Chapter 8 Nucleophilic Substitution

1
Chapter 8Nucleophilic Substitution
2
8.1Functional Group Transformation By
Nucleophilic Substitution
3
Nucleophilic Substitution


R
Y
R
X

• Nucleophile is a Lewis base (electron-pair
  donor),
• often negatively charged and used as Na or K
  salt.
• Substrate is usually an alkyl halide.

4
Nucleophilic Substitution
Substrate cannot be an a vinylic halide or
an aryl halide, except under certain conditions
to be discussed in Chapter 12.
X
5
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile

6
Example
(CH3)2CHCH2ONa CH3CH2Br
Isobutyl alcohol
7
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile

..

O
R'C
..
8
Example

CH3(CH2)16C
OK
CH3CH2I
acetone, water
9
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile

10
Example
KSH CH3CH(CH2)6CH3
Br
ethanol, water
11
Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile


12
Example
NaCN

DMSO
13
Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile
14
Example
NaN3 CH3CH2CH2CH2CH2I
2-Propanol-water
15
Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile


16
Example
acetone
NaI is soluble in acetone NaCl and NaBr are not
soluble in acetone.
17
8.2Relative Reactivity of Halide Leaving Groups
18
Generalization

• Reactivity of halide leaving groups in
  nucleophilic substitution is the same as for
  elimination.

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Problem 8.2
A single organic product was obtained when
1-bromo-3-chloropropane was allowed to react
with one molar equivalent of sodium cyanide in
aqueous ethanol. What was this product?
BrCH2CH2CH2Cl NaCN

• Br is a better leaving group than Cl

20
Problem 8.2
A single organic product was obtained when
1-bromo-3-chloropropane was allowed to react
with one molar equivalent of sodium cyanide in
aqueous ethanol. What was this product?
BrCH2CH2CH2Cl NaCN
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8.3The SN2 Mechanism of Nucleophilic Substitution
22
Kinetics

• Many nucleophilic substitutions follow
  asecond-order rate law. CH3Br HO ?
  CH3OH Br
• rate kCH3BrHO
• inference rate-determining step is bimolecular

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Bimolecular Mechanism

• one step

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Stereochemistry

• Nucleophilic substitutions that
  exhibitsecond-order kinetic behavior are
  stereospecific and proceed withinversion of
  configuration.

25
Inversion of Configuration
26
Stereospecific Reaction

• A stereospecific reaction is one in
  whichstereoisomeric starting materials
  yieldproducts 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

27
Stereospecific Reaction
NaOH
(S)-()-2-Bromooctane
28
Problem 8.4

• The Fischer projection formula for
  ()-2-bromooctaneis shown. Write the Fischer
  projection of the()-2-octanol formed from it by
  nucleophilic substitution with inversion of
  configuration.

29
Problem 8.4

• The Fischer projection formula for
  ()-2-bromooctaneis shown. Write the Fischer
  projection of the()-2-octanol formed from it by
  nucleophilic substitution with inversion of
  configuration.

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8.4Steric Effects and SN2 Reaction Rates
31
Crowding at the Reaction Site
The rate of nucleophilic substitutionby the SN2
mechanism is governedby steric effects.
Crowding at the carbon that bears the leaving
group slows the rate ofbimolecular nucleophilic
substitution.
32
Table 8.2 Reactivity Toward Substitution by the
SN2 Mechanism
RBr LiI ? RI LiBr

• Alkyl Class Relativebromide rate
• CH3Br Methyl 221,000
• CH3CH2Br Primary 1,350
• (CH3)2CHBr Secondary 1
• (CH3)3CBr Tertiary too small to measure

33
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
34
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
35
Crowding Adjacent to the Reaction Site
The rate of nucleophilic substitutionby the SN2
mechanism is governedby steric
effects. Crowding at the carbon adjacentto the
one that bears the leaving groupalso slows the
rate of bimolecularnucleophilic substitution,
but the effect is smaller.
36
Table 8.3 Effect of Chain Branching on Rate of
SN2 Substitution
RBr LiI ? RI LiBr

• Alkyl Structure Relativebromide rate
• Ethyl CH3CH2Br 1.0
• Propyl CH3CH2CH2Br 0.8
• Isobutyl (CH3)2CHCH2Br 0.036
• Neopentyl (CH3)3CCH2Br 0.00002

37
8.5Nucleophiles and Nucleophilicity
38
Nucleophiles
All nucleophiles, however, are Lewis bases.
39
Nucleophiles
Many of the solvents in which nucleophilic
substitutions are carried out are
themselvesnucleophiles.
..
for example
40
Solvolysis
The term solvolysis refers to a
nucleophilic substitution in which the
nucleophile is the solvent.
41
Solvolysis
substitution by an anionic nucleophile
RX Nu
RNu X
42
Solvolysis
substitution by an anionic nucleophile
RX Nu
RNu X
solvolysis

RNuH X
RX NuH
products of overall reaction
RNu HX
43
Example Methanolysis
Methanolysis is a nucleophilic substitution in
which methanol acts as both the solvent andthe
nucleophile.

