Nucleophilic Substitution and ?-Elimination

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Nucleophilic Substitution and ?-Elimination
Chapter 9

• Chapter 9

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Nucleophilic Substitution

• Nucleophilic substitution any reaction in which
  one nucleophile substitutes for another at a
  tetravalent carbon
• Nucleophile a molecule or ion that donates a
  pair of electrons to another molecule or ion to
  form a new covalent bond a Lewis base

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9.1 Nucleophilic Substitution, Table 9-1

• Some nucleophilic substitution reactions

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9.2 Solvents

• Protic solvent a solvent that is a hydrogen bond
  donor
• the most common protic solvents contain -OH
  groups
• Aprotic solvent a solvent that cannot serve as a
  hydrogen bond donor
• nowhere in the molecule is there a hydrogen
  bonded to an atom of high electronegativity

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Dielectric Constant

• Solvents are classified as polar and nonpolar
• the most common measure of solvent polarity is
  dielectric constant
• Dielectric constant a measure of a solvents
  ability to insulate opposite charges from one
  another
• the greater the value of the dielectric constant
  of a solvent, the smaller the interaction between
  ions of opposite charge dissolved in that solvent
• polar solvent dielectric constant gt 15
• nonpolar solvent dielectric constant lt 15

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Protic Solvents, Table 9-2
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Aprotic Solvents, Table 9-3
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9.3 Mechanisms

• Chemists propose two limiting mechanisms for
  nucleophilic substitution
• a fundamental difference between them is the
  timing of bond-breaking and bond-forming steps
• At one extreme, the two processes take place
  simultaneously designated SN2
• S substitution
• N nucleophilic
• 2 bimolecular (two species are involved in the
  rate-determining step)

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Mechanism - SN2

• both reactants are involved in the transition
  state of the rate-determining step

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Mechanism - SN2, Fig. 9-1
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Mechanism - SN1

• Bond breaking between carbon and the leaving
  group is entirely completed before bond forming
  with the nucleophile begins
• This mechanism is designated SN1 where
• S substitution
• N nucleophilic
• 1 unimolecular (only one species is involved in
  the rate-determining step)

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Mechanism - SN1

• Step 1 ionization of the C-X bond gives a
  carbocation intermediate

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Mechanism - SN1

• Step 2 reaction of the carbocation (an
  electrophile) with methanol (a nucleophile) gives
  an oxonium ion
• Step 3 proton transfer completes the reaction

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Mechanism - SN1, Fig. 9-2
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9.4 Evidence of SN reactions

• 1. What is relationship between the rate of an SN
  reaction and
• the structure of Nu?
• the structure of RLv?
• the structure of the leaving group?
• the solvent?
• 2. What is the stereochemical outcome if the
  leaving group is displaced from a chiral center?
• 3. Under what conditions are skeletal
  rearrangements observed?

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A. Kinetics

• For an SN1 reaction
• reaction occurs in two steps
• the reaction leading to formation transition
  state for the carbocation intermediate involves
  only the haloalkane and not the nucleophile
• the result is a first-order reaction

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Kinetics

• For an SN2 reaction,
• reaction occurs in one step
• the reaction leading to the transition state
  involves the haloalkane and the nucleophile
• the result is a second-order reaction first
  order in haloalkane and first order in nucleophile

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B. Nucleophilicity

• Nucleophilicity a kinetic property measured by
  the rate at which a Nu causes a nucleophilic
  substitution under a standardized set of
  experimental conditions
• Basicity a equilibrium property measured by the
  position of equilibrium in an acid-base reaction
• Because all nucleophiles are also bases, we study
  correlations between nucleophilicity and basicity

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Nucleophilicity, Table 9-4
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Nucleophilicity, Table 9-5

• Relative nucleophilicities of halide ions in
  polar aprotic solvents are quite different from
  those in polar protic solvents
• How do we account for these differences?

Increasing Nucleophilicity
Solvent
Polar aprotic
Polar protic
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Nucleophilicity

• A guiding principle is the freer the nucleophile,
  the greater its nucleophilicity
• Polar aprotic solvents (e.g., DMSO, acetone,
  acetonitrile, DMF)
• are very effective in solvating cations, but not
  nearly so effective in solvating anions.
• because anions are only poorly solvated, they
  participate readily in SN reactions, and
• nucleophilicity parallels basicity F- gt Cl- gt
  Br- gt I-

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Nucleophilicity

• Polar protic solvents (e.g., water, methanol)
• anions are highly solvated by hydrogen bonding
  with the solvent
• the more concentrated the negative charge of the
  anion, the more tightly it is held in a solvent
  shell
• the nucleophile must be at least partially
  removed from its solvent shell to participate in
  SN reactions
• because F- is most tightly solvated and I- the
  least, nucleophilicity is I- gt Br- gt Cl- gt F- and
  nucleophilicity increases with polarizability.

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Nucleophilicity, Table 9-6

• Generalization
• within a row of the Periodic Table,
  nucleophilicity increases from left to right
  that is, nucleophilicity increases with basicity

Increasing Nucleophilicity
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Nucleophilicity, Table 9-7

• Generalization
• in a series of reagents with the same
  nucleophilic atom, anionic reagents are stronger
  nucleophiles than neutral reagents this trend
  parallels the basicity of the nucleophile

Increasing Nucleophilicity
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Nucleophilicity, Table 9-8

• Generalization
• when comparing groups of reagents in which the
  nucleophilic atom is the same, the stronger the
  base, the greater the nucleophilicity

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C. Stereochemistry

• For an SN1 reaction at a chