Chapter 8
Nucleophilic Substitution (in depth)
& Competing Elimination
8.1
8.1
Functional Group
Transformation By Nucleophilic
Substitution
Functional Group
Transformation By Nucleophilic
Substitution
Nucleophilic Substitution
–
Y:
+
R
R +
Y
X
Nucleophilic Substitution
–
:X
Substrate cannot be an a vinylic halide or an
aryl halide, except under certain conditions to
be discussed in Chapter 23.
nucleophile is a Lewis base (electron-pair donor)
often negatively charged and used as
Na+ or K+ salt
X
C
X
C
substrate is usually an alkyl halide
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile
R'
..–
O
.. :
+
..
O
..
R
R
(CH3)2CHCH 2ONa + CH3CH2Br
X
gives an ether
R'
+
Example
–
:X
Isobutyl alcohol
(CH3)2CHCH 2OCH2CH3 + NaBr
NaBr
Ethyl isobutyl ether (66%)
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile
O
..–
R
X
R'C O
.. : +
Example
O
CH3(CH2)16C
O
O
CH3(CH2)16C
R'C
R
–
:X
+
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile
H
..–
S
.. :
CH3CH2I
acetone, water
gives an ester
..
O
..
+
OK
CH2CH3 +
O
KI
Ethyl octadecanoate (95%)
Example
KSH + CH3CH(CH 2)6CH3
Br
+
R
X
ethanol, water
gives a thiol
H
..
S
..
KBr
CH3CH(CH2)6CH3 + KBr
R
–
:X
+
SH
2-Nonanethiol
2-Nonanethiol (74%)
Table 8.1 Examples of Nucleophilic Substitution
NaCN
Cyanide ion as the nucleophile
:N
–
C:
+
R
Example
+
Br
X
DMSO
CN
+
NaBr
NaBr
gives a nitrile
:N
C
R
+
:X
–
Cyclopentyl cyanide (70%)
Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile
–
:N
..
+
N
–
N
.. :
gives an alkyl azide
+
–
:N
..
.. N N
+
NaN
NaN3 + CH3CH2CH2CH2CH2I
R
X
2-Propanol
-water
2-Propanol-water
CH3CH2CH2CH2CH2N3 + NaI
NaI
R
+
:X
Iodide ion as the nucleophile
+
Pentyl azide (52%)
–
Table 8.1 Examples of Nucleophilic Substitution
..–
: ..I:
Example
Example
CH3CHCH 3 + NaI
R
X
Br
acetone
gives an alkyl iodide
..
: ..I
NaBr
CH3CHCH 3 + NaBr
R
+
:X
–
I
63%
NaI is soluble in acetone;
NaCl and NaBr are not
soluble in acetone.
Generalization
8.2
Relative Reactivity of Halide
Leaving Groups
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
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?
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?
BrCH
BrCH2CH2CH2Cl + NaCN
NaCN
BrCH
BrCH2CH2CH2Cl + NaCN
NaCN
Br is a better leaving
group than Cl
:N
C
CH2CH2CH2Cl + NaBr
NaBr
Leaving Groups
8.12
Improved Leaving Groups Alkyl Sulfonates
We have seen numerous examples of
nucleophilic substitution in which X in RX
RX is a
halogen.
Halogen is not the only possible leaving
group, though.
Other RX Compounds
O
ROSCH3
O
Alkyl
methanesulfonate
(mesylate)
Preparation
O
ROS
CH3
Tosylates are prepared by the reaction of
alcohols with p-toluenesulfonyl chloride
(usually in the presence of pyridine).
O
Alkyl
p-toluenesulfonate
(tosylate)
undergo same kinds of reactions as alkyl halides
ROH + CH3
SO2Cl
pyridine
O
ROS
O
CH3
(abbreviated as ROTs)
Tosylates Undergo Typical Nucleophilic
Substitution Reactions
H
KCN
H
CH2OTs
ethanolwater
CH2CN
(86%)
Table 8.8
Approximate Relative Reactivity of Leaving Groups
Leaving
Group
Relative
Rate
F–
Cl–
Br –
I–
H 2O
TsO –
CF 3SO 2O–
10 -5
1
10
10 2
10 1
10 5
10 8
Conjugate acid
of leaving group
pKa of
conj. acid
HF
HCl
HBr
HI
H3 O +
TsOH
CF 3SO 2OH
3.5
-7
-9
-10
-1.7
-2.8
-6
Tosylates can be Converted to Alkyl
Halides
CH3CHCH 2CH3
OTs
NaBr
NaBr
DMSO
The best leaving groups are weakly basic.
