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 23.
5
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile

gives an ether
6
Example
(CH3)2CHCH2ONa CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH3 NaBr
Ethyl isobutyl ether (66)
7
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile

..

O
R'C
..
gives an ester
..


X
R
O
R'C
..
8
Example

CH3(CH2)16C
OK
CH3CH2I
acetone, water

KI
O
CH3(CH2)16C
CH2CH3
Ethyl octadecanoate (95)
9
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile

gives a thiol
10
Example
KSH CH3CH(CH2)6CH3
Br
ethanol, water
KBr
CH3CH(CH2)6CH3
SH
2-Nonanethiol (74)
11
Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile


gives a nitrile


X
R
12
Example
NaCN
DMSO
NaBr
CN
Cyclopentyl cyanide (70)
13
Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile

gives an alkyl azide



X
R
14
Example
NaN3 CH3CH2CH2CH2CH2I
2-Propanol-water
CH3CH2CH2CH2CH2N3 NaI
Pentyl azide (52)
15
Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile


gives an alkyl iodide


X
R
16
Example
acetone

NaBr
CH3CHCH3
NaI is soluble in acetone NaCl and NaBr are not
soluble in acetone.
I
63
17
8.2Relative Reactivity of Halide Leaving Groups
18
Generalization

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

19
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
21
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

23
Bimolecular mechanism

• one step

24
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
  givestereoisomeric products.
• 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-bromooctane is shown. Write the Fischer
  projection of the()-2-octanol formed from it by
  nucleophilic substitution with inversion of
  configuration.

29
8.4Steric Effects in SN2 Reactions
30
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.
31
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

32
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
33
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
34
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.
35
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

36
8.5Nucleophiles and Nucleophilicity
37
Nucleophiles
The nucleophiles described in Sections
8.1-8.6have been anions.
etc.
Not all nucleophiles are anions. Many are
neutral.
..

NH3
for example
All nucleophiles, however, are Lewis bases.
38
Nucleophiles
Many of the solvents in which nucleophilic
substitutions are carried out are
themselvesnucleophiles.
..
for example
The term solvolysis refers to a
nucleophilic substitution in which the
nucleophile is the solvent.
39
Solvolysis
substitution by an anionic nucleophile
RX Nu
RNu X
solvolysis

RNuH X
RX NuH
step in which nucleophilicsubstitution occurs
40
Solvolysis
substitution by an anionic nucleophile
RX Nu
RNu X
solvolysis

RNuH X
RX NuH
products of overall reaction
RNu HX
41
Example Methanolysis
Methanolysis is a nucleophilic substitution in
which methanol acts as both the solvent andthe
nucleophile.
H

RX
The product is a methyl ether.
42
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
43
Nucleophilicity is a measureof 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.

44
Table 8.4 Nucleophilicity

• Rank Nucleophile Relative rate
• strong 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

45
Major factors that control nucleophilicity

• 1) basicity
• 2) solvation
• small negative ions are highly solvated in
  protic solvents
• large negative ions are less solvated
• 3) polarizability

46
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.
47
Major factors that control nucleophilicity

• 1) basicity
• 2) solvation
• small negative ions are highly solvated in
  protic solvents
• large negative ions are less solvated
• 3) polarizability

48
Table 8.4 Nucleophilicity

• Rank Nucleophile Relative rate
• strong 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.
49
Major factors that control nucleophilicity

• 1) basicity
• 2) solvation
• small negative ions are highly solvated in
  protic solvents
• large negative ions are less solvated
• 3) polarizability

50
Table 8.4 Nucleophilicity

• Rank Nucleophile Relative reactivity
• strong I- gt105
• good Br- 104
• fair Cl-, F- 103

More polarizable ions are more nucleophilic
thanless polarizable ones. Polarizability
increases with increasing ionic size.