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Chapter 78 Substitution and Elimination
Chapter 78 Substitution and Elimination
Chapter 7
Lecture Outline
Prepared by Layne A. Morsch
The University of Illinois - Springfield
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
1
Alkyl Halides
• Alkyl halides are organic molecules containing a halogen
atom bonded to an sp3 hybridized carbon atom.
• Alkyl halides are classified as primary (1°), secondary (2°), or
tertiary (3°), depending on the number of carbons bonded to
the carbon with the halogen atom.
• The halogen atom in halides is often denoted by the symbol
“X”.
2
Types of Alkyl Halides
3
Types of Alkyl Halides
Figure 7.1
Figure 7.2
4
Naming Alkyl Halides
5
Common Names of Alkyl Halides
• Common names are often used for simple alkyl halides.
To assign a common name:
• Name all the carbon atoms of the molecule as a single
alkyl group.
• Name the halogen bonded to the alkyl group.
• Combine the names of the alkyl group and halide,
separating the words with a space.
6
Polarity of Alkyl Halides
• Alkyl halides are weak polar molecules.
• They exhibit dipole-dipole interactions because of their
polar C–X bond.
• Since the rest of the molecule contains only C–C and C–H
bonds, they are incapable of intermolecular hydrogen
bonding.
7
Physical Properties of Alkyl Halides
8
Simple Alkyl Halides
Figure 7.4
9
Common Alkyl Halides
10
The Polar Carbon–Halogen Bond
• The electronegative halogen atom in alkyl halides creates a
polar C–X bond, making the carbon atom electron deficient.
• Electrostatic potential maps of four simple alkyl halides
illustrate this point.
• This electron deficient carbon is a key site in the reactivity
of alkyl halides.
Figure 7.5
11
Reaction Types for Alkyl Halides
12
Substitution Reactions
• Three components are necessary in any substitution reaction.
13
Nucleophiles in Substitution Reactions
• Nucleophiles are Lewis bases that can be negatively charged
or neutral.
• Negatively charged nucleophiles like HO¯ and HS¯ are used
as salts with Li+, Na+, or K+ counterions to balance the charge.
• Since the identity of the counterion is usually inconsequential,
it is often omitted from the chemical equation.
14
Neutral Nucleophiles
• When a neutral nucleophile is used, the substitution product
bears a positive charge.
15
Drawing Products of Nucleophilic
Substitution Reactions
18
Good Leaving Groups
19
Poor Leaving Groups
• Conjugate bases of weaker acids are poorer leaving
groups.
20
Nucleophiles and Bases
21
Nucleophiles versus Bases
22
Nucleophilicity Parallels Basicity
Nucleophilicity parallels basicity in three instances:
1. For two nucleophiles with the same nucleophilic atom, the
stronger base is the stronger nucleophile.
• The relative nucleophilicity of HO¯ and CH3COO¯, is
determined by comparing the pKa values of their conjugate
acids (H2O = 15.7 and CH3COOH = 4.8).
• HO¯ is a stronger base and stronger nucleophile than
CH3COO¯.
2. A negatively charged nucleophile is always a stronger
nucleophile than its conjugate acid.
• HO¯ is a stronger base and stronger nucleophile than H2O.
3. Right-to-left across a row of the periodic table, nucleophilicity
increases as basicity increases:
23
Steric Effects on Nucleophile Strength
• Nucleophilicity does not parallel basicity when steric
hindrance becomes important.
• Steric hindrance is a decrease in reactivity resulting from
the presence of bulky groups at the site of a reaction.
• Steric hindrance decreases nucleophilicity but not basicity.
• Sterically hindered bases that are poor nucleophiles are
called nonnucleophilic bases.
24
Solvent Effects on Nucleophilicity
• Most organic reactions are performed in a liquid solvent
capable of dissolving the reactants, at least to some extent.
25
Solvation by Polar Protic Solvents
• Polar protic solvents solvate both cations and anions well.
• If the salt NaBr is used as a source of the nucleophile Br¯ in H2O:
• The Na+ cations are solvated by ion-dipole interactions with
H2O molecules.
