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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.
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
(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
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.
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
2014 by John Wiley & Sons, Inc. All rights reserved.
1. Alkyl Halides
C X
X = Cl, Br, I
Cl
Attached to
Attached to
2 carbon atoms 3 carbon atoms
C
Br
a 1o chloride a 2o bromide
2014 by John Wiley & Sons, Inc. All rights reserved.
C
I
a 3o iodide
Aryl halides
sp2
X
benzene or aromatic ring
sp
C
Alkyl halides
sp2
Prone to undergo
Nucleophilic
Substitutions (SN) and
Elimination Reactions
(E) (the focus of this
Chapter)
sp2
sp
2. Nucleophilic Substitution
Reactions
Nu + C
(nucleophile)
The Nu
donates
an e pair
to the
substrate
(substrate)
The bond
between
C and LG
breaks,
giving both
e from the
bond to LG
Nu
(product)
The Nu uses
+ X
(leaving
group)
The LG
its e pair to
gains the
form a new
pair of e
covalent bond originally
with the
bonded
substrate C
in the
substrate
HO
Br
C
R
R
R
(k1)
R C Br
R C +Br
slow
R
R
r.d.s.
k1 << k2 and
Step (2)
R
R
H
(k2)
R C +H2O
R C O
H
fast
R
R
fast
2014 by John Wiley & Sons, Inc. All rights reserved.
k3
3. Nucleophiles
(negative charge)
(neutral)
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
e.g.: I, Br, Cl
,
TsO
,
MsO
, H2O, NH3
O
OTs =
O S
O
CH3 (Tosylate)
O
OMs = O S CH3 (Mesylate)
O
2014 by John Wiley & Sons, Inc. All rights reserved.
. Kinetics of a Nucleophilic
Substitution Reaction:
An SN2 Reaction
H
+
H
C Cl
HO C
H
(substrate)
H
(product)
+ Cl
(leaving
group)
Concentration, M
Graphically
Rate =
[CH3Cl]
[CH3OH]
Time, t
[CH3Cl]
t
[CH3Cl]t=t [CH3Cl]t=0
Time in seconds
Concentration, M
Initial Rate
[CH3Cl]t=0
[CH3Cl]t=t
[CH3Cl]
Time, t
[CH3Cl]t=t [CH3Cl]t=0
Initial Rate
=
(from slope)
t
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-
Result
1.0 M
0.0010 M
4.9 10-7
1.0 M
0.0020 M
2.0 M
0.0010 M
2.0 M
0.0020 M
19.6 10
-7
Quadruple
d
Conclusion:
HO + Cl CH3
60oC
H2O
HO CH3 + Cl
60oC
H2O
HO CH3 + Cl
Rate [OH][CH3Cl]
Rate = k[OH][CH3Cl]
k=
Initial Rate
[OH][CH3Cl]
Br
H
H
HO
Br
C
H
negative HO
OC bond
brings an e
partially
pair to +C; Br
formed; CBr
begins to move bond partially
away with an
broken.
Configuration
e pair
ofWileyC& begins
toreserved.
2014 by John
Sons, Inc. All rights
OC bond
formed; Br
departed.
Configuratio
n of C
inverted
At 60oC (333 K)
Go = -100 kJ/mol
This reaction is highly
exergonic
Ho = -75 kJ/mol
This reaction is exothermic
2014 by John Wiley & Sons, Inc. All rights reserved.
Go = RT ln Keq
Go
=
RT
=
(100 kJ/mol)
= 36.1
Keq = 5.0 x 1015
2014 by John Wiley & Sons, Inc. All rights reserved.
A 10C increase
in temperature
will cause the
reaction rate to
double for
many reactions
taking place
near room
temperature
The relationship
between the rate
constant (k) and
G is
G
/RT
exponential
:
k = k0 e
k0 = absolute rate
constant, which equals
the rate at which all
transition states
proceed to products
(At 25oC,
12
A reaction with a
lower free energy
of activation (G)
will occur
exponentially
faster than a
reaction with a
higher G, as
dictated byG/RT
k = k0 e
T.S.
