Chapter 6
Ionic Reactions
Nucleophilic Substitution
and Elimination Reactions
of Alkyl Halides
Created by
Professor William Tam & Dr. Phillis Chang
Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.
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.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
(hyperlinked)
Alkyl Halides
Nucleophilic Substitution Reactions
Nucleophiles
Leaving Groups
Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction
A Mechanism for the SN2 Reaction
Transition State Theory: Free-Energy Diagrams
The Stereochemistry of SN2 Reactions
The Reaction of tert-Butyl Chloride with Water: An SN1 Reaction
A Mechanism for the SN1 Reaction
Carbocations
The Stereochemistry of SN1 Reactions
Factors Affecting the Rates of SN1 and SN2 Reactions
Organic Synthesis: Functional Group Transformations Using SN2
Reactions
Elimination Reactions of Alkyl Halides
The E2 Reaction
The E1 Reaction
How to Determine Whether Substitution or Elimination Is Favored
Overall Summary
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Alkyl Halides
Nucleophilic Substitution Reactions
Nucleophiles
Leaving Groups
Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction
A Mechanism for the SN2 Reaction
Transition State Theory: Free-Energy Diagrams
The Stereochemistry of SN2 Reactions
The Reaction of tert-Butyl Chloride with Water: An SN1 Reaction
A Mechanism for the SN1 Reaction
Carbocations
The Stereochemistry of SN1 Reactions
Factors Affecting the Rates of SN1 and SN2 Reactions
Organic Synthesis: Functional Group Transformations Using SN2
Reactions
Elimination Reactions of Alkyl Halides
The E2 Reaction
The E1 Reaction
How to Determine Whether Substitution or Elimination Is Favored
Overall Summary
© 2014 by John Wiley & Sons, Inc. All rights reserved.
In this chapter we will consider:

What groups can be replaced (i.e.,
substituted) or eliminated

The various mechanisms by which such
processes occur

The conditions that can promote such
reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
1. Alkyl Halides

An alkyl halide has a halogen atom
bonded to an sp3-hybridized
(tetrahedral) carbon atom

The carbon–chlorine and carbon–
bromine bonds are polarized because
the halogen is more electronegative
than carbon
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Iodine does not have a permanent
dipole, but the bond is easily
polarizable

Iodine is a good leaving group due to
its polarizability, i.e. its ability to
stabilize a negative charge due to its
large atomic size
© 2014 by John Wiley & Sons, Inc. All rights reserved.




C X
X = Cl, Br, I

Halogens are more electronegative
than carbon
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Different Types of Organic Halides

Alkyl halides (haloalkanes)
sp3
Attached to
1 carbon atom
C
Cl
a 1o chloride
Attached to
2 carbon atoms
C
C
Attached to
3 carbon atoms
C
Br
a 2o bromide
© 2014 by John Wiley & Sons, Inc. All rights reserved.
C
C
I
a 3o iodide

Vinyl halides (Alkenyl halides)
sp2
X

Aryl halides
sp2
X
benzene or aromatic ring

Acetylenic halides (Alkynyl halides)
sp
X
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
+ X
(leaving
group)
The LG
gains the
pair of e⊖
originally
bonded
in the
substrate
Timing of The Bond Breaking & Bond
Making Process

Two types of mechanisms
● 1st type: SN2 (concerted mechanism)
R

HO

Br
C
R
R
transition state (T.S.)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
● 2nd type: SN1 (stepwise mechanism)
Step (1):
R
R
(k 1 )
R C Br
R C + Br
slow
R
R
r.d.s.
k1 <<
Step (2)
R
R
H
(k 2 )
R C + H 2O
R C O
H
fast
R
R
fast
© 2014 by John Wiley & Sons, Inc. All rights reserved.
k2 and k3
3. Nucleophiles

A reagent that seeks a positive center

Nucleophile – “nucleus” “loving”

“phile” – derived from the Greek word
philia meaning “loving”
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Has an unshared pair of e⊖
e.g.:
HO , CH3O , H2N
H2O, NH3
(negative charge)
(neutral)
This is the positive
center that the
Nu⊖ seeks


C
© 2014 by John Wiley & Sons, Inc. All rights reserved.


