Organic Chemistry, Second Edition

Janice Gorzynski Smith

University of Hawai’i

Chapter 7
Alkyl Halides and
Nucleophilic Substitution
Prepared by Rabi Ann Musah
State University of New York at Albany

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
1

7.1 Introduction to 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”.

1
• There are other types of organic halides. These include vinyl halides,
aryl halides, allylic halides and benzylic halides.
• Vinyl halides have a halogen atom (X) bonded to a C—C double
bond.
• Aryl halides have a halogen atom bonded to a benzene ring.
• Allylic halides have X bonded to the carbon atom adjacent to a C—C
double bond.
• Benzylic halides have X bonded to the carbon atom adjacent to a
benzene ring.

Figure 7.1 Examples of 1°, 2°, and 3° alkyl halides

Figure 7.2 Four types of organic halides (RX) having X near a π bond

2
7.2 Nomenclature

7.2B Common Names

ƒ 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.

3
7.3 Physical Properties

• Alkyl halides are weak polar molecules. They exhibit dipole-dipole

interactions because of their polar C—X bond, but because the rest of the
molecule contains only C—C and C—H bonds, they are incapable of
intermolecular hydrogen bonding.

4
7.4 Interesting Alkyl Halides
Figure 7.4 Some simple alkyl halides

10

5
7.5 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.

Figure 7.5 Electrostatic potential maps of four halomethanes (CH3X)

11

12

6
7.6 General Features of Nucleophilic Substitution
• Three components are necessary in any substitution reaction.

13

• 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.

• When a neutral nucleophile is used, the substitution product bears a

positive charge.

14

7
• Furthermore, when the substitution product bears a positive charge and
also contains a proton bonded to O or N, the initially formed substitution
product readily loses a proton in a BrØnsted-Lowry acid-base reaction,
forming a neutral product.

• To draw any nucleophilic substitution product:

Find the sp3 hybridized carbon with the leaving group.
Identify the nucleophile, the species with a lone pair or π bond.
Substitute the nucleophile for the leaving group and assign charges (if
necessary) to any atom that is involved in bond breaking or bond
formation.

15

7.7 The Leaving Group

• In a nucleophilic substitution reaction of R—X, the C—X bond is
heterolytically cleaved, and the leaving group departs with the electron pair
in that bond, forming X:¯. The more stable the leaving group X:¯, the better
able it is to accept an electron pair.

• For example, H2O is a better leaving group than HO¯ because H2O is a
weaker base.

16

8
• There are periodic trends in leaving group ability:

17

18

9
 19

7.8 The Nucleophile

• Nucleophiles and bases are structurally similar: both have a lone pair or a π
bond. They differ in what they attack.

20

10
• Although nucleophilicity and basicity are interrelated, they are
fundamentally different.
Basicity is a measure of how readily an atom donates its
electron pair to a proton. It is characterized by an equilibrium
constant, Ka in an acid-base reaction, making it a
thermodynamic property.
Nucleophilicity is a measure of how readily an atom donates its
electron pair to other atoms. It is characterized by a rate
constant, k, making it a kinetic property.

21

• 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¯, two oxygen
nucleophiles, 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:

22

11
• 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.

23

• 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, and the
Br¯ anions are solvated by strong hydrogen bonding interactions.

24

12
• 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 Example of polar protic solvents

25

• Polar aprotic solvents also exhibit dipole—dipole interactions, but they

have no O—H or N—H bonds. Thus, they are incapable of hydrogen
bonding.

Figure 7.7 Examples of polar aprotic solvents

26

13
• 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”.

27

• 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.

28

14
 29

7.9 Possible Mechanisms of Nucleophilic Substitution

In a nucleophilic substitution:

But what is the order of bond making and bond breaking? In theory, there are
three possibilities.
[1] Bond making and bond breaking occur at the same time.

In this scenario, the mechanism is comprised of one step. In such a

bimolecular reaction, the rate depends upon the concentration of both
reactants, that is, the rate equation is second order.
30

15
[2] Bond breaking occurs before bond making.

