1. Chapter 8 Substitution and Elimination Reactions of Alkyl Halides
Paula Yurkanis Bruice
University of California,
Santa Barbara

2. The Families of Group III
Substitution Reactions of Alkyl Halides
alkyl halides:
the first of the families
in Group III

3. The Compounds in Group III
are Electrophiles
All the compounds in Group III have an electron withdrawing atom or group that is attached to an sp3 carbon.

4. Because Group III Compounds are
Electrophiles, they react with Nucleophiles
Substitution reaction—the electronegative group is replaced by another group.
Elimination reaction—the electronegative group is eliminated along with a hydrogen.

5. Alkyl Halides
This chapter discusses the substitution reactions of alkyl halides.
Alkyl halides have good leaving groups.

6. Nucleophilic Substitution
NUCLEOPHILIC DISPLACEMENT
leaving
group
substrate - - N u : + R X R N u + :X
nucleophile
product
The nucleophile “displaces” the leaving group.
This is a “substitution” reaction:
Nu substitutes for X (takes its place).

7. A Closer Look at Alkyl Halides
Carbon and halogens have different electronegativity.
Carbon-halogen bonds are polarized.
Carbon is thought to be positive end of dipole.
Nucleophiles can attack at positively charged carbon.

8. A Closer Look at the Reactions
All substitution reactions follow a general scheme
RBr + NaOH ROH + NaBr
Two reactions follow ...
From the outcome they look identical; however, a closer inspection shows they are different!

9. TWO “LOOK-ALIKE” REACTIONS
RBr + NaOH ROH + NaBr C H 3 B r + O -
20% water N a
80% ethanol 1)
55oC
Speed of reaction depends
on two concentrations
rate = k2[RBr][NaOH]
high conc. NaOH C H 3 O + B r
20% water - N a
80% ethanol 2)
(+ some alkene by E1, E2)
55oC
rate = k1[RBr]
Speed of reaction independent
of nucleophile concentration
low conc. NaOH

10. Two Different Substitution Reactions
We can distinguish two reactions based on their kinetics.
First is SN2, depends on substrate and nucleophile concentration.
Second is SN1, depends only on substrate concentration.

11. 8.1 The SN2 Reaction
The substitution reaction is more precisely called a nucleophilic substitution reaction because the atom replacing the halogen is a nucleophile.

12. What is the Mechanism of the Reaction? an SN2 reaction
The kinetics of a reaction—the factors that affect the rate of the reaction—can help determine the mechanism.
an SN2 reaction

14. Relative Rates of an SN2 Reaction

15. Stereochemistry: Inverted Configuration
If the halogen is bonded to an asymmetric center, the product will have the inverted configuration.

17. Summary of the Experimental Evidence
for the Mechanism of an SN2 Reaction
The rate of the reaction is dependent on the concentration of both the alkyl halide and the nucleophile.
The relative rate of the reaction is:
primary alkyl halide > secondary alkyl halide > tertiary alkyl halide.
The configuration of the product is inverted compared to the configuration of the reacting chiral alkyl halide.

18. Mechanism for the SN2 Reaction
of an Alkyl Halide

19. Why Bimolecular?

20. SN2 Reaction Rate dependence is 2nd order
Two molecules have to come together to form new bonds
Bimolecular reaction

21. Mechanism
ENERGY PROFILE E N R G Y

22. Mechanism
ENERGY PROFILE E N R G Y

23. Mechanism
ENERGY PROFILE E N R G Y

24. Mechanism
ENERGY PROFILE E N R G Y

25. Mechanism
ENERGY PROFILE E N R G Y

26. Mechanism
ENERGY PROFILE E N R G Y

27. Mechanism
ENERGY PROFILE E N R G Y

28. Why do Methyl Halides react the fastest and Tertiary the Slowest?
steric hindrance

29. Why do Methyl Halides react the fastest and Tertiary the slowest?
The relative lack of steric hindrance causes methyl halides and primary alkyl halides to be the most reactive alkyl halides in SN2 reactions.
Tertiary alkyl halides cannot undergo SN2 reactions.

