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ch07 - Lecture (MNA)
ch07 - Lecture (MNA)
Azmi MOHAMAD
Universiti Sains Malaysia
Chapter 7
Alkyl Halides & Nucleophilic Substitutions
Copyright © 2017 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education.
1
Alkyl Halides
• Alkyl halides are organic molecules containing a halogen
atom bonded to an sp3 hybridized carbon atom.
• The halogen atom in halides is often denoted by the symbol
“X”.
• 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.
2
Types of Alkyl Halides
3
Types of Alkyl Halides
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 weakly 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
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.
11
Reaction Types for Alkyl Halides
12
Substitution Reactions
• Three components are necessary in any substitution reaction.
13
Nucleophiles in Substitution Reactions
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 vs. 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
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.
27
Polar Aprotic Solvents
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 vs. Basicity in Polar
Aprotic Solvents
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
SN2 Kinetics
39
Energy Diagrams for SN2 Reactions
40
Stereochemistry of the SN2 Reaction
• There are two possibilities for which direction the
nucleophile will approach the substrate.
• Frontside Attack: The nucleophile approaches from the
same side as the leaving group.
41
Stereochemistry of the SN2 Reaction
• The products of frontside and backside attack are different
compounds.
• They are enantiomers.
43
Inversion in SN2 Reactions
44
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.
46
Characteristics of the SN2 Mechanism
47
The SN2 Reaction in the Synthesis of Drugs
48
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.
49
SN1 Kinetics
50
Energy Diagrams for SN1 Reactions
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
54
Substrate Reactivity in SN1 Reactions
• The rate of an SN1 reaction is affected by the type of alkyl halide
involved.
56
Carbocation Stability
57
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.
58
Carbocation Stability
59
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 .
60
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.
61
The Hammond Postulate
• The rate of SN1 reaction increases as the number of R
groups on carbon increases.
• The stability of a carbocation increases as the number of
R groups on the C+ increases.
62
The Hammond Postulate and SN1 reactions
63
Transition State Energy and the Hammond
Postulate
64
Endothermic Reaction Transition States
65
Transition State Energy of an
Endothermic Reaction
66
Exothermic Reaction Transition States
67
Transition State Energy of an
Exothermic Reaction
68
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.
69
Application of the Hammond Postulate to
the SN1 Reaction
• Since CH3+ is less stable than (CH3)3C+
• Ea[1] > Ea[2]
• Reaction [1] is slower
70
Predicting the Mechanism of Nucleophilic
Substitutions Reactions
• Four factors are relevant in predicting whether a
given reaction is likely to proceed by an SN1 or an SN2
mechanism:
72
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.
73
Predicting SN1 or an SN2–Nucleophile
• The strong nucleophile favors an SN2 mechanism.
74
Effect of Leaving Groups
• A better leaving group increases the rate of both SN1 and SN2
reactions.
75
Effect of Solvent
76
Predicting SN1 or an SN2–Summary
77
Nucleophilic Substitution Reactions in
Biological Systems
• Nucleophilic substitution reactions are important in biological
systems as well.
78
SN2 Reaction in Adrenaline Synthesis
79
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.
80
Organic Synthesis
81
Organic Synthesis Using Alkyl Halides
82
Thinking Backwards in Organic Synthesis
• To carry out the synthesis of a particular compound, we must
think backwards, and ask ourselves the question:
“What starting material and reagents are needed to make it?”
83
Approaches Used in Organic Synthesis
• To determine the two components needed for synthesis,
remember that the carbon atoms come from the organic
starting material, in this case, a 1° alkyl halide.
• The functional group comes from the nucleophile, HO¯ in
this case.
• With these two components, we can “fill in the boxes” to
complete the synthesis.
84