X

Examples:
HO
(Nu
O
H
(Nu
H H
+
C
CH3 Cl
) (substrate)
H H
+
C
H
CH3 Cl
)
(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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
5. Kinetics of a Nucleophilic
Substitution Reaction:
An SN2 Reaction
The rate of the substitution reaction is
linearly dependent on the
concentration of HO⊖ and CH3Br
 Overall, a second-order reaction 
bimolecular

© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Concentration, M
Graphically…
[CH3Cl] ↓
[CH3OH] ↑
Time, t
Rate =
Δ[CH3Cl]
Δt
=−
[CH3Cl]t=t − [CH3Cl]t=0
Time in seconds
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Concentration, M
Initial Rate
[CH3Cl]t=0
[CH3Cl]t=t
[CH3Cl]
Time, t
[CH3Cl]t=t − [CH3Cl]t=0
Initial Rate
=−
(from slope)
Δt
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
5B. What is the Order of This
Reaction?
This reaction is said to be second
order overall
 We also say that the reaction is
bimolecular
 We call this kind of reaction an SN2
reaction, meaning substitution,
nucleophilic, bimolecular

© 2014 by John Wiley & Sons, Inc. All rights reserved.
6. A Mechanism for the SN2
Reaction
H
HO
H


C

HO


Br
H
C
H
H
negative HO⊖
brings an e⊖ pair
to δ+C; δ–Br
begins to move
away with an e⊖
pair

Br
H
transition state (T.S.)
O–C bond
partially formed;
C–Br bond
partially broken.
Configuration of
C begins to invert
© 2014 by John Wiley & Sons, Inc. All rights reserved.
O–C bond
formed; Br⊖
departed.
Configuration
of C inverted
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

© 2014 by John Wiley & Sons, Inc. All rights reserved.

At 60oC (333 K)
DGo = -100 kJ/mol
● This reaction is highly exergonic
DHo = -75 kJ/mol
● This reaction is exothermic
© 2014 by John Wiley & Sons, Inc. All rights reserved.
● 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 x 1015
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A Free Energy Diagram for a Hypothetical SN2
Reaction That Takes Place with a Negative DGo
© 2014 by John Wiley & Sons, Inc. All rights reserved.




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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A Free Energy Diagram for a Hypothetical
Reaction with a Positive Free-Energy Change
© 2014 by John Wiley & Sons, Inc. All rights reserved.
7A. Temperature & Reaction 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.
A 10°C increase
in temperature
will cause the
reaction rate to
double for many
reactions taking
place near room
temperature
© 2014 by John Wiley & Sons, Inc. All rights reserved.

The relationship
between the rate
constant (k) and DG‡
is exponential :
k = k0 e
DG‡/RT
e = 2.718, the base of
natural logarithms
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.
k0 = absolute rate
constant, which equals
the rate at which all
transition states proceed
to products (At 25oC,
k0 = 6.2 ╳ 1012 s1 )
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
DG‡/RT
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

© 2014 by John Wiley & Sons, Inc. All rights reserved.
8. The Stereochemistry of SN2
Reactions

Inversion of configuration
HO
CH3
+
C Br
H
CH2CH3
(R)
(inversion)
CH3
HO
C
H
(S) CH2CH3
© 2014 by John Wiley & Sons, Inc. All rights reserved.
+ Br

Example:
CH3
Nu⊖ attacks from the TOP face.
I
+
OCH3
(inversion of configuration)
CH3
OCH3
+I
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Example:
Nu⊖ attacks from the BACK side.
(inversion of
configuration)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
9. The Reaction of tert -Butyl
Chloride with Water:
An SN1 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.

The rate of SN1 reactions depends only
on concentration of the alkyl halide and
is independent of concentration of the
Nu⊖
Rate = k[tBuCl]
In other words, it is a first-order
reaction
 unimolecular nucleophilic substitution
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Product

Fig. 6.5

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
reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
10. A Mechanism for the SN1
Reaction

A multistep process
slow
r.d.s.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of SN1 Reactions
intermediate
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Step (2)
CH3
CH3 C + H2O
CH3
(k 2 )
fast
CH3 H
CH3 C O
CH3 H
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of SN1 Reactions
intermediate
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Step (2)
CH3
CH3 C + H2O
CH3
(k 2 )
fast
CH3 H
CH3 C O
CH3 H
fast
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of SN1 Reactions
intermediate
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Step (2)
CH3
CH3 C + H2O
CH3
(k2)
fast
CH3 H
CH3 C O
CH3 H
k1 << k2 and k3
fast
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Stability of cations
most stable (positive inductive effect)
R
R
C
>
R
C
>
R
>
C
H
C
R R
H
H H
H H
 Resonance stabilization of allylic and
benzylic cations
CH2
CH2
© 2014 by John Wiley & Sons, Inc. All rights reserved.
etc.
12. Stereochemistry of SN1 Reactions
Ph
CH3
CH3OH
Br
CH2CH3
(S )
Ph
C
CH3OH
CH3 CH2CH3
50:50
chance
CH3
C
OCH3
CH2CH3
(R) and (S)
racemic mixture
(trigonal planar)
CH3OH
attack from left
Ph
CH3OH
attack from right
(1 : 1)
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
H
H2O attack from
BOTTOM face
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
O
H

