Download Ch. 6 - Department of Chemistry and Biochemistry

Chapter 6
Nucleophilic Substitution
and Elimination Reactions
of Alkyl Halides
Created by
Professor William Tam & Dr. Phillis Chang
Ch. 6 - 1
About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor
William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in
1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an
NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard
University (USA). He joined the Department of Chemistry at the University of
Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and
Associate Chair in the department. Professor Tam has received several awards
in research and teaching, and according to Essential Science Indicators, he is
currently ranked as the Top 1% most cited Chemists worldwide. He has
published four books and over 80 scientific papers in top international journals
such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her
M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She
lives in Guelph with her husband, William, and their son, Matthew.
Ch. 6 - 2
1. Organic Halides




C X
X = Cl, Br, I

Halogens are more electronegative
than carbon
Ch. 6 - 3
Carbon-Halogen Bond Lengths
and Bond Strength
H
H C F
H
C–X Bond
Length (Å)
1.39
H
H
H
C Br
H
H
H
H C I
H
1.78
1.93
2.14
C Cl
H
increase
C–X Bond
Strength
(kJ/mol)
472
350
293
decrease
239
Ch. 6 - 4
1A. Physical Properties of Organic Halides:
Boiling Point (bp/oC)
Group
Fluoride
Chloride
Bromide
Iodide
Me
-78.4
-23.8
3.6
42.5
Et
-37.7
13.1
38.4
72
Bu
32
78.4
101
130
s
Bu
-
68
91.2
120
i
Bu
-
69
91
119
12
51
73.3
100(dec)
t
Bu
Ch. 6 - 5
Physical Properties of Organic Halides:
Density (r)
Group
Fluoride
Chloride
Bromide
Iodide
Me
0.84(-60)
0.92
1.73(0)
2.28
Et
0.72
0.91(15)
1.46
1.95
Bu
0.78
0.89
1.27
1.61
s
Bu
-
0.87
1.26
1.60
i
Bu
-
0.87
1.26
1.60
0.75(12)
0.84
1.22
1.57(0)
t
Bu
Ch. 6 - 6
Different Types of Organic Halides
 Alkyl halides (haloalkanes)
C
Attached to
1 carbon atom
X
Attached to
2 carbon atoms
sp3
Attached to
3 carbon atoms
C
C
Cl
a 1o chloride
C
C
Br
a 2o bromide
C
C
I
a 3o iodide
Ch. 6 - 7

Vinyl halides (Alkenyl halides)
sp2
X

Aryl halides
sp2
X
benzene or aromatic ring

Acetylenic halides (Alkynyl halides)
sp
X
Ch. 6 - 8
sp
 C
X
3

Alkyl halides
sp2
X


Prone to undergo
Nucleophilic Substitutions
(SN) and Elimination
Reactions (E) (the focus
of this Chapter)
sp2
X
sp
X
Different reactivity than alkyl halides,
and do not undergo SN or E reactions
Ch. 6 - 9
2. Nucleophilic Substitution Reactions
Nu +
(nucleophile)
The Nu⊖
donates
an e⊖ pair
to the
substrate



C X
(substrate)
The bond
between
C and LG
breaks,
giving both
e⊖ from the
bond to LG
Nu
C
(product)
The Nu⊖ uses
its e⊖ pair to
form a new
covalent bond
with the
substrate C
+ X
(leaving
group)
The LG
gains the
pair of e⊖
originally
bonded
in the
substrate
Ch. 6 - 10
Timing of The Bond Breaking & Bond
Making Process

Two types of mechanisms
● 1st type: SN2 (concerted mechanism)
R
HO
R

C
R
R

Br
R



HO

Br
C
R
R
transition state (T.S.)
HO
C
R
R
+ BrCh. 6 - 11
● 2nd type: SN1 (stepwise mechanism)
Step (1):
R
R C Br
R
(k 1 )
slow
r.d.s.
R
R C
R
+ Br
k1 << k2 and k3
Step (2)
R
R
H
(k 2 )
R C + H 2O
R C O
fast
H
R
R
Step (3)
R
R
H
(k3)
+
+
+
R C O
H 2O
R C OH H3O
fast
H
R
R
Ch. 6 - 12
3. Nucleophiles
A reagent that seeks a positive center
 Has an unshared pair of e⊖
e.g.: HO , CH3O , H2N (negative charge)

