate-determining step)

13. Mechanism - SN1
Step 1: ionization of the C-X bond gives a carbocation intermediate

14. Mechanism - SN1
Step 2: reaction of the carbocation with methanol gives an oxonium ion. Attack occurs with equal probability from either face of the planar carbocation
Step 3: proton transfer completes the reaction

15. Mechanism - SN1

16. Evidence of SN reactions
1. What is the rate of an SN reaction affected by:
the structure of Nu?
the structure of RX?
the structure of the leaving group?
the solvent?
2. What is the stereochemistry of the product if the Nu attacks at a stereocenter?
3. When and how does rearrangement occur?

17. Kinetics
For an SN1 reaction, the rate of reaction is first order in haloalkane and zero order in nucleophile

18. Kinetics
For an SN2 reaction, the rate is first order in haloalkane and first order in nucleophile

19. Nucleophilicity
Nucleophilicity: a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditions
Basicity: a equilibrium property measured by the position of equilibrium in an acid-base reaction
Because all nucleophiles are also bases, we study correlations between nucleophilicity and basicity

20. Nucleophilicity

21. Nucleophilicity
Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents
How do we account for these differences?

22. Nucleophilicity
A guiding principle is the freer the nucleophile, the greater its nucleophilicity
Polar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF)
are very effective in solvating cations, but not nearly so effective in solvating anions.
because anions are only poorly solvated, they participate readily in SN reactions, and
nucleophilicity parallels basicity: F- > Cl- > Br- > I-

23. Nucleophilicity Polar protic solvents (e.g., water, methanol)
anions are highly solvated by hydrogen bonding with the solvent
the more concentrated the negative charge of the anion, the more tightly it is held in a solvent shell
the nucleophile must be at least partially removed from its solvent shell to participate in SN reactions
because F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F-

24. Nucleophilicity Generalizations
within a period, nucleophilicity increases from left to right; that is, it increases with basicity

25. Nucleophilicity Generalizations
in a series of reagents with the same nucleophilic atom, anionic reagents are stronger nucleophiles than neutral reagents

26. Nucleophilicity
when comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity

27. Stereochemistry
For an SN1 reaction at a stereocenter, the product is almost completely racemized

28. Stereochemistry For SN1 reactions at a stereocenter
examples of complete racemization have been observed, but
partial racemization with a slight excess of inversion is more common

29. Stereochemistry
For SN2 reactions at a stereocenter, there is inversion of configuration at the stereocenter
Experiment of Hughes and Ingold

30. Hughes-Ingold Expt the reaction is 2nd order, therefore, SN2
the rate of racemization of enantiomerically pure 2-iodooctane is twice the rate of incorporation of I-131

31. Structure of RX SN1 reactions governed by electronic factors;
the relative stabilities of carbocation intermediates
SN2 reactions governed by steric factors;
the relative ease of approach of the nucleophile to the site of reaction

32. Effect of -Branching

33. Effect of -Branching

34. Allylic Halides
Allylic cations are stabilized by resonance delocalization of the positive charge
a 1° allylic cation is about as stable as a 2° alkyl cation

35. Allylic Cations 2° & 3° allylic cations are even more stable
As also are benzylic cations

36. The Leaving Group
The more stable the anion, the better the leaving ability
the most stable anions are the conjugate bases of strong acids

37. The Solvent - SN2
The most common type of SN2 reaction involves a negative Nu and a negative leaving group
the weaker the solvation of Nu, the less the energy required to remove it from its solvation shell and the greater the rate of SN2

38. The Solvent - SN2

39. The Solvent - SN1
SN1 reactions involve creation and separation of unlike charge in the transition state of the rate-determining step
Rate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cation
Polar protic solvents (formic acid, water, methanol) are the most effective solvents for SN1 reactions

40. The Solvent - SN1

41. Rearrangements in SN1
Rearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one

42. Rearrangements in SN1
Mechanism of a carbocation rearrangement

43. Summary of SN1 & SN2

44. Neighboring Groups
In an SN1 reaction, departure of the leaving group is not assisted by Nu
In an SN2 reaction, departure of the leaving group is assisted by Nu
These two types are distinguished by their order of reaction; SN2 reactions are 2nd order, and SN1 reactions are 1st order
But some reactions are 1st order and yet involve two successive SN2 reactions

45. Mustard Gases Mustard gases contain either S-C-C-X or N-C-C-X
what is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water, a very poor nucleophile

46. Mustard Gases
the reason is neighboring group participation by the adjacent heteroatom
proton transfer to solvent completes the reaction

47. SN1/SN2 Problems
Problem 1: predict the mechanism for this reaction, and the stereochemistry of each product
Problem 2: predict the mechanism of this reaction

48. SN1/SN2 Problems
Problem 3: predict the mechanism of this reaction and the configuration of product
Problem 4: predict the mechanism of this reaction

49. SN1/SN2 Problems
Problem 5: predict the mechanism of this reaction

50. Phase-Transfer Catalysis
A substance that transfers ions from an aqueous phase to an organic phase
An effective phase-transfer catalyst must have sufficient
hydrophilic character to dissolve in water and form an ion pair with the ion to be transported
hydrophobic character to dissolve in the organic phase and transport the ion into it
The following salt is an effective phase-transfer catalysts for the transport of anions

51. Phase-Transfer Catalysis

52. -Elimination
-Elimination: a reaction in which a small molecule, such as HCl, HI, or HOH, is split out or eliminated from a larger molecule

53. -Elimination
Zaitsev rule: the major product of a -elimination is the more stable (the more highly substituted) alkene

