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Substitution%20Reactions

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Title: Substitution%20Reactions


1
Organic Chemistry 6th Edition Paula Yurkanis
Bruice
Chapter 8 Substitution Reactions of Alkyl
Halides
2
What is a substitution reaction?
The atom or group that is substituted or
eliminated in these reactions is called a
leaving group.
3
Alkyl halides have relatively good leaving groups
How do alkyl halides react?
4
Alternatively
5
The substitution is more precisely called a
nucleophilic substitution because the atom or
group replacing the leaving group is a nucleophile
The reaction mechanism which predominates depends
on the following factors
  • the structure of the alkyl halide
  • the reactivity of the nucleophile
  • the concentration of the nucleophile
  • the solvent of the reaction

6
Experimental Evidence for the SN2 Reaction
Mechanism
1. The rate of the reaction is dependent on the
concentration of both the alkyl halide and the
nucleophile.
2. The rate of the reaction with a given
nucleophile decreases with increasing
branching of the alkyl halide at the reacting
center.
3. The configuration of the substituted product
is inverted compared to the configuration of
the reacting chiral alkyl halide.
7
The Rate Law of an SN2 Reaction
Obtained experimentally
8
The Influence of Branching on the SN2 Rate
9
Why Does Branching Lower the SN2 Rate?
Because the nucleophile attacks the back side of
the carbon that is bonded to the leaving group
10
Why does the nucleophile attack from the back
side?
11
Reaction coordinate diagrams for (a) the SN2
reaction of methyl bromide and (b) an SN2
reaction of a sterically hindered alkyl bromide
12
Inversion of configuration (Walden inversion) in
an SN2 reaction is due to back-side attack
13
SN2 Reactions Are Affected by the Leaving Group
14
Good leaving groups are the conjugate bases of
strong acids, i.e., they are weak bases
15
List of Common Good Leaving Groups
Anionic Leaving Groups
Neutral Leaving Groups
16
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17
Second-Row Nucleophiles in the SN2 Reaction
  • Second-row nucleophiles
  • Are approximately the same size.
  • The stronger the base, the better the nucleophile.

stronger base, better nucleophile
weaker base, poorer nucleophile
OH gt H2O CH3O
gt CH3OH H2N gt NH3 CH3CH2NH
gt CH3CH2NH2
18
Therefore the strength of second-row nucleophiles
is determined by conjugate acid strength
19
An SN2 reaction proceeds in the direction that
allows the stronger base to displace the weaker
base
Chloride is a weaker base than hydroxide and the
reaction is not reversible.
20
Because of their small size, second-row
nucleophiles are solvated by polar solvents
hindering back-side attack
Therefore water and alcohol solvents are not
suitable for SN2 reactions with second-row
nucleophiles.
21
SN2 reactions with second-row nucleophiles are
carried out in polar aprotic solvents
Includes DMSO, DMF, and acetonitrile (CH3CN)
22
Non-nucleophilic bases Uncoupling basicity from
nucleophilicity
Bulk decreases nucleophilicity, but not basicity.
Why? Nucleophilic attack more sterically
congested than proton abstraction.
23
Higher-Row Nucleophiles in the SN2 Reaction

Down a column of the periodic table nucleophiles
become larger and more polarizable, but less
solvated and less basic.
24
The Influence of Solvent on Higher-Row
Nucleophiles
25
Synthetic Utility of the SN2 Reaction
A variety of functional groups can be prepared
employing a good nucleophile and an electrophile
with a good leaving group
26
Iodide SN2 reactions are reversible because the
basicities of the nucleophile and leaving group
are similar.
Solution Use acetone as a reaction solvent.
27
Fluoride SN2 reactions are problematic because
fluoride salts are too ionic to dissolve in
aprotic solvents.
Solution, use a crown ether
28
Intermolecular Versus Intramolecular SN2
Reactions
29
An intramolecular reaction is favored when a
five- or six- membered ring product is formed
30
Carrying out an internal SN2 reaction
Use sodium metal to generate the oxygen anion.
Use a non-nucleophilic base to generate the
oxygen anion.
31
Experimental Evidence for an SN1 Reaction
1. The rate of the reaction depends only on the
concentration of the alkyl halide.
2. The rate of the reaction increases with
branching of the alkyl halide at the reacting
center.
3. An SN1 reaction with an enantiomeric pure
alkyl halide affords a racemic or partially
racemic product.
32
Reaction Coordinate Diagram for an SN1 Reaction
33
An SN1 is a two-step reaction and the leaving
group departs before the nucleophile approaches
34
Influence of Alkyl Halide Branching at the
Reacting Center
35
The Stereochemistry of SN1 Reactions
The carbocation reaction intermediate leads to
the formation of a racemic mixture
36
The SN1 reaction of an enantiomeric pure alkyl
halide affords a racemic mixture
37
Sometimes extra inverted product is formed in an
SN1 reaction because
38
The products resulting from substitution of
cyclic compounds
Inversion versus racemization
39
The Rate of an SN1 Reaction
The rate of the reaction is affected by 1) The
better the leaving group, the larger the rate. 2)
The more stable the carbocation, the larger the
rate. 3) The higher the polarity of the solvent,
the larger the rate.
The nucleophile concentration has no effect on
the rate of an SN1 reaction because it is not in
the rate-determining step.
40
The effect of a solvent on the rate of an SN1
reaction
41
The dielectric constant is a measure of how the
solvent can insulate opposite charges from one
another
42
If the charge on the transition state is greater
than the charge on the reactants, a polar solvent
will stabilize the transition state more
43
SN1 Side Reactions
Rearrangement of the carbocation intermediate can
occur
The carbocation intermediate can also lose a
proton
Called an E1 reaction
44
Benzylic and Allylic Halides
Benzylic and allylic halides can undergo SN2 or
SN1 reactions
SN2 conditions Aprotic solvent and good
nucleophile.
Tertiary benzylic and tertiary allylic halides
are unreactive in the SN2 reaction because of
steric hindrance.
45
Benzylic and allylic halides can undergo SN1
reactions because benzylic and allylic
carbocations are stable.
SN1 conditions Protic solvent and poor
nucleophile.
46
More than one product may result from an SN1
reaction of an allylic halide
47
Vinyl and aryl halides do not undergo SN2 because
48
Vinyl and aryl halides do not undergo SN1 because
49
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50
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51
SAM, a Biological Methylating Agent
A sulfide leaving group
52
Methyltetrahydrofolate, Another Biological
Methylating Agent
53
Hypoxanthine Guanine Phosphoribo Transferase
(HGPRTase) An SN2-Type Enzymatic Reaction
HGPRTase deficiency severe mental
retardation (Lesch Nyhan Syndrome)
54
Glutathione
This is the biological nucleophile that protects
us from electrophiles that react with proteins
and DNA
55
Alkylating Agents Cancer Drugs
These agents add alkyl groups to DNA by an SN2
reaction.
Leaving groups
56
Mechlorethamine, a Nitrogen Mustard
Mustard refers to odor and color of the impure
warfare agent. Now used to treat lymphomas,
breast and lung cancers.
Affects only rapidly dividing cells, both normal
and cancerous.
57
Triethylenemelamine, an Aziridinyl Triple
Alkylating Agent
Used to treat Hodgkins lymphoma Requires
protonation to be activated as an alkylating agent
Protonation and ring opening
  • Ring opening driven by
  • Amine leaving group
  • Relief of ring strain

58
Sulfur Mustard, Chemical Warfare Agent
59
Temozolomide Used to Treat Senator Kennedys
Brain Tumor
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