H2O, NH3
(neutral)
This is the positive
center that the
Nu⊖ seeks

C

X
Ch. 6 - 13

Examples:
H H
HO +
C
CH3 Cl
(Nu ) (substrate)
H H
+
O
C
H
H
CH3 Cl
(Nu )
(substrate)
H H
+ Cl
C
CH3 OH
(product) (L.G.)
H H
C
H + Cl
CH3 O
(L.G.)
H
H H
(product)
C
+ H3O
CH3 OH
Ch. 6 - 14
4. Leaving Groups

To be a good leaving group, the substituent
must be able to leave as a relatively stable,
weakly basic molecule or ion
e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3
OTs =
O
O S
O
OMs =
O
O S CH3 (Mesylate)
O
CH3 (Tosylate)
Ch. 6 - 15
5. Kinetics of a Nucleophilic Substitution
Reaction: An SN2 Reaction
HO + CH3 Br
HO CH3 + Br
-
Rate = k[CH3Br][OH ]
The rate of the substitution reaction is
linearly dependent on the
concentration of OH⊖ and CH3Br
 Overall, a second-order reaction 
bimolecular

Ch. 6 - 16
5A. How Do We Measure the Rate of
This Reaction?
e.g.:
HO
(Nu )

H
+
H
H
C Cl
H
(substrate)
HO C
H
H
(product)
+ Cl
(leaving
group)
The rate of reaction can be measured by
● The consumption of the reactants
(HO⊖ or CH3Cl) or
● The appearance of the products
(CH3OH or Cl⊖) over time
Ch. 6 - 17
Concentration, M
Graphically…
[CH3Cl] ↓
[CH3OH] ↑
Time, t
Rate =
Δ[CH3Cl]
Δt
=−
[CH3Cl]t=t − [CH3Cl]t=0
Time in seconds
Ch. 6 - 18
Concentration, M
Initial Rate
[CH3Cl]t=0
[CH3Cl]t=t
[CH3Cl]
Time, t
[CH3Cl]t=t − [CH3Cl]t=0
Initial Rate
=−
(from slope)
Δt
Ch. 6 - 19

Example:
HO + Cl CH3
[OH⊖]t=0
60oC
H2O
[CH3Cl]t=0
HO CH3 + Cl
Initial rate
mole L-1, s-1
Result
1.0 M
0.0010 M
4.9 × 10-7
1.0 M
0.0020 M
9.8 × 10-7 Doubled
2.0 M
0.0010 M
9.8 × 10-7 Doubled
2.0 M
0.0020 M
19.6 × 10-7 Quadrupled
Ch. 6 - 20

Conclusion:
HO + Cl CH3
60oC
H2O
HO CH3 + Cl
● The rate of reaction is directly
proportional to the concentration of
either reactant.
● When the concentration of either
reactant is doubled, the rate of
reaction doubles.
Ch. 6 - 21
The Kinetic Rate Expression
HO + Cl CH3
60oC
H2O
HO CH3 + Cl
Rate α [OH⊖][CH3Cl]
Rate = k[OH⊖][CH3Cl]
k=
Initial Rate
[OH⊖][CH3Cl]
= 4.9 × 10-7 L mol-1 s-1
Ch. 6 - 22
6. A Mechanism for the SN2 Reaction
H
HO
H


C


Br
H
H
negative OH⊖
brings an e⊖
pair to δ+ C; δ–
Br begins to
move away with
an e⊖ pair
H



HO

Br
C
H
H
transition state (T.S.)
O–C bond
partially formed;
C–Br bond
partially broken.
Configuration of
C begins to invert
HO
C
H
H
+ Br-
O–C bond
formed; Br⊖
departed.
Configuration
of C inverted
Ch. 6 - 23
7. Transition State Theory:
Free Energy Diagrams
A reaction that proceeds with a
negative free-energy change (releases
energy to its surroundings) is said to
be exergonic
 A reaction that proceeds with a positive
free-energy change (absorbs energy
from its surroundings) is said to be
endergonic

