11. Reactions of Alkyl Halides:
Nucleophilic Substitutions and
Eliminations
Based on McMurry’s Organic Chemistry, 6th
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 also Brønsted bases can
produce elimination
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11.1 The Discovery of the Walden
Inversion
 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
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Reactions of the Walden Inversion
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Significance of the Walden
Inversion
 The reactions alter the configuration 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
Walden’s cycle
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11.2 Stereochemistry of Nucleophilic
Substitution
 In the 1920’s and 1930’s Kenyon and
Phillips carried out a series of
experiments to find out how inversion
occurs and determine the precise
mechanism of nucleophilic substitution
reactions.
 Instead of halides they used tosylates
(OTos) which are better “leaving groups”
than halides.
 (alkyl toluene sulfonates)
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Only the second and fifth steps are reactions at carbon
So inversion certainly occurs in these substitution steps
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Problem 11.1
Write a stereochemical equation for this
nucleophilic substitution reaction:
(S)-2-bromohexane + CH3COO- 
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11.3 Kinetics of Nucleophilic
Substitution
 Rate is change in concentration with time
 Depends on concentration(s), temperature, inherent
nature of reaction (activation energy)
 A rate law describes relationship between the
concentration of reactants and rate of conversion to
products – determined by experiment.
 A rate constant (k) is the proportionality factor
between concentration and rate
Example: for S  P
an experiment might find
Rate = k [S]
(first order)
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Reaction Kinetics
 The study of rates of reactions is called kinetics
 Rates decrease as concentrations decrease but the
rate constant does not
 The rate law depends on the mechanism
 The order of a reaction is sum of the exponents of the
concentrations in the rate law – the example below is
second order
Experiments show that for the reaction
OH- + CH3Br  CH3OH + BrRate = k[OH-][CH3Br]
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11.4 The SN2 Reaction
 One type of nucleophilic substitution reaction
has the following characteristics:
Reaction occurs with inversion at reacting center
Follows second order reaction kinetics
rate = k [Nu:-][RX]
 Nomenclature suggested by Hughes and
Ingold in 1937:



S=substitution
N (subscript) = nucleophilic
2 = bimolecular - both nucleophile and substrate in
rate determining step
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SN2 Transition State
 The transition state of an SN2 reaction has a planar
arrangement of the carbon atom and the remaining
three groups
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11.5 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
Higher reactant
energy level (red
curve) = faster
reaction (smaller
G‡).
Higher transitionstate 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-2-methylpropane
(tertiary) are successively more hindered, resulting in successively slower SN2
reactions.
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Steric Hindrance Raises Transition
State Energy
Very hindered
 Steric effects destabilize transition states
 Severe steric effects can also destabilize ground
state
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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 (for similar
structures. See Table 11-2)
 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
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Poor Leaving Groups
 If a group is very basic or very small, it is prevents
reaction
Problem 11.6 Rank in order of SN2 reactivity
CH3Br, CH3OTs, (CH3)3Cl, (CH3)2CHCl
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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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Problem 11.7
Benzene, ether, chloroform are not protic
or very polar. How would they affect SN2
reactions?
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11.6 The SN1 Reaction
Previously we learned that tertiary alkyl halides
react extremely slowly in SN2 reactions. But tert-butyl
bromide reacts with water 1,000,000 times faster than
methyl bromide.
 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 two distinct steps
while SN2 occurs with both events in same step
 If nucleophile is present in reasonable concentration
(or it is the solvent), then ionization is the slowest
step
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SN1 Energy Diagram
Step through highest energy
point is rate-limiting
rate = k[RX]
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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)
 This is the not the greatest difference but the
absolute highest point (Figures 11.8 – the same step
is rate-determining in both directions)
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Stereochemistry of SN1 Reaction
 The planar
intermediate
should lead to
loss of
chirality