• The Br¯ anions are solvated by strong hydrogen bonding
interactions.
26
Nucleophilicity in Polar Protic Solvents
• Smaller, more electronegative anions are solvated more
strongly, effectively shielding them from reaction.
• In polar protic solvents, nucleophilicity increases down a
column of the periodic table as the size of the anion
increases.
• This is the opposite of basicity.
Figure 7.6
27
Polar Aprotic Solvents
Figure 7.7
28
Nucleophilicity in Polar Aprotic Solvents
• Polar aprotic solvents solvate cations by ion–dipole
interactions.
• Anions are not well solvated because the solvent cannot
hydrogen bond to them.
• These anions are said to be “naked” and therefore, more
reactive.
29
Nucleophilicity versus Basicity in Polar
Aprotic Solvents
• In polar aprotic solvents, nucleophilicity parallels
basicity, and the stronger base is the stronger
nucleophile.
• Because basicity decreases as size increases down a
column, nucleophilicity decreases as well.
30
Common Nucleophiles
31
Bond Breaking and Making in Nucleophilic
Substitution Mechanisms
32
Nucleophilic Substitution Mechanisms—
Concerted
1. Bond making and bond breaking occur at the same time.
33
Nucleophilic Substitution Mechanisms—
Bond Breaking First
2. Bond breaking occurs before bond making.
34
Nucleophilic Substitution Mechanisms—
Bond Making First
3. Bond making occurs before bond breaking.
38
Energy Diagrams for SN2 Reactions
Figure 7.8
39
Transition States of SN2 Reactions
• The transition state always has partial bonds to the nucleophile
and the leaving group.
• There can also be partial charges on the nucleophile and/or
leaving group.
Figure 7.9
40
Inversion in SN2 Reactions
• The bond to the nucleophile in the product is always on the
opposite side relative to the bond of the leaving group in the
starting material.
• This is called backside attack.
• This results in inversion of configuration at a stereogenic center.
Figure 7.10
41
Substrate Reactivity in SN2 Reactions
• As the number of R groups on the carbon with the leaving
group increases, the rate of an SN2 reaction decreases.
Figure 7.11
43
Energy Diagrams for SN2 Reactions
• The higher the Ea, the slower the reaction rate.
• Thus, any factor that increases Ea decreases the reaction rate.
Figure 7.12
44
Effect of Sterics on Rate of SN2 Reactions
45
Characteristics of the SN2 Mechanism
46
The SN2 Reaction in the Synthesis of Two
Drugs
Figure 7.13
47
Nucleophilic Substitution Reactions in
Biological Systems
• Nucleophilic substitution reactions are important in biological
systems as well.
48
SN2 Reaction in Adrenaline Synthesis
Figure 7.14
Adrenaline synthesis
from noradrenaline in
response to stress
49
SN1 Reaction Mechanism
• The mechanism of an SN1 reaction would be drawn as
follows: Note the curved arrow formalism that is used to
show the flow of electrons.
• Key features of the SN1 mechanism are that it has two steps,
and carbocations are formed as reactive intermediates.
50
Energy Diagrams for SN1 Reactions
Figure 7.15
51
Stereochemistry of SN1 Reactions
52
Racemization in SN1 Reactions
• Loss of the leaving group in Step [1] generates a planar
carbocation that is achiral.
• In Step [2], attack of the nucleophile can occur on either side to
afford two products which are a pair of enantiomers.
• Because there is no preference for nucleophilic attack from
either direction, an equal amount of the two enantiomers is
formed—a racemic mixture.
• This process is called racemization.
53
Racemization in SN1 Reactions
Figure 7.16
54
Substrate Reactivity in SN1 Reactions
55
Carbocation Stability
56
Inductive Effects and Carbocation Stability
• The order of carbocation stability can be rationalized
through inductive effects and hyperconjugation.
• Inductive effects occur by the pull of electron density
through s bonds caused by electronegativity differences
between atoms.
• Alkyl groups are electron donor groups that stabilize a
positive charge because they contain several s bonds, each
containing electron density.
• As a result, alkyl groups are more polarizable than a
hydrogen atom, and better able to donate electron density.