30. 8.2 Factors Affecting SN2

31. Why Steric Hindrance
decreases the rate

32. but they react at different rates
Both are Primary Alkyl Halides
but they react at different rates

33. Figure: UN.T1
Title:
Table Relative Rates of SN2 Reactions
Caption:
The relative rates for several alkyl halides are given. The methyl bromide is the most reactive.
Notes:
The methyl halides are the fastest that can undergo an SN2 reaction, tertiary alkyl halides are too slow to measure.

34. Why the configuration of the Product is inverted

35. Factors that Affect SN2 Reactions
Leaving Group
I– > Br– > Cl– > F–
The lower the basicity, the better the leaving group.
Nucleophile
HO– > H2O; CH3O– > CH3OH
The better the base, the better the nucleophile
NH2– > HO– > F–

36. The rate of an SN2 Reaction is affected by the Leaving Group

37. The Weakest Base is the best Leaving Group

39. Base Strength and Nucleophile Strength
If atoms are in the same row, the strongest base is the best nucleophile.

40. Base Strength and Nucleophile Strength
A negatively charged atom is a stronger base and a better nucleophile than the same atom that is neutral.

42. Steric Hindrance Decreases
Nucleophilicity
Even though the tert-butoxide ion is a stronger base, it is a poorer nucleophile because nucleophilic attack is more sterically hindered than proton removal.

44. SN2 Reactions can be used to make a variety of Compounds
The reactions are irreversible because a strong base displaces a weak base.

45. A tertiary alkyl halide and a poor nucleophile
8.3 The SN1 Reaction
A tertiary alkyl halide and a poor nucleophile
The reaction is surprisingly fast, so it must be taking place by a different mechanism.
Most SN1 reactions are solvolysis reactions: the solvent is the nucleophile.

46. The rate of an SN1 Reaction depends only on the Alkyl Halide Concentration

47. Summary of the Experimental Evidence
for the Mechanism of an SN1 Reaction
The rate of the reaction depends only on the concentration of the alkyl halide.
Tertiary alkyl halides react the fastest.
If the halogen is attached to an asymmetric center the product will be a pair of enantiomers.

48. The Mechanism
The leaving group departs before the nucleophile approaches.

49. SN1 Assuming the formation of a carbocation intermediate3 3
80% ethanol - H C C B r + N a O H H C C O H + B r 3 3
20% water C H C H 3 3
slow O H
fast C H 3 H C C + - + B r 3 C H 3
Assuming the formation of a carbocation intermediate
as the rate-determining step, explains speed of reaction

50. SN1
Reaction profile

51. SN1
Reaction profile
Bond gets longer

52. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2

53. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2

54. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2
sp2-Hybridized intermediate formed

55. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2
sp2-Hybridized intermediate formed
Nucleophile approaches
Rehybridization sp2  sp3 takes place

56. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2
sp2-Hybridized intermediate formed
Nucleophile approaches
Rehybridization sp2  sp3 takes place

57. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2
sp2-Hybridized intermediate formed
Nucleophile approaches
Rehybridization sp2  sp3 takes place
Bond forms

58. SN1 Reaction profile Bond gets longer and longer
Rehybridization sp3  sp2
sp2-Hybridized intermediate formed
Nucleophile approaches
Rehybridization sp2  sp3 takes place
Bond forms

59. Formation of the Carbocation
The Slow Step is
Formation of the Carbocation
Tertiary alkyl halides react the fastest; they form the most stable carbocations.
Secondary and primary alkyl halides do not undergo SN1 reactions.

60. SN1 Energy Profile of SN1 carbocation intermediate transition state2 N E
activation energy2 2 R G
activation energy1 Y
starting
step 1
step 2 D H
material
product
REACTION COORDINATE

61. The Product is a Pair of Enantiomers

62. The Product is a Pair of Enantiomers
If the halogen is bonded to an asymmetric center, the product will be a pair of enantiomers.

