Chapter 11
Introduction
• Alkyl halides – are polarized at the carbonhalide bond, making the carbon
electrophilic
– are electrophiles
• Alkyl halides – react with nucleophiles and bases
– undergo substitution of X by Nu
– undergo elimination of HX to
yield an alkene
• Substitution: Nucleophiles will replace the X in
C-X bonds (act as Lewis bases)
• Elimination: Nucleophiles that are Brønsted bases
produce elimination
A.
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
Reactions of the Walden Inversions
Discovery of the Walden Inversion
• 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 (-)-malic acid
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
Walden’s cycle
B.
Stereochemistry of Nucleophilic
Substitution
Kenyon and Phillips, 1929, studied the interconversion
of 1-phenyl-2-propanol enantiomers to isolate step:
• Only the second and fifth steps are reactions at
carbon
• So inversion certainly occurs in the substitution
step
The inversion of stereochemical configuration takes place in
the second step, the nucleophilic substitution of tosylate ion by
acetate ion
Practice Problem: What product would you expect to obtain from
a nucleophilic substitution reaction of (S)-2bromohexane with acetate ion, CH3CO2-?
Assume that inversion of configuration occurs,
and show the stereochemistry of both reactant
and product
C.
Kinetics of Nucleophilic Substitution
• Reaction rate – is the exact rate at which a
reactant is converted into
product
• Kinetics
– is useful for helping determine
reaction mechanisms
Definitions of Terms
• 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]
• Kinetics – is the study of rates of reactions
• 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
• Second-order reaction – is a reaction in which the
rate is linearly dependent on the concentration of two
species
Reaction rate = k x [RX] x [OH-]
where [RX] = CH3Br concentration
[OH-] = OH- concentration
k = a constant value
D.
The SN2 Reaction
• SN2 reaction – Substitution
– Nucleophilic
– Bimolecular
– Bimolecular - Nu and RX take part in the step
whose kinetics are measured
– Second-order kinetics: rate = k x [RX] x [Nu]
– Inversion of stereochemistry at the carbon atom
– No intermediate/ Single step
The entering Nu approaches the halide from a direction 180o away from
the leaving group, resulting in an umbrella-like inversion
The transition state is planar
Practice Problem: What product would you expect to obtain from
SN2 reaction of OH- with (R)-2-bromobutane?
Show the stereochemistry of both reactant and
product.
Practice Problem: Assign configuration to the following
substance, and draw the structure of the
product that would result on nucleophilic
substitution reaction with HS- (reddish-brown =
Br)
E.
SN2 Reaction Characteristics
• The effects of four variables on SN2 reactions:
– Substrate: SN2 reactions are best for methyl and
primary substrates
– Nucleophile: Basic, negatively charged nucleophiles
are more effective than neutral
ones
– Leaving group: Stable anions that are weak bases
are good leaving groups
– Solvent: Polar aprotic solvents
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‡).
The Substrate: Steric Effects in the SN2 Reaction
• SN2 reactions are sensitive to steric effects
• SN2 reactions occur only at relatively unhindered sites
– 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) and aryl halides
SN2 reactions are sensitive to steric effects
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.
Order of Reactivity in SN2
• The more alkyl groups connected to the reacting
carbon or near it, the slower the reaction
–
–
–
–
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) and
aryl halides
– This is due to steric factors
The Substrate: Steric Effects in the SN2 Reaction
• SN2 reactions are best for methyl and primary substrates
• Steric Hindrance raises Transition State Energy, thus
increasing G‡ and decreasing the reaction rate
– Steric effects destabilize transition states
– Severe steric effects can also destabilize ground state
The Nucleophile
• Neutral or negatively charged Lewis base
• Reaction increases coordination at nucleophile
– Neutral nucleophile acquires positive charge
– Anionic nucleophile becomes neutral
Relative Reactivity of Nucleophiles
• It depends on substrate, solvent, and reactant
concentration
– More basic nucleophiles react faster (for similar
structures)
– Better nucleophiles are lower in a column of the
periodic table
– Anions are usually more reactive than neutrals
Relative Reactivity of Nucleophiles
• Nucleophilicity roughly parallels basicity
– More basic nucleophiles react faster (for similar
structures)
– Nucleophilicity measures the affinity of a Lewis base for
carbon atom
– Basicity measures the affinity of a base for a proton
Relative Reactivity of Nucleophiles
• Nucleophilicity roughly parallels basicity
• Nucleophilicity usually increases going down a
column of the periodic table
• Negatively charged Nu are usually more
reactive than neutral ones
Practice Problem: What product would you expect from SN2
reaction of 1-bromobutane with each of the
following?