Ch. 6 - 24

At 60oC (333 K)
CH3 Br
+
OH
CH3 OH
+
Cl
DGo = -100 kJ/mol
● This reaction is highly exergonic
DHo = -75 kJ/mol
● This reaction is exothermic
Ch. 6 - 25
CH3 Br
+
OH
CH3 OH
+
Cl
● Its equilibrium constant (Keq) is
ln Keq =
=
DGo = –RT ln Keq
–DGo
RT
–(–100 kJ/mol)
(0.00831 kJ K-1 mol-1)(333 K)
= 36.1
Keq = 5.0 ╳ 1015
Ch. 6 - 26
A Free Energy Diagram for a Hypothetical SN2
Reaction That Takes Place with a Negative DGo
Ch. 6 - 27




The reaction coordinate indicates the
progress of the reaction, in terms of the
conversion of reactants to products
The top of the energy curve corresponds to
the transition state for the reaction
The free energy of activation (DG‡) for
the reaction is the difference in energy
between the reactants and the transition
state
The free energy change for the
reaction (DGo) is the difference in energy
between the reactants and the products
Ch. 6 - 28
A Free Energy Diagram for a Hypothetical
Reaction with a Positive Free-Energy Change
Ch. 6 - 29
7A. Temperature, Reaction Rate,
and the Equilibrium Constant

Distribution of energies at two
different temperatures. The number
of collisions with energies greater
than the free energy of activation is
indicated by the corresponding
shaded area under each curve.
A 10°C increase
in temperature
will cause the
reaction rate to
double for many
reactions taking
place near room
temperature
Ch. 6 - 30

The relationship
between the rate
constant (k) and DG‡
is exponential :
k = k0 e
DG‡/RT
e = 2.718, the base of
natural logarithms
k0 = absolute rate
Distribution of energies at two
different temperatures. The number
of collisions with energies greater
than the free energy of activation is
indicated by the corresponding
shaded area under each curve.
constant, which equals
the rate at which all
transition states proceed
to products (At 25oC,
k0 = 6.2 ╳ 1012 s1 )
Ch. 6 - 31

Distribution of energies at two
different temperatures. The number of
collisions with energies greater than
the free energy of activation is
indicated by the corresponding
shaded area under each curve.
A reaction with a
lower free energy of
activation (DG‡) will
occur exponentially
faster than a
reaction with a
higher DG‡, as
dictated by
k = k0 e
DG‡/RT
Ch. 6 - 32
Free Energy Diagram of SN2 Reactions
Free Energy
T.S.
DG
HO- + CH3Br
DGo
DG = free energy of
activation
DGo = free energy
change
CH3OH + Br-
Reaction Coordinate
Exothermic (DGo is negative)
 Thermodynamically favorable process

Ch. 6 - 33
8.The Stereochemistry of SN2 Reactions

Inversion of configuration
HO
CH3
+
C Br
H
CH2CH3
(R)
(inversion)
CH3
HO
C
H
(S) CH2CH3
+ Br
Ch. 6 - 34

Example:
CH3
Nu⊖ attacks from the TOP face.
I +
OCH3
(inversion of configuration)
CH3
OCH3 +
I
Ch. 6 - 35

Example:
Nu⊖ attacks from the BACK face.
+
Br
+ Br
CN
(inversion of
configuration)
CN
Ch. 6 - 36
9.
The Reaction of tert-Butyl Chloride
with Hydroxide Ion: An SN1 Reaction
CH3
CH3 C Br + H2O
CH3

CH3
CH3 C OH + HBr
CH3
The rate of SN1 reactions depends only on
concentration of the alkyl halide and is
independent on concentration of the Nu⊖
Rate = k[RX]
In other words, it is a first-order reaction
 unimolecular nucleophilic substitution
Ch. 6 - 37
9A. Multistep Reactions & the RateDetermining Step

In a multistep reaction, the rate of the
overall reaction is the same as the rate
of the SLOWEST step, known as the
rate-determining step (r.d.s)

For example:
Reactant
k1
k2
Intermediate
(slow)
(fast)
1
k3
Intermediate
(fast)
2
k1 << k2 or k3
Product
Ch. 6 - 38


A
B
C

The opening A is
much smaller than
openings B and C
The overall rate at
which sand reaches
to the bottom of
the hourglass is
limited by the rate
at which sand falls
through opening A
Opening A is
analogous to the
rate-determining
step of a multistep
Ch. 6 - 39
reaction
10. A Mechanism for the SN1 Reaction
A multistep process
Step (1):

