Chapter 8
Nucleophilic Substitution
Dr. Wolf's CHM 201 & 202
8-1
Functional Group
Transformation By Nucleophilic
Substitution
Dr. Wolf's CHM 201 & 202
8-2
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
Dr. Wolf's CHM 201 & 202
8-3
Nucleophilic Substitution
Substrate cannot be an a vinylic halide or an
aryl halide, except under certain conditions to
be discussed in Chapter 12.
X
C
Dr. Wolf's CHM 201 & 202
C
X
8-4
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile
R'
..–
O:
..
+
..
O
..
R
R
X
gives an ether
R'
Dr. Wolf's CHM 201 & 202
+
:X
–
8-5
Example
(CH3)2CHCH2ONa + CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH3 + NaBr
Ethyl isobutyl ether (66%)
Dr. Wolf's CHM 201 & 202
8-6
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile
O
..–
+
R
X
R'C O:
..
gives an ester
O
R'C
Dr. Wolf's CHM 201 & 202
..
O
..
R
+
:X
–
8-7
Example
O
CH3(CH2)16C
OK
+
CH3CH2I
acetone, water
O
CH3(CH2)16C
O
CH2CH3 +
KI
Ethyl octadecanoate (95%)
Dr. Wolf's CHM 201 & 202
8-8
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile
H
..–
S:
..
+
H
..
S
..
R
R
X
gives a thiol
Dr. Wolf's CHM 201 & 202
+
:X
–
8-9
Example
KSH + CH3CH(CH2)6CH3
Br
ethanol, water
CH3CH(CH2)6CH3 + KBr
SH
2-Nonanethiol (74%)
Dr. Wolf's CHM 201 & 202
8-10
Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile
:N
–
C:
+
C
R
R
X
gives a nitrile
:N
Dr. Wolf's CHM 201 & 202
+
:X
–
8-11
Example
NaCN +
Br
DMSO
CN
+ NaBr
Cyclopentyl cyanide (70%)
Dr. Wolf's CHM 201 & 202
8-12
Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile
–
:N
..
–
:
N
..
+
gives an alkyl azide
+
–
:N N N
..
..
R
Dr. Wolf's CHM 201 & 202
+
N
R
+
X
:X
–
8-13
Example
NaN3 + CH3CH2CH2CH2CH2I
2-Propanol-water
CH3CH2CH2CH2CH2N3 + NaI
Pentyl azide (52%)
Dr. Wolf's CHM 201 & 202
8-14
Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile
..–
: ..I:
+
R
X
gives an alkyl iodide
..
: ..I
Dr. Wolf's CHM 201 & 202
R
+
:X
–
8-15
Example
CH3CHCH3 + NaI
Br
acetone
CH3CHCH3 + NaBr
I
Dr. Wolf's CHM 201 & 202
NaI is soluble in acetone;
NaCl and NaBr are not
soluble in acetone.
63%
8-16
Relative Reactivity of Halide
Leaving Groups
Dr. Wolf's CHM 201 & 202
8-17
Generalization
•Reactivity of halide leaving groups in
nucleophilic substitution is the same
as for elimination.
RI
most reactive
RBr
RCl
RF
Dr. Wolf's CHM 201 & 202
least reactive
8-18
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
Dr. Wolf's CHM 201 & 202
8-19
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
:N
Dr. Wolf's CHM 201 & 202
C
CH2CH2CH2Cl + NaBr
8-20
The SN2 Mechanism of
Nucleophilic
Substitution
Dr. Wolf's CHM 201 & 202
8-21
Kinetics
•Many nucleophilic substitutions follow a
second-order rate law.
CH3Br + HO –  CH3OH + Br –
• rate = k[CH3Br][HO – ]
• inference: rate-determining step is bimolecular
Dr. Wolf's CHM 201 & 202
8-22
Bimolecular
mechanism

HO

Br
CH3
transition state
HO – + CH3Br
Dr. Wolf's CHM 201 & 202
•one step
HOCH3 +
Br –
8-23
Stereochemistry
•Nucleophilic substitutions that exhibit
second-order kinetic behavior are
stereospecific and proceed with
inversion of configuration.
