Chapter 11. Reactions of Alkyl Halides:
Nucleophilic Substitutions and Eliminations
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
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
Reactions of the Walden Inversion
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
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)
Only the second and fifth steps are reactions at
carbon. So inversion certainly occurs in these
substitution steps
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)
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]
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]
The SN2 Reaction
HO -
H3C
HO - +
H
Br
H3CH 2C
(S)-2Bromobutane
H3C
H
H3CH 2C
H
Br
HO
CH3
CH3
Br
CH2CH3
Transition State
HO
H + Br
CH2CH3
(R)-2-Butanol
SN2 Transition State
• The transition state of an SN2 reaction has a
planar arrangement of the carbon atom and the
remaining three groups.
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)
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‡).
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.
Steric Hindrance Raises
Transition State Energy
Very hindered
• Steric effects destabilize transition states
• Severe steric effects can also destabilize ground state
Order of Reactivity in SN2
• The more alkyl groups connected to the
reacting carbon, the slower the reaction
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
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
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
Poor Leaving Groups
• If a group is very basic or very small, it is prevents
reaction
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
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
SN1 Energy Diagram
Step through highest energy
point is rate-limiting
rate = k[RX]
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)
Stereochemistry of SN1
Reaction
• The planar
intermediate
should lead
to loss of
chirality
– A free
carbocation
is achiral
• Product
should be
racemic
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
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
11.9 Characteristics of the SN1
Reaction
• Tertiary alkyl halide is most reactive
by this mechanism
– Controlled by stability of carbocation
Delocalized Carbocations
• Delocalization of cationic charge enhances
stability
• Primary allyl is more stable than primary alkyl
• Primary benzyl is more stable than allyl
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
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
Nucleophiles in SN1
• Since nucleophilic addition occurs after
formation of carbocation, reaction rate is
not affected normally affected by nature or
concentration of nucleophile
Solvent Is Critical in SN1
• Stabilizing carbocation also stabilizes
associated transition state and controls
rate
Solvation of a carbocation by
water
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
Effects of Solvent on Energies
• Polar solvent stabilizes transition state and
intermediate more than reactant and product
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
Zaitsev’s Rule for Elimination
Reactions (1875)
• In the elimination of HX from an alkyl halide, the
more highly substituted alkene product
predominates
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
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
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
Geometry of Elimination – E2
• Antiperiplanar allows orbital overlap and
minimizes steric interactions
E2 Stereochemistry
• Overlap of the developing  orbital in the
transition state requires periplanar geometry,
anti arrangement
Allows orbital overlap
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
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
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
11.14 The E1 Reaction
• Competes with SN1 and E2 at 3° centers
• V = k [RX]
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
Comparing E1 and E2
• Strong base is needed for E2 but not for E1
• E2 is stereospecifc, E1 is not
• E1 gives Zaitsev orientation
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)