63. SN1 Rate dependence is 1st order
Rate depends only on formation of carbocation
Unimolecular reaction
The intermediate requires rehybridization sp3sp2

64. The Leaving Group in
an SN1 Reaction

65. The Nucleophile in an SN1 Reaction
Most SN1 reactions are solvolysis reactions; the nucleophile is the solvent.

66. 8.4 Factors Affecting SN1

67. Figure: UN
Title:
Relative Reactivities of Alkyl Halides in an SN1 Reaction
Caption:
The most reactive alkyl halide is a tertiary alkyl halide while the least reactive is the primary alkyl halide. The alkyl iodides are more reactive than the other alkyl halides since it is a better leaving group.
Notes:
The formation of a tertiary carbocation intermediate is the most stable.

68. Figure: UN.T2
Title:
Table Relative Rates of SN1 Reactions
Caption:
In these reactions the solvent and nucleophile are water. As can be seen the tertiary alkyl bromide is more reactive than the secondary. The primary and methyl are approximately equal and are fairly unreactive in this type of reaction.
Notes:
The tertiary carbocation is more stable which is why its reaction is faster.

70. 8.5 Comparing SN2 and SN1 Reaction

71. Comparing SN2 and SN1 Reactions

74. 8.6 Intermolecular versus Intramolecular SN2 Reactions

75. The Intramolecular Reaction is favored when a Five- or Six-Membered Ring can be formed

77. Substitution and Elimination Reactions
8.7 Alkyl Halides undergo
Substitution and Elimination Reactions
In an elimination reaction:
a halogen is removed from one carbon and
a hydrogen is removed from an adjacent carbon.
a double bond is formed between the two carbons
from which the atoms were removed.

78. Elimination Reactions of Alkyl Halides
In an elimination reaction the starting material
loses the elements of a small molecule such as HCl or HBr during the course of the reaction to form the product.

79. An E2 Reaction

80. Mechanism for an E2 Reaction

81. An E1 Reaction

82. The Mechanism for an E1 Reaction

83. 8.8 An E2 Reaction is Regioselective
The major product is the most stable alkene.
The most stable alkene is (generally) obtained by removing a hydrogen from the beta carbon that is bonded to the fewest hydrogens.

84. The Halogen comes off the Alpha Carbon;
the Hydrogen comes off the Beta Carbon
dehydrohalogenation

85. E2 Reaction THE REACTION IS A b-ELIMINATION The b-hydrogen b-carbon.
is attached to the
b-carbon.
a-carbon
b-carbon
The functional
group is attached
to the a-carbon.
Since the b-hydrogen is lost this reaction is
called a b-elimination.

86. Mechanism of E2 B: B H H C C C C C l C l THE BASE TAKES THE b-HYDROGEN.. .. : C l : ..
Bond formation (p bond) and breaking bonds
(C-H and C-X s bond) take place simultaneously

87. WHAT HAPPENS IF THERE IS MORE
Regioselectivity
WHAT HAPPENS IF THERE IS MORE
THAN ONE b-HYDROGEN?
b ’ b a

88. Regioselectivity b b’ Major product is the one with lowest energy
Major product - b-H
2-butene
2-bromobutane
1-butene
Minor product – b’-H
Major product is the one
with lowest energy

89. Regioselectivity b’ ’ b’ b b’’ = b
In some cases we have more than two b-hydrogens
b’ ’ b’
1-methylcyclohexene
Major product
- b-H
Minor product
– b’-H C H 3 N a O C H 3 C l C H O H / D 3
methylenecyclohexane b
b’’ = b
1-methylcyclohexene

90. Alkene-Like Transition State

91. has the more stable Transition State
The more stable Alkene
has the more stable Transition State

92. More Regioselective E2 Reactions

94. An E1 Reaction is Regioselective
The major product is the more stable alkene.
The most stable alkene is obtained by removing a hydrogen from the beta carbon that is bonded to the fewest hydrogens.

95. E1 ALKYL HALIDES + WEAK BASE (SOLVOLYSIS)
The removal of a b-hydrogen becomes difficult without
a strong base and a different mechanism (ionization)
begins to take place …
… if the substrate is capable.