G
HO- + CH3Br
Go
G = free energy of
activation
Go =free energy
change
CH3OH + Br-
Reaction Coordinate
Inversion of configuration
HO
CH3
+
C Br
H
CH2CH3
(R)
(inversion)
CH3
HO
H
(S) CH2CH3
+ Br
Example:
CH3
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)
Fork1example:
Reactant
k2
Intermediate
(slow)
(fast)
1
k3
Intermediate
(fast)
2
k1 << k2 or
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
A multistep process
slow
r.d.s.
intermediate
Step (2)
CH3
(k2)
CH3 C +H2O
fast
CH3
CH3 H
CH3 C O
CH3 H
intermediate
Step (2)
CH3
(k2)
CH3 C +H2O
fast
CH3
CH3 H
CH3 C O
CH3 H
fast
2014 by John Wiley & Sons, Inc. All rights reserved.
intermediate
Step (2)
CH3
(k2)
CH3 C +H2O
fast
CH3
CH3 H
CH3 C O
CH3 H
k1 << k2 and
k3
fast
2014 by John Wiley & Sons, Inc. All rights reserved.
Br
CH3
2014 by John Wiley & Sons, Inc. All rights reserved.
11.Carbocations
11A. The Structure of
Carbocations are
Carbocations
H3C
H3C
trigonal planar
The central carbon
atom in a
carbocation is
electron deficient; it
C
CH3
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
2014 by John Wiley & Sons, Inc.carbocation
All rights reserved.
Stability of cations
most stable (positive inductive
effect)
R
H
R
R
>
>
>
R R
H
H H
H H
Resonance stabilization of allylic
and benzylic cations
CH2
CH2
etc.
Ph
CH3OH
Br
CH2CH3
(S)
CH3OH
CH3 CH2CH3
50:50
chance
CH3
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
(R)
( 1 : 1 ) (S)
Example:
(R)
Br
H2O
(SN1)
(one
enantiomer)attack from
slow
TOP face
r.d.s
H2O
.
(carbocation)
OH
OH
H2O
H2O
BOTTOM
face
2014 by John Wiley & Sons, Inc. All rights reserved.
Example:
I
Bu
Me
OMe
Me MeOH tBu
Me +tBu
OMe
MeOH
slow
r.d.s
.
t
Bu
Me
t
MeOH
Bu
MeOH
Me
Me
CH3
MeOH
Bu
trigonal planar
2014 by John Wiley & Sons, Inc. All rights reserved.
O
Me
For example:
R Br +HO
R OH + Br
methyl
6
CH3
Br CH3 C CH2Br
CH3CHo2 Br CH3CH
o
neopent
1
2
CH3
CH3
2 10 4 10
Most
reactiv
e
500
yl
1
CH3
CH3 C
o Br
3CH3
<1
Least
reactiv
e
Compare
H
HO
C
H
H
HO
C
CH3
Br
faster
HO
C
H
Br
+ Br
slower
HO
+ Br
CH3
CH3
CH3
2014 by John Wiley & Sons, Inc. All rights reserved.
HO
Bu
C
CH3
Br
CH3
HO
CH3
very
slow
Br
HO
extremely
slow
CH3
+ Br
C
CH3
CH3
sp2
sp
Stability of cations
R
>
R
>
H H
>
H
an allylic bromide
a benzylic iodide
Identity of the Nu
The relative strength of a Nu
(its nucleophilicity) is
measured in terms of the
relative rate of its SN2 reaction
rapid
with a given
substrate
Good Nu
Poor Nu:
Very
slow
2014 by John Wiley & Sons, Inc. All rights reserved.
Classification of solvents
Non-polar solvents
(e.g. hexane,
benzene)
Solvents
Polar
solvent
s
CH3
CH3
(DMSO)
N
CH3
(DMF)
P NMe
Me2N NMe2 2
(HMPA)
CH3CN
(Acetonitrile)
Polar
Tremendous
acceleration in
SN2 reactions with polar
aprotic solvent
CH3Br + NaI
CH3I + NaBr
Solvent
Relative
Rate
MeOH
DMF
106
OR
RO
I > Br OR
> Cl > F
H
H
H
RO H
H OR
RO
OR
(strongly solvated)
RO H
OR
(weakly solvated)
SN1 Reaction:
C X
slow
r.d.s.