Dr. Wolf's CHM 201 & 202
8-24
Inversion of Configuration
nucleophile attacks carbon
from side opposite bond
to the leaving group
Dr. Wolf's CHM 201 & 202
three-dimensional
arrangement of bonds in
product is opposite to
that of reactant
8-25
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
Dr. Wolf's CHM 201 & 202
8-26
Stereospecific Reaction
H (CH ) CH
2 5
3
CH3(CH2)5 H
NaOH
C
Br
CH3
(S)-(+)-2-Bromooctane
Dr. Wolf's CHM 201 & 202
HO
C
CH3
(R)-(–)-2-Octanol
8-27
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
Dr. Wolf's CHM 201 & 202
HO
H
CH2(CH2)4CH3
8-28
Steric Effects in SN2
Reactions
Dr. Wolf's CHM 201 & 202
8-29
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.
Dr. Wolf's CHM 201 & 202
8-30
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
too small
to measure
Dr. Wolf's CHM 201 & 202
Tertiary
8-31
Decreasing SN2
Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Dr. Wolf's CHM 201 & 202
8-32
Decreasing SN2
Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Dr. Wolf's CHM 201 & 202
8-33
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.
Dr. Wolf's CHM 201 & 202
8-34
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
Dr. Wolf's CHM 201 & 202
0.00002
8-35
Nucleophiles and Nucleophilicity
Dr. Wolf's CHM 201 & 202
8-36
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.
Dr. Wolf's CHM 201 & 202
8-37
Nucleophiles
Many of the solvents in which nucleophilic
substitutions are carried out are themselves
nucleophiles.
..
HOH
..
..
CH3OH
..
for example
The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent.
Dr. Wolf's CHM 201 & 202
8-38
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X—
solvolysis
R—X + :Nu—H
+
R—Nu—H + :X—
step in which nucleophilic
substitution occurs
Dr. Wolf's CHM 201 & 202
8-39
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X—
solvolysis
R—X + :Nu—H
+
R—Nu—H + :X—
products of overall reaction
R—Nu + HX
Dr. Wolf's CHM 201 & 202
8-40
Example: Methanolysis
Methanolysis is a nucleophilic substitution in
which methanol acts as both the solvent and
the nucleophile.
CH3
R—X + : O:
+
R O:
H
H
Dr. Wolf's CHM 201 & 202
CH3
CH3
–H+
R
O
.. :
The product
is a methyl
ether.
8-41
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)
Dr. Wolf's CHM 201 & 202
ROCH
O
ROCCH3
8-42
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.
Dr. Wolf's CHM 201 & 202
8-43
Table 8.4 Nucleophilicity
Rank
Nucleophile
strong
good
I-, HS-, RSBr-, HO-,
RO-, CN-, N3NH3, Cl-, F-, RCO2H2O, ROH
RCO2H
fair
weak
very weak
Dr. Wolf's CHM 201 & 202
Relative
rate
>105
104
103
1
10-2
8-44
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
Dr. Wolf's CHM 201 & 202
8-45
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.
Dr. Wolf's CHM 201 & 202
8-46
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
Dr. Wolf's CHM 201 & 202
8-47
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.
Dr. Wolf's CHM 201 & 202
8-48
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
Dr. Wolf's CHM 201 & 202
8-49
Table 8.4 Nucleophilicity
Rank
Nucleophile
Relative
reactivity
strong
I-
>105
good
Br-
104
fair
Cl-, F-
103
More polarizable ions are more nucleophilic than
less polarizable ones. Polarizability increases
with increasing ionic size.
Dr. Wolf's CHM 201 & 202
8-50
Unimolecular Nucleophilic
Substitution
SN1
Dr. Wolf's CHM 201 & 202
8-51
Tertiary alkyl halides are very unreactive in
substitutions that proceed by the SN2 mechanism.
But they do undergo nucleophilic
substitution.
But by a mechanism different from SN2.
The most common examples are seen in
solvolysis reactions.
Dr. Wolf's CHM 201 & 202
8-52
Example of a solvolysis: Hydrolysis of tert-butyl bromide
CH3
CH3
C
H
..
Br :
..
+
: O:
H
CH3
CH3
CH3
C
..
OH
..
+
H
..
Br :
..
CH3
Dr. Wolf's CHM 201 & 202
8-53
Example of a solvolysis: Hydrolysis of tert-butyl bromide
CH3
CH3
C
H
..
Br :
..
+
CH3
: O:
H
+
O:
C
H
CH3
CH3
H
CH3
+
CH3
CH3
C
..
OH
..
+
H
..
Br :
..
.. –
: Br :
..
CH3
Dr. Wolf's CHM 201 & 202
8-54
Example of a solvolysis: Hydrolysis of tert-butyl bromide
CH3
CH3
C
CH3
H
..
Br :
..
+
: O:
CH3
CH3
H
+
O:
C
H
H
CH3
+
This is the nucleophilic substitution
stage of the reaction; the one with
which we are concerned.