a) NaI
b) KOH
c) H-CΞC-Li
d) NH3
Practice Problem: Which substance in each of the following pairs
is more reactive as a nucleophile?
a) (CH3)2N- or (CH3)2NH
b) (CH3)3B or (CH3)3N
c) H2O or H2S
The Leaving Group
• A good leaving group
– reduces the barrier to a reaction
– stabilizes the negative charge well
– is a weak base (i.e. anion derived from strong
acids)
• Stable anions that are weak bases are usually
excellent leaving groups
– They can delocalize charge
• Stable anions that are weak bases are usually
excellent leaving groups due to T.S formed
– They distribute the negative charge over both the Nu and
the leaving group
– The greater the extent of charge stabilization, the lower
the energy of the transition state and the more rapid the
reaction
Poor Leaving Groups
• If a group is very basic or very small, it prevents
reaction
Practice Problem: Rank the following compounds in order of their
expected reactivity toward SN2 reaction:
CH3Br, CH3OTos, (CH3)3CCl, (CH3)2CHCl
CH3Br
CH3OTos
(CH3)3CCl
(CH3)2CHCl
The Solvent
• Protic solvents (with -OH or -NH groups) that can
form hydrogen bonds slow SN2 reactions by
associating with reactants (solvation)
– 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
• Protic solvents i.e. solvents that can form hydrogen
bonds (-OH or -NH) slow SN2 reactions
– They cluster around or solvate the reactant nucleophile
lowering its ground-state energy and reactivity
• Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster reaction
– They increase the rate of SN2 reactions by raising the
ground-state energy of the Nu.
HMPA = hexamethylphosphoramide
• Examples of polar aprotic solvents (no NH, OH, SH)
include:
– DMF = dimethyl formamide (CH3)2NCHO
– DMSO = dimethyl sulfoxide (CH3)2SO
– HMPA = hexamethylphosphoramide
[(CH3)2N]3PO
– acetonitrile CH3CN
• Due to their high polarity, these solvents solvate
metal cations rather than nucleophilic anions
Practice Problem: Organic solvents such as benzene, ether, and
chloroform are neither protic nor strongly polar.
What effect would you expect these solvents to
have on the reactivity of a nucleophile in SN2
reactions?
SN2 Reaction Characteristics: Summary
Substrate: SN2 reactions are best for methyl and
primary substrates
– Steric hindrance raises the energy of the transition
state, thus increasing G‡ and decreasing the reaction
rate.
Nucleophile: Basic, negatively charged nucleophiles
are more effective than neutral
ones
– More reactive nucleophiles are less stable and have a
higher ground-state energy, thereby decreasing G‡
Leaving group: Stable anions that are weak bases
are good leaving groups
– Good leaving groups (more stable anions) lower the
energy of the transition state, thus decreasing G‡ and
increasing the reaction rate.
Solvent: Polar aprotic solvents are the best.
– Protic solvents solvate the nucleophile, thereby lowering the
ground-state energy, increasing G‡ , and decreasing the
reaction rate. Polar aprotic solvents surround the
accompanying cation but not the nucleophilic anion, thereby
raising the ground-state energy of the nucleophile,
decreasing G‡, and increasig the reaction rate
F.
The SN1 Reaction
• SN1 reaction – Substitution
– Nucleophilic
– Unimolecular
– Unimolecular - Only RX takes part in the step whose
kinetics are measured
– First-order kinetics: rate = k x [RX]
– Carbocation intermediate/ Two-step
G.
Kinetics of the SN1 Reaction
• The overall rate of a reaction:
– is controlled by the rate of the slowest step (i.e
rate-limiting step)
– depends on the concentration of the species
and the rate constant of the step:
Rate = k[RX]
• The rate-determining step - is the highest energy transition
state point on the diagram (which is not always the highest
barrier)
– This is the greatest difference but not necessarily the absolute
highest point (the same step is rate-determining in both
directions)
The SN1 reaction occurs when the substrate spontaneously dissociates to a carbocation
in a slow rate-limiting step, followed by a rapid reaction with nucleophile
The rate-limiting step is spontaneous dissociation of the alkyl
halide to give a carbocation
H.