• In general, the more alkyl groups attached to a carbon with a
positive charge, the more stable the cation will be.
57
Carbocation Stability
Figure 7.17
Electrostatic potential maps for
different carbocations
58
Hyperconjugation and Carbocation Stability
• The order of carbocation stability is also a consequence of
hyperconjugation.
• Hyperconjugation is the spreading out of charge by the
overlap of an empty p orbital with an adjacent s bond.
• This overlap delocalizes the positive charge on the
carbocation over a larger volume, thus stabilizing it.
• For example: (CH3)2CH+ can be stabilized by hyperconjugation
but CH3+ cannot .
59
60
Characteristics of the SN1 Mechanism
61
The Hammond Postulate
• The Hammond postulate relates reaction rate to stability.
• It provides a quantitative estimate of the energy of a
transition state.
• The Hammond postulate states that the transition state
of a reaction resembles the structure of the species
(reactant or product) to which it is closer in energy.
62
Transition State Energy
63
Endothermic Reaction Transition States
64
Transition State Energy of an
Endothermic Reaction
Figure 7.18
65
Exothermic Reaction Transition States
66
Transition State Energy of an
Exothermic Reaction
Figure 7.19
67
Application of the Hammond Postulate to
the SN1 Reaction
• In the SN1 reaction, the rate-determining step is the formation
of the carbocation, an endothermic process.
• According to the Hammond postulate, the stability of the
carbocation determines the rate of its formation.
Figure 7.20
Energy diagram for carbocation
formation in two different
SN1 reactions
68
Predicting the Mechanism of Nucleophilic
Substitutions Reactions
70
Effect of the Nucleophile
• Strong nucleophiles (which usually bear a negative charge)
present in high concentrations favor SN2 reactions.
• Weak nucleophiles, such as H2O and ROH favor SN1 reactions
by decreasing the rate of any competing SN2 reaction.
• Consider what happens when the 2° alkyl halide A, which can
react by either mechanism, is treated with either the strong
nucleophile HO¯ or the weak nucleophile H2O.
71
Predicting SN1 or an SN2 Nucleophile
• The strong nucleophile favors an SN2 mechanism.
72
Effect of Leaving Groups
• A better leaving group increases the rate of both SN1 and SN2
reactions.
73
Effect of Solvent
74
Predicting SN1 or an SN2—Summary
75
Vinyl and Aryl Halides
• SN1 or SN2 reactions occur on sp3 hybridized carbons.
• Vinyl and aryl halides, which have a halogen attached to a
sp2 hybridized carbon, do not undergo SN1 or SN2 reactions.
• Heterolysis of the C–X bond would form a highly unstable
vinyl or aryl cation.
76
Organic Synthesis
77
Organic Synthesis Using Alkyl Halides
78
General Features of Elimination
79
Elimination of HX
• In both example reactions a base removes the elements
of an acid, HX, from the organic starting material.
80
Dehydrohalogenation
81
Common Bases for Dehydrohalogenation
82
Drawing Products of Dehydrohalogenation
• Find the a carbon.
• Identify all b carbons with H atoms.
• Remove the elements of H and X from the a and b carbons
and form a p bond.
83
Alkene Structure
• The double bond of an alkene consists of a s bond and a
p bond.
84
Classifying Alkenes
Figure 8.1
85
Restricted Rotation About Double Bonds
• Recall that even though there is free rotation around single
bonds, rotation about double bonds is restricted.
Figure 8.2
86
Stereoisomers of Alkenes
• Because of restricted rotation, two stereoisomers of 2-
butene are possible.
• cis-2-Butene and trans-2-butene are diastereomers (i.e.,
nonmirror image stereoisomers).
87
Alkene Diastereomers
88
Stability of Trans Alkenes
• In general, trans alkenes are more stable than cis alkenes
because the groups bonded to the double bond carbons
are further apart, reducing steric interactions.
89
Stability in Alkenes
90
Stability in Alkenes
91
Relative Stability of Butenes
• The 2-butenes (disubstituted) are more stable than
1-butene (monosubstituted).
• trans-2-Butene is more stable than cis-2-butene (less
crowding).