Dr. Wolf's CHM 201 & 202
.. –
: Br :
..
8-55
Example of a solvolysis: Hydrolysis of tert-butyl bromide
CH3
CH3
C
CH3
H
..
Br :
..
+
CH3
: O:
CH3
H
+
O:
C
H
H
CH3
+
The reaction rate is independent
of the concentration of the nucleophile
and follows a first-order rate law.
rate = k[(CH3)3CBr]
Dr. Wolf's CHM 201 & 202
.. –
: Br :
..
8-56
Example of a solvolysis: Hydrolysis of tert-butyl bromide
CH3
CH3
C
CH3
H
..
Br :
..
+
CH3
: O:
CH3
H
+
O:
C
H
H
CH3
+
The mechanism of this step is
not SN2. It is called SN1 and
begins with ionization of (CH3)3CBr.
Dr. Wolf's CHM 201 & 202
.. –
: Br :
..
8-57
rate = k[alkyl halide]
First-order kinetics implies a unimolecular
rate-determining step.
Proposed mechanism is called SN1, which stands
for
substitution nucleophilic unimolecular
Dr. Wolf's CHM 201 & 202
8-58
CH3
CH3
..
Br :
..
C
CH3
unimolecular
slow
H3C
+
C
CH3
+
.. –
: Br :
..
CH3
Dr. Wolf's CHM 201 & 202
8-59
H3C
CH3
+
C
H
: O:
CH3
H
bimolecular
fast
CH3
CH3
H
+
C
CH3
Dr. Wolf's CHM 201 & 202
O:
H
8-60
carbocation
formation
carbocation
capture
R+
proton
transfer
RX
+
ROH2
Dr. Wolf's CHM 201 & 202
ROH
8-61
Characteristics of the SN1 mechanism
first order kinetics: rate = k[RX]
unimolecular rate-determining step
carbocation intermediate
rate follows carbocation stability
rearrangements sometimes observed
reaction is not stereospecific
much racemization in reactions of
optically active alkyl halides
Dr. Wolf's CHM 201 & 202
8-62
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.
Dr. Wolf's CHM 201 & 202
8-63
Table 8.5 Reactivity toward substitution
by the SN1 mechanism
RBr solvolysis in aqueous formic acid
Alkyl bromide Class
Relative rate
CH3Br
Methyl
1
CH3CH2Br
Primary
2
(CH3)2CHBr
Secondary
(CH3)3CBr
Tertiary
Dr. Wolf's CHM 201 & 202
43
100,000,000
8-64
Decreasing SN1 reactivity
(CH3)3CBr
(CH3)2CHBr
CH3CH2Br
Dr. Wolf's CHM 201 & 202
CH3Br
8-65
Stereochemistry of SN1 Reactions
Dr. Wolf's CHM 201 & 202
8-66
Nucleophilic substitutions that exhibit
first-order kinetic behavior are
not stereospecific.
Dr. Wolf's CHM 201 & 202
8-67
Stereochemistry of an SN1 Reaction
CH3
H
C
R-(–)-2-Bromooctane
Br
CH3(CH2)5
H
HO
CH3
CH3
H2O
H
C
OH
C
(CH2)5CH3
(S)-(+)-2-Octanol (83%)
Dr. Wolf's CHM 201 & 202
CH3(CH2)5
(R)-(–)-2-Octanol (17%)
8-68
Figure 8.8
Ionization step
gives carbocation; three
bonds to stereogenic
center become coplanar
+
–
Dr. Wolf's CHM 201 & 202
8-69
Figure 8.8
+
–
Leaving group shields
one face of carbocation;
nucleophile attacks
faster at opposite face.
Dr. Wolf's CHM 201 & 202
8-70
Figure 8.8
–
+
–
–
More than 50%
Dr. Wolf's CHM 201 & 202
Less than 50%
8-71
Carbocation Rearrangements in
SN1 Reactions
Dr. Wolf's CHM 201 & 202
8-72
Because carbocations are intermediates
in SN1 reactions, rearrangements
are possible.
