Chapter 11

Reactions of Alkyl Halides:

Nucleophilic Substitutions and
Eliminations

Class 12 & 13

One of the most important

concepts in organic Chem!

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 (11.1)

The discovery of nucleophilic substitution reactions

(11.2)

Learning The SN2 reaction

Objectives (11.3)

Characteristics of the SN2 reaction

(11.4)

The SN1 reaction

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Learning Objectives

(11.5)
 Characteristics of the SN1 reaction
(11.6)
 Biological substitution reactions
(11.7)
 Elimination reactions: Zaitsev’s rule
(11.8)
 The E2 reaction and the deuterium isotope effect
(11.9)
 The E2 reaction and cyclohexane conformation

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Learning Objectives

(11.10)
 The E1 and E1cB reactions
(11.11)
 Biological elimination reactions
(11.12)
 A summary of reactivity: SN1,SN2, E1, E1cB, and E2

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In 1896, Walden showed pure enantiomeric (+)-

and (–)- malic acids can be interconverted
through a series of simple substitution reactions

Reaction of (-)- Further reaction The same reaction

The malic acid with
PCl5 gives (+)-
with wet silver
oxide gives (+)-
series starting with
(+) malic acid gives
chlorosuccinic acid malic acid (-) acid
Discovery of
Nucleophilic
Substitution
Reactions
Series of steps taking place in Walden’s cycle
are called nucleophilic substitution reactions

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 Figure 11.1 -
Walden’s Cycle
of Reactions
Interconverting

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Figure 11.2 - Interconversion of (+) and (-)

Enantiomers of 1-phenyl-2-propanol

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Worked Example

 Mention the product of a nucleophilic substitution

reaction of (S)-2-bromohexane with acetate ion,
CH3CO2-
 Assume that inversion of configuration occurs, and show
the chemistry of both the reactant and product

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The SN2 Reaction

 Kinetics of a reaction refer to the concentrations of the

reactants and the rate at which the reaction occurs
 Second order reaction: A reaction in which the rate is
linearly dependent on the concentration of the
reactants

Reaction rate = Rate of disappearance of reactant

–
 = k × [RX] × [ OH]
SN2 reaction is short for substitution, nucleophilic,
bimolecular

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Figure 11.3 - Mechanism of
the SN2 Reaction

Example: for S converting to P

V = d[S]/dt = k [S]
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Figure 11.4 - Transition of an

SN2 Reaction

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Worked Example

 Mention the product obtained from the SN2 reaction of

OH– with (R)-2-bromobutane
 Show the chemistry of the reactant and the product

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Characteristics of the SN2

Reaction
 Understanding of reaction rates is required
 Activation energy, ΔGǂ , determines the rate of reaction
 ΔGǂ is the energy difference between the reactant ground
state and transition state
 ΔGǂ is increased by a decrease in reactant energy or an
increase in transition state energy
 ΔGǂ is decreased by an increase in reactant energy or a
decrease in transition state energy

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 Figure 11.5 - The Effects of Changes in
Reactant and Transition-State Energy
Levels

Higher reactant
energy level (red Higher transition
curve) = Faster state energy level
reaction (smaller (red curve) =
G‡) Slower reaction
(larger G‡)
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Steric Effects on SN2

Reactions
 Partial bond is formed between the incoming
nucleophile and the alkyl halide carbon atom
 Bond formation is difficult with the nucleophile
 The substrate possesses a higher energy than a less
hindered substrate

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Order of Reactivity in SN2

 The more the alkyl groups connected to the reacting

carbon, the slower the reaction

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The Nucleophile

 Neutral or negatively charged Lewis base

 Negatively charged nucleophile yields a neutral product
 Neutral nucleophile yields a positively charged product

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Table 11.1 - Some SN2
Reactions With Bromo Ethane

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The Nucleophile

 Based on the reactions of nucleophilic substances with

bromoethane, some reactants seem to be more
nucleophilic than others
 Nucleophilicity is based on the concentration of the
substrate, the solvent, and the reactant
 Trends observed in nucleophiles:
 Nucleophilicity roughly parallels basicity
 Nucleophilicity increases with downward progression in
the periodic table
 Nucleophiles with a negative charge are generally more
reactive than those that are neutral