92
Elimination Mechanisms
93
E2 Mechanism
• The most common mechanism for dehydrohalogenation
is the E2 mechanism.
• It exhibits second-order kinetics, and both the alkyl
halide and the base appear in the rate equation.
rate = k[(CH3)3CBr][¯OH]
94
E2 Mechanism
95
Bases in E2 Mechanisms
• E2 reactions are generally run with strong, negatively charged
bases like ¯OH and ¯OR.
• The base appears in the rate equation, so the rate of the
E2 reaction increases as the strength of the base increases.
• Two strong, sterically hindered nitrogen bases called DBN and
DBU are also sometimes used.
96
E2 Reaction with DBN
Figure 8.4
97
Effects of Leaving Group and Solvent on
E2 Reactions
• Because the bond to the leaving group is partially
broken in the transition state, the better the leaving
group the faster the E2 reaction.
• Polar aprotic solvents increase the rate of E2 reactions.
98
Effect of Alkyl Halide Structure on
E2 Reactions
• The SN2 and E2 mechanisms differ in how the alkyl halide
structure affects the reaction rate.
• As the number of R groups on the carbon with the leaving
group increases, the rate of the E2 reaction increases.
99
Transition States in E2 Mechanisms
• The increase in E2 reaction rate with increasing alkyl
substitution can be rationalized in terms of transition state
stability.
• In the transition state, the double bond is partially formed.
• This increases the stability of the double bond with alkyl
substituents stabilizing the transition state (i.e., lowers Ea),
which increases the rate of the reaction.
100
Product Stability and Rate of E2 Reactions
• Increasing the number of R groups on the carbon with the
leaving group forms more highly substituted, more stable
alkenes in E2 reactions.
• In the reactions below, since the disubstituted alkene is more
stable, the 3° alkyl halide reacts faster than the 1° alkyl
halide.
101
The Zaitsev (Saytzeff) Rule
102
Regioselectivity of E2 Reactions
• A reaction is regioselective when it yields predominantly or
exclusively one constitutional isomer when more than one is
possible.
• Thus, the E2 reaction is regioselective.
103
Stereoselectivity of E2 Reactions
• A reaction is stereoselective when it forms predominantly or
exclusively one stereoisomer when two or more are possible.
• The E2 reaction is stereoselective because the more stable
stereoisomer is formed preferentially.
104
Stereochemistry of E2 Reactions
• The transition state of an E2 reaction consists of four atoms
from an alkyl halide—one hydrogen atom, two carbon atoms,
and the leaving group (X)—all aligned in a plane.
• There are two ways for the C–H and C–X bonds to be coplanar.
105
Two Possible Geometries for E2 Reactions
• E2 elimination occurs most often in the anti periplanar geometry.
• This arrangement allows the molecule to react in the lower
energy staggered conformation, and allows the incoming base
and leaving group to be further away from each other.
Figure 8.7
106
Anti Periplanar Geometry
• The requirement of anti periplanar geometry in an E2
reaction has important consequences for compounds
containing six-membered rings.
• Chlorocyclohexane exists as two chair conformations.
• Conformation A is preferred since the bulkier Cl group
is in the equatorial position.
107
E2 Mechanism Summary
108
E1 Mechanism
rate = k[(CH3)3CCI].
109
E1 Mechanism
110
Effect of Alkyl Halide Structure on
E1 Reactions
• The rate of an E1 reaction increases as the number of
R groups on the carbon with the leaving group increases.
111
Effect of Base on the E1 Reaction
112
Regioselectivity of E1 Reactions
113
E1 Mechanism Summary
115
Comparison of E1 and E2 Mechanisms
• The strength of the base is the most important factor in
determining the mechanism for elimination.
116
When is the Reaction SN1, SN2, E1, or E2?
117
Bulky Bases Favor Elimination
118
Predicting Reaction Mechanisms
(SN1, SN2, E1, or E2)
Figure 8.10
119
Predicting Reaction Mechanisms
(SN1, SN2, E1, or E2)
Figure 8.10 continued
120
Predicting Reaction Mechanisms
Figure 8.10 continued
(SN1, SN2, E1, or E2)
121