Chapter 7-2.
Reactions of Alkyl Halides:
Nucleophilic Substitutions
Based on McMurry’s Organic Chemistry, 6th edition
Polarity and Reactivity




Halogens are more electronegative than C.
Carbon-halogen bond is polar, so carbon has
partial positive charge.
Carbon can be attacked by a nucleophile.
Halogen can leave with the electron pair.
H + H C Br
H
2
Alkyl Halides React with Nucleophiles
and Bases


Alkyl halides are polarized at the carbonhalide bond, making the carbon electrophilic
Nucleophiles will replace the halide in C-X
bonds of many alkyl halides (reaction as Lewis
base)
3
Alkyl Halides React with Nucleophiles
and Bases

Nucleophiles that are Brønsted bases produce
elimination
4
Substitution vs. Elimination
5
The Nature of Substitution


Substitution requires that a "leaving group", which
is also a Lewis base, departs from the reacting
molecule.
A nucleophile is a reactant that can be expected
to participate as a Lewis base in a substitution
reaction.
6
SN2 Mechanism




One step: bond forming and bond
breaking at same time.
“concerted” process
Bimolecular nucleophilic substitution.
Rate = k [HO-] [CH3Br],
first order in each reactant
second order overall
Inversion of configuration.
H
H
H O
H
C Br
H
HO C Br
H H
H
HO C
H
+
-
Br
H
7
Kinetics of Nucleophilic
Substitution
Rate = d[CH3Br]/dt = k[CH3Br][OH-1]
This reaction is second order: two
concentrations appear in the rate law
SN2: Substitution Nucleophilic 2nd order
8
SN1 Mechanism(1)
Formation of carbocation (slow)
(CH3)3C Br
+
(CH3)3C
-
+ Br
=>
9
10
SN1 Mechanism (2)

Nucleophilic attack
+
(CH3)3C
+ H O H
(CH3)3C O H
H
• Loss of H+ (if needed)
(CH3)3C O H + H O H
(CH3)3C O H
+
+ H3O
H
11
SN1 Energy Diagram


Forming the
carbocation is
endothermic
Carbocation
intermediate is in
an energy well.
12
SN1 Mechanism




Unimolecular nucleophilic substitution.
Two step reaction with carbocation
intermediate.
Rate = k [RX]
first order in the alkyl halide
zero order in the nucleophile.
Racemization occurs.
13
Factors affecting the rates
of SN Reactions





Concentration
Nature of the alkyl group
Nature of the nucleophile
Nature of the leaving group
Nature of the solvent
14
Structure of Substrate


Relative rates for SN2:
CH3X > 1° > 2° >> 3°
Tertiary halides do not react via the
SN2 mechanism, due to steric
hindrance.
15
SN2: Reactivity of
Substrate



Carbon must be partially positive.
Must have a good leaving group
Carbon must not be sterically hindered.
16
The Nucleophile


Neutral or negatively charged Lewis base
Reaction increases coordination (adds a new
bond) at the nucleophile
 Neutral nucleophile acquires positive
charge
 Anionic nucleophile becomes neutral
17
For example:
Br
CH2
C
+ CN-
Cl
+ H2O
CH2
OH2
N
+ Br-
+ Cl-
18
Relative Reactivity of Nucleophiles

Depends on reaction and conditions

More basic nucleophiles react faster


Better nucleophiles are lower in a column of the
periodic table
Anions are usually more reactive than neutrals
19
Nucleophilic Strength


Stronger nucleophiles react faster in
SN2.
Strong bases are strong nucleophiles, but
not all strong nucleophiles are basic.
20
Bulky Nucleophiles
Sterically hindered for attack on carbon,
so weaker nucleophiles.
CH3 CH2 O
ethoxide (unhindered)
weaker base, but stronger nucleophile
CH3
H3C
C
O
CH3
t-butoxide (hindered)
stronger base, but weaker nucleophile
21
Trends in Nuc. Strength



Decreases left to right on Periodic Table. More
electronegative atoms less likely to form new
bond:
OH- > FNH3 > H2O
Increases down Periodic Table, as size and
polarizability increase:
I- > Br- > ClOf a conjugate acid-base pair, the base is
stronger:
OH- > H2O, NH2- > NH3
22
23
24
Polarizability Effect
25
The Leaving Group



