11.
Reactions of Alkyl Halides:
Nucleophilic Substitutions
and Eliminations
Based on McMurry’s Organic Chemistry, 7th edition
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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 Brønsted bases produce
elimination
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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
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11.1 The Discovery of Nucleophilic Substitution
Reactions—Walden
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
Walden’s cycle
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11.2 The SN2 Reaction
Reaction is with inversion at reacting center (substrate)
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)
Nucleophile Electrophile
Leaving Group
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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
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
A + B -----> C + D
Experimentally determine the effect of increasing A/B
First Order: rate = k[A] (only depends on [A], not [B])
Second Order: rate = k[A][B] (depends on both [A],[B])
Third order: rate = k[A]2[B]
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SN2 Process
The reaction involves a transition state in which both
reactants are together
Rate = k[ROTs][OAc]
Electrophile Nucleophile
Leaving Group
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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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11.3 Characteristics of the SN2
Reaction
Occurs with inversion of chiral
center
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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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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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
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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
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Poor Leaving Groups
If a group is very basic or very small, it prevents
reaction
Alkyl fluorides, alcohols, ethers, and amines do not
typically undergo SN2 reactions.
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Poor Leaving Groups
Poor Leaving groups can be made into good
leaving groups
“Tosyl chloride”
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The Leaving Group
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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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The Solvent
O O
S P
N(CH3)2
H3C CH3 (H3C)2N
N(CH3)2
DMSO HMPA
Dimethyl Sulfoxide Hexamethylphosphoramide
O O
H3C C
C N H
H3C CH3
CH3
Acetone DMF
Dimethylformamide
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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 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 and Mechanism
Rate-determining step is
formation of carbocation
rate = k[RX]
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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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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 (Ion Pair)
Alternative that SN2 is also occurring is unlikely
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11.5 Characteristics of the SN1 Reaction
Substrate
Tertiary alkyl halide is most reactive by this mechanism
Controlled by stability of carbocation
Remember Hammond postulate,”Any factor that
stabilizes a high-energy intermediate stabilizes transition
state leading to that intermediate”
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11.5 Characteristics of the SN1 Reaction
Substrate
Allylic and benzylic intermediates stabilized by
delocalization of charge
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 normally
affected by nature or concentration of
nucleophile
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Solvent in SN1
Stabilizing carbocation also stabilizes associated transition
state and controls rate
Protic solvents favoring the SN1 reaction are due largely to
stabilization of the transition state
Protic solvents disfavor the SN2 reaction by stabilizing the
ground state
Polar, protic and unreactive Lewis base solvents facilitate
formation of R+
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11.7 Elimination Reactions of Alkyl Halides:
Zaitsev’s 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
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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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Zaitsev’s Rule for Elimination Reactions
Mechanisms of Elimination Reactions
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
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
Rate = k[RX][B]
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Geometry of Elimination – E2
Syn arrangement requires eclipsed conformation = disfavored
Anti arrangement allows orbital overlap and minimizes steric
interactions
Overlap of the developing orbital in the transition state requires
periplanar geometry, anti arrangement
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Predicting Product
E2 is stereospecific
Meso-1,2-dibromo-1,2-diphenylethane with base
gives cis-1,2-diphenyl
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Predicting Product
E2 is stereospecific
RR or SS 1,2-dibromo-1,2-diphenylethane gives
trans 1,2-diphenyl
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E2 Reactions and Cyclohexene 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 E1 Reaction
Competes with SN1 and E2 at
3° centers
Rarely have “clean” SN2 or E1
single products
Rate = k [RX], same as SN1
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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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E1cB Reaction
Takes place through a carbanion intermediate
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E1cB Reaction
Takes place through a carbanion intermediate
Common with very poor leaving group (OH-)
HO-C-C=O fragment often involved
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Summary of Reactivity: SN2, SN1, 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
Good L.G. 2o alkyl halide
Poor Nucleophile
Polar Protic Solvent
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SN1 and E1 products
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Summary of Reactivity: SN2, SN1, E1, E2
Alkyl halides undergo different reactions in competition,
depending on the reacting molecule and the conditions
Primary Haloalkanes
SN2 with any fairly good nucleophile
E2 only if Bulky, strong base
Secondary Haloalkanes
SN2 with good nucleophiles, weak base, Polar Aprotic
Solvent
SN1/E1 with good LG, weak Nu, Polar Protic Solvent
E2 with strong base
Tertiary Haloalkane
SN1/E1 with good LG, no base (solvolysis)
E2 with strong base
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