A free
carbocation
is achiral
 Product
should be
racemic
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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
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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
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11.9 Characteristics of the SN1
Reaction
 Tertiary alkyl halide is most reactive by
this mechanism
 Controlled by stability of carbocation
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Delocalized Carbocations
 Delocalization of cationic charge enhances stability
 Primary allyl is more stable than primary alkyl
 Primary benzyl is more stable than allyl
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Allylic and Benzylic Halides
 Allylic and benzylic intermediates stabilized by
delocalization of charge (See Figure 11-13)
 Primary allylic and benzylic are also more reactive
in the SN2 mechanism
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Effect of Leaving Group on SN1
 Critically dependent on leaving group
Reactivity: the larger halides ions are better
leaving groups
 In acid, OH of an alcohol is protonated and leaving
group is H2O, which is still less reactive than halide
 p-Toluensulfonate (TosO-) is excellent leaving group

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Nucleophiles in SN1
 Since nucleophilic addition occurs after
formation of carbocation, reaction rate is not
affected normally affected by nature or
concentration of nucleophile
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Solvent Is Critical in SN1
 Stabilizing carbocation also stabilizes
associated transition state and controls rate
Solvation of a carbocation by
water
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Polar Solvents Promote Ionization
 Polar, protic and unreactive Lewis base solvents
facilitate formation of R+
 Solvent polarity is measured as dielectric
polarization (P) (Table 11-3)
 Nonpolar solvents have low P
 Polar SOLVENT have high P values
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Effects of Solvent on Energies
 Polar solvent stabilizes transition state and
intermediate more than reactant and product
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11.10 Alkyl Halides: Elimination
 Elimination is an alternative pathway to substitution
 Opposite of addition
 Generates an alkene
 Can compete with substitution and decrease yield,
especially for SN1 processes
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Zaitsev’s Rule for Elimination
Reactions (1875)
 In the elimination of HX from an alkyl halide, the more
highly substituted alkene product predominates
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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 (one step) transfer of a proton
to a base and departure of leaving group

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11.11 The E2 Reaction Mechanism
 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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E2 Reaction Kinetics
 One step – rate law has base and alkyl halide
 Transition state bears no resemblance to
reactant or product
 Rate = k[R-X][B]
 Reaction goes faster with stronger base,
better leaving group
58
Geometry of Elimination – E2
 Antiperiplanar allows orbital overlap and
minimizes steric interactions
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E2 Stereochemistry
 Overlap of the developing  orbital in the transition
state requires periplanar geometry, anti arrangement
Allows orbital overlap
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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
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Practice problem 11.4 E2 rxn of
(1S,2S)-1,2-dibromo-1,2-diphenylethane
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11.12 Elimination From Cyclohexanes
 Abstracted proton and leaving group should align
trans-diaxial to be anti periplanar (app) in
approaching transition state (see Figures 11-19 and
11-20)
 Equatorial groups are not in proper alignment
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Kinetic Isotope Effect
 Substitute deuterium for hydrogen at  position
 Effect on rate is kinetic isotope effect (kH/kD =
deuterium isotope effect)
 Rate is reduced in E2 reaction
 Heavier isotope bond is slower to break
 Shows C-H bond is broken in or before ratelimiting step
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11.14 The E1 Reaction
 Competes with SN1 and E2 at 3° centers
 V = k [RX]
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Stereochemistry of E1 Reactions
 E1 is not stereospecific and there is no requirement
for alignment
 Product has Zaitsev orientation because step that
controls product is loss of proton after formation of
carbocation
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Comparing E1 and E2
 Strong base is needed for E2 but not for E1
 E2 is stereospecifc, E1 is not
 E1 gives Zaitsev orientation
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Homework problems for Chapter 11
21 – 23, 25 (SN2 only), 26, 27,
29 – 32, 36, 37, 39 – 41
OWL for Chapter 11 due Jan 22
Problems 24, 25, 28, 34, 35, 38, 39,
46, 47, 49, 50, 55, 59, 62, 65
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11.15 Summary of Reactivity: SN1,
SN2, E1, E2
 Alkyl halides undergo different reactions in
competition, depending on the reacting molecule and
the conditions
 Based on patterns, we can predict likely outcomes
(See Table 11.4)
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