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Worked Example

 Mention the product formed in an SN2 reaction between

1-bromobutane and NaI
 Solution:

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The Leaving Group

 Group that is displaced by the incoming nucleophile in

the SN2 reaction
 Leaving groups that provide optimal stability to the
negative charge in the transition state are considered
the best
 Weak bases are good leaving groups, and strong bases
are poor leaving groups

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The Leaving Group

 An SN2 reaction with an alcohol requires conversion to

an alkyl chloride or an alkyl bromide

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Poor Leaving Groups

 Generally, ethers do not undergo SN2 reactions

 Epoxides are an exception as they are more reactive than
ethers

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Worked Example

 Rank the following compounds in order of their

expected reactivity toward SN2 reaction:
 CH3Br, CH3OTos, (CH3)2CHCl

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Influence of Solvents in the

SN2 Reaction
 Poor solvents comprise an –OH or –NH group
 Good solvents do not have an –OH or –NH group but are
polar
 Solvation: Process that occurs in the reactant
nucleophile caused by protic solvents that slow the rate
of SN2 reactions

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Influence of Solvents in the
SN2 Reaction
 Polar aprotic solvents increase the rate of SN2 reaction
by increasing the ground energy of the nucleophile
 High polarity gives it the ability to dissolve a number of
salts, but they also dissolve metal cations instead of
nucleophilic anions

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Worked Example

 Discuss the effect of organic solvents such as benzene,

ether, and chloroform on the reactivity of a nucleophile
in SN2 reactions

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SN1 Reaction

 Nucleophilic substitution reaction by an alternative

mechanism
 SN1 reaction: Substitution, nucleophilic, unimolecular
 Tertiary alkyl halides react rapidly in protic solvents

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SN1 Reaction

 SN1 reactions are first-order reactions

 The rate equation does not contain the concentration of
the nucleophile
Reaction rate = Rate of disappearance of alkyl halide
= k  [RX]
 Kinetics measurements
 Rate-limiting step or rate-determining step - The step that
has the highest energy transition state than other steps in
an organic reaction

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Figure 11.8 - Mechanism of
the SN1 Reaction

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SN1 Energy Diagram

 Spontaneous dissociation of alkyl halide gives a

carbocation intermediate

V = k[RX]

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SN1 Reaction

 Carbocation causes a difference in the stereochemical

result of an SN1 reaction as compared to an SN2 reaction
 Characteristics of carbocations:
 Planar
 sp2-hybridized
 Achiral
 A symmetric intermediate carbocation reacts with a
nucleophile equally from either sides to produce a
racemic, 50:50 enantiomer mixture

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Figure 11.10 - Stereochemistry

of the SN1 Reaction

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SN1 Reaction

 In some cases, SN1 reactions with enantiomerically pure

substrates result in racemization with an excess of 0–
20%

 Occurs due to the presence of ion pairs

 Saul Winstein proposed that the presence of the two ions
by dissociation of the substrate shields the carbocation at
one side from reacting with the departing ion

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Worked Example

 Configure the following substrate

 Show the stereochemistry and identify the product that
can be obtained by SN1 reaction with water (reddish brown
= Br)

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Characteristics of the SN1
Reaction
 SN1 reactions occur at a higher rate when ΔGǂ is
decreased
 Decreased energy level of the transition state
 Increased energy level of the ground state
 SN1 reactions occur at a slower rate when ΔGǂ is
increased
 Increased energy level of the transition state
 Decreased energy level of the ground state

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Influence of the Substrate on

the SN1 reaction
 Hammond postulate - Any factor that stabilizes a high-
energy intermediate also stabilizes transition state
leading to that intermediate
 Stability of the carbocation intermediate determines
the rate of the SN1 reaction
 Includes the resonance-stabilized allyl and benzyl
cations in the stability order of alkyl carbocations

