Transcript Organic Chemistry Fifth Edition

Chapter 8
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 12.
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
8.3
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
HO – + CH3Br
one step
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 yield
products 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
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 8.1-8.4
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
very good
good
I-, HS-, RSBr-, HO-,
fair
weak
very weak
NH3, Cl-, F-, RCO2H2O, ROH
RCO2H
Relative
rate
>105
104
RO-, CN-, N3103
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
Very good
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.
8.6
The SN1 Mechanism
of
Nucleophilic Substitution
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.
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
CH3
CH3
H
H
CH3
CH3
..
+
+ : O:
O:
C Br :
C
..
H
H
CH
CH
3
3
+
CH3
CH3
C
CH3
..
OH
..
+
H
..
Br :
..
.. –
: Br :
..
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
CH3
CH3
H
H
CH3
CH3
..
+
+ : O:
O:
C Br :
C
..
H
H
CH
CH
3
3
+
This is the nucleophilic substitution
stage of the reaction; the one with
which we are concerned.
.. –
: Br :
..
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
CH3
CH3
H
H
CH3
CH3
..
+
+ : O:
O:
C Br :
C
..
H
H
CH
CH
3
3
+
The reaction rate is independent
of the concentration of the nucleophile
and follows a first-order rate law.
rate = k[(CH3)3CBr]
.. –
: Br :
..
Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
CH3
CH3
H
H
CH3
CH3
..
+
+ : O:
O:
C Br :
C
..
H
H
CH
CH
3
3
+
The mechanism of this step is
not SN2. It is called SN1 and
begins with ionization of (CH3)3CBr.
.. –
: Br :
..
Kinetics and Mechanism
rate = k[alkyl halide]
First-order kinetics implies a unimolecular
rate-determining step.
Proposed mechanism is called SN1, which
stands for
substitution nucleophilic unimolecular
CH3
CH3
Mechanism
..
Br:
..
C
CH3
unimolecular
slow
H3C
+
C
CH3
CH3
+
.. –
: Br :
..
Mechanism
H3C
CH3
+
C
H
: O:
CH3
H
bimolecular
fast
CH3
CH3
H
+
C
CH3
O:
H
carbocation
formation
R+
carbocation
capture
proton
transfer
RX
+
ROH2
ROH
Characteristics of the SN1 mechanism
first order kinetics: rate = k[RX]
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
8.7
Carbocation Stability and SN1
Reaction Rates
Electronic Effects Govern SN1 Rates
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.
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
Decreasing SN1 Reactivity
(CH3)3CBr
(CH3)2CHBr
CH3CH2Br
CH3Br
8.8
Stereochemistry of SN1 Reactions
Generalization
Nucleophilic substitutions that exhibit
first-order kinetic behavior are
not stereospecific.
Stereochemistry of an SN1 Reaction
CH3
H
C
R-(–)-2-Bromooctane
Br
CH3(CH2)5
H
HO
CH3
C
(CH2)5CH3
(S)-(+)-2-Octanol (83%)
CH3
H2O
H
C
OH
CH3(CH2)5
(R)-(–)-2-Octanol (17%)
Figure 8.6
Ionization step
gives carbocation; three
bonds to chirality
center become coplanar
+
Leaving group shields
one face of carbocation;
nucleophile attacks
faster at opposite face.
8.9
Carbocation Rearrangements
in SN1 Reactions
Because...
carbocations are intermediates
in SN1 reactions, rearrangements
are possible.
Example
CH3
CH3
CH3
H2O
C
CHCH3
H
Br
CH3
C
CH2CH3
OH
(93%)
H2O
CH3
CH3
C
H
CH3
CHCH3
+
CH3
C
+
CHCH3
H
8.10
Effect of Solvent
on the
Rate of Nucleophilic Substitution
In general...
SN1 Reaction Rates Increase
in Polar Solvents
 R
X 
R+
Energy of RX
not much
affected by
polarity of
solvent.
RX
transition
state
stabilized by
polar solvent
 R
X 
R+
Energy of RX
not much
affected by
polarity of
solvent.
RX
activation energy
decreases;
rate increases
In general...
SN2 Reaction Rates Increase in
Polar Aprotic Solvents
An aprotic solvent is one that does
not have an —OH group.