CH3
CH3 C Br
CH3
(k 1 )
slow
r.d. step
CH3
CH3 C + Br
CH3
(ionization
of alkyl
halide)
Ch. 6 - 40
Free Energy
Free Energy Diagram of SN1 Reactions
T.S. (1)
T.S. (2)
T.S. (3)
(CH3)3C
+ BrDG1
(CH3)3CBr
+ H2O
(CH3)3C -OH2
+ Br-
intermediate
(CH3)3C-OH
+ Br-
Reaction Coordinate
Ch. 6 - 41
Step (2)
CH3
CH3 C + H2O
CH3
(k 2 )
fast
CH3 H
CH3 C O
CH3 H
Ch. 6 - 42
Free Energy
Free Energy Diagram of SN1 Reactions
T.S. (1)
T.S. (2)
T.S. (3)
(CH3)3C
-
+ Br
DG1
(CH3)3C -OH2
-
+ Br
(CH3)3CBr
+ H2O
intermediate
(CH3)3C-OH
-
+ Br
Reaction Coordinate
Ch. 6 - 43
Step (2)
CH3
CH3 C + H2O
CH3
(k2)
fast
CH3 H
CH3 C O
CH3 H
Step (3)
CH3 H
CH3 C O + H2O
CH3 H
(k 3 )
fast
CH3
CH3 C OH
CH3
+
+ H3OCh. 6 - 44
Free Energy
Free Energy Diagram of SN1 Reactions
T.S. (1)
T.S. (2)
T.S. (3)
(CH3)3C
-
+ Br
DG1
(CH3)3C -OH2
-
+ Br
(CH3)3CBr
+ H2O
intermediate
(CH3)3C-OH
-
+ Br
Reaction Coordinate
Ch. 6 - 45
Step (2)
CH3
CH3 C + H2O
CH3
(k2)
fast
Step (3)
CH3 H
CH3 C O + H2O
CH3 H
CH3 H
CH3 C O
CH3 H
k1 << k2 and k3
(k3)
fast
CH3
CH3 C OH
CH3
+ H3O+
Ch. 6 - 46

2 intermediates and 3 transition states
(T.S.)

The most important T.S. for SN1
reactions is T.S. (1) of the ratedetermining step (r.d.s.)
CH3
CH3

C

Br
CH3
Ch. 6 - 47
11. Carbocations
11A. The Structure of Carbocations
Carbocations are
trigonal planar
 The central carbon
atom in a carbocation
is electron deficient; it
has only six e⊖ in its
valence shell
 The p orbital of a
carbocation contains
no electrons, but it can
accept an electron pair
when the carbocation
undergoes further
reaction

H3C
H3C
C
CH3
sp2-sp3 p bond
Ch. 6 - 48
11B. The Relative Stabilities of
Carbocations

General order of reactivity (towards
SN1 reaction)
● 3o > 2o >> 1o > methyl

The more stable the carbocation
formed, the faster the SN1 reaction
Ch. 6 - 49

Stability of cations
most stable (positive inductive effect)
R
R

C
R
>
R
R
C
R
>
H
H
C
H
>
H
H
C
H
Resonance stabilization of allylic and
benzylic cations
CH2
CH2
etc.
Ch. 6 - 50
12. The Stereochemistry of SN1 Reactions
Ph
CH3
Ph
CH3OH
Br
CH2CH3
(S )
C
CH3 CH2CH3
Ph
CH3
CH2CH3
(R)
CH3
C
OCH3
CH2CH3
(R) and (S)
racemic mixture
(trigonal planar)
CH3OH
attack from left
CH3O
CH3OH
Ph
CH3OH
attack from right
50:50
chance
Ph
CH3
(1 : 1)
OCH3
CH2CH3
(S )
Ch. 6 - 51

racemic mixture
( 1 : 1 )
Example:
(R)
Br
H2O
(SN1)
(R)
(carbocation)
OH
H2O
attack from
TOP face
H2O
+
OH
(one enantiomer)
slow
r.d.s.
(S)
H2O
H
O
H2O attack from
H
BOTTOM face
H
O
H
Ch. 6 - 52

Example:
I
t
Me
OMe
Me MeOH tBu
Bu
Me +tBu
OMe
MeOH
slow
r.d.s.
Me
t
MeOH
Bu

trigonal planar
MeOH
Me
Me
CH3

t
Bu
O
H
t
MeOH
Bu
O
Me
H
Ch. 6 - 53
13. Factors Affecting the Rates of
SN1 and SN2 Reactions