SN2 Reaction:
Nu:
C
X
slow
C X
r.d.s.
Nu C
Nu C
+X
Best
X
Worst X
HO ,
H2N,<<F < Cl < Br < I < TsO
RO
~0
200
a poor
leaving group
R O
Nu
a good
a strong
basic anion
R Nu
leaving group
2014 by John Wiley & Sons, Inc. All rights reserved.
H2O
weak
base
HO
CN
Br
MeS
MeO
HS
SMe
2014 by John Wiley & Sons, Inc. All rights reserved.
SH
Me
Me C C
Me
NMe3
Br
I
Br
N3
MeCOO
Me3N
N3
2014 by John Wiley & Sons, Inc. All rights reserved.
Examples:
NaOEt,??DMSO
Br
NaSMe,
?? DMSO
SMe
Examples:
??
I
CN
??
I
CN
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.
X
vinylic halide
phenyl halide
Examples
Br
NaCN
DMSO
NaSMe
HMPA
No Reaction
No Reaction
Substitution
Elimination
e.g.
I
BuOK
BuOH
O Bu +
SN2: 15%
E2: 85%
15A. Dehydrohalogenation
hydrogen
carbon
Br
LG
H
C
carbon
C
X halide as LG
BuOK
t
o
BuOH, 60 C
+ KBr + BuOH
hydrogen
OtBu
2014 by John Wiley & Sons, Inc. All rights reserved.
16.The E2 Reaction
Br
EtO +
+ EtOH + Br
Rate = k[CH3CHBrCH3][EtO]
A bimolecular reaction
C C H
H
Br
H
H
Et O
CH3
C C H
H
Br
H
H
H
H
C C
+
CH3
H
Et OH + Br
forms
depart
Br
2014 by John Wiley & Sons, Inc. All rights reserved.
T.S.
CH3CHBrCH3
+ EtO-
CH2=CHCH3
+ EtOH + Br-
Reaction Coordinate
Rate = k[CH3CHBrCH3][EtO]
Second-order overall
bimolecular
17.The E1 Reaction
H2O as
CH3
nucleophile
CH3 C
CH3
H2O as
base
Mechanism of an E1 Reaction
carbon
hydrogen
H
H2O
slow
fast (E1 product)
r.d.s
. fast H O
2
O
H HO
2
H
H3O
OH + H3O
(SN1 product)
Step (1):
CH3
CH3 C Cl
CH3
H2O
(k1)
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
2014 by John Wiley & Sons, Inc. All molecules
rights reserved.
Aided by the
polar solvent,
a chlorine
departs with
the e pair
that bonded it
to the carbon
Step (2)
H3C
H
C C H +H2O
H3C
(k2)
H3C
fast
H3C
CH2
H
(b)
Nu
(a)
H C
C X
(a)
H C
SN2
Nu C
(b)
E2
+X
+ Nu H + X
Primary Substrate
NaOEt
Br EtOH
OEt
SN2: 90%
+
E2: (10%)
Secondary Substrate
Br
NaOEt
EtOH
E2: 80%
+
OEt
SN2: 20%
Tertiary Substrate
Br
NaOEt
EtOH
+
E2: 91%
OEt
SN1: 9%
+
OMe
SN2: 99%
E2: 1%
KO Bu
Br t
BuOH
+
O Bu
SN2: 15% E2: 85%
t
Br
EtO
(strong base)
SN2: 100%
E2: 0%
OEt
+
SN2: 20%
E2: 80%
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
E1
CH3X
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
E2
Very little
Strong bases
promote E2;
e.g. with RO, HO
Strong bases
Always competes
promote E2;
with SN1
e.g. with RO, HO
Review Problems
CN
t
Bu
(2)
I
NaH
Et2O
H
I
Intramolecular SN2
2014 by John Wiley & Sons, Inc. All rights reserved.
(3)
CH3
OH
HCl
Bu
Cl attacks
from top face
Bu
CH3
H
O
H
CH3
t
Bu
Cl attacks
from bottom
face
sp2 hybridized
carbocation
END OF CHAPTER 6