A good leaving group reduces the energy of
activation of a reaction
Stable anions that are weak bases (conjugate
bases of strong acids) are usually excellent
leaving groups
Stronger bases (conjugate bases of weaker
acids) are usually poorer leaving groups
26
Leaving Group Ability



Electron-withdrawing
Stable once it has left (not a strong base)
Polarizable to stabilize the transition state.
27
28
Poor Leaving Groups

If a group is very basic or very small, it does
not undergo nucleophilic substitution.
29
Solvent Effects (1)
Polar protic solvents (O-H or N-H) reduce the
strength of the nucleophile. Hydrogen bonds
must be broken before nucleophile can attack
the carbon.
30
Solvent Effects (2)


Polar aprotic solvents (no O-H or N-H) do not
form hydrogen bonds with nucleophile
Examples:
O
CH3 C N
acetonitrile
H
C
N
CH3
CH3
dimethylformamide
(DMF)
O
C
H3C
CH3
acetone
31
Rates of SN1 Reactions

3° > 2° > 1° >> CH3X




Order follows stability of carbocations (opposite to
SN2)
More stable ion requires less energy to form
Better leaving group, faster reaction (like
SN2)
Polar protic solvent best: It solvates ions
strongly with hydrogen bonding.
32
The Discovery of the Walden
Inversion


In 1896, Paul Walden showed that (-)-malic acid
could be converted to (+)-malic acid by a series of
chemical steps with achiral reagents
This established that optical rotation was directly
related to chirality and that it changes with
chemical alteration



Reaction of (-)-malic acid with PCl5 gives (+)chlorosuccinic acid
Further reaction with wet silver oxide gives (+)-malic acid
The reaction series starting with (+) malic acid gives (-)
acid
33
Stereochemistry of SN2
Walden inversion
SN2: Substitution Nucleophilic 2nd order
34
SN2 Energy Diagram


One-step reaction.
Transition state is highest in energy.
35
SN2 Transition State


The transition state of an SN2 reaction has a
planar arrangement of the carbon atom and
the remaining three groups
Hybridization is sp2
36
37
Stereochemistry of SN1
Racemization:
inversion and retention
=>
38
Two Stereochemical Modes of
Substitution

Substitution with inversion:
H3C
X
R

CH3
OH-
+ X-
HO
H
H
R
Substitution with retention:
H3C
X
R
H
OH-
H3C
OH + XR
H
39
The Walden Inversion (1896)
40
O
O
HO
PCl5
OH
H
O
HO
OH
ether
(retention)
OH
H
O
R(-)-Malic acid
[]D= -2.3o
Cl
R(-)-Chlorosuccinic acid
Ag2O,
Ag2O,
H2O
H2O
(inversion)
(inversion)
O
O
PCl5
HO
OH
O
Cl
H
S(+)-Chlorosuccinic acid
ether
(retention)
HO
OH
O
HO
H
S(+)-Malic acid
[]D= +2.3o
41
Significance of the Walden Inversion


The reactions involve substitution at the
chiral center
Therefore, nucleophilic substitution can
invert the configuration at a chirality center
42
Stereochemistry of Nucleophilic
Substitution



A more rigorous Walden
cycle using 1-phenyl-2propanol (Kenyon and
Phillips, 1929)
Only the second and fifth
steps are reactions at
carbon
Inversion must occur in
the substitution step
43
44
Hughes’ Proof of Inversion



React (S)-2-iodo-octane
with radioactive iodide
Observe that racemization
(loss of optical activity) of
mixture is twice as fast as
incorporation of label
Racemization in one
reaction step would occur
at same rate as
incorporation
45
Hughes’ Proof of Inversion
inversion
H
I
I
H
}
two molecules of
racemic mixture
no reaction
H
H
I
I
racemization
H
I
{
I
H
}
two molecules of
racemic mixture
racemization
H
I
H
I
46
Rearrangements