RX
44
Typical solvents in solvolysis
solvent product from RX water
(HOH) ROH methanol (CH3OH) ROCH3 ethanol
(CH3CH2OH) ROCH2CH3 formic acid
(HCOH) acetic acid (CH3COH)
ROCH
ROCCH3
45
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 relativerate of
  1.0.

46
Table 8.4 Nucleophilicity

• Rank Nucleophile Relative rate
• very good I-, HS-, RS- gt105
• good Br-, HO-, 104
• RO-, CN-, N3-
• fair NH3, Cl-, F-, RCO2- 103
• weak H2O, ROH 1
• very weak RCO2H 10-2

47
Major factors that control nucleophilicity

• Basicity
• Solvation
• Small negative ions are highly solvated in
  protic solvents.
• Large negative ions are less solvated.

48
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 (oxygenin
this case), nucleophilicity increases with
increasing basicity.
49
Major factors that control nucleophilicity

• Basicity
• Solvation
• Small negative ions are highly solvated in
  protic solvents.
• Large negative ions are less solvated.

50
Figure 8.3
Solvation of a chloride ion by ion-dipole
attractiveforces with water. The negatively
charged chlorideion interacts with the
positively polarized hydrogensof water.
51
Table 8.4 Nucleophilicity

• Rank Nucleophile Relative rate
• Very good I- gt105
• good Br- 104
• fair Cl-, F- 103

A tight solvent shell around an ion makes itless
reactive. Larger ions are less solvated
thansmaller ones and are more nucleophilic.
52
8.6The SN1 Mechanism ofNucleophilic
Substitution
53
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.

54
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
55
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
This is the nucleophilic substitutionstage of
the reaction the one withwhich we are
concerned.
56
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
The reaction rate is independentof the
concentration of the nucleophileand follows a
first-order rate law. rate k(CH3)3CBr
57
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
The mechanism of this step isnot SN2. It is
called SN1 and begins with ionization of
(CH3)3CBr.
58
Kinetics and Mechanism
rate kalkyl halide First-order kinetics
implies a unimolecularrate-determining step.

• Proposed mechanism is called SN1, which stands
  forsubstitution nucleophilic unimolecular

59
Mechanism

60
Mechanism
61
carbocation capture
carbocation formation
62
Characteristics of the SN1 mechanism

• first order kinetics rate kRX
• unimolecular rate-determining step
• carbocation intermediate
• ate follows carbocation stability
• rearrangements sometimes observed
• reaction is not stereospecific
• much racemization in reactions of optically
  active alkyl halides

63
8.7Carbocation Stability and SN1 Reaction Rates
64
Electronic Effects Govern SN1 Rates
The rate of nucleophilic substitutionby the SN1
mechanism is governedby electronic
effects. Carbocation formation is
rate-determining.The more stable the
carbocation, the fasterits rate of formation,
and the greater the rate of unimolecular
nucleophilic substitution.
65
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

66
Decreasing SN1 Reactivity
(CH3)3CBr
(CH3)2CHBr
CH3CH2Br
CH3Br
67
8.8Stereochemistry of SN1 Reactions
68
Generalization

• Nucleophilic substitutions that
  exhibitfirst-order kinetic behavior are not
  stereospecific.

69
Stereochemistry of an SN1 Reaction
R-()-2-Bromooctane
70
Figure 8.6
Ionization stepgives carbocation threebonds to
chiralitycenter become coplanar

Leaving group shieldsone face of
carbocationnucleophile attacks faster at
opposite face.
71
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8.9Carbocation Rearrangementsin SN1 Reactions
73
Because...

• carbocations are intermediatesin SN1 reactions,
  rearrangementsare possible.

