1. Chapter 8 Nucleophilic Substitution
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2. 8.1 Functional Group Transformation By Nucleophilic Substitution

3. Nucleophilic Substitution
Y : –
: X – + + R X Y R
Nucleophile is a Lewis base (electron-pair donor),
often negatively charged and used as Na+ or K+ salt, e.g. NaBr.
Substrate is usually an alkyl halide (an sp3 carbon). 2

4. Nucleophilic Substitution
Substrate cannot be an a vinylic halide or an
aryl halide, except under certain conditions to
be discussed in Chapter 12. In these environments (sp2) it is difficult to displace Xˉ. C X X
vinylic halide
aryl halide 3

5. Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile .. O: R' – + R X
gives an ether. +
: X R .. O R' – 4

6. Ethyl isobutyl ether (66%)
Example
(CH3)2CHCH2ONa CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH NaBr
Ethyl isobutyl ether (66%) 5

7. Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile O .. –
R'C O: + R X .. ..
gives an ester. +
: X R O
R'C – 4

8. Ethyl octadecanoate (95%)
Example O
CH3(CH2)16C OK +
CH3CH2I
acetone, water + KI O
CH2CH3
CH3(CH2)16C
Ethyl octadecanoate (95%) 7

9. Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile S: – .. H + R X
gives a thiol. +
: X R .. S H – 4

10. Example KSH + CH3CH(CH2)6CH3 Br ethanol, water CH3CH(CH2)6CH3 + KBr SH
2-Nonanethiol (74%)
CH3CH(CH2)6CH3 SH 9

11. Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile – C N : + R X
gives a nitrile. +
: X R – C N : 4

12. Cyclopentanecarbonitrile (70%) CN + NaBr
Example Br
NaCN +
DMSO
Cyclopentanecarbonitrile (70%) CN +
NaBr 11

13. Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile .. – N : + R X ..
gives an alkyl azide. +
: X R – N : 4

14. Example NaN3 + CH3CH2CH2CH2CH2I 2-Propanol-water
CH3CH2CH2CH2CH2N NaI
Pentyl azide (52%) 13

15. Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile – .. : I + R X
gives an alkyl iodide. +
: X R – .. I : 4

16. Example + NaI CH3CHCH3 Br acetone + NaBr CH3CHCH3 I
NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.
acetone +
NaBr
CH3CHCH3 I
Isopropyl iodide 63% 16

17. 8.2 Relative Reactivity of Halide Leaving Groups17

18. RI most reactive RBr RCl RF least reactive Generalization
Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination (weakest base is the best LG). RI
RBr
RCl RF
most reactive
least reactive 18

19. What is the single organic product obtained ?
Problem 8.2
When 1-bromo-3-chloropropane is allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol.
What is the single organic product obtained ?
BrCH2CH2CH2Cl + NaCN
Br is a better leaving group than Cl 19

20. What is the single organic product obtained ?
Problem 8.2
When 1-bromo-3-chloropropane is allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol.
What is the single organic product obtained ?
BrCH2CH2CH2Cl + NaCN
CH2CH2CH2Cl + NaBr C N : 19

21. 8.3 The SN2 Mechanism of Nucleophilic Substitution17

22. Second-order kinetics infers a bimolecular rate-determining step
Many nucleophilic substitutions follow a second-order rate law. CH3Br + HO –  CH3OH + Br –
rate = k[CH3Br][HO – ]
Second-order kinetics infers a bimolecular rate-determining step
Proposed mechanism is called SN2, which stands for substitution nucleophilic bimolecular 21

23. Bimolecular Mechanism, SN2HO
CH3 Br

transition state
one step
HO –
CH3Br +
HOCH3
Br – 22

24. This is the Walden inversion.
Stereochemistry
Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration.
This is the Walden inversion. 24

25. Inversion of Configuration
Nucleophile attacks carbon from side opposite the bond to the leaving group.
Three-dimensional arrangement of bonds in the product is opposite to that of the reactant. 25

26. Stereospecific Reaction
A stereospecific reaction is one in which stereoisomeric starting materials yield products that are stereoisomers of each other.
The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific.
(+)-2-Bromooctane  (–)-2-Octanol
(–)-2-Bromooctane  (+)-2-Octanol 24

27. Stereospecific Reaction
(CH2)5CH3 C H
CH3 HO
(R)-(–)-2-Octanol C H
CH3 Br
CH3(CH2)5
NaOH
(S)-(+)-2-Bromooctane 25

28. Problem 8.4
The Fischer projection formula for (+)-2-bromooctane is shown alnog with the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. H Br
CH3
CH2(CH2)4CH3 HO H
CH3
CH2(CH2)4CH3 29

29. 8.4 Steric Effects and SN2 Reaction Rates17

30. Crowding at the Reaction Site
The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects.
Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. 33