The structure of the substrate

The concentration and reactivity of the
nucleophile (for SN2 reactions only)

The effect of the solvent

The nature of the leaving group
Ch. 6 - 54
13A. The Effect of the Structure of the Substrate

General order of reactivity (towards
SN2 reaction)
● Methyl > 1o > 2o >> 3o > vinyl or aryl
DO NOT
undergo
SN2 reactions
Ch. 6 - 55

For example:
R Br + HO
R OH + Br
Relative Rate (towards SN2)
CH3
CH3CH2 Br CH3CH Br CH3 C CH2Br
CH3
CH3
CH3 Br
methyl
2  10
6
Most
reactive
1
o
4  10
2
4
o
500
CH3
CH3 C Br
CH3
o
neopentyl
3
1
<1
Least
reactive
Ch. 6 - 56
Compare
H 
HO
C
H
H

H
HO


C
CH3
CH3
H


Br
faster
HO
C
H
H


Br
H
+ Br
slower
HO
+ Br
CH3
CH3
C
Ch. 6 - 57
H
HO

C
t
Bu
HO



C
CH3

Br
H
CH3
CH3
H

very
slow
C
HO
CH3
+ Br
C
CH3
CH3


Br
+ Br
t
Bu
CH3
HO
extremely
slow
Ch. 6 - 58
Note NO SN2 reaction on sp2 or sp
carbons
e.g.
sp2
H
I
No reaction
+ Nu
H
H

sp2
I
+ Nu
No reaction
sp
I + Nu
No reaction
Ch. 6 - 59
Reactivity of the Substrate in SN1
Reactions

General order of reactivity (towards SN1
reaction)
● 3o > 2o >> 1o > methyl

The more stable the carbocation
formed, the faster the SN1 reaction
Ch. 6 - 60

Stability of cations
most stable (positive inductive effect)
R
R

C
R
>
R
R
C
R
>
H
H
C
H
>
H
H
C
H
Allylic halides and benzylic halides also
undergo SN1 reactions at reasonable
I
rates
Br
an allylic bromide
a benzylic iodide
Ch. 6 - 61

Resonance stabilization for allylic and
benzylic cations
CH2
CH2
etc.
Ch. 6 - 62
13B. The Effect of the Concentration
& Strength of the Nucleophile

For SN1 reaction
Recall: Rate = k[RX]
● The Nu⊖ does NOT participate in
the r.d.s.
● Rate of SN1 reactions are NOT
affected by either the
concentration or the identity of
the Nu⊖
Ch. 6 - 63

For SN2 reaction
Recall: Rate = k[RX][RX]
● The rate of SN2 reactions depends
on both the concentration and
the identity of the attacking Nu⊖
Ch. 6 - 64
Identity of the Nu⊖
● The relative strength of a Nu⊖ (its
nucleophilicity) is measured in
terms of the relative rate of its SN2
reaction with a given substrate
rapid
CH3O + CH3I
CH3OCH3 + I
Good Nu⊖
Very
CH3OH + CH3I slow
CH3OCH3 + I
Poor Nu⊖

Ch. 6 - 65

The relative strength of a Nu⊖ can be
correlated with 3 structural features
● A negatively charged Nu⊖ is always a
more reactive Nu⊖ than its conjugated
acid
 e.g. HO⊖ is a better Nu⊖ than H2O
and RO⊖ is better than ROH
● In a group of Nu⊖s in which the
nucleophilic atom is the same,
nucleophilicities parallel basicities
 e.g. for O compounds,
RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O
Ch. 6 - 66
● When the nucleophilic atoms are
different, then nucleophilicities may
not parallel basicities
 e.g. in protic solvents HS⊖, CN⊖,
and I⊖ are all weaker bases than
HO⊖, yet they are stronger Nu⊖s
than HO⊖
HS⊖ > CN⊖ > I⊖ > HO⊖
Ch. 6 - 67
13C. Solvent Effects on SN2 Reactions:
Polar Protic & Aprotic Solvents

Classification of solvents
Non-polar solvents
(e.g. hexane, benzene)
Solvents
Polar
solvents
Polar protic solvents
(e.g. H2O, MeOH)
Polar aprotic solvents
(e.g. DMSO, HMPA)
Ch. 6 - 68

