11.

Reactions of Alkyl Halides:

Nucleophilic Substitutions and
Eliminations

Based on McMurrys Organic Chemistry, 7th edition

Alkyl Halides React with

Nucleophiles and Bases
Alkyl halides are polarized at the carbon-halide bond,

making the carbon electrophilic

Nucleophiles will replace the halide in C-X bonds of
many alkyl halides(reaction as Lewis base)
Nucleophiles that are Brnsted bases produce
elimination

Why this Chapter?

Nucleophilic substitution, base induced

elimination are among most widely occurring

and versatile reaction types in organic
chemistry
Reactions will be examined closely to see:
- How they occur
- What their characteristics are
- How they can be used

11.1 The Discovery of Nucleophilic

Substitution Reactions
In 1896, Walden showed that (-)-malic acid could be

converted to (+)-malic acid by a series of chemical

steps with achiral reagents
This established that optical rotation was directly
related to chirality and that it changes with chemical
alteration

Reaction of (-)-malic acid with PCl5 gives (+)chlorosuccinic acid

Further reaction with wet silver oxide gives (+)-malic
acid
The reaction series starting with (+) malic acid gives (-)
acid

Reactions of the Walden Inversion

Significance of the Walden

Inversion
The reactions alter the array at the chirality center
The reactions involve substitution at that center
Therefore, nucleophilic substitution can invert the

configuration at a chirality center

The presence of carboxyl groups in malic acid led to
some dispute as to the nature of the reactions in
Waldens cycle

11.2 The SN2 Reaction

Reaction is with inversion at reacting center
Follows second order reaction kinetics
Ingold nomenclature to describe characteristic step:

S=substitution
N (subscript) = nucleophilic
2 = both nucleophile and substrate in
characteristic step (bimolecular)

 The SN2 reaction (also known as bimolecular

nucleophilic substitution) is a type of

nucleophilic substitution, where a lone pair
from a nucleophile attacks an electron deficient
electrophilic center and bonds to it, expelling
another group called a leaving group.
The reaction most often occurs at an aliphatic
sp3 carbon center with an electronegative,
stable leaving group attached to it - 'X' frequently a halide atom.
8

Kinetics of Nucleophilic
Substitution
Rate (V) is change in concentration with time
Depends on concentration(s), temperature, inherent

nature of reaction (barrier on energy surface)

A rate law describes relationship between the
concentration of reactants and conversion to
products
A rate constant (k) is the proportionality factor
between concentration and rate
Example: for S converting to P
V = d[S]/dt = k [S]

10

Reaction Kinetics
The study of rates of reactions is called kinetics
Rates decrease as concentrations decrease but the

rate constant does not

Rate units: [concentration]/time such as L/(mol x s)
The rate law is a result of the mechanism
The order of a reaction is sum of the exponents of the
concentrations in the rate law the example is
second order

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SN2 Process
The reaction involves a transition state in which both reactants are

together

12

SN2 Transition State

The transition state of an SN2 reaction has a planar

arrangement of the carbon atom and the remaining

three groups

13

11.3 Characteristics of the SN2

Reaction
Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Secondary might react
Tertiary are unreactive by this path
No reaction at C=C (vinyl halides)

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Reactant and Transition State

Energy Levels Affect Rate
Higher reactant
energy level (red
curve) = faster
reaction (smaller
G).
Higher transition
state energy level
(red curve) =
slower reaction
(larger G).

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Steric Effects on SN2 Reactions

The carbon atom in (a) bromomethane is readily accessible

resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane
(primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2methylpropane (tertiary) are successively more hindered, resulting in
successively slower SN2 reactions.
16

Order of Reactivity in SN2

The more alkyl groups connected to the reacting

carbon, the slower the reaction

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The Nucleophile
Neutral or negatively charged Lewis base
Reaction increases coordination at nucleophile

Neutral nucleophile acquires positive charge

Anionic nucleophile becomes neutral
See Table 11-1 for an illustrative list

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Relative Reactivity of Nucleophiles

Depends on reaction and conditions
More basic nucleophiles react faster
Better nucleophiles are lower in a column of the

periodic table
Anions are usually more reactive than neutrals

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The Leaving Group

A good leaving group reduces the barrier to a

reaction
Stable anions that are weak bases are usually
excellent leaving groups and can delocalize charge

22

Poor Leaving Groups

If a group is very basic or very small, it is prevents reaction
Alkyl fluorides, alcohols, ethers, and amines do not typically undergo S N2 reactions.