31. Table 8.2 Reactivity Toward Substitution by the SN2 Mechanism
RBr LiI  RI LiBr
Alkyl Class Relative bromide rate
CH3Br Methyl 221,000
CH3CH2Br Primary 1,350
(CH3)2CHBr Secondary 1
(CH3)3CBr Tertiary too small to measure 33

32. Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
Ball and stick models.
(CH3)3CBr 34

33. Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
Space filling models.
(CH3)3CBr 34

34. Crowding Adjacent to the Reaction Site
The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects.
Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller. 33

35. Table 8.3 Effect of Chain Branching on Rate of SN2 Substitution
RBr LiI  RI LiBr
Alkyl Structure Relative bromide rate
Ethyl CH3CH2Br 1.0
Propyl CH3CH2CH2Br 0.8
Isobutyl (CH3)2CHCH2Br 0.036
Neopentyl (CH3)3CCH2Br 35

36. 8.5 Nucleophiles and Nucleophilicity17

37. The nucleophiles described in Sections 8.1-8.4 have been anions... HO : –
CH3O HS C N
etc.
Not all nucleophiles are anions. Many are neutral. ..
HOH
CH3OH
NH3 :
for example
All nucleophiles, however, are Lewis bases. 6

38. Nucleophilicity is a measure of the reactivity of a nucleophile
Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relative rate of 1.0. 2

39. Table 8.4 Nucleophilicity
Rank Nucleophile Relative rate
very good I-, HS-, RS- >105
good Br-, HO-, 104
RO-, CN-, N3-
fair NH3, Cl-, F-, RCO2- 103
weak H2O, ROH 1
very weak RCO2H 10-2 5

40. Table 8.4 Nucleophilicity
Rank Nucleophile Relative rate
good HO–, RO– 104
fair RCO2– 103
weak H2O, ROH 1
When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity.
Charged is better than neutral (HO– vs H2O). 7

41. Major factors that control nucleophilicity
Basicity
In a horizontal row of the periodic table, nucleophilicity parallels basicity.
Solvation
Small negative ions are highly solvated in protic solvents.
Large negative ions are less solvated. 10

42. Table 8.4 Nucleophilicity
Rank Nucleophile Relative rate
Very good I- >105
good Br- 104
fair Cl-, F- 103
A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic. 9

43. Figure 8.3
Solvation of a chloride ion by ion-dipole attractive forces with water. The negatively charged chloride ion interacts with the positively polarized hydrogens of water. 10

44. The term solvolysis refers to a nucleophilic
Nucleophiles
Many of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles. ..
CH3OH .. ..
HOH
for example
The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent. 6

45. 1. Substitution by an anionic nucleophile.
Solvolysis
1. Substitution by an anionic nucleophile.
R—X + :Nu—
R—Nu + :X—
2. Solvolysis. +
R—X + :Nu—H
R—Nu—H + :X—
products of overall reaction:
R—Nu + HX 2

46. Example: Methanolysis
Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. H O
CH3 : H O
CH3 : R +
–H+
The product is a methyl ether. O : ..
CH3 R
R—X + 3

47. Typical solvents in solvolysis
solvent product from RX
water (HOH) ROH
methanol (CH3OH) ROCH3
ethanol (CH3CH2OH) ROCH2CH3
formic acid (HCOH)
acetic acid (CH3COH) O O
ROCH O O
ROCCH3 4

48. 8.6 The SN1 Mechanism of Nucleophilic Substitution17

49. Yes. But by a mechanism different from SN2.
A question...
Tertiary alkyl halides are very unreactive in substitutions that proceed by the SN2 mechanism. Do they undergo nucleophilic substitution at all ?
Yes. But by a mechanism different from SN2.
The most common examples are seen in solvolysis reactions. 2

50. Kinetics and Mechanism
Some nucleophilic substitutions follow a first-order rate law.
rate = k[alkyl halide]
First-order kinetics implies a unimolecular rate-determining step.
Proposed mechanism is called SN1, which stands for substitution nucleophilic unimolecular 2

51. Example of a solvolysis. Hydrolysis of tert-butyl bromide... + H Br : O C
CH3 OH .. C + O : H Br –
CH3 13

52. Example of a solvolysis. Hydrolysis of tert-butyl bromide... + O : H C
CH3 Br .. C + O : H Br –
CH3
This is the nucleophilic substitution stage of the reaction. It involves two steps, loss of Brˉ then attack by water. 13

53. Example of a solvolysis. Hydrolysis of tert-butyl bromide.
The reaction rate is independent of the concentration of the nucleophile and follows a first-order rate law.
rate = k[(CH3)3CBr]
The first step (slow) begins with ionization of (CH3)3CBr.
The mechanism of this step is SN1 rather than SN2. 13