SN2 Reactions in Polar Aprotic Solvents
● The best solvents for SN2 reactions
are
 Polar aprotic solvents, which
have strong dipoles but do not
have OH or NH groups
 Examples
CH3
O
S
O
H
CH3
(DMSO)
CH3
N
CH3
(DMF)
O
P NMe
Me2N NMe2 2
(HMPA)
CH3CN
(Acetonitrile)
Ch. 6 - 69

Polar aprotic solvents tend to
solvate metal cations rather than
nucleophilic anions, and this
results in “naked” anions of the
Nu⊖ and makes the e⊖ pair of
the Nu⊖ more available
CH3O Na
DMSO
CH3O + DMSO Na
"naked anion"
Ch. 6 - 70
Tremendous acceleration in SN2
reactions with polar aprotic
solvent
CH3Br + NaI
CH3I + NaBr

Solvent
Relative Rate
MeOH
1
DMF
106
Ch. 6 - 71

SN2 Reactions in Polar Protic Solvents
● In polar protic solvents, the Nu⊖
anion is solvated by the surrounding
protic solvent which makes the e⊖
pair of the Nu⊖ less available and
thus less reactive in SN2 reactions
H
OR
RO H Nu H OR
H
OR
Ch. 6 - 72

Halide Nucleophilicity in Protic Solvents
● I⊖ > Br⊖ > Cl⊖ > F⊖

 OR
RO 
H

RO H

H
-


H
F

H OR

H
RO H
OR
I-

H
RO
OR
(strongly solvated)
H
OR
(weakly solvated)
 Thus, I⊖ is a stronger Nu⊖ in protic
solvents, as its e⊖ pair is more available
to attack the substrate in the SN2 reaction.
Ch. 6 - 73

Halide Nucleophilicity in Polar Aprotic
Solvents (e.g. in DMSO)
● F⊖ > Cl⊖ > Br⊖ > I⊖

Polar aprotic solvents do not solvate
anions but solvate the cations

The “naked” anions act as the Nu⊖

Since F⊖ is smaller in size and the
charge per surface area is larger
than I⊖, the nucleophilicity of F⊖ in
this environment is greater than I⊖
Ch. 6 - 74
13D. Solvent Effects on SN1 Reactions:
The Ionizing Ability of the Solvent

Solvent plays an important role in SN1
reactions but the reasons are different
from those in SN2 reactions

Solvent effects in SN1 reactions are due
largely to stabilization or destabilization
of the transition state
Ch. 6 - 75

Polar protic solvents stabilize the
development of the polar transition
state and thus accelerate this ratedetermining step (r.d.s.):
CH3
-
CH3
C Cl
CH3
Cl + CH3
slow
r.d.s.
CH2
C
CH3
H3C 

CH3 C
 CH3
R O
H
 OR
H


Cl

H
OR
Ch. 6 - 76
13E. The Nature of the Leaving Group
The better a species can stabilize a
negative charge, the better the LG in
an SN2 reaction
SN1 Reaction:

C X

C
slow
r.d.s.
SN2 Reaction:
Nu:

slow
C X
r.d.s.


Nu C

X
C
+
X


X
Nu C
+X
Ch. 6 - 77
Examples of the reactivity of some X⊖:
CH3O + CH3–X  CH3–OCH3 + X
Relative Rate:
⊖
Best
X
⊖
OH, Worst X
NH2, <<F < Cl < Br < I < TsO
RO

~0
1
200
10,000 30,000 60,000
 Note: Normally R–F, R–OH, R–NH2,
R–OR’ do not undergo SN2
reactions.
Ch. 6 - 78
Nu

R OH
R Nu
+
a poor
leaving group
OH
a strong
basic anion
H
R O
H
Nu
✔
a good
H
leaving group
R Nu
+
H2O
weak
base
Ch. 6 - 79
14. Organic Synthesis: Functional Group
Transformation Using SN2 Reactions
OH
CN CN
HO
Me
Br
MeS
SMe
MeO
HS
SH
Ch. 6 - 80
Me
O
I
I
Me C C
Br
N3
N3
O
Me
NMe3
Br
MeCOO
Me3N
Ch. 6 - 81