Stereochemistry of the SN1 Reaction
• SN1 occurs via a carbocation intermediate
– A carbocation is planar, sp2-hybridized and
achiral
• The planar intermediate leads to loss of chirality
– A free carbocation is achiral
– It can react with a Nu equally well from either side
• Product is racemic with a slight more inversion
SN1 in Reality
• Carbocation is biased to react on side opposite
leaving group
– This suggests that reaction occurs with carbocation loosely
associated with leaving group during nucleophilic addition
(Winstein)
– The alternative that SN2 is also occurring is unlikely
Effects of Ion Pair Formation
• If leaving group remains loosely associated, then
product has more inversion than retention
– Associated carbocation and leaving group is an ion pair
• Product is only partially racemic with more inversion
than retention
– The leaving group shields one side of the carbocation
from the Nu
Practice Problem: What product would you expect from reaction
of (S)-3-chloro-3-methyloctane with acetic
acid? Show the stereochemistry of both
reactant and product.
Practice Problem: Among the numerous examples of SN1
reactions that occur with incomplete racemization is one
reported by Winstein in 1952. The optically pure tosylate of
2,2-dimethyl-1-phenyl-1-propanol ([a]D = -30.3o) was
heated in acetic acid to yield the corresponding acetate
([a]D = +5.3o). If complete inversion had occurred, the
optically pure acetate would have had [a]D = +53.6o. What
percentage racemization and what percentage inversion
occurred in this reaction?
Practice Problem: Assign configuration to the following substrate,
and show the stereochemistry and identity of
the product you would obtain by SN1 reaction
with water (reddish-brown = Br).
I.
Characteristics of the SN1 reaction
• The effects of four variables on SN1 reactions:
– Substrate: SN1 reactions are best for tertiary, allylic,
and benzylic halides
– Nucleophile: Neutral nucleophiles are as effective as
negatively charged ones
– Leaving group: Stable anions that are weak bases
are good leaving groups
– Solvent: Polar solvents
The Substrate
• The more stable the carbocation intermediate,
the faster the SN1 reaction
• The best substrates yield the most stable
carbocations.
• Delocalization of cationic charge enhances stability
– Allylic and benzylic carbocations are unusually stable
Allylic carbocation has 2 resonance forms
Benzylic carbocation has 4 resonance foms
• Delocalization of cationic charge enhances stability
– Primary allyl cation is more stable than primary alkyl
– Primary benzyl cation is more stable than allyl
– Secondary allyl or benzyl cation is as stable as tertiary
alkyl
• Tertiary alkyl halide is most reactive by SN1 mechanism
– Controlled by stability of carbocation
Allylic and Benzylic Halides
• Allylic and benzylic C-X bonds are weaker than the
corresponding saturated bonds and are therefore more
easily broken.
– Allylic and benzylic intermediates are stabilized by
delocalization of charge
– Primary allylic and benzylic are also more reactive in the
SN2 mechanism
Practice Problem: Rank the following substances in order of their
expected SN1 reactivity:
CH3CH2Br
H2C=CHCH(Br)CH3
H2C=CHBr
CH3CH(Br)CH3
Practice Problem: 3-Bromo-1-butene and 1-bromo-2-butene
undergo SN1 reaction at nearly the same rate
even though one is a secondary halide and the
other is primary. Explain.
The Leaving Group
• SN1 is 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-Toluenesulfonate (TosO-) is excellent leaving group
In acid, OH of an alcohol is protonated and leaving group is H2O, which
is still less reactive than halide
The Nucleophile
• Since nucleophilic addition occurs after formation
of carbocation, reaction rate is not normally
affected by nature or concentration of nucleophile
Practice Problem: 1-Chloro-1,2-diphenylethane reacts with the
nucleophiles fluoride ion and triethylamine at
the same rate, even though one is charged
and one is neutral. Explain.