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The Solvent
Solvents that can donate hydrogen bonds (-OH or NH)

slow SN2 reactions by associating with reactants

Energy is required to break interactions between reactant
and solvent
Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster reaction

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Types of solvent
In chemistry a protic solvent is a solvent that has a

hydrogen atom bound to an oxygen (as in a hydroxyl

group) or a nitrogen (as in an amine group). In
general terms, any molecular solvent that contains
dissociable H+ is called a protic solvent. The
molecules of such solvents can donate an H+
(proton). Conversely, aprotic solvents cannot
donate hydrogen.

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Polar protic solvent

Polar protic solvents are solvents that share ion dissolving

power with aprotic solvents but have an acidic hydrogen. In

general, these solvents have high dielectric constants and high
polarity.
Common characteristics of protic solvents :
solvents display hydrogen bonding
solvents have an acidic hydrogen (although they may be very
weak acids)
solvents are able to stabilize ions
cations by unshared free electron pairs
anions by hydrogen bonding
Examples are water, methanol, ethanol, formic acid,
hydrogen fluoride, and ammonia.
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Polar aprotic solvent

Polar aprotic solvents are solvents that share ion

dissolving power with protic solvents but lack an

acidic hydrogen. These solvents generally have
intermediate dielectric constants and polarity.
Common characteristics of aprotic solvents:
solvents do not display hydrogen bonding
solvents do not have an acidic hydrogen
solvents are able to stabilize ions
Examples are dimethyl sulfoxide, dimethylformamide,
dioxane and hexamethylphosphorotriamide,
tetrahydrofuran.
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 Polar protic solvents are favorable for SN1

reactions, while polar aprotic solvents are

favorable for SN2 reactions.

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 The solvent affects the rate of reaction

because solvents may or may not surround a

nucleophile, thus hindering or not hindering
its approach to the carbon atom. Polar aprotic
solvents, like tetrahydrofuran, are better
solvents for this reaction than polar protic
solvents because polar protic solvents will be
solvated by the solvent hydrogen bonding to
the nucleophile and thus hindering it from
attacking the carbon with the leaving group.
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11.4 The SN1 Reaction

Tertiary alkyl halides react rapidly in protic solvents

by a mechanism that involves departure of the

leaving group prior to addition of the nucleophile
Called an SN1 reaction occurs in three distinct steps
while SN2 occurs with both events in same step

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SN1 Energy Diagram

Rate-determining step is formation of carbocation

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Rate-Limiting Step
The overall rate of a reaction is controlled by

the rate of the slowest step

The rate depends on the concentration of the
species and the rate constant of the step
The highest energy transition state point on
the diagram is that for the rate determining
step (which is not always the highest barrier)

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Mechanism of SN1 reaction

36

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Stereochemistry of SN1
Reaction

The planar

intermediate
leads to loss of
chirality
A free
carbocation
is achiral
Product is
racemic or has
some inversion

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39

SN1 in Reality
Carbocation is biased to react on side opposite

leaving group
Suggests reaction occurs with carbocation loosely
associated with leaving group during nucleophilic
addition
Alternative that SN2 is also occurring is unlikely

40

Effects of Ion Pair Formation

If leaving group

remains associated,
then product has
more inversion than
retention
Product is only
partially racemic with
more inversion than
retention
Associated
carbocation and
leaving group is an
ion pair

41

11.5 Characteristics of the SN1

Reaction
Substrate
Tertiary alkyl halide is most reactive by this mechanism
Controlled by stability of carbocation
Since the rate-limitings tep in a n SN1 reaction is the spontaneous, unimolecular
dissociation of the substrate to yield a carbocation, the reaction is favored whenever a
stabilized carbocation intermediate is formed.
The more stable the carbocation intermediate, the faster the S N1 reaction.

