Chapter 8
Nucleophilic Substitution (in depth)
& Competing Elimination
8.1
Functional Group
Transformation By Nucleophilic
Substitution
8.1
Functional Group
Transformation By Nucleophilic
Substitution
Nucleophilic Substitution
–
Y:
+
R
X
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
Nucleophilic Substitution
Substrate cannot be an a vinylic halide or an
aryl halide, except under certain conditions to
be discussed in Chapter 23.
X
C
C
X
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile
R'
..–
O:
..
+
R
X
gives an ether
R'
..
O
..
R
+
:X
–
Example
(CH3)2CHCH2ONa + CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH3 + NaBr
Ethyl isobutyl ether (66%)
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile
O
..–
+
R
X
R'C O:
..
gives an ester
O
R'C
..
O
..
R
+
:X
–
Example
O
CH3(CH2)16C
OK
+
CH3CH2I
acetone, water
O
CH3(CH2)16C
O
CH2CH3 +
Ethyl octadecanoate (95%)
KI
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile
H
..–
S:
..
H
..
S
..
+
R
X
gives a thiol
R
+
:X
–
Example
KSH + CH3CH(CH2)6CH3
Br
ethanol, water
CH3CH(CH2)6CH3 + KBr
SH
2-Nonanethiol (74%)
Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile
:N
–
C:
+
C
R
R
X
gives a nitrile
:N
+
:X
–
Example
NaCN
+
Br
DMSO
CN
+
NaBr
Cyclopentyl cyanide (70%)
Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile
–
:N
..
–
:
N
..
+
gives an alkyl azide
+
–
:N N N
..
..
R
+
N
R
+
X
:X
–
Example
NaN3 + CH3CH2CH2CH2CH2I
2-Propanol-water
CH3CH2CH2CH2CH2N3 + NaI
Pentyl azide (52%)
Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile
..–
: ..I:
+
R
X
gives an alkyl iodide
..
: ..I
R
+
:X
–
Example
CH3CHCH3 + NaI
Br
acetone
CH3CHCH3 + NaBr
I
63%
NaI is soluble in acetone;
NaCl and NaBr are not
soluble in acetone.
8.2
Relative Reactivity of Halide
Leaving Groups
Generalization
Reactivity of halide leaving groups in
nucleophilic substitution is the same as
for elimination.
RI
most reactive
RBr
RCl
RF
least reactive
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
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
:N
C
CH2CH2CH2Cl + NaBr
8.12
Improved Leaving Groups Alkyl Sulfonates
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.
Other RX Compounds
O
ROSCH3
O
Alkyl
methanesulfonate
(mesylate)
O
ROS
CH3
O
Alkyl
p-toluenesulfonate
(tosylate)
undergo same kinds of reactions as alkyl halides
Preparation
Tosylates are prepared by the reaction of
alcohols with p-toluenesulfonyl chloride
(usually in the presence of pyridine).
ROH + CH3
SO2Cl
pyridine
O
ROS
O
CH3
(abbreviated as ROTs)
Tosylates Undergo Typical Nucleophilic
Substitution Reactions
H
KCN
H
CH2OTs
ethanolwater
CH2CN
(86%)
The best leaving groups are weakly basic.
Table 8.8
Approximate Relative Reactivity of Leaving Groups
Leaving Relative
Group
F–
Cl–
Br–
I–
H 2O
TsO–
CF3SO2O–
Conjugate acid pKa of
Rate
of leaving group
10-5
1
10
102
101
105
108
HF
HCl
HBr
HI
H 3 O+
TsOH
CF3SO2OH
conj. acid
3.5
-7
-9
-10
-1.7
-2.8
-6
Table 8.8
Approximate Relative Reactivity of Leaving Groups
Leaving Relative
Group
Conjugate acid pKa of
Rate
of leaving group
F–
10-5
HF
Cl–
1
HCl
Br–
10
HBr
Sulfonate
esters
are
extremely
good
–
2
I
10
HI
sulfonate
ions are
very weakH bases.
+
H 2O
101
3O
TsO–
105
TsOH
CF3SO2O–
108
CF3SO2OH
conj. acid
3.5
-7
leaving-9groups;
-10
-1.7
-2.8
-6
Tosylates can be Converted to Alkyl
Halides
CH3CHCH2CH3
OTs
NaBr
DMSO
CH3CHCH2CH3
Br
(82%)
Tosylate is a better leaving group than bromide.
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.
H
H
CH3(CH2)5
TsCl
C
CH3(CH2)5
C
OH
pyridine
H3C
H3C
OTs
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.