CH3CHCH 2CH3
Table 8.8
Approximate Relative Reactivity of Leaving Groups
Leaving
Group
Conjugate acid
of leaving group
F–
10 -5
HF
Cl–
1
HCl
Br –
HBr
Sulfonate
esters10are
extremely
good
I–
10 2
HI
sulfonate
ions
are
very
weak
bases.
1
H 2O
10
H3O+
TsO –
10 5
TsOH
CF 3SO 2O–
10 8
CF 3SO 2OH
pKa of
conj. acid
3.5
-7
leaving-9 groups;
-10
-1.7
-2.8
-6
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.
Br
(82%)
Relative
Rate
H
CH3(CH 2)5
TsCl
C
Tosylate is a better leaving group than bromide.
CH3(CH 2)5
H
OH
C
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.
CH3(CH 2)5
H
H
C
OTs
Nu –
8.3
The SN2 Mechanism of
Nucleophilic Substitution
(CH2)5CH3
Nu
C
SN2
CH3
H3C
Kinetics
Many nucleophilic substitutions follow a
second-order rate law.
Bimolecular Mechanism
δ−
HO
CH3
δ−
Br
transition state
CH3Br + HO – → CH3OH + Br –
rate = k[CH 3Br][HO – ]
inference: rate-determining step is bimolecular
HO – + CH3Br
Stereochemistry
one step
HOCH3
+
Br –
Inversion of Configuration
Nucleophilic substitutions that exhibit
second-order kinetic behavior are
stereospecific and proceed with
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.
Stereospecific Reaction
CH3(CH2)5 H
C
The reaction of 2-bromooctane with NaOH
(in ethanol-water) is stereospecific.
NaO
NaOH
Br
H (CH ) CH
2 5
3
HO
C
CH3
CH3
(+)-2-Bromooctane → (–
(–)-2-Octanol
(–)-2-Bromooctane → (+)-2-Octanol
(S)-(+)-2-Bromooctane
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.
(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.
CH3
H
CH3
Br
CH2(CH2)4CH3
HO
H
CH2(CH2)4CH3
Crowding at the Reaction Site
8.4
Steric Effects and
SN2 Reaction Rates
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
Decreasing SN2 Reactivity
RBr + LiI → RI + LiBr
Alkyl
bromide
Class
Relative
rate
CH3Br
Methyl
221,000
CH3CH2Br
Primary
1,350
(CH 3)2CHBr
Secondary
1
(CH 3)3CBr
Tertiary
too small
to measure
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.
CH3Br
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.
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
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
Nucleophiles
The nucleophiles described in Sections 8.1-8.6
have been anions.
–
.. –
.. –
.. –
: N C:
etc.
HS:
HS
HO:
CH3O
HO
.. :
.. :
.. :
Not all nucleophiles are anions. Many are neutral.
..
..
: NH3 for example
HOH
CH3OH
..
..
Many of the solvents in which nucleophilic
substitutions are carried out are themselves
nucleophiles.
nucleophiles.
..
HOH
..
..
CH3OH
..
for example
All nucleophiles,
nucleophiles, however, are Lewis bases.
Solvolysis
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent.
R—Nu + :X—
solvolysis
+
R—Nu—
Nu—H + :X—
R—X + :Nu—
Nu—H
step in which nucleophilic
substitution occurs
Solvolysis
Example: Methanolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X—
solvolysis
R—X + :Nu—
Nu—H
+
R—Nu—
Nu—H + :X—
Methanolysis is a nucleophilic substitution in
which methanol acts as both the solvent and
the nucleophile.
nucleophile.
CH3
R—X + : O:
H
products of overall reaction
R—Nu + HX
CH3
+
–H +
R O:
CH3
R
O
.. :
H
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
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.
ROCCH3
Major factors that control
nucleophilicity
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
basicity
solvation
small negative ions are highly
solvated in protic solvents
large negative ions are less solvated
Major factors that control
nucleophilicity
Table 8.4 Nucleophilicity
Rank
Nucleophile
Relative
rate
good
HO–, RO–
104
RCO2–
103
small negative ions are highly
solvated in protic solvents
H2O, ROH
1
large negative ions are less solvated
fair
weak
When the attacking atom is the same (oxygen
in this case), nucleophilicity increases with
increasing basicity.
basicity.
basicity
solvation
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-
>10 5
good
Br-
10 4
fair
Cl-, F -
10 3
A tight solvent shell around an ion makes it
less reactive. Larger ions are less solvated than
smaller ones and are more nucleophilic.
nucleophilic.