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Figure 11.12 - Resonance Forms of
Allylic and Benzylic Carbocations

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Allylic and Benzylic Halides

 Primary allylic and benzylic substrates react well in

both SN2 and SN1 reactions

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Worked Example

 Explain why 3-Bromo-1-butane and 1-bromo-2-butane

undergo SN1 reaction at a similar rate, despite one
being a secondary halide and the other being a primary
halide

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Effect of Leaving Group on

SN1
 The influence of the leaving group in SN1 reactions is
similar to that of SN2 reactions
 The leaving group is closely associated with the rate-
limiting step

 Neutral water is the leaving group in SN1 reactions

occurring under acidic conditions

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Figure 11.3 - Mechanism of
the SN1 Reaction

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Effect of the Nucleophile in

SN1 Reaction
 The added nucleophile is not associated with the rate-
limiting method of the SN1 reaction and hence has no
influence on the reaction rate

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Effect of Solvent in SN1
Reaction
 According to the Hammond postulate, the factor that
increases the rate of an SN1 reaction also stabilizes the
intermediate carbocation
 Solvation of the carbocation is that factor

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Effect of Solvent in SN1

Reaction
 SN1 reactions have a faster rate in strongly polar
solvents than in less polar solvents

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Effect of Solvent in SN1
Reaction
 Solvation by protic solvents decreases the ground-state
energy of the nucleophile
 Not optimal for SN2 reactions
 Solvation by protic solvents decreases the transition-
state energy leading to carbocation intermediate
 Favorable for SN1 reactions

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Worked Example

 Predict whether the following substitution reaction is

likely to be SN1 or SN2

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Biological Substitution
Reactions
 SN1 and SN2 reactions occur in the biosynthesis pathways
of terpenoids
 Biological substitution reactions use an
organodiphosphate instead of an alkyl halide as the
substrate

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Figure 11.15 - Biosynthesis

of Geraniol from Dimethyl

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Worked Examples

 Based on the mechanism of geraniol biosynthesis,

propose a mechanism for the biosynthesis of limoene
from linalyl diphosphate

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Elimination Reactions :
Zaitsev’s Rule
 A nucleophile/Lewis base reacts with an alkyl halide
resulting in a substitution or an elimination

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Zaitsev’s Rule for Elimination
Reactions
 In the elimination of HX from an alkyl halide, the more
highly substituted alkene product predominates

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Mechanisms of Elimination
Reactions
 E1 reaction
 Breaking of C–X bond produces a carbocation intermediate
that yields the alkene by base removal of a proton

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Mechanisms of Elimination
Reactions
 E2 reaction
 Simultaneous cleavage of C–H bond and C–X bond produces
the alkene without intermediates

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Mechanisms of Elimination
Reactions
 E1cB reaction
 Proton undergoes base abstraction, yielding a carbanion
(R-) intermediate
 Carbanion loses X-, yielding the alkene

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Worked Example

 Mention the alkyl halide source of the following alkene

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The E2 Reaction and the

Deuterium Isotope Effect
 E2 reaction: Reaction involving treatment of an alkyl
halide with a strong base
 The most common elimination pathway
 Abides by the rate law
 Rate = k ×[RX] ×[Base]

 Deuterium isotope effect: C–H bond is more easily

broken than a corresponding C–D bond

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Figure 11.17 - Mechanism of the
E2 Reaction with an Alkyl Halide

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Geometry of Elimination - E2

 Termed periplanar geometry

 Hydrogen atom, the two carbons, and the leaving group lie
in the same plane
 Syn periplanar: H and X are on the same side of the
molecule

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Geometry of Elimination - E2

 Anti periplanar: H and X are on the opposite sides of the

molecule

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Significance of Periplanar
Geometry
 When all orbitals are periplanar, overlap in the
transition state can easily occur

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Geometry of Elimination - E2

 E2 is stereospecific
 Meso-1,2-dibromo-1,2-diphenylethane with base gives
cis 1,2-diphenyl
 RR or SS 1,2-dibromo-1,2-diphenylethane gives trans
1,2-diphenyl