The Solvent
• The solvent is critical in SN1
• Stabilizing carbocation also stabilizes associated
transition state and controls rate
Solvation of a carbocation
by water
• Solvation of carbocation stabilizes carbocation and
increases the rate of SN1
– Solvent molecules orient around the carbocation so
that the electron-rich ends of the solvent dipoles
face the positive charge, thereby lowering the
energy of the ion and favoring its formation
Solvation of a carbocation
by water
Polar Solvents Promote Ionization
• Polar, protic and unreactive Lewis base
solvents facilitate formation of R+
– Polar solvents, such as water, methanol and
DMSO are good at solvating ions
– Nonpolar ether and hydrocarbon solvents are
very poor at solvating ions
• Solvent polarity is measured as dielectric
polarization (P)
– Polar solvents have high P values
– Nonpolar solvents have low P
• SN1 takes place much more rapidly in polar solvents
than in nonpolar solvents
• SN1 is favored in protic solvents
– the transition-state energy leading to carbocation
intermediate is lowered by solvation
– Polar solvent stabilizes transition state and intermediate
more than reactant and product
SN1 Reaction Characteristics: Summary
Substrate: SN1 reactions are best for tertiary, allylic,
and benzylic halides
– The best substrates yield the most stable carbocations
Nucleophile: Neutral nucleophiles are as effective
as negatively charged ones
– The nucleophile does not affect the reaction rate, but it
must be nonbasic to prevent a competitive elimination
of HX.
Leaving group: Stable anions that are weak bases
are good leaving groups
– Good leaving groups (more stable anions) lower the
energy of the transition state, thus decreasing G‡ and
increasing the reaction rate.
Solvent: Polar solvents stabilize the carbocation
intermediate by solvation, thereby
increasing
the reaction rate.
Practice Problem: Predict whether each of the following
substitution reactions is likely to be SN1 or SN2:
J.
Elimination Reactions of Alkyl Halides:
Zaitsev’s Rule
• Nu can either:
– react at carbon and substitute for X or
– react at a neighboring H and cause elimination
• Elimination is an alternative pathway to substitution
– It is opposite of addition
– It generates an alkene
– It can compete with substitution and decrease
yield, especially for SN1 processes
Zaitsev’s Rule for Elimination Reactions (1875)
• Zaitsev’s Rule: 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 transfer of a proton to a base
and departure of leaving group
Practice Problem: Ignoring double-bond stereochemistry, what
products would you expect from elimination
reactions of the following alkyl halides? Which
product will be major in each case?
Practice Problem: What alkyl halides might the following alkenes
have been made from?
K.
The E2 Reaction
• E2 reaction – Elimination
– Bimolecular
– Bimolecular - Base and RX take part in the step
whose kinetics are measured
– Second-order kinetics: rate = k x [RX] x [Base]
– Periplanar geometric requirement (stereochemistry)
– No intermediate/ Single step
The E2 reaction takes place in a single step through a transition state in which
the double bond begins to form at the same time H and X groups are leaving
• E2 reaction mechanism occurs in one step without
intermediates:
– 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
• E2 has second-order kinetics:
rate = k x [RX] x [Base]
• E2 has a single, rate-limiting step:
rate law has base and alkyl halide
• E2 goes faster with stronger base, better leaving
group
Stereochemistry of E2 Reactions
• E2 always occurs with periplanar geometry:
– all four reacting atoms lie in the same plane
• Two periplanar geometries are possible:
– syn periplanar: H and X are on the same side
– anti periplanar: H and X are on opposite sides
Anti periplanar geometry is lower in energy because it allows the substituents
to be staggered; syn periplanar requires that the substituents be eclipsed
• E2 must have anti periplanar geometry:
– Anti periplanar allows orbital overlap and
minimizes steric interactions
• E2 must have anti periplanar geometry:
– Overlap of the developing  orbital in the transition
state requires periplanar geometry, anti arrangement
Allows orbital overlap
• E2’s anti periplanar geometry is somewhat similar to
SN2 180o geometry:
– SN2: Electron pair from Nu pushes out X on opposite side
– E2: Electron pair from C-H pushes out X on opposite side
• E2 is stereospecific
Example: Meso-1,2-dibromo-1,2-diphenylethane with
base gives (E)-1-bromo-1,2-diphenylethylene
Practice Problem: What stereochemistry do you expect for the
alkene obtained by E2 elimination of (1R,2R)1,2-dibromo-1,2-diphenylethane? Draw a
Newman projection of the reacting
conformation
Practice Problem: What stereochemistry do you expect for the
trisubstituted alkene obtained by E2
elimination of the following alkyl halide on
treatment with KOH (Reddish-brown = Br)
L.