Dr. Wolf's CHM 201 & 202
8-73
Example
CH3
CH3
CH3
H2O
C
CHCH3
H
Br
Dr. Wolf's CHM 201 & 202
CH3
C
OH
CH2CH3
(93%)
8-74
Example
CH3
CH3
CH3
C
CHCH3
H
Br
CH3
C
CH2CH3
OH
(93%)
H2O
CH3
CH3
C
H
Dr. Wolf's CHM 201 & 202
CH3
CHCH3
+
CH3
C
+
CHCH3
H
8-75
Solvent Effects
Dr. Wolf's CHM 201 & 202
8-76
SN1 Reaction Rates Increase
in Polar Solvents
Dr. Wolf's CHM 201 & 202
8-77
Table 8.6
SN1 Reactivity versus Solvent
Polarity
Solvent
acetic acid
methanol
formic acid
water
Dielectric
constant
Relative
rate
6
33
58
78
1
4
5,000
150,000
Most polar
Dr. Wolf's CHM 201 & 202
Fastest rate
8-78
transition
state
stabilized by
polar solvent
+ R
X 
R+
energy of RX
not much
affected by
polarity of
RX
solvent
Dr. Wolf's CHM 201 & 202
8-79
transition
state
stabilized by
polar solvent
activation energy
decreases;
rate increases
+ R
X 
R+
energy of RX
not much
affected by
polarity of
RX
solvent
Dr. Wolf's CHM 201 & 202
8-80
SN2 Reaction Rates Increase in
Polar Aprotic Solvents
An aprotic solvent is one that does
not have an —OH group.
So it does not solvate anion well
allowing it to be effective nucleophile
Dr. Wolf's CHM 201 & 202
8-81
Table 8.7
SN2 Reactivity
versus Type
Solvent
Table
8.7 SN2 Reactivity
vs of
Solvent
CH3CH2CH2CH2Br + N3–
Solvent
CH3OH
H2O
DMSO
DMF
Acetonitrile
Dr. Wolf's CHM 201 & 202
Type
polar protic
polar protic
polar aprotic
polar aprotic
polar aprotic
Relative
rate
1
7
1300
2800
5000
8-82
Mechanism Summary
SN1 and SN2
Dr. Wolf's CHM 201 & 202
8-83
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
Dr. Wolf's CHM 201 & 202
8-84
Substitution And Elimination
As Competing Reactions
Dr. Wolf's CHM 201 & 202
8-85
We have seen that alkyl halides can react with Lewis
bases in two different ways. They can undergo
nucleophilic substitution or elimination.
b-elimination
C
H
C
C
+ :Y
X
C + H Y + :X
–
–
H
C
C
+ :X
–
Y
Dr. Wolf's CHM 201 & 202
nucleophilic substitution
8-86
How can we tell which reaction pathway is followed
for a particular alkyl halide?
b-elimination
C
H
C
C
+ :Y
X
C + H Y + :X
–
–
H
C
C
+ :X
–
Y
Dr. Wolf's CHM 201 & 202
nucleophilic substitution
8-87
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.
Dr. Wolf's CHM 201 & 202
8-88
Example
CH3CHCH3
Br
NaOCH2CH3
ethanol, 55°C
CH3CHCH3
+
CH3CH=CH2
OCH2CH3
(13%)
Dr. Wolf's CHM 201 & 202
(87%)
8-89
Figure 8.11
E2
CH3CH2
Dr. Wolf's CHM 201 & 202
..
O:
..
–
Br
8-90
Figure 8.11
SN2
CH3CH2
Dr. Wolf's CHM 201 & 202
..–
O:
..
Br
8-91
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
Dr. Wolf's CHM 201 & 202
8-92
Decreased crowding at carbon that bears the
leaving group increases substitution relative
to elimination.
primary alkyl halide
CH3CH2CH2Br
NaOCH2CH3
ethanol, 55°C
CH3CH2CH2OCH2CH3 +
(91%)
Dr. Wolf's CHM 201 & 202
CH3CH=CH2
(9%)
8-93
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
(13%)
Dr. Wolf's CHM 201 & 202
(87%)
8-94
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 nucleophile
Dr. Wolf's CHM 201 & 202
8-95
Weakly basic nucleophile increases
substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
CH3CH(CH2)5CH3
Cl
KCN
SN2
pKa (HCN) = 9.1
DMSO
CH3CH(CH2)5CH3
CN
(70%)
Dr. Wolf's CHM 201 & 202
8-96
Weakly basic nucleophile increases
substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
I
SN2
pKa (HN3) = 4.6
NaN3
(even weaker base)
N3
(75%)
Dr. Wolf's CHM 201 & 202
8-97
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.
Dr. Wolf's CHM 201 & 202
8-98
(CH3)2CCH2CH3
Example
Br
CH3
CH3CCH2CH3
CH3
+
CH2=CCH2CH3 +
CH3
CH3C=CHCH3
OCH2CH3
ethanol, 25°C
36%
64%
2M sodium ethoxide in ethanol, 25°C
1%
99%
Dr. Wolf's CHM 201 & 202
8-99
Mechanism Summary
SN1 and SN2 and E1 and E2
Under 2nd order conditions…..