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Worked Example

 Exhibit the stereochemistry of the alkene obtained by

E2 elimination of (1R,2R)-1,2-dibromo-1,2-
diphenylethane
 Draw a Newman projection of the reacting confirmation

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Worked Example

 The alkene resulting from E2 elimination is (Z)-1-bromo-

1,2-diphenylethylene

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The E2 Reaction and

Cyclohexene Formation
 Cyclohexane rings need to possess anti-planar geometry
in order to undergo E2 reactions
 Hydrogen and leaving group in cyclohexanes need to be
transdiaxial

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The E2 Reaction and
Cyclohexane Formation
 The trans-diaxial requirement is met in isomeric
menthyl and neomethyl by the removal of HCl
 HCl is removed from neomethyl chloride upon reaction
with ethoxide ion
 200 times faster than menthyl chloride

 Conformations of methyl chloride and neomethyl

chloride are responsible for the difference in reactivity

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Figure 11.20 - Dehydrochlorination

of Menthyl and Neo-Menthyl
Chlorides

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Worked Example

 Between trans-1-bromo-4-tert-butylcyclohexane or cis-

1-bromo-4-tert-butylcyclohexane, identify the isomer
that undergoes E2 elimination at a faster rate
 Draw each molecule in its more stable chair configuration
and provide an explanation

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The E1 and E1cB Reactions

 E1 reaction: Comprises two steps and involves a

carbocation

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The E1 and E1cB Reactions

 E1 reactions start out along the same lines as SN1

reactions
 Dissociation leads to loss of H+ from the neighboring
carbon rather than substitution in SN1 reactions
 Substrates optimal for SN1 reactions also work well for
E1 reactions

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Evidence Supporting E1
Mechanism
 E1 reactions exhibit first-order kinetics that are
consistent with a rate-limiting, unimolecular
dissociation process
 E1 reactions do not exhibit the deuterium isotope effect
 Rate difference between a deuterated and nondeuterated
substrate cannot be quantified
 E1 reactions do not have specific geometric
requirements like E2 reactions

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Figure 11.22 - Eliminations
of Menthyl Chloride

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The E1cB Reaction

 Takes place through a carbanion intermediate

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Biological Elimination
Reactions
 Elimination reactions occur in biological pathways
 E1cB is a common reaction
 Eliminations convert 3-hydroxyl carbonyl compounds to
unsaturated carbonyl compounds on a regular basis

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Summary of Reactivity:
SN1, SN2, E1, E1cB, and E2
 Primary alkyl halides
 Use of a good nucleophile is required for SN2 substitution
 Strong hindered base is required for E2 elimination
 Carbonyl group comprising a leaving group two carbons
away is required for E1cB elimination reactions
 Secondary alkyl halides
 Nucleophile in a protic solvent is necessary for SN2
substitution

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Summary of Reactivity:
SN1, SN2, E1, E1cB, E2
 A strong base is required for E2
elimination reactions
 Carbonyl group comprising a leaving
group two carbons away is required
for E1cB elimination reactions
 Teritary alkyl halides
 A base is necessary for E2 eliminations
 Use of pure ethanol or water favors simultaneous SN1
substitution and E1 elimination
 Carbonyl group comprising a leaving group two carbons
away is required for E1cB elimination reactions

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Worked Example

 Classify the following reaction as an SN1, Sn2, E1, E1cB,

or E2 reaction

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Summary

 An SN2 reaction is a second-order reaction characterized

by an umbrella-like inversion at the carbon atom caused
by the method of approach of the entering nucleophile
 SN1 reactions are first-order reactions characterized by
dissociation to a carbocation by a slow, rate-limiting
step
 Elimination of alkyl halides occur by E2, E1, and E1cB
reactions

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Summary

 In an antiperiplanar transition, the hydrogen, two

carbons, and the leaving group are in the same plane
 E2 reactions are characterized by a deuterium isotope
effect and follows Zaitsev’s rule

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