Example:
I
t
Me
OMe
Me MeOH tBu
Bu
Me +tBu
OMe
MeOH
slow
r.d.s.
Me
t
MeOH
t
Bu

Bu
O
H
MeOH
Me
Me
CH3
t
MeOH
Bu
trigonal planar
© 2014 by John Wiley & Sons, Inc. All rights reserved.
O
Me
H
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
1
o
4  10
2
4
o
500
CH3
CH3 C Br
CH3
o
neopentyl
3
1
<1
Most
reactive
Least
reactive
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Compare
H 
HO
C
H
H

H
HO


C
CH3
H


Br
faster
HO
C
H
H


Br
H
+ Br
slower
HO
CH3
© 2014 by John Wiley & Sons, Inc. All rights reserved.
+ Br
CH3
CH3
C
H
HO
C
t
Bu
HO

Br
H
CH3


C
CH3



Br
CH3
very
slow
HO
extremely
slow
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
+ Br
C
CH3
CH3

Note NO SN2 reaction on sp2 or sp carbons
sp2
sp2
sp
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Resonance stabilization for allylic and
benzylic cations
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.

For SN2 reaction
Recall: Rate = k[Nu⊖][RX]
● The rate of SN2 reactions depends
on both the concentration and
the identity of the attacking Nu⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
Good Nu⊖
Poor Nu:
Very
slow
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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 conjugate
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
● When the nucleophilic atoms are
different, then nucleophilicities may
not parallel basicities
 e.g. in protic solvents HS⊖, NC⊖,
and I⊖ are all weaker bases than
HO⊖, yet they are stronger Nu⊖s
than HO⊖
HS⊖ > NC⊖ > I⊖ > HO⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.
13C. Solvent Effects in SN2 & SN1
Reactions

SN2 reactions are favored by polar
aprotic solvents (e.g., acetone, DMF,
DMSO)

SN1 reactions are favored by polar
protic solvents (e.g., EtOH, MeOH,
H2O)
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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)
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3CN
(Acetonitrile)

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"
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Tremendous acceleration in SN2
reactions with polar aprotic
solvent
CH3Br + NaI
CH3I + NaBr

Solvent
Relative Rate
MeOH
1
DMF
106
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
OR
H
RO H Nu H OR
H
OR
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Halide Nucleophilicity in Protic Solvents
● I⊖ > Br⊖ > Cl⊖ > F⊖


RO 
H
RO

H

H

RO
 OR
H

F

-

H OR

H
H

OR
(stro n g ly so lv a te d )
RO
H
I
OR
-
H
OR
(w e a k ly so lv a te d )
 Thus, I⊖ is a stronger Nu⊖ in protic
solvents, as its e⊖ pair is more available
to attack the substrate in the SN2 reaction.
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Polar protic solvents stabilize the
development of the polar transition
state and thus accelerate this ratedetermining step (r.d.s.):
© 2014 by John Wiley & Sons, Inc. All rights reserved.
13D. The Nature of the Leaving Group

Leaving groups depart with the
electron pair that was used to bond
them to the substrate

The best leaving groups are those that
become either a relatively stable anion
or a neutral molecule when they depart
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Nu C
+X
Examples of the reactivity of some X⊖:
CH3O + CH3–X  CH3–OCH3 + X
Relative Rate:
⊖
Best
X
⊖

HO , Worst X
H2N, <<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.
© 2014 by John Wiley & Sons, Inc. All rights reserved.

a poor
leaving group
R O
H
Nu
✔
a good
H
a strong
basic anion
R Nu
leaving group
© 2014 by John Wiley & Sons, Inc. All rights reserved.
+
H2O
weak
base

Other weak bases that are good
leaving groups:
© 2014 by John Wiley & Sons, Inc. All rights reserved.
14. Organic Synthesis: Functional
Group Transformation Using
SN2 Reactions
OH
HO
CN
Br
MeS
MeO
HS
SMe
© 2014 by John Wiley & Sons, Inc. All rights reserved.
SH
Me
O
I
I
Me C C
Br
N3
O
Me
NMe3
Br
MeCOO
Me3N
N3
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Examples:
NaOEt,?? DMSO
Br
I
O
NaSMe,?? DMSO
© 2014 by John Wiley & Sons, Inc. All rights reserved.
SMe

Examples:
??
I
CN
(o ptically active , chiral)
(o ptically 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”
© 2014 by John Wiley & Sons, Inc. All rights reserved.
??
I
CN
(o ptically active , chiral)
(o ptically 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.)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
14A. The Nonreactivity 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
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Examples
NaCN
Br
DMSO
I
NaSMe
HMPA
No Reaction
No Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
15. Elimination Reactions of Alkyl
Halides

Substitution

Elimination
© 2014 by John Wiley & Sons, Inc. All rights reserved.

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%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
E2: 85%
15A. Dehydrohalogenation
β hydrogen
β carbon
Br
β

H
LG
H
C
 carbon
C
X halide as LG
t
BuOK
t
o
BuOH, 60 C
+ KBr
β hydrogen
⊖OtBu
© 2014 by John Wiley & Sons, Inc. All rights reserved.
t
+ BuOH
15B. Bases Used in Dehydrohalogenation

Conjugate base of alcohols is often used
as the base in dehydrohalogenations
Na
R−O−H
NaH
R−O⊖ + Na⊕ + H2
R−O⊖ + Na⊕ + H2
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Mechanism for an E2 Reaction
Et O
Et O
CH3
α
Cβ C H
H
Br
H
H
H
H
EtO⊖ removes a
b proton; C−H
breaks; new p
bond forms and
Br begins to
depart
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
H
C C
+
Et OH
CH3
H
+ Br
C=C is fully
formed and
the other
products are
EtOH and Br⊖
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
-
17. The E1 Reaction
E1: Unimolecular elimination
CH3
CH3
CH3
H 2O
CH3 C OH + CH2 C
CH3 C Cl
CH3
CH3
CH3
slow
(major (SN1)) (minor (E1))
r.d.s

H2O as
CH3
nucleophile
CH3 C
CH3
H2O as
base
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Mechanism of an E1 Reaction
 carbon
β hydrogen
H
H2O
slow
r.d.s.
fast
+
H3O
(E1 product)
fast H2O
O
H HO
2
H
OH + H3O
(SN1 product)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of E1 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of E1 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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 
carbon atoms
CH2
+ H O
H
H
Produces alkene and
hydronium ion
© 2014 by John Wiley & Sons, Inc. All rights reserved.
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

© 2014 by John Wiley & Sons, Inc. All rights reserved.
18A. SN2 vs. E2
(a)
(b)
Nu
(a)
H C
C X
SN2
H C
Nu
(b)
C
E2
C
C
+ X
+ Nu H + X
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Primary Substrate

With a strong base, e.g. EtO⊖
● Favor SN2
Br
N aO Et
OEt
SN2: 90%
+
E tO H
E 2 : (1 0 % )
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Secondary Substrate

With a strong base, e.g. EtO⊖
● Favor E2
+
N aO Et
Br
E2: 80%
+
E tO H
OEt
SN2: 20%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Tertiary Substrate

With a strong base, e.g. EtO⊖
● E2 is highly favored
Br
NaOEt
EtOH
+
E2: 91%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
OEt
SN1: 9%
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%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Basicity vs. Polarizability
O
O
O
CH3
CH3 C O
(weak base)
Br
EtO
(strong base)
+
SN2: 100% E2: 0%
OEt
+
SN2: 20%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
E2: 80%
Tertiary Halides: SN1 vs. E1 & E2
Br
EtO
OEt
+
(strong
base) E2: 100% SN1: 0%
EtOH
OEt
+
heat
E1 + E2: 20% SN1: 80%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
19. Overall Summary
SN1
SN2
CH 3 X
RCH2X
R'
RCHX
R'
RCX
R"
─
─
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
─
E1
E2
─
─
─
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⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Review Problems
CN
SN2 with inversion
t
Bu
(2 )
I
O
H
O
NaH
Et 2 O
H⊖
I
O
Intramolecular SN2
© 2014 by John Wiley & Sons, Inc. All rights reserved.
(3 )
CH 3
HCl
OH
t
Bu
Cl⊖ attacks
from top face
CH 3
O
t
H
H
CH 3
t
Bu
SN1 with racemization
Bu
Cl⊖ attacks
from bottom
face
sp2 hybridized
carbocation
© 2014 by John Wiley & Sons, Inc. All rights reserved.
 END OF CHAPTER 6 
© 2014 by John Wiley & Sons, Inc. All rights reserved.