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
Mechanism Summary
SN1 and SN2
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.
8.11
Substitution and Elimination
as Competing Reactions
Two Reaction Types
Alkyl halides can react with Lewis bases by
nucleophilic substitution and/or elimination.
-elimination
C
H
C
C
X
+ :Y
C + H Y + :X
–
H
C
C
+ :X
–
Y
nucleophilic substitution
–
Two Reaction Types
How can we tell which reaction pathway is
followed for a particular alkyl halide?
-elimination
C
H
C
C
X
+ :Y
C + H Y + :X
–
H
C
C
+ :X
–
Y
nucleophilic substitution
–
Elimination versus Substitution
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.
Example
CH3CHCH3
Br
NaOCH2CH3
ethanol, 55°C
CH3CHCH3
+
CH3CH=CH2
OCH2CH3
(13%)
(87%)
Figure 8.8
E2
CH3CH2
•• –
O ••
••
Br
When is Substitution Favored?
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
Uncrowded Alkyl Halides
Decreased crowding at carbon that bears the leaving
group increases substitution relative to elimination.
primary alkyl halide
CH3CH2CH2Br
NaOCH2CH3
ethanol, 55°C
CH3CH2CH2OCH2CH3 +
(91%)
CH3CH=CH2
(9%)
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%)
(87%)
When is Substitution Favored?
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 the nucleophile.
Weakly Basic Nucleophile
Weakly basic nucleophile increases
substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
CH3CH(CH2)5CH3
Cl
KCN
pKa (HCN) = 9.1
DMSO
CH3CH(CH2)5CH3
(70%)
CN
Weakly Basic Nucleophile
Weakly basic nucleophile increases
substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
I
NaN3
N3
(75%)
pKa (HN3) = 4.6
Tertiary Alkyl Halides
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.
(CH3)2CCH2CH3
Example
Br
CH3
CH3CCH2CH3
CH3
CH3
+
CH2=CCH2CH3 +
CH3C=CHCH3
OCH2CH3
ethanol, 25°C
64%
36%
2M sodium ethoxide in ethanol, 25°C
99%
1%
8.12
Nucleophilic Substitution of 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 Leaving Group
Abilities
Leaving
Group
F–
Cl–
Br–
I–
H2O
TsO–
CF3SO2O–
Relative
Rate
10-5
1
10
102
101
105
108
Conjugate acid pKa of
of leaving group conj. acid
HF
HCl
HBr
HI
H3O+
TsOH
CF3SO2OH
3.5
-7
-9
-10
-1.7
-2.8
-6
Table 8.8 Approximate Relative Leaving Group
Abilities
Leaving
Group
F–
Cl–
Br–
I–
H2O
TsO–
CF3SO2O–
Relative
Rate
10-5
1
10
102
101
105
108
Conjugate acid pKa of
of leaving group conj. acid
HF
HCl
HBr
HI
H3O+
TsOH
CF3SO2OH
3.5
-7
-9
-10
-1.7
-2.8
-6
Sulfonate esters are extremely good leaving groups; sulfonate ions
are very weak bases.
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
Tosylates also undergo Elimination
CH3CHCH2CH3
OTs
NaOCH3
CH3OH
heat
CH2=CHCH2CH3
+
CH3CH=CHCH3
E and Z
Secondary Alcohols React with Hydrogen Halides
Predominantly with Net Inversion of Configuration
H
CH3
Br
C
87%
H
H3C
(CH2)5CH3
HBr
C
CH3(CH2)5
OH
H
13%
H3C
C
CH3(CH2)5
Br
Secondary Alcohols React with Hydrogen
Halides with Net Inversion of Configuration
H
Most reasonable mechanism
is SN1 with front side of carbocation
shielded by leaving group.
CH3
Br
C
87%
H
H3C
(CH2)5CH3
HBr
C
CH3(CH2)5
OH
H
13%
H3C
C
CH3(CH2)5
Br
Rearrangements can Occur in the Reaction of
Alcohols with Hydrogen Halides
OH
HBr
Br
+
Br
93%
7%
Rearrangements can Occur in the Reaction of
Alcohols with Hydrogen Halides
HBr
OH
7%
+
+
93%
Br –
Br
+
Br
Br –