Examples:
NaOEt,??DMSO
Br
I
O
NaSMe,?? DMSO
SMe
Ch. 6 - 82

Examples:
??
I
CN
(optically active, chiral)
(optically active, chiral)
● Need SN2 reactions to control
stereochemistry
● But SN2 reactions give the inversion of
configurations, so how do you get the
“retention” of configuration here??
● Solution:
“double inversion”  “retention”
Ch. 6 - 83
??
I
CN
(optically active, chiral)
(optically active, chiral)
NaBr
DMSO
NaCN
DMSO
(SN2 with
inversion)
Br
(SN2 with
inversion)
(Note: Br⊖ is a stronger Nu than
I⊖ in polar aprotic solvent.)
Ch. 6 - 84
14A. The Unreactivity of Vinylic and
Phenyl Halides
X
C
C
X
vinylic halide

phenyl halide
Vinylic and phenyl halides are generally
unreactive in SN1 or SN2 reactions
Ch. 6 - 85

Examples
NaCN
Br
DMSO
I
NaSMe
HMPA
No Reaction
No Reaction
Ch. 6 - 86
15. Elimination Reactions of Alkyl
Halides

Substitution
H
C C
Br

OCH3
(acts as a
Nu )
H
C C
OCH3
+ Br
-
Elimination
H
OCH3
C C (acts as a C C + CH3OH + Br
H
Br base)
Ch. 6 - 87

Substitution reaction (SN) and
elimination reaction (E) are processes
in competition with each other
e.g.
I
t
BuOK
t
BuOH
t
O Bu +
SN2: 15%
E2: 85%
Ch. 6 - 88
15A. Dehydrohalogenation
β hydrogen
β carbon
Br
β
α
H
LG
H
C
α carbon
C
X halide as LG
t
BuOK
t
BuOH, 60oC
+ KBr
t
+ BuOH
β hydrogen
⊖OtBu
Ch. 6 - 89
15B. Bases Used in Dehydrohalogenation

Conjugate base of alcohols is often used
as the base in dehydrohalogenations
Na
R−O−H
e.g.
EtO Na
NaH
R−O⊖ + Na⊕ + H2
R−O⊖ + Na⊕ + H2
t
BuO K
sodium ethoxide potassium tert-butoxide
Ch. 6 - 90
16. The E2 Reaction
Br
EtO
+
+ EtOH + Br
H

Rate = k[CH3CHBrCH3][EtO⊖]

Rate determining step involves both
the alkyl halide and the alkoxide anion

A bimolecular reaction
Ch. 6 - 91
Mechanism for an E2 Reaction
Et O
CH3
α
Cβ C H
H
Br
H
H
EtO⊖ removes
a b proton;
C−H breaks;
new p bond
forms and Br
begins to
depart
Et O
H
H
C
CH3
C H
H
Br


Partial bonds in
the transition
state: C−H and
C−Br bonds
break, new p
C−C bond forms
H
H
C C
+
Et OH
CH3
H
+ Br
C=C is fully
formed and
the other
products are
EtOH and Br⊖
Ch. 6 - 92
Free Energy Diagram of E2 Reaction
Free Energy
T.S.
DG‡
E2 reaction has ONE
transition state
CH3CHBrCH3
-
+ EtO
CH2=CHCH3
+ EtOH + Br
-
Reaction Coordinate
Rate = k[CH3CHBrCH3][EtO⊖]