Carbocations can rearrange to form a
more stable carbocation.
Hydride shift: H- on adjacent carbon
bonds with C+.
Methyl shift: CH3- moves from adjacent
carbon if no H’s are available.
47
Hydride Shift
H
Br H
CH3
CH3
C C CH3
C C CH3
H CH3
H CH3
H
H
CH3
CH3
C C CH3
C C CH3
H CH3
H CH3
H
CH3
C C CH3
H CH3
H Nuc
Nuc
CH3
C C CH3
H CH3
48
Methyl Shift
CH3
Br CH3
CH3
CH3
C C CH3
C C CH3
H CH3
H CH3
CH3
CH3
CH3
CH3
C C CH3
H CH3
H CH3
CH3
CH3
C C CH3
H CH3
C C CH3
Nuc
CH3
CH3 Nuc
C C CH3
H CH3
49
SN2
or

Primary or methyl
Strong nucleophile

Polar aprotic solvent




Rate = k[halide][Nuc]
Inversion at chiral
carbon
No rearrangements
SN1?






Tertiary
Weak nucleophile (may
also be solvent)
Polar protic solvent, silver
salts
Rate = k[halide]
Racemization of optically
active compound
Rearranged products
50
Substitution Mechanisms

SN1



Two steps with carbocation intermediate
Occurs in 3°, allyl, benzyl
SN2


Two steps combine - without intermediate
Occurs in primary, secondary
51
Characteristics of the SN2 Reaction






Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Unhindered secondary halides react under
some conditions
Tertiary are unreactive by this path
No reaction at C=C (vinyl or aryl halides)
52
Steric Effects on SN2 Reactions
53
Order of Reactivity in SN2

The more alkyl groups connected to the
reacting carbon, the slower the reaction
54
Vinyl and Aryl Halides:
55
Summary of SN2 Characteristics:





Substrate: CH3->1o>2o>>3o (Steric effect)
Nucleophile: Strong, basic nucleophiles favor the
reaction
Leaving Groups: Good leaving groups (weak
bases) favor the reaction
Solvent: Aprotic solvents favor the reaction; protic
reactions slow it down by solvating the nucleophile
Stereochemistry: 100% inversion
56
Prob.: Arrange in order of SN2
reactivity
57
The SN1 Reaction



Tertiary alkyl halides react rapidly in protic
solvents by a mechanism that involves
departure of the leaving group prior to the
addition of the nucleophile.
Reaction occurs in two distinct steps, while SN2
occurs in one step (concerted).
Rate-determining step is formation of
carbocation:
58
SN1 Reactivity:
59
SN1 Energy Diagram
60
Rate-Limiting Step



The overall rate of a reaction is controlled by
the rate of the slowest step
The rate depends on the concentration of the
species and the rate constant of the step
The step with the largest energy of activation
is the rate-limiting or rate-determining step.
61
SN1 Energy Diagram
62
63
Stereochemistry of SN1 Reaction


The planar carbocation intermediate leads to
loss of chirality
Product is racemic or has some inversion
64
65
Characteristics of the SN1 Reaction

Tertiary alkyl halide is most reactive by this
mechanism

Controlled by stability of carbocation
66
Relative Reactivity of Halides:
67
Allylic and Benzylic Halides


Allylic and benzylic intermediates stabilized by
delocalization of charge
Primary allylic and benzylic are also more
reactive in the SN1 mechanism
68
69
Effect of Leaving Group on SN1

Critically dependent on leaving group



Reactivity: the larger halides ions are better leaving
groups
In acid, OH of an alcohol is protonated and leaving
group is H2O, which is still less reactive than halide
p-Toluensulfonate (TosO-) is an excellent leaving group
70
Summary of SN1 Characteristics:





Substrate: Benzylic~allylic > 3o > 2o
Nucleophile: Does not affect reaction (although
strong bases promote elimination)
Leaving Groups: Good leaving groups (weak
bases) favor the reaction
Solvent: Polar solvents favor the reaction by
stabilizing the carbocation.
Stereochemistry: racemization (with some
inversion)
71
Prob.: Arrange in order of SN1
reactivity
72
Practice Problem: SN1 or SN2?
73
Problem: SN1 or SN2?
74
Chapter 7-2, Questions
27, 29, 31, 32, 34,
39, 46, 47
75