Elimination From Cyclohexanes
• To undergo E2 reaction, a cyclohexane in chair
conformation should have anti periplanar geometry
– The hydrogen and the leaving group must be trans
diaxial
– This overrides Zaitsev‘s rule
• Abstracted proton and leaving group should align trans-diaxial
to be anti periplanar in approaching transition state
– Equatorial groups are not in proper alignment
• Anti periplanar requirement for E2 overrides Zaitsev‘s rule
Zaitsev’s product
Higher-energy chair conformation
Non- Zaitsev’s product
Practice Problem: Which isomer would you expect to undergo E2
elimination faster, trans-1-bromo-4-tertbutylcyclohexane or cis-1-bromo-4-tertbutylcyclohexane ? Draw each molecule in its
more stable chair conformation, and explain
your answer.
M.
The Deuterium Isotope Effect
• The deuterium isotope effect can be used to
determine E2 mechanism:
– C-H is weaker than C-D
– C-H is easier and faster to break than C-D
– Substitute deuterium for hydrogen
• 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 the rate-limiting step
N.
The E1 Reaction
• E1 reaction – Elimination
– Unimolecular
– Unimolecular - Only RX takes part in the step whose
kinetics are measured
– First-order kinetics: rate = k x [RX]
– No geometric requirement (stereochemistry)
– Carbocation intermediate/ Two- step
The E1 reaction occurs when the substrate spontaneously dissociates
to a carbocation in a slow rate-limiting step, followed by loss of H+
• E1 reaction competes with SN1 mechanism in a
protic solvent and with a nonbasic nucleophile:
– E1 mechanism: Unimolecular dissociation of
substrate to produce a carbocation intermediate in a
rate-limiting step followed by loss of H+
– Best E1 substrates are also best SN1 substrates
SN1
E1
E1 Reaction Kinetics
• E1 has first-order kinetics:
rate = k x [RX]
• E1 has a rate-limiting first step
Unimolecular spontaneous dissociation is
the slowest step
• E1 does not go any faster with stronger base
Stereochemistry of E1 Reactions
• E1 is not stereospecific
– It does not have any geometric requirement
– There is no requirement for alignment
– X and H are lost in different steps
• E1 product has Zaitsev’s orientation
– because step that controls product is loss of
proton after formation of carbocation
• E1 gives Zaitsev’s product as the major product
– It is the more stable product
Comparing E1 and E2
• Strong base is needed for E2 but not for E1
• E2 is stereospecifc, E1 is not
• E1 gives Zaitsev orientation
O.
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
Primary alkyl halides
– SN2:
If there is a good Nu such as RS-, I-, CN-,
NH3, or Br-
– E2:
If there is a strong, sterically hindered base such
as tert-butoxide
Secondary alkyl halides
SN2 and E2 occur
– SN2:
If there is a weakly basic Nu in a polar
aprotic solvent
– E2:
If there is a strong base such as CH3CH2O-, OH-,
or NH2SN2
E2
Secondary alkyl halides
Secondary allylic and benzylic halides undergo SN1 and E1 if
weakly basic Nu in protic solvents
Tertiary alkyl halides
– E2:
– SN1:
– E1:
If there is a strong base such OH- or ORIf there is a protic solvent
competes with SN1
E2
SN1
E1
Practice Problem: Tell whether each of the following reactions is
likely to be SN1, SN2, E1, or E2:
P.
Substitution Reactions in Synthesis
• Examples of other substitution reactions include:
– Acetylide ion alkylation
– Synthesis of alkyl halides from alcohols
Acetylide ion alkylation
• It is an SN2 reaction
– Substrates: Primary alkyl halides and tosylates
– Nucleophile: Acetylide ion is a strong base and a good
nucleophile
• E2 competes with SN2
– Substrate is secondary or tertiary substrate
Synthesis of alkyl halides from alcohols
Synthesis of alkyl halides from alcohols
Chapter 11