Second-order overall  bimolecular
Ch. 6 - 93
17. The E1 Reaction

E1: Unimolecular elimination
CH3
CH3
CH
3
H 2O
CH3 C OH + CH2 C
CH3 C Cl
CH3
CH3
CH3
(major (SN1)) (minor (E1))
slow
r.d.s
H
O
as
H
O
as
2
2
CH3
base
nucleophile
CH C
3
CH3
Ch. 6 - 94
Mechanism of an E1 Reaction
α carbon
β hydrogen
Cl
H2O
H
H2O
slow
r.d.s.
fast
+
H3O
(E1 product)
fast H2O
O
H HO
2
H
OH + H3O
(SN1 product)
Ch. 6 - 95
Free Energy
Free Energy Diagram of E1 Reaction
T.S. (1)
T.S. (2)
(CH3)3C
DG1
(CH3)3CCl
+ Cl(CH3)2C=CH2
+ H3O + Cl-
+ H2O
Reaction Coordinate
Ch. 6 - 96
Step (1):
CH3
CH3 C Cl
CH3
Aided by the
polar solvent, a
chlorine departs
with the e⊖ pair
that bonded it to
the carbon
H 2O
(k 1 )
slow
r.d. step
CH3
CH3 C + Cl
CH3
Produces relatively
stable 3o carbocation
and a Cl⊖. The ions
are solvated (and
stabilized) by
surrounding H2O
molecules
Ch. 6 - 97
Free Energy
Free Energy Diagram of E1 Reaction
T.S. (1)
T.S. (2)
(CH3)3C
-
DG1
+ Cl
(CH3)2C=CH2
-
(CH3)3CCl
+ H3O + Cl
+ H2O
Reaction Coordinate
Ch. 6 - 98
Step (2)
H 3C
H 3C
H
C C H + H 2O
(k 2 )
H 3C
fast
H 3C
H
H2O molecule removes one of
the b hydrogens which are
acidic due to the adjacent
positive charge. An e⊖ pair
moves in to form a double
bond between the b and a
carbon atoms
CH2
+ H O
H
H
Produces alkene and
hydronium ion
Ch. 6 - 99
18. How To Determine Whether
Substitution or Elimination Is Favoured

All nucleophiles are potential bases and
all bases are potential nucleophiles

Substitution reactions are always in
competition with elimination reactions

Different factors can affect which type
of reaction is favoured
Ch. 6 - 100
18A. SN2 vs. E2
(b)
Nu
(a)
H C
C X
(a)
H C
S N2
Nu C
(b)
C
E2
C
+X
+ Nu H + X
Ch. 6 - 101
Primary Substrate

With a strong base, e.g. EtO⊖
● Favor SN2
NaOEt
Br EtOH
OEt
SN2: 90%
+
E2: (10%)
Ch. 6 - 102
Secondary Substrate

With a strong base, e.g. EtO⊖
● Favor E2
+
Br
NaOEt
EtOH
E2: 80%
+
OEt
SN2: 20%
Ch. 6 - 103
Tertiary Substrate

With a strong base, e.g. EtO⊖
● E2 is highly favored
Br
NaOEt
EtOH
+
E2: 91%
OEt
SN1: 9%
Ch. 6 - 104
Base/Nu⊖: Small vs. Bulky

Unhindered “small” base/Nu⊖
NaOMe
Br MeOH

+
OMe
SN2: 99%
E2: 1%
Hindered “bulky” base/Nu⊖
t
KO Bu
Br t
BuOH
t
+
O Bu
SN2: 15% E2: 85%
Ch. 6 - 105
Basicity vs. Polarizability
O
O
O
CH3
CH3 C O
(weak base)
Br
EtO
(strong base)
+
SN2: 100% E2: 0%
OEt
+
SN2: 20%
E2: 80%
Ch. 6 - 106
Tertiary Halides: SN1 vs. E1 & E2
Br
EtO
OEt
+
(strong
base) E2: 100% SN1: 0%
EtOH
OEt
+
heat
E1 + E2: 20% SN1: 80%
Ch. 6 - 107
19. Overall Summary
CH3X
RCH2X
R'
RCHX
R'
RCX
R"
SN1
SN2
E1
E2
─
Very fast
─
─
─
Mostly
Very little;
Mostly SN2 with
Solvolysis possible;
weak bases;
e.g. with H2O;
e.g. with CH3COO⊖
MeOH
Very favorable
with weak bases;
e.g. with H2O;
MeOH
─
─
Hindered bases give
mostly alkenes;
e.g. with tBuO⊖
Very little
Strong bases
promote E2;
e.g. with RO⊖, HO⊖
Strong bases
Always competes
promote E2;
with SN1
e.g. with RO⊖, HO⊖
Ch. 6 - 108
Review Problems
(1)
t
Bu
Br
Na CN
CN
DMF, 25oC
SN2 with inversion
t
Bu
(2)
I
O
H
O
NaH
Et2O
H⊖
I
O
Intramolecular SN2
Ch. 6 - 109
(3)
t
CH3
OH
CH3
Cl
HCl
t
Bu
Bu
Cl
+
CH3
t
Bu
( 50 : 50)
Cl⊖ attacks
from top face
t
Bu
CH3
H
O
H
SN1 with racemization
CH3
t
Bu
Cl⊖ attacks
from bottom
face
sp2 hybridized
carbocation
Ch. 6 - 110
 END OF CHAPTER 6 
Ch. 6 - 111