1. Substitution and Elimination Reactions of Alkyl Halides
Essential Organic Chemistry
Paula Yurkanis Bruice
Chapter 9
Substitution and Elimination Reactions of Alkyl Halides

2. 9.1 How Alkyl Halides React
Figure: UN
Title:
Substitution versus Elimination Reaction
Caption:
In the substitution reaction the leaving group (usually an electronegative atom or electron-withdrawing group) is replaced by another atom or group. In the elimination reaction, the electronegative atom or electron-withdrawing group is removed along with an adjacent hydrogen atom to form a double bond.
Notes:
The atom or group that is being substituted or eliminated is called the leaving group.

3. Substitution Reactions
One group takes the place of another. Y + R X R Y + X
Y takes the place of X (Substitution)
Y “displaces” X

4. 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).

5. Example 1
iodide displaces bromide at carbon

6. DISPLACEMENT REACTIONS
NUCLEOPHILIC SUBSTITUTION REACTIONS
(substitution at carbon)
can be compared to …
ACID–BASE REACTIONS
(substitution at hydrogen)

7. COMPARE THESE REACTIONSu : - + R X :X
nucleophile
substrate
product
leaving
group
DISPLACEMENT AT CARBON
base
acid
conjugate :X - + B H X :
DISPLACEMENT AT HYDROGEN

8. FIND WIDE APPLICATION SINCE WE CAN USE A WIDE RANGE OF NUCLEOPHILES
THESE REACTIONS
FIND WIDE APPLICATION SINCE WE CAN USE A WIDE RANGE OF NUCLEOPHILES

9. NUCLEOPHILES Nucleophile Product Class alkyl halides alcohols R'O-
A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE THE SYNTHESIS
OF MANY TYPES OF ORGANIC COMPOUNDS:
R-Y + Nu R-Nu Y
Nucleophile
Product
Class R X
alkyl halides
alcohols R O H
R'O- R O R'
ethers R C N
nitriles O
esters R ' C O R R ' C C R
alkynes R S H
thiols

10. THE NUCLEOPHILE DOES NOT NEED TO BE CHARGED
HOWEVER, REACTIVE ATOMS BEAR A LONE PAIR + - H O + R B r H O R + B r H H O H
Under some circumstances
water will react. H + - H O R + H O + B r 3
Nucleophile
Product
Class H O H R O H
alcohols '
ethers R O H R' O R
amines R N H N H 2 3
amines R ' N H R ' N H R 2

11. 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.

12. 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!

13. 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

14. 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.

15. 9.2 The Mechanism of An SN2 Reaction
Figure:
Title:
Example and Mechanism of an SN2 Reaction
Caption:
An SN2 reaction is a bimolecular reaction. This reaction requires two molecules in the rate-determining step of the mechanism. As the nucleophile approaches, the leaving group is displaced all at the same time.
Notes:
This reaction results in the inversion of configuration if the leaving group is attached to an asymmetric carbon.

16. SN2 - C H B r + N a O H C H O H + B r rate = k2[RBr][NaOH]
80% ethanol - C H B r + N a O H C H O H + B r 3 3
20% water
55oC
rate = k2[RBr][NaOH] - H O
80% ethanol - C H B r C H O H + B r 3 3
20% water
Rate dependence of the reaction
is interpreted in a way that
we expect a bimolecular reaction
with a concerted mechanism
SN2
substitution
nucleophilic
bimolecular

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

19. Mechanism
ENERGY PROFILE E N R G Y

20. Mechanism
ENERGY PROFILE E N R G Y

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. Stereochemistry
Old bond is broken simultaneously with the new bond formed.
Well-defined outcome
Stereochemistry is inverted

27. Factors Affecting SN2 Steric effects
Approaching the polarized carbon gets more and more difficult.

28. Energy Profile of SN2
SN2

29. 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.

32. 9.3 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–

33. Figure: UN
Title:
Factors Affecting SN2 Reactions
Caption:
If an alkyl iodide reacts under the same conditions as any other alkyl halide (with the same alkyl group), it will react the fastest. Alkyl fluorides react the slowest.
Notes:
The weaker the basicity of a group the better is its leaving ability. The weaker the base the better the leaving group.

34. Figure: UN
Title:
Various Nucleophiles Used in SN2 Reactions
Caption:
Many different nucleophiles can react with alkyl halides in a variety of synthesis reactions.
Notes:
All the nucleophiles have lone pairs of electrons to donate in the reaction.

38. 9.4 The Mechanism of An SN1 Reaction
Figure:
Title:
Example and Mechanism of an SN2 Reaction
Caption:
An SN2 reaction is a bimolecular reaction. This reaction requires two molecules in the rate-determining step of the mechanism. As the nucleophile approaches, the leaving group is displaced all at the same time.
Notes:
This reaction results in the inversion of configuration if the leaving group is attached to an asymmetric carbon.

