Chapter 8
I. Nucleophilic Substitution (in depth)
II. Competion with Elimination
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Nucleophilic Substitution
Substrate is a sp3 hybridized carbon atom
(cannot be an a vinylic halide or an
aryl halide except under special conditions to
be discussed in Chem 227)
X
C
C
X
Kinetics
Many nucleophilic substitutions follow a
second-order rate law.
CH3Br + HO –
CH3OH + Br –
rate = k [CH3Br] [HO – ]
What is the reaction order of each starting material?
What can you infer on a molecular level?
What is the overall order of reaction?
Bimolecular mechanism
one step
concerted
HO – + CH3Br
HOCH3 +
Br –
Bimolecular mechanism
one step
concerted
HO – + CH3Br
HOCH3 +
Br –
Bimolecular mechanism
dHO
dBr
CH3
transition state
one step
concerted
HO – + CH3Br
HOCH3 +
Br –
Stereochemistry of SN2 Reactions
Generalization
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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
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
Inversion of configuration (Walden inversion) in an SN2
reaction is due to “back side attack”
P.Walden, Berichte, 29(1): 133-138 (1896)
Riga Polytechnical College
Could there be another mechanism that provides the same
results?
Roundabout SN2 Mechanism
Traditional SN2 Mechanism
Videos courtesy of William L. Hase, Texas Tech University
SN2 Reaction Mechanisms: Gas Phase (2008)
http://pubs.acs.org/cen/news/86/i02/8602notw1.html
Traditional
Physicist Roland Wester and his team in Matthias Weidemüller's group
at the University of Freiburg, in Germany, in collaboration with William
L. Hase's group at Texas Tech University, provide direct evidence for
this mechanism in the gas phase. However, they also detected an
additional, unexpected mechanism. In this new pathway, called the
roundabout mechanism, chloride bumps into the methyl group and
spins the entire methyl iodide molecule 360° before chloride
substitution occurs.
The team imaged SN2 reactions at different collision energies, which
depend on the speed at which chloride smashes into methyl iodide.
Data at lower collision energies support the traditional SN2
mechanism. However, at higher collision energies, about 10% of the
iodide ions fell outside of the expected distribution. "We saw a group of
iodide ions with a much slower velocity than the rest," says Wester.
"Since energy is conserved, if iodide ions are slow, the energy has to
be somewhere else."
On the basis of calculations performed by their colleagues at Texas
Tech, the team concluded that the energy missing from the iodide
transfers to the methyl chloride product in the form of rotational
excitation, supporting the proposed roundabout mechanism.
Roundabout
Fig. 1. Calculated MP2(fc)/ECP/aug-cc-pVDZ Born-Oppenheimer potential energy along the reaction
coordinate g = RC-I - RC-Cl for the SN2 reaction Cl- + CH3I and obtained stationary points
J. Mikosch et al., Science 319, 183 -186 (2008)
Published by AAAS
Fig. 2. (A to D) Center-of-mass images of the I- reaction product velocity from the reaction of Cl- with
CH3I at four different relative collision energies
J. Mikosch et al., Science 319, 183 -186 (2008)
Published by AAAS
Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV that
proceeds via CH3 rotation
J. Mikosch et al., Science 319, 183 -186 (2008)
Published by AAAS
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 (CH2)5CH3
CH3(CH2)5 H
NaOH
C
Br
CH3
(+)-2-Bromooctane
HO
C
CH3
(–)-2-Octanol
Question
(+)-2-Bromooctane
(–)-2-Octanol
H (CH2)5CH3
CH3(CH2)5 H
NaOH
C
Br
HO
C
CH3
CH3
The absolute configurations of (+)-2-bromooctane
and (–)-2-octanol are respectively:
A) R- & R-
B) S- and S-
C) R- & S- D) S- & R-
Answer
(+)-2-Bromooctane
(–)-2-Octanol
H (CH2)5CH3
CH3(CH2)5 H
NaOH
C
Br
HO
C
CH3
CH3
The absolute configurations of (+)-2-bromooctane
and (–)-2-octanol are respectively:
A) R- & R-
B) S- and S-
C) R- & S- D) S- & R-
1) Draw the Fischer projection formula for (+)-S-2-bromooctane.
2) 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
R-
Question
True (A) / False (B)
A racemic mixture of (R- ) and (S- )-2bromobutane produces an optically active
product.
Answer
True (A) / False (B)
A racemic mixture of (R- ) and (S- )-2bromobutane produces an optically active
product.
Optically inactive starting materials
produce optically inactive products. The
products in this case are also racemic.
Inversion occurs with both enantiomers.
A conceptual view of SN2 reactions
Why does the nucleophile attack from the back side?
Steric Effects in SN2 Reactions
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.
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
A bulky substituent in the alkyl halide reduces the
reactivity of the alkyl halide: steric hindrance
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Reaction coordinate diagrams for (a) the SN2 reaction of
methyl bromide and (b) an SN2 reaction of a sterically
hindered alkyl bromide
Question
Which chloride will react faster with NaI in
acetone?
A)
B)
C)
D)
Answer
Which chloride will react faster with NaI in
acetone?
A)
B)
C)
D)
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.
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
Question
Which alkyl chloride will react faster with NaI in
acetone?
A)
B)
C)
D)
Answer
Which alkyl chloride will react faster with NaI in
acetone?
A)
B)
C)
D)
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, (most often 1o)
Nucleophiles
The nucleophiles described in Sections 8.1-8.6
are anions.
–
.. –
.. –
.. –
–
:
N3
: N C:
:
:
HS
HO
CH
O
3
..
..
..
But, all nucleophiles (neutral electron rich molecules)
are Lewis bases.
..
HOH
..
..
CH3OH
..
: NH3
Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile
R'
..–
O:
..
+
R
X
gives an ether
R'
..
O
..
R
+
:X
–
Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile
O
R'C
..–
O:
..
+
R
X
gives an ester
O
R'C
..
O
..
R
+
:X
–
Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile
H
..–
S:
..
H
..
S
..
+
R
X
gives a thiol
R
+
:X
–
Question
Select the major organic product when (S)-2propanol is reacted with SOCl2 in pyridine
followed by the addition of NaSH in ethanol.
A)
B)
C)
D)
Answer
Select the major organic product when (S)-2propanol is reacted with SOCl2 in pyridine
followed by the addition of NaSH in ethanol.
A)
B)
C)
D)
Question
The best combination of reactants for preparing
(CH3)3CSCH3 is:
A) (CH3)3CCl + CH3SK
B) (CH3)3CBr + CH3SNa
C) (CH3)3CSK + CH3OH
D) (CH3)3CSNa + CH3Br
Answer
The best combination of reactants for preparing
(CH3)3CSCH3 is:
A) (CH3)3CCl + CH3SK
B) (CH3)3CBr + CH3SNa
C) (CH3)3CSK + CH3OH
D) (CH3)3CSNa + CH3Br
Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile
:N
–
C:
+
C
R
R
X
gives a nitrile
:N
+
:X
–
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
–
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
Question
What is the major product of the reaction of the
dihalide at the right with 1 equivalent of
NaSH in dimethyl sulfoxide?
A)
B)
C)
D)
Question 8
What is the major product of the reaction of the
dihalide at the right with 1 equivalent of
NaSH in dimethyl sulfoxide?
A)
B)
C)
D)
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
O
ROS
CH3
O
Alkyl
Alkyl
methanesulfonate
p-toluenesulfonate
(mesylate)
(tosylate)
(triflate = -CF3 )
Behave in the same way 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
Nucleophiles and 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
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.
Nucleophiles and Nucleophilicity
SN1 vs. SN2
Nucleophiles
Many of the protic solvents in which
nucleophilic substitutions can be carried out
are themselves nucleophiles.
..
HOH
..
..
CH3OH
.. and EtOH for example
Solvolysis
The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent.
SN2 Reactions are favored in
Polar Aprotic Non-nucleophilic Solvents
An aprotic solvent is one that does
not have an —OH group.
SN1 Reactions are favored in
Polar Protic Solvents
Solvolysis
Substitution by an anionic nucleophile: SN2 kinetics
R—X + :Nu—
R—Nu + :X—
Solvolysis: SN1 kinetics
+
R—Nu—H + :X—
R—X + :Nu—H
Carbocation
intemediate
2nd
intermediate
Solvolysis
Substitution by an anionic nucleophile in an aprotic
non-nucleophilic solvent SN2 kinetics
R—X + :Nu—
R—Nu + :X—
Solvolysis (protic solvents) : SN1 kinetics
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.
Some 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
Question
Which of the following is not a good nucleophile
in an SN1 solvolysis reaction?
A) NaOCH3
B) CH3OH
C) CH3CH2OH
D) H2O
Answer
Which of the following is not a good nucleophile
in an SN1 solvolysis reaction?
A) NaOCH3
B) CH3OH
C) CH3CH2OH
D) H2O