54. C ..
CH3 Br :
Mechanism
unimolecular slow C
H3C
CH3 + .. Br – : + 16

55. Mechanism C
H3C
CH3 + O : H
bimolecular fast C + O : H
CH3 17

56. carbocation formation
carbocation capture R+
carbocation formation
proton transfer
ROH RX
ROH2 + 21

57. Characteristics of the SN1 mechanism
first order kinetics: rate = k[RX]
unimolecular rate-determining step
carbocation intermediate
follows carbocation stability
rearrangements sometimes observed
reaction is not stereospecific
much racemization in reactions of optically active alkyl halides 19

58. 8.7 Carbocation Stability and SN1 Reaction Rates17

59. Electronic Effects Govern SN1 Rates
The rate of nucleophilic substitution by the SN1 mechanism is governed by electronic effects.
Carbocation formation is rate-determining. The more stable the carbocation, the faster its rate of formation, and the greater the rate of unimolecular nucleophilic substitution. 33

60. RBr solvolysis in aqueous formic acid
Table 8.5 Reactivity of Some Alkyl Bromides Toward Substitution by the SN1 Mechanism
RBr solvolysis in aqueous formic acid
Alkyl bromide Class Relative rate
CH3Br Methyl 0.6
CH3CH2Br Primary 1.0
(CH3)2CHBr Secondary 26
(CH3)3CBr Tertiary ~100,000,000 33

61. Decreasing SN1 Reactivity
(CH3)3CBr
(CH3)2CHBr
CH3CH2Br
Ball and stick models.
CH3Br 34

62. 8.8 Stereochemistry of SN1 Reactions17

63. They do not favor preparation of one stereoisomer over another.
Generalization
Nucleophilic substitutions that exhibit first-order kinetic behavior are not stereospecific.
They do not favor preparation of one stereoisomer over another.
If stereoisomers are formed they are usually racemic. 24

64. Stereochemistry of an SN1 ReactionBr
CH3(CH2)5
R-(–)-2-Bromooctane
(R)-(–)-2-Octanol (17%) H C
CH3 OH
CH3(CH2)5 HO
(CH2)5CH3
(S)-(+)-2-Octanol (83%)
H2O 24

65. Figure 8.6
The Ionization step gives a carbocation and the three bonds to the chiral center become coplanar.
If an ion-pair forms, the leaving group shields one face of carbocation and the nucleophile attacks faster at opposite face.
If the leaving group dissociates, no shielding occurs and the nucleophile attacks equally at either face. 25

66. Figure 8.6 25

67. 8.9 Carbocation Rearrangements in SN1 Reactions17

68. Because...
Carbocations are intermediates in SN1 reactions, therefore, rearrangements are possible. 24

69. Example CH3 C H CHCH3 Br H2O OH CH2CH3 (93%) CH3 C H CHCH3 + H2O CH3 C27

70. 8.10 Effect of Solvent on the Rate of Nucleophilic Substitution17

71. SN1 Reaction Rates Increase in Polar Solvents
In general...
SN1 Reaction Rates Increase in Polar Solvents 29

72. R X  R+ Energy of RX not much affected by polarity of solvent. RX6

73. activation energy decreases;
transition state stabilized by polar solvent
activation energy decreases;
rate increases
R
X  R+
Energy of RX not much affected by polarity of solvent. RX 6

74. SN2 Reaction Rates Increase in Polar Aprotic Solvents
In general...
SN2 Reaction Rates Increase in Polar Aprotic Solvents
An aprotic solvent is one that can not for hydrogen bonds. 24

75. Table 8.7 Relative Rate of SN2 Reactivity versus Type of Solvent
CH3CH2CH2CH2Br N3–
Solvent Type Relative rate
CH3OH polar protic 1
H2O polar protic 7
DMSO polar aprotic 1300
DMF polar aprotic 2800
Acetonitrile polar aprotic 5000 30

76. Mechanism Summary SN1 and SN2
Primary alkyl halides undergo nucleophilic substitution: they always react by the SN2 mechanism.
Tertiary alkyl halides undergo nucleophilic substitution: they always react by the SN1 mechanism.
Secondary alkyl halides undergo nucleophilic substitution: they react by the
SN1 mechanism in the presence of a weak nucleophile (solvolysis).
SN2 mechanism in the presence of a good nucleophile. 1

77. 8.11 Substitution and Elimination as Competing Reactions17

78. Two Reaction Types
Alkyl halides can react with Lewis bases by nucleophilic substitution and/or elimination. C Y H X : – +
-elimination
nucleophilic substitution C H X + Y : – 2

79. Two Reaction Types
How can we tell which reaction pathway is followed for a particular alkyl halide? C Y H X : – +
-elimination
nucleophilic substitution C H X + Y : – 2