39. SN1 SN1 rate = k1[RBr] Rate depends only on substrate concentration.H C H 3 3
80% ethanol - H C C B r + N a O H H C C O H + B r 3 3
20% water
55oC C H C H 3 3
rate = k1[RBr]
Rate depends only on substrate concentration.
Two independent steps that differ significantly in speed.
Unimolecular
SN1
substitution
nucleophilic
unimolecular

40. 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

41. SN1
Reaction profile

42. SN1
Reaction profile
Bond gets longer

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

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

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

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

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

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

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

50. 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

51. Figure: 10-04UN
Title:
Reaction Coordinate Diagram for an SN1 Reaction
Caption:
Reaction coordinate diagram for an SN1 reaction. This illustrates that the rate-determining step is the first step, which is the formation of the carbocation. It has the highest activation energy.
Notes:
Note the formation of the carbocation intermediate.

52. Figure: UN
Title:
Mechanism for an SN1 Reaction
Caption:
The mechanism for an SN1 reaction illustrates the formation of equal amounts of two products due to the formation of a carbocation intermediate. The nucleophile can attack either from the front or the back of the carbocation since it is planar in nature.
Notes:
If the leaving group is attached to an asymmetric carbon, then one product will have retention of configuration and the other product has inversion of configuration. This results in a pair of enantiomers being formed.

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

54. Stereochemistry
First, old bond is broken. In a second step, we form new bond.
We have a carbocation intermediate.
This requires rehybridization sp3  sp2
Stereochemical information is lost.
Racemate formed.

55. 9.5 Factors that Affect SN1 Reactions
Cation stability
3o alkyl halide > 2o alkyl halide > 1o alkyl halide.
Leaving group
The weaker the bond, the easier to break.
RI > RBr > RCl > RF
Nucleophile
NO EFFECT.

56. 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.

57. 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.

60. 9.6 Comparing SN2 and SN1 Reactions

61. Figure: UN
Title:
Comparison of SN1 and SN2 Reactions of a Cyclic Compound
Caption:
Comparison of an SN1 and an SN2 reaction on the same cyclic compound. This illustrates the differences in the products that are formed in each reaction.
Notes:
The SN1 reaction results in two products whereas the SN2 reaction results in one with the opposite configuration.

63. 9.7 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.

64. Example
Alkyl halide + strong base and heat  LOSS OF HCl

65. Elimination
In this case the nucleophile reacts as a base; we observe elimination reactions.
A hydrogen is removed from a carbon atom.
The halogen is removed from the adjacent carbon.
Note that the elimination reaction is the reverse of an addition reaction.

66. 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.

67. 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

68. Figure: UN
Title:
E2 Reaction - Elimination
Caption:
This is an example of an E2 reaction. This reaction is bimolecular. The mechanism shows that this reaction occurs in one step with the base removing the proton from a carbon that is adjacent to the carbon bonded to the halogen.
Notes:
The electrons that were bonded to the hydrogen in the reactant form the new p bond in the product.

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

70. 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

71. 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

72. Figure: UN
Title:
Elimination Reaction
Caption:
In the elimination reaction the hydrogen that is removed is from a  carbon. The  carbon is the carbon that is directly attached to the leaving group. The  carbon is the carbon adjacent to the  carbon.
Notes:
If the  carbons are identical there will be only one product.

73. Figure: 10-05x
Title:
Reaction Coordinate Diagram for an E2 Reaction
Caption:
Reaction coordinate diagram for the E2 reaction of 2-bromobutane and methoxide ion.
Notes:
The formation of 2-butene is more stable, as illustrated.

74. Figure: UN
Title:
Relative Reactivities of Alkyl Halides in an E2 Reaction
Caption:
In an E2 reaction the elimination from a tertiary alkyl halide will produce a more substituted alkene; therefore, it reacts the fastest in this type of reaction.
Notes:
The tertiary alkyl halide will produce an alkene with three alkyl substituents.

75. 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.

76. 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
Works best in a
polar solvent.
IONS
FORMED

77. 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.

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

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

80. Figure: UN
Title:
Elimination Reaction
Caption:
In the case of 2-bromobutane the two  carbons are not identical so two products can be formed. The major product will be the one that forms the more stable alkene.
Notes:
Remember that the most stable alkene is generally the most substituted alkene.

81. Figure: 10-06
Title:
Reaction Coordinate Diagram for an E1 Reaction
Caption:
Reaction coordinate diagram for the E1 reaction of 2-chloro-2-methylbutane. The major product is the more substituted alkene because its greater stability causes the transition state leading to its formation to be more stable.
Notes:
Note the formation of a carbocation intermediate. The activation energy for the formation of the carbocation is high and therefore this is the rate-determining step.

87. 9.9 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.

92. 10.10 Competition Between Substitution and Elimination
Figure: UN
Title:
SN2 and E2 Reaction Conditions
Caption:
SN2 and E2 reactions occur under similar conditions. Both use high concentrations of a good nucleophile or strong base.
Notes:
These two reactions compete with each other.

93. Figure: UN
Title:
Primary Alkyl Halide Under SN2/E2 Conditions
Caption:
A primary alkyl halide can undergo both a substitution or an elimination reaction when reacted with a good nucleophile such as the methoxide ion. The SN2 product is favored in the case of a primary alkyl halide.
Notes:
Primary alkyl halides undergo mainly substitution reactions.

95. 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.

96. 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: