11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

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11. Reactions of Alkyl Halides Nucleophilic
Substitutions and Eliminations

• Based on McMurrys 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)

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Alkyl Halides React with Nucleophiles and Bases

• Nucleophiles that are Brønsted bases produce
  elimination

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Substitution vs. Elimination
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The Nature of Substitution

• Substitution requires that a "leaving group",
  which is also a Lewis base, departs from the
  reacting molecule.
• A nucleophile is a reactant that can be expected
  to participate as a Lewis base in a substitution
  reaction.

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11.1 The Discovery of the Walden Inversion

• In 1896, Paul 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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The Walden Inversion (1896)
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Significance of the Walden Inversion

• The reactions involve substitution at the chiral
  center
• Therefore, nucleophilic substitution can invert
  the configuration at a chirality center

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11.2 Stereochemistry of Nucleophilic Substitution

• A more rigorous Walden cycle using
  1-phenyl-2-propanol (Kenyon and Phillips, 1929)
• Only the second and fifth steps are reactions at
  carbon
• Inversion must occur in the substitution step

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The inversion step (step 2)
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Two Stereochemical Modes of Substitution

• Substitution with inversion

• Substitution with retention (Note if both occur
  simultaneously, the result is racemization)

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Hughes Proof of Inversion

• React S-2-iodo-octane with radioactive iodide
• Observe that racemization (loss of optical
  activity) of mixture is twice as fast as
  incorporation of label
• Racemization in one reaction step would occur at
  same rate as incorporation

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Hughes Proof of Inversion
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Substitution Mechanisms

• SN1
• Two steps with carbocation intermediate
• Occurs in 3, allyl, benzyl
• SN2
• Concerted mechanism - without intermediate
• Occurs in primary, secondary

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11.3 Kinetics of Nucleophilic Substitution

• Rate is the change in concentration with time
• Depends on concentration(s), temperature,
  inherent nature of reaction (energy of
  activation)
• A rate law describes the relationship between the
  concentration of reactants and the overall rate
  of the reaction
• A rate constant (k) is the proportionality factor
  between concentration and rate

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Kinetics of Nucleophilic Substitution
Rate dCH3Br/dt kCH3BrOH-1
This reaction is second order two concentrations
appear in the rate law SN2 Substitution
Nucleophilic 2nd order
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11.2 The SN2 Reaction

• Reaction occurs with inversion at reacting center
• Follows second order reaction kinetics
• Ingold nomenclature to describe rate-determining
  step
• Ssubstitution
• N (subscript) nucleophilic
• 2 both nucleophile and substrate in
  rate-determining step (bimolecular)

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SN2 Process
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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
• Hybridization is sp2

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11.3 Characteristics of the SN2 Reaction

• Sensitive to steric effects
• Methyl halides are most reactive
• Primary are next most reactive
• Unhindered secondary halides react under some
  conditions
• Tertiary are unreactive by this path
• No reaction at CC (vinyl or aryl 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-2-methylpropane (tertiary) are
successively more hindered, resulting in
successively slower SN2 reactions.
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Steric Effect in SN2
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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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Vinyl and Aryl Halides
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Order of Reactivity in SN2
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The Nucleophile

• Neutral or negatively charged Lewis base
• Reaction increases coordination (adds a new bond)
  at the nucleophile
• Neutral nucleophile acquires positive charge
• Anionic nucleophile becomes neutral
• See Table 11-1 for an illustrative list

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For example
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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 energy of
  activation of a reaction
• Stable anions that are weak bases (conjugate
  bases of strong acids) are usually excellent
  leaving groups
• Stronger bases (conjugate bases of weaker acids)
  are usually poorer leaving groups

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The Leaving Group
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Poor Leaving Groups

• If a group is very basic or very small, it does
  not undergo nucleophilic substitution.

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Converting a poor LG to a good LG
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The Solvent

• Protic solvents (which can donate hydrogen bonds
  -OH or NH) slow SN2 reactions by associating
  with reactants (anions).
• 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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Some Polar Aprotic Solvents
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Summary of SN2 Characteristics

• Substrate CH3-gt1ogt2ogtgt3o (Steric effect)
• Nucleophile Strong, basic nucleophiles favor the
  reaction
• Leaving Groups Good leaving groups (weak bases)
  favor the reaction
• Solvent Aprotic solvents favor the reaction
  protic reactions slow it down by solvating the
  nucleophile
• Stereochemistry 100 inversion

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Prob. 11.37 Arrange in order of SN2 reactivity
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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 the addition of the
  nucleophile.
• Reaction occurs in two distinct steps, while SN2
  occurs in one step (concerted).
• Rate-determining step is formation of
  carbocation

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SN1 Reactivity
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SN1 Energy Diagram
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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 step with the largest energy of activation is
  the rate-limiting or rate-determining step.
• See Figure 11.9 the same step is
  rate-determining in both directions)

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SN1 Energy Diagram
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Stereochemistry of SN1 Reaction

• The planar carbocation intermediate leads to loss
  of chirality
• Product is racemic or has some inversion

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Stereochemistry of SN1 Reaction

• Carbocation is usually biased to react on side
  opposite leaving group because it is
  unsymmetrically solvated
• The second step may occur with the carbocation
  loosely associated with leaving group.
• The result is racemization with some inversion

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Effects of Ion Pair Formation
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Prob. 11.9 What is the inversion
racemization?
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Prob. 11.9 What is the inversion
racemization?
Product is 9.9 optically pure, which rounds off
to 55 inverted, 45 retained. There is 10
inversion accompanied by 90 racemization, a
typical SN1 result.
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11.5 Characteristics of the SN1 Reaction

• Tertiary alkyl halides are the most reactive
  simple halides by this mechanism
• Controlled by stability of carbocation

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Relative Reactivity of Halides
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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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Relative SN1 rates (formolysis)RCl HCOO-1
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Formation of the allylic cation
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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 an 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 Is Critical in SN1

• The solvent stabilizes the carbocation, and also
  stabilizes the associated transition state. This
  controls the rate of the reaction.

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)

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Effect of Solvent
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Solvent Polarity
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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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Summary of SN1 Characteristics

• Substrate Benzylicallylicgt3o gt2o
• Nucleophile Does not affect reaction (although
  strong bases promote elimination)
• Leaving Groups Good leaving groups (weak bases)
  favor the reaction
• Solvent Polar solvents favor the reaction by
  stabilizing the carbocation.
• Stereochemistry racemization (with some
  inversion)

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Prob. 11.36 Arrange in order of SN1 reactivity
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Practice Problem 11.2 SN1 or SN2?
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Problem 11.13 SN1 or SN2?
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Biological Substitution Reactions
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Biological Substitution Reactions
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Biological Substitution Reactions
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11.7 Alkyl Halides Elimination

• Elimination is an alternative pathway to
  substitution
• Elimination is formally the opposite of addition,
  and generates an alkene
• It can compete with substitution and decrease
  yield, especially for SN1 processes

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Zaitsevs 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 (1st order) X- leaves first to generate a
  carbocation
• a base abstracts a proton from the carbocation
• E2 (2nd order) Concerted transfer of a proton to
  a base and departure of leaving group
• E1cb Carbanion intermediate is formed in the
  rate-determining step

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E1 mechanism starts out like SN1
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E2 mechanism concerted
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E1cb common in biochemical reactions
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11.8 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 (concerted) rate law dependent on base
  and alkyl halide
• Rate kR-XB
• Reaction goes faster with stronger base, better
  leaving group

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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
  rate-limiting step

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kH/kD
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Geometry of Elimination E2

• Antiperiplanar allows orbital overlap and
  minimizes steric interactions

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E2 Stereochemistry
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Comparison of SN2 and E2
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Predicting Product

• E2 is stereospecific
• Meso-1,2-dibromo-1,2-diphenylethane with base
  gives cis 1,2-diphenyl-1-bromoethene
• RR or SS 1,2-dibromo-1,2-diphenylethane gives
  trans 1,2-diphenyl-1-bromoethene

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Anti periplanar geometry
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11.9 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 cannot be in proper
  alignment

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11.9 Elimination From Cyclohexanes
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Axial vs. Equatorial Leaving Groups
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11.10 The E1 Reaction

• Competes with SN1 and E2 at 3 centers
• Rate 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 the step
  that controls product formation 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 E2 may not due to
  stereospecificity
• E1 is favored in protic solvents competes with
  SN1

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Comparing E1 and E2
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E1cb
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A biochemical example (from fat biosynthesis)
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Reactivity Summary SN1, SN2, E1, E2
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General Pattern by Substrate
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Primary alkyl halides (SN2 vs E2)
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Secondary alkyl halides (SN2 vs E2)
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Tertiary alkyl halides (SN1/E1 vs E2)
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Practice Problem 11.5
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Answers
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Problem 11.20
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Problem 11.45 This halide does not undergo SN1
or SN2 reactions. Why?
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It also fails to eliminate HBr under basic
conditions. Why?