74
Example
75
8.10Effect of Solventon the Rate of
Nucleophilic Substitution
76
In general...

• SN1 Reaction Rates Increase in Polar Solvents

77
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78
R
Energy of RX not much affected by polarity of
solvent.
RX
79
transition state stabilized by polar solvent
activation energy decreases rate increases
R
Energy of RX not much affected by polarity of
solvent.
RX
80
In general...

• SN2 Reaction Rates Increase inPolar Aprotic
  Solvents

An aprotic solvent is one that doesnot have an
OH group.
81
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

82

• Mechanism SummarySN1 and SN2

83
When...

• 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.

84
8.11Substitution and Eliminationas Competing
Reactions
85
Two Reaction Types
Alkyl halides can react with Lewis bases by
nucleophilic substitution and/or elimination.
86
Two Reaction Types
How can we tell which reaction pathway is
followed for a particular alkyl halide?
87
Elimination versus Substitution
A systematic approach is to choose as a
referencepoint the reaction followed by a
typical alkyl halide(secondary) with a typical
Lewis base (an alkoxideion).

• The major reaction of a secondary alkyl
  halidewith an alkoxide ion is elimination by the
  E2mechanism.

88
Example
NaOCH2CH3 ethanol, 55C
89
Figure 8.8
E2
Br
90
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91
When is Substitution Favored?
Given that the major reaction of a
secondaryalkyl 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

92
Uncrowded Alkyl Halides
Decreased crowding at carbon that bears the
leaving group increases substitution relative to
elimination.

• primary alkyl halide

93
But a Crowded Alkoxide Base Can Favor Elimination
Even with a Primary Alkyl Halide

• primary alkyl halide bulky base

94
When is Substitution Favored?
Given that the major reaction of a
secondaryalkyl 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.

95
Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution
relative to elimination
secondary alkyl halide weakly basic nucleophile
96
Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution
relative to elimination
secondary alkyl halide weakly basic nucleophile
97
Tertiary Alkyl Halides
Tertiary alkyl halides are so sterically
hinderedthat elimination is the major reaction
with allanionic nucleophiles. Only in
solvolysis reactionsdoes substitution
predominate over eliminationwith tertiary alkyl
halides.
98
Example


99
8.12Nucleophilic Substitution of Alkyl Sulfonates
100
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.

101
Other RX Compounds
Alkylmethanesulfonate(mesylate)
Alkylp-toluenesulfonate(tosylate)

• undergo same kinds of reactions as alkyl halides

102
Preparation
Tosylates are prepared by the reaction of
alcohols with p-toluenesulfonyl
chloride(usually in the presence of pyridine).
pyridine

• (abbreviated as ROTs)

103
Tosylates Undergo Typical Nucleophilic
Substitution Reactions
KCN
ethanol-water
104

• The best leaving groups are weakly basic.

105
Table 8.8 Approximate Relative Leaving Group
Abilities

• Leaving Relative Conjugate acid pKa ofGroup
  Rate of leaving group conj. acid
• F 10-5 HF 3.5
• Cl 1 HCl -7
• Br 10 HBr -9
• I 102 HI -10
• H2O 101 H3O -1.7
• TsO 105 TsOH -2.8 CF3SO2O 108
  CF3SO2OH -6

106
Table 8.8 Approximate Relative Leaving Group
Abilities

• Leaving Relative Conjugate acid pKa ofGroup
  Rate of leaving group conj. acid
• F 10-5 HF 3.5
• Cl 1 HCl -7
• Br 10 HBr -9
• I 102 HI -10
• H2O 101 H3O -1.7
• TsO 105 TsOH -2.8 CF3SO2O 108
  CF3SO2OH -6

Sulfonate esters are extremely good leaving
groups sulfonate ions are very weak bases.
107
Tosylates can be Converted to Alkyl Halides
NaBr
DMSO
(82)

• Tosylate is a better leaving group than bromide.

108
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.

TsCl
pyridine
109
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.

110
Tosylates also undergo Elimination
CH2CHCH2CH3
NaOCH3

CH3OH heat
CH3CHCHCH3
E and Z
111
Secondary Alcohols React with Hydrogen Halides
Predominantly with Net Inversion of Configuration
112
Secondary Alcohols React with Hydrogen Halides
with Net Inversion of Configuration
Most reasonable mechanism is SN1 with front side
of carbocation shielded by leaving group.
113
Rearrangements can Occur in the Reaction of
Alcohols with Hydrogen Halides
HBr

93
7
114
Rearrangements can Occur in the Reaction of
Alcohols with Hydrogen Halides
HBr
7
93
Br
Br