96. The E1 Elimination Reaction (two steps)
weak
base
carbocation B : H H
slow :X C C C C +
step one + X
3o > 2o > 1o
also favored
if a resonance-
stabilized
carbocation
is formed
unimolecular
step
two
fast
rate = k[RX] C C

97. Figure: UN
Title:
E1 Reaction - Elimination
Caption:
This an example of an E1 reaction along with its mechanism. This reaction is unimolecular and involves the formation of a carbocation intermediate in the rate-determining step.
Notes:
This is a two-step mechanism. The stability of the carbocation intermediate influences this reaction.

98. E1 ENERGY PROFILE two-step reaction carbocation intermediate TS1 E N R
starting
material
step 1
step 2 DH
slow
product

99. Regioselectivity
Major products in E1 eliminations are the alkenes that
are thermodynamically most stable.

100. The more stable Alkene is the major product

101. Both E2 and E1 Reactions
are Regioselective

102. E2 and E1 Reactions
are Stereoselective

103. E2 and E1 Reactions
are Stereoselective

104. E2 and E1 Reactions
are Stereoselective

106. 8.9 Relative Reactivities of Alkyl Halides
in an E2 Reaction

108. 8.10 Does a Tertiary Alkyl Halide undergo
SN2/E2 or SN1/E1 Reactions?

109. Substitution and Elimination
8.11 Competition between
Substitution and Elimination

110. Competition Between SN2/E2 and SN1/E1
Consider “concentration” and “reactivity”
SN2/E2 are favored by a high concentration of a good nucleophile/strong base.
SN1/E1 are favored by a poor nucleophile/ weak base.

111. Under SN2/E2 conditions, a Primary Alkyl Halide forms primarily a Substitution Product

112. Under SN2/E2 conditions, a Secondary Alkyl Halide forms Substitution and Elimination Products
Substitution is favored by a weak base.
Elimination is favored by a strong base.

113. Under SN2/E2 conditions, a Tertiary Alkyl Halide
forms only an Elimination Product

114. Under SN1/E1 conditions, a Tertiary Alkyl Halide forms Substitution and Elimination Products

115. Tertiary (SN1/E1): Substitution is Favored
Tertiary (SN2/E2): Only Elimination

116. Summary of the products obtained from Substitution and Elimination Reactions

119. Figure: 10-06T05
Title:
Table Summary of Products Expected in Substitution and Elimination Reactions
Caption:
Comparison of the products that are expected in substitution and elimination reactions with primary, secondary, and tertiary alkyl halides.
Notes:
Primary alkyl halides react only under SN2/E2 conditions, whereas tertiary alkyl halides will only undergo elimination reactions under these same conditions.

120. Figure: 10-06T06
Title:
Table Stereochemistry of Substitution and Elimination Reactions
Caption:
A summary of the products formed in the different substitution and elimination reactions.
Notes:

121. Polar solvents stabilize charged species.
Solvation
Polar solvents stabilize charged species.

122. If a reactant is charged, increasing the polarity of the solvent decreases the Rate

123. If the reactants are neutral, increasing the polarity of the solvent increases the Rate

124. How a solvent affects the Rate of a Reaction that does not have a Charged Reactant
If a reactant is not charged:
the charge on the reactants will be greater than the charge on the transition state.
Increasing the polarity of the solvent will increase the rate of the reaction.

125. How a solvent affects the Rate of an Reaction that has a Charged Reactant
If a reactant is charged:
the charge on the reactants will be greater than the charge on the transition state.
Increasing the polarity of the solvent will decrease the rate of the reaction.

126. DMF and DMSO
These solvents can solvate cations (+) better than they can solvate anions (–).

130. William Ether Synthesis:
an SN2 Reaction

131. Forming an Alkoxide Ion

132. Synthesizing Butyl Propyl Ether

133. Synthesizing tert-Butyl Ethyl Ether
The less hindered group should be provided by the alkyl halide.