42

43

 An allyl group is a substituent with the

structural formula H2C=CH-CH2R, where R is

the connection to the rest of the molecule. It
is made up of a methylene (-CH2-), attached
to a vinyl group (-CH=CH2).

44

Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by

delocalization of charge (resonance-stabilized)

Primary allylic and benzylic are also more reactive
in the SN2 mechanism

allylic and benzylic catbocatious are unusually

stable because the unpaired electron can be
delocalized over an extended orbital system

45

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Effect of Leaving Group on SN1

Critically dependent on leaving group

Reactivity: the larger halides ions are better

leaving groups
p-Toluensulfonate (TosO-) is excellent leaving group

48

Nucleophiles in SN1
Since nucleophilic addition occurs after

formation of carbocation, reaction rate is not

normally affected by nature or concentration
of nucleophile

49

Solvent in SN1
Solvent effects in the SN1 reaction are due largely to

stabilization or destabilization of the transition state

50

Polar Solvents Promote Ionization

Polar, protic and unreactive Lewis base solvents facilitate

formation of R+
Solvent polarity is measured as dielectric polarization (P)
Nonpolar solvents have low P
Polar solvents have high P values

51

Solvent effect of SN1 rxn

Since the SN1 reaction involves formation of

an unstable carbocation intermediate in the

rate-determining step, anything that can
facilitate this will speed up the reaction. The
normal solvents of choice are both polar (to
stabilize ionic intermediates in general) and
protic (to solvate the leaving group in
particular). Typical polar protic solvents
include water and alcohols, which will also act
as nucleophiles.
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11.6 Biological Substitution

Reactions
SN1 and SN2 reactions are well known in

biological chemistry
Unlike what happens in the laboratory,
substrate in biological substitutions is often
organodiphosphate rather than an alkyl halide

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11.7 Elimination Reactions of

Alkyl Halides: Zaitsevs Rule
Elimination is an alternative pathway to substitution
Opposite of addition
Generates an alkene
Can compete with substitution and decrease yield,

especially for SN1 processes

56

Zaitsevs Rule for Elimination

Reactions
In the elimination of HX from an alkyl halide, the more

highly substituted alkene product predominates

57

Mechanisms of Elimination
Reactions
Ingold nomenclature: E elimination
E1: X- leaves first to generate a carbocation

a base abstracts a proton from the carbocation

E2: Concerted transfer of a proton to a base and
departure of leaving group

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11.8 The E2 Reaction and the

Deuterium Isotope Effect
A proton is

transferred to base
as leaving group
begins to depart
Transition state
combines leaving of
X and transfer of H
Product alkene forms
stereospecifically

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Geometry of Elimination E2
Antiperiplanar allows orbital overlap and minimizes

steric interactions

60

E2 Stereochemistry
Overlap of the developing orbital in the transition

state requires periplanar geometry, anti arrangement

61

Predicting Product
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

62

11.9 The E2 Reaction and

Cyclohexane Formation
Abstracted proton and leaving group should

align trans-diaxial to be anti periplanar (app)

in approaching transition state
Equatorial groups are not in proper alignment

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11.10 The E1and E1cB Reactions

Competes with SN1 and E2 at 3 centers
V = k [RX], same as SN1

64

Comparing E1 and E2
Strong base is needed for E2 but not for E1
E2 is stereospecifc, E1 is not
E1 gives Zaitsev orientation

65

E1cB Reaction
Takes place through a carbanion intermediate

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11.11 Biological Elimination

Reactions
All three elimination reactions occur in

biological pathways
E1cB very common
Typical example occurs during biosynthesis of
fats when 3-hydroxybutyryl thioester is
dehydrated to corresponding thioester

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11.12 Summary of Reactivity: SN1,

SN1, E1,E1cB, E2
Alkyl halides undergo different reactions in competition,

depending on the reacting molecule and the conditions

Based on patterns, we can predict likely outcomes

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How to know what mechanism a reaction follows??

SN1? SN2? E1? E2?

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