80. Elimination versus Substitution
A systematic approach is to choose as a reference point the reaction followed by a typical alkyl halide (secondary) with a typical Lewis base (an alkoxide ion).
The major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism. 2

81. Example CH3CHCH3 Br NaOCH2CH3 ethanol, 55°C CH3CHCH3 OCH2CH3 CH3CH=CH2+
(87%)
(13%) 4

82. Figure 8.8 E2
CH3CH2 O ••
• • – Br 5

83. 5

84. When is Substitution Favored?
Given that the major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with:
1) decreased crowding at the carbon that bears the leaving group 2

85. Uncrowded Alkyl Halides
Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination.
primary alkyl halide
CH3CH2CH2Br
NaOCH2CH3
ethanol, 55°C
CH3CH=CH2 +
CH3CH2CH2OCH2CH3
(9%)
(91%) 8

86. primary alkyl halide + bulky base
But a Crowded Alkoxide Base Can Favor Elimination Even with a Primary Alkyl Halide
primary alkyl halide + bulky base
CH3(CH2)15CH2CH2Br
KOC(CH3)3
tert-butyl alcohol, 40°C +
CH3(CH2)15CH2CH2OC(CH3)3
CH3(CH2)15CH=CH2
(87%)
(13%) 9

87. When is Substitution Favored?
Given that the major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with:
1) decreased crowding at the carbon that bears the leaving group.
2) decreased basicity of the nucleophile. 2

88. Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
KCN
CH3CH(CH2)5CH3 Cl
pKa (HCN) = 9.1
DMSO
(70%)
CH3CH(CH2)5CH3 CN 10

89. Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
NaN3
pKa (HN3) = 4.6 I
(75%) N3 10

90. Tertiary Alkyl Halides
Tertiary alkyl halides are so sterically hindered that elimination is the major reaction with all anionic nucleophiles. Only in solvolysis reactions does substitution predominate over elimination with tertiary alkyl halides. 2

91. 2M sodium ethoxide in ethanol, 25°C 1% 99%
(CH3)2CCH2CH3 Br
Example
CH3CCH2CH3
OCH2CH3
CH3
CH2=CCH2CH3
CH3
CH3C=CHCH3
CH3 + +
ethanol, 25°C
64%
36%
2M sodium ethoxide in ethanol, 25°C 1%
99% 12

92. 8.12 Nucleophilic Substitution of Alkyl Sulfonates17

93. Leaving Groups
We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen.
Halogen is not the only possible leaving group, though.

94. Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate)
Other RX Compounds
ROSCH3 O
ROS O
CH3
Alkyl methanesulfonate (mesylate)
Alkyl p-toluenesulfonate (tosylate)
undergo same kinds of reactions as alkyl halides

95. Preparation
Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine).
ROH +
CH3
SO2Cl
pyridine
ROS O
CH3
(abbreviated as ROTs)

96. Tosylates Undergo Typical Nucleophilic Substitution Reactions
KCN H
CH2OTs H
CH2CN
(86%)
ethanol- water

97. Table 8.8 Approximate Relative Leaving Group Abilities
The best leaving groups are weakly basic.
Leaving Relative Conjugate acid pKa of Group Rate of leaving group conj. acid
F– HF 3.5
Cl– 1 HCl -7
Br– 10 HBr -9
I– HI -10
H2O H3O
TsO– TsOH CF3SO2O– CF3SO2OH -6
Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

98. Tosylates can be Converted to Alkyl Halides
NaBr
OTs
CH3CHCH2CH3 Br
CH3CHCH2CH3
DMSO
(82%)
Tosylate is a better leaving group than bromide.

99. Tosylates Allow Control of Stereochemistry
Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. C H
H3C OH
CH3(CH2)5 C H
H3C
OTs
CH3(CH2)5
TsCl
pyridine

100. Tosylates Allow Control of Stereochemistry
Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes. C H
CH3
(CH2)5CH3 Nu
Nu–
SN2 C H
H3C
OTs
CH3(CH2)5

101. Tosylates also undergo Elimination
CH2=CHCH2CH3
NaOCH3
OTs
CH3CHCH2CH3 +
CH3OH
heat
CH3CH=CHCH3
E and Z

102. Secondary Alcohols React with Hydrogen Halides Predominantly with Net Inversion of Configuration
H3C Br
CH3(CH2)5
CH3
(CH2)5CH3
HBr
87%
13% C H
H3C OH
CH3(CH2)5

103. Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration
H3C Br
CH3(CH2)5
CH3
(CH2)5CH3
HBr
Most reasonable mechanism
is SN1 with front side of carbocation
shielded by leaving group.
87%
13% C H
H3C OH
CH3(CH2)5

104. Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides
HBr Br + Br
93% 7%

105. Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides
HBr 7% + +
93%
Br –
Br – Br + Br

106. End of Chapter 8 Nucleophilic Substitution17