STRONG base/nucleophile eg. -OH, -OR
ELIMINATION favored with 30 , 20,
(and 10 with bulky base eg. -OtBu)
SUBSTITUTION favored with 10 (aprotic solvent helps)
With WEAK base but good nucleophile e.g. -CN, -N3
Or Under 1st order conditions…..
WEAK base/nucleophile (solvolysis) e.g. H2O, ROH,
SUBSTITUTION favored (increased solvent polarity helps)
Dr. Wolf's CHM 201 & 202
8-100
Nucleophilic Substitution
of Alkyl Sulfonates
Dr. Wolf's CHM 201 & 202
8-101
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
Dr. Wolf's CHM 201 & 202
8-102
Other RX compounds
O
O
HOSOH
ROSCH3
O
O
Sulfuric
acid
O
ROS
Alkyl
methanesulfonate
(mesylate)
CH3
O
Alkyl
p-toluenesulfonate
(tosylate)
• undergo same kinds of reactions as alkyl halides
Dr. Wolf's CHM 201 & 202
8-103
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
CH3
• (abbreviated as ROTs)
O
Dr. Wolf's CHM 201 & 202
8-104
Tosylates undergo typical
nucleophilic substitution
reactions
H
KCN
H
CH2OTs
ethanolwater
CH2CN
(86%)
SN2
Dr. Wolf's CHM 201 & 202
8-105
•The best leaving groups are weakly basic
Dr. Wolf's CHM 201 & 202
8-106
Table 8.8
Approximate Relative Reactivity of
Leaving Groups
•Leaving GroupRelative Conjugate acid Ka of
Rate
of leaving group conj. acid
•
F–
10-5
HF
3.5 x 10-4 wk acid
•
Cl–
1
HCl
107
•
Br–
10
HBr
109
•
I–
102
HI
1010
•
H2O
101
H3O+
56
•
TsO–
105
TsOH
600
• CF3SO2O–
108
CF3SO2OH
106
Dr. Wolf's CHM 201 & 202
8-107
Table 8.8
Approximate Relative Reactivity of
Leaving Groups
•Leaving GroupRelative Conjugate acid Ka of
Rate
of leaving group conj. acid
•
F–
10-5
HF
3.5 x 10-4
•
Cl–
1
HCl
107
Sulfonate esters are extremely good leaving groups;
9
•sulfonate
Br– ions are
10 very weakHBr
10
bases.
•
I–
102
HI
1010
•
H2O
101
H3O+
56
•
TsO–
105
TsOH
600
• CF3SO2O– 108
CF3SO2OH
106
Dr. Wolf's CHM 201 & 202
8-108
Tosylates can be converted to
alkyl halides
CH3CHCH2CH3
OTs
NaBr
DMSO
SN2
CH3CHCH2CH3
Br
(82%)
• Tosylate is a better leaving group than bromide.
Dr. Wolf's CHM 201 & 202
8-109
Tosylates allow control of
stereochemistry
•
Preparation of tosylate does not affect any of
the bonds to the stereogenic 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
OTs
pyridine
H3C
Dr. Wolf's CHM 201 & 202
H3C
8-110
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
Dr. Wolf's CHM 201 & 202
CH3
8-111
Looking Back:
Reactions of Alcohols
with
Hydrogen Halides
Dr. Wolf's CHM 201 & 202
8-112
Secondary alcohols
react with hydrogen halides
with net inversion of
configuration
H
CH3
Br
C
87%
H
H3C
(CH2)5CH3
HBr
C
CH3(CH2)5
OH
H
13%
Since some racemization,
can’t be SN2
Dr. Wolf's CHM 201 & 202
H3C
C
Br
CH3(CH2)5
8-113
Secondary alcohols
react with hydrogen halides
with net inversion of
configuration
H
•
H
CH3
Br
C
87%
(CH2)5CH3
H3C
Most reasonableHBr
mechanism is SN1 with front side of
C shielded
carbocation
by leaving group
OH
CH3(CH2)5
H
13%
H3C
C
Br
CH3(CH2)5
Dr. Wolf's CHM 201 & 202
8-114
Rearrangements
can occur in the
reaction of
alcohols with
hydrogen halides
OH
HBr
Br
+
Br
93%
Dr. Wolf's CHM 201 & 202
7%
8-115
Rearrangements
HBr
OH
7%
+
+
93%
Br –
Br
Br –
+
Br
Dr. Wolf's CHM 201 & 202
8-116
End of Chapter 8
Dr. Wolf's CHM 201 & 202
8-117