H
H
CH3(CH2)5
C
Nu–
OTs
(CH2)5CH3
Nu
C
SN2
H3C
CH3
8.3
The SN2 Mechanism of
Nucleophilic Substitution
Kinetics
Many nucleophilic substitutions follow a
second-order rate law.
CH3Br + HO –  CH3OH + Br –
rate = k[CH3Br][HO – ]
inference: rate-determining step is bimolecular
Bimolecular Mechanism

HO

Br
CH3
transition state
one step
HO – + CH3Br
HOCH3 +
Br –
Stereochemistry
Nucleophilic substitutions that exhibit
second-order kinetic behavior are
stereospecific and proceed with
inversion of configuration.
Inversion of Configuration
Nucleophile attacks carbon
from side opposite bond
to the leaving group.
Three-dimensional
arrangement of bonds in
product is opposite to
that of reactant.
Stereospecific Reaction
A stereospecific reaction is one in which
stereoisomeric starting materials give
stereoisomeric products.
The reaction of 2-bromooctane with NaOH
(in ethanol-water) is stereospecific.
(+)-2-Bromooctane  (–)-2-Octanol
(–)-2-Bromooctane  (+)-2-Octanol
Stereospecific Reaction
H (CH ) CH
2 5
3
CH3(CH2)5 H
NaOH
C
Br
CH3
(S)-(+)-2-Bromooctane
HO
C
CH3
(R)-(–)-2-Octanol
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.
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.
CH3
H
CH3
Br
CH2(CH2)4CH3
HO
H
CH2(CH2)4CH3
8.4
Steric Effects and
SN2 Reaction Rates
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.
Table 8.2 Reactivity Toward Substitution by the
SN2 Mechanism
RBr + LiI  RI + LiBr
Alkyl
bromide
Class
Relative
rate
CH3Br
Methyl
221,000
CH3CH2Br
Primary
1,350
(CH3)2CHBr
Secondary
1
(CH3)3CBr
Tertiary
too small
to measure
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
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.
Table 8.3 Effect of Chain Branching on Rate of
SN2 Substitution
RBr + LiI  RI + LiBr
Alkyl
bromide
Structure
Relative
rate
Ethyl
CH3CH2Br
1.0
Propyl
CH3CH2CH2Br
0.8
Isobutyl
(CH3)2CHCH2Br
0.036
Neopentyl
(CH3)3CCH2Br
0.00002
8.5
Nucleophiles and Nucleophilicity
Nucleophiles
The nucleophiles described in Sections 8.1-8.6
have been anions.
–
.. –
.. –
.. –
:
etc.
: N C:
:
:
HS
HO
CH
O
3
..
..
..
Not all nucleophiles are anions. Many are neutral.
..
..
: NH3 for example
CH3OH
HOH
..
..
All nucleophiles, however, are Lewis bases.
Nucleophiles
Many of the solvents in which nucleophilic
substitutions are carried out are themselves
nucleophiles.
..
HOH
..
..
CH3OH
..
for example
Solvolysis
The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent.
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X—
solvolysis
R—X + :Nu—H
step in which nucleophilic
substitution occurs
+
R—Nu—H + :X—
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X—
solvolysis
R—X + :Nu—H
products of overall reaction
+
R—Nu—H + :X—
R—Nu + HX
Example: Methanolysis
Methanolysis is a nucleophilic substitution in
which methanol acts as both the solvent and
the nucleophile.
CH3
CH3
CH3
R—X + : O:
+
R O:
H
H
–H+
R
O
.. :
The product is a
methyl ether.
Typical solvents in solvolysis
solvent
product from RX
water (HOH)
methanol (CH3OH)
ethanol (CH3CH2OH)
ROH
ROCH3
ROCH2CH3
O
O
formic acid (HCOH)
O
acetic acid (CH3COH)
ROCH
O
ROCCH3
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.
Table 8.4 Nucleophilicity
Rank
Nucleophile
strong
good
I-, HS-, RSBr-, HO-,
RO-, CN-, N3NH3, Cl-, F-, RCO2H2O, ROH
RCO2H
fair
weak
very weak
Relative
rate
>105
104
103
1
10-2
Major factors that control
nucleophilicity
basicity
solvation
small negative ions are highly
solvated in protic solvents
large negative ions are less solvated
Table 8.4 Nucleophilicity
Rank
Nucleophile
Relative
rate
good
HO–, RO–
104
RCO2–
103
H2O, ROH
1
fair
weak
When the attacking atom is the same (oxygen
in this case), nucleophilicity increases with
increasing basicity.
Major factors that control
nucleophilicity
basicity
solvation
small negative ions are highly
solvated in protic solvents
large negative ions are less solvated
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.
Table 8.4 Nucleophilicity
Rank
Nucleophile
Relative
rate
strong
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.