54. -Elimination
There are two limiting mechanisms for -elimination reactions
E1 mechanism: at one extreme, breaking of the R-X bond is complete before reaction with base to break the C-H bond
only R-X is involved in the rate-determining step
E2 mechanism: at the other extreme, breaking of the R-X and C-H bonds is concerted
both R-X and base are involved in the rate-determining step

55. E1 Mechanism ionization of C-X gives a carbocation intermediate
proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene

56. E1 Mechanism

57. E2 Mechanism

58. Kinetics of E1 and E2
E1 is a 1st order reaction; 1st order in RX and zero order is base
E2 is a 2nd order reaction; 1st order in base and 1st order in RX

59. Regioselectivity of E1/E2
E1: major product is the more stable alkene
E2: with strong base, the major product is the more stable alkene
double bond character is highly developed in the transition state
thus, the transition state of lowest energy is that leading to the most stable (the most highly substituted) alkene

60. Stereoselectivity of E2
E2 is most favorable (lowest activation energy) when H and X are oriented anti and coplanar

61. Stereochemistry of E2
Consider E2 of these stereoisomers

62. Stereochemistry of E2
in the more stable chair of the cis isomer, the larger isopropyl is equatorial and chlorine is axial

63. Stereochemistry of E2
in the more stable chair of the trans isomer, there is no H anti and coplanar with X, but there is one in the less stable chair

64. Stereochemistry of E2
it is only the less stable chair conformation of this isomer that can undergo an E2 reaction

65. Stereochemistry of E2
Problem: account for the fact that E2 reaction of the meso-dibromide gives only the E-alkene

66. Summary of E2 vs E1

67. SN vs E
Many nucleophiles are also strong bases (OH- and RO-) and SN and E reactions often compete
The ratio of SN/E products depends on the relative rates of the two reactions

68. SN vs E

69. SN vs E (cont’d)

70. Prob 8.9
Draw a structural formula for the most stable carbocation of each molecular formula.

71. Prob 8.11
From each pair, select the stronger nucleophile.

72. Prob 8.12
Draw a structural formula for the product of each SN2 reaction.

73. Prob 8.12 (cont’d)

74. Prob 8.14
Account for the fact that the rate of this reaction is 1000 times faster in DMSO than it is in ethanol.

75. Prob 8.15
The following reaction involves two successive SN2 reactions. Propose a structural formula for the product.

76. Prob 8.16
Which member of each pair shows the greater rate of SN2 reaction with KI in acetone?

77. Prob 8.17
Which member of each pair gives the greater rate of SN2 reaction with KN3 in acetone?

78. Prob 8.19
Limiting yourself to a single 1,2-shift, suggest a structural formula for a more stable carbocation.

79. Prob 8.21
Draw a structural formula for the product of each SN1 reaction.

80. Prob 8.24
From each pair, select the compound that undergoes SN1 solvolysis in ethanol more rapidly.

81. Prob 8.25
Account for the following relative rates on solvolysis under SN1 conditions.

82. Prob 8.26
Explain why the following compound is very unreactive under SN1 conditions.

83. Prob 8.27
Propose a synthesis for each compound from a haloalkane and a nucleophile.

84. Prob 8.29
Propose a mechanism for the formation of each product.

85. Prob 8.30
Propose a mechanism for the formation of this product. If the configuration of the starting material is S, what is the configuration of the product?

86. Prob 8.31
Propose a mechanism for the formation of the products of this solvolysis reaction.

87. Prob 8.32
Propose a mechanism for the formation of each product.

88. Prob 8.33
Which compound in each set undergoes more rapid solvolysis when refluxed in ethanol?

89. Prob 8.34
Account for these relative rates of solvolysis in acetic acid.

90. Prob 8.35
On SN1 solvolysis in acetic acid, (1) reacts 1011 times faster than (2). Furthermore, solvolysis of (1) occurs with complete retention of configuration. Draw structural formulas for the products of each solvolysis and account for the difference in rates.

91. Prob 8.36
Draw structural formulas for the alkene(s) formed on treatment of each compound with sodium ethoxide in ethanol. Assume reaction by an E2 mechanism.

92. Prob 8.37
Draw structural for all chloroalkanes that undergo dehydrohalogenation when treated with KOH to give each alkene as the major product.

93. Prob 8.38
On treatment with sodium ethoxide in ethanol, each compound gives 3,4-dimethyl-3-hexene. One compound gives an E alkene, the other gives a Z alkene. Which compound gives which alkene?

94. Prob 8.39
On treatment with sodium ethoxide in ethanol, this compound gives a single stereoisomer. Predict whether the alkene has the E or Z configuration.

95. Prob 8.40
Elimination of HBr from 2-bromonorbornane gives only 2-norbornene. Account for the regiospecificity of this elimination reaction.

96. Prob 8.43
Arrange these haloalkanes in order of increasing ratio of E2 to SN2 products on reaction of each with sodium ethoxide in ethanol.

97. Prob 8.44
Draw a structural formula for the major product of each reaction and specify the most likely mechanism for its formation.

98. Prob 8.44 (cont’d)

99. Prob 8.45
Propose a mechanism for the formation of each product.

100. Prob 8.46
Show how to bring about each conversion.

101. Prob 8.46 (cont’d)
Show how to bring about each conversion.

102. Prob 8.47
Which reaction gives the tert-butyl ether in good yield? What is the product of the other reaction?

103. Prob 8.48
Each ether can, in principle, by synthesized by a Williamson ether synthesis forming bond (1) or bond (2). Which combination gives the better yield?

104. Prob 8.49
Propose a mechanism for this reaction.

105. Prob 8.50
Each compound can be synthesized by an SN2 reaction. Propose a combination of haloalkane and nucleophile that will give each product.

106. Prob 8.50 (cont’d)

107. Nucleophilic Substitution and -Elimination
End Chapter 8