In this scenario, the mechanism has two steps and a carbocation is formed as
an intermediate. Because the first step is rate-determining, the rate depends
on the concentration of RX only; that is, the rate equation is first order.

31

[3] Bond making occurs before bond breaking.

This mechanism has an inherent problem. The intermediate generated in the

first step has 10 electrons around carbon, violating the octet rule. Because
two other mechanistic possibilities do not violate a fundamental rule, this last
possibility can be disregarded.

32

16
7.10 Two Mechanisms for Nucleophilic Substitution
Consider reaction [1] below:

Kinetic data show that the rate of reaction [1] depends on the concentration of
both reactants, which suggests a bimolecular reaction with a one-step
mechanism. This is an example of an SN2 (substitution nucleophilic
bimolecular) mechanism.

33

Consider reaction [2] below:

Kinetic data show that the rate of reaction [2] depends on the concentration of
only the alkyl halide. This suggests a two-step mechanism in which the rate-
determining step involves the alkyl halide only. This is an example of an SN1
(substitution nucleophilic unimolecular) mechanism.

34

17
7.11 The SN2 Mechanisms

The mechanism of an SN2 reaction would be drawn as follows. Note the

curved arrow notation that is used to show the flow of electrons.

35

Figure 7.8 An energy diagram for the SN2 reaction:

36

18
7.11C Stereochemistry of the SN2 Reaction
• All SN2 reactions proceed with backside attack of the nucleophile, resulting
in inversion of configuration at a stereogenic center.

Figure 7.9 Stereochemistry of the SN2 reaction

37

Figure 7.10
Two examples of inversion
of configuration in
the SN2 reaction

38

19
7.11D The Identity of the R Group

• Methyl and 1° alkyl halides undergo SN2 reactions with ease.

• 2° Alkyl halides react more slowly.
• 3° Alkyl halides do not undergo SN2 reactions. This order of reactivity can
be explained by steric effects. Steric hindrance caused by bulky R groups
makes nucleophilic attack from the backside more difficult, slowing the
reaction rate.

39

Electrostatic potential maps illustrate the effects of steric hindrance

around the carbon bearing the leaving group in a series of alkyl
halides.

Figure 7.11 Steric effects in the SN2 reaction

40

20
• The higher the Ea, the slower the reaction rate. Thus, any factor that
increases Ea decreases the reaction rate.

Figure 7.12 Two energy diagrams depicting the effect of steric hindrance in SN2 reactions

41

• Increasing the number of R groups on the carbon with the leaving group
increases crowding in the transition state, thereby decreasing the reaction
rate.
• The SN2 reaction is fastest with unhindered halides.

42

21
 43

7.12 Application: Useful SN2 Reactions

The SN2 reaction is a key step in the laboratory synthesis of many important
drugs.

Figure 7.13 Nucleophilic substitution in the synthesis of two useful drugs

44

22
Nucleophilic substitution reactions are important in biological systems as
well.

This reaction is called methylation because a CH3 group is transferred from

one compound (SAM) to another (:Nu¯).

45

Figure 7.14
Adrenaline synthesis
from noradrenaline in
response to stress

46

23
7.13 The SN1 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.
47

Figure 7.15 An energy diagram for the SN1 reaction:

48

24
7.13C Stereochemistry of the SN1 Reaction

To understand the stereochemistry of the SN1 reaction, we must

examine the geometry of the carbocation intermediate.

49

• 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. We
say that racemization has occurred.

50

25
 Figure 7.16 Two examples of racemization in the SN1 reaction

51

7.13C The Identity of the R Group

• The rate of an SN1 reaction is affected by the type of alkyl halide involved.

• This trend is exactly opposite to that observed in SN2 reactions.

52

26
 53

7.14 Carbocation Stability

• The effect of the type of alkyl halide on SN1 reaction rates can be
explained by considering carbocation stability.
• Carbocations are classified as primary (1°), secondary (2°), or
tertiary (3°), based on the number of R groups bonded to the
charged carbon atom. As the number of R groups increases,
carbocation stability increases.

54

27
7.14A Inductive Effect

• The order of carbocation stability can be rationalized through

inductive effects and hyperconjugation.
• Inductive effects are electronic effects that occur through σ bonds.
Specifically, the inductive effect is the pull of electron density
through σ bonds caused by electronegativity differences between
atoms.
• Alkyl groups are electron donating groups that stabilize a positive
charge. Since an alkyl group has several σ bonds, each containing
electron density, it is more polarizable than a hydrogen atom, and
better able to donate electron density.
• In general, the greater the number of alkyl groups attached to a
carbon with a positive charge, the more stable will be the cation.

55

Figure 7.17 Electrostatic potential maps for differerent carbocations

56

28
7.14B Hyperconjugation
• 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 σ bond. This overlap (hyperconjugation)
delocalizes the positive charge on the carbocation, spreading it over a
larger volume, and this stabilizes the carbocation.
• Example: CH3+ cannot be stabilized by hyperconjugation, but (CH3)2CH+
can.

57

7.15 The Hammond Postulate

58

29
• 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.

59

7.15A The General Features of the Hammond Postulate

60

30
• In an endothermic reaction, the transition state resembles the
products more than the reactants, so anything that stabilizes the
product stabilizes the transition state also. Thus, lowering the
energy of the transition state decreases Ea, which increases the
reaction rate.

• If there are two possible products in an endothermic reaction, but

one is more stable than the other, the transition state that leads to
the formation of the more stable product is lower in energy, so this
reaction should occur faster.

61

Figure 7.18 An endothermic reaction—How the energy of the transition state and products are related

62

31
• In the case of an exothermic reaction, the transition state
resembles the reactants more than the products. Thus, lowering
the energy of the products has little or no effect on the energy of
the transition state.

• Since Ea is unaffected, the reaction rate is unaffected.

• The conclusion is that in an exothermic reaction, the more stable
product may or may not form faster, since Ea is similar for both
products.

63

Figure 7.19 An exothermic reaction—How the energy of the transition state and products are related

64

32
7.15B The Hammond Postulate and the SN1 Reaction
• The Hammond postulate estimates the relative energy of transition states,
and thus it can be used to predict the relative rates of two reactions.
• 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

65

7.16 Application: SN1 Reactions, Nitrosamines and Cancer

• SN1 reactions are thought to play a role in how nitrosamines, compounds

having the general structure R2NN=O, act as toxins and carcinogens.

66

33
7.17A The Alkyl Halide-The Most Important Factor
• Four factors are relevant in predicting whether a given reaction is likely to
proceed by an SN1 or an SN2 reaction—The most important is the identity
of the alkyl halide.

67

7.17B The Nucleophile

• The nature of the nucleophile is another factor.
• 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.
• Let us compare the substitution products formed when the 2° alkyl halide
A is treated with either the strong nucleophile HO¯ or the weak nucleophile
H2O. Because a 2° alkyl halide can react by either mechanism, the strength
of the nucleophile determines which mechanism takes place.

68

34
• The strong nucleophile favors an SN2 mechanism.

• The weak nucleophile favors an SN1 mechanism.

69

7.17C The Leaving Group

• A better leaving group increases the rate of both SN1 and SN2 reactions.

70

35
7.17D The Solvent

• The nature of the solvent is a fourth factor.

• Polar protic solvents like H2O and ROH favor SN1 reactions
because the ionic intermediates (both cations and anions) are
stabilized by solvation.
• Polar aprotic solvents favor SN2 reactions because nucleophiles
are not well solvated, and therefore, are more nucleophilic.

71

72

36
7.18 Vinyl Halides and Aryl Halides.
• Vinyl and aryl halides do not undergo SN1 or SN2 reactions, because
heterolysis of the C—X bond would form a highly unstable vinyl or aryl
cation.

Figure 7.22 Vinyl halides and nucleophilic substitution mechanisms

73

74

37
7.19 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?
• If we are using nucleophilic substitution, we must determine what alkyl
halide and what nucleophile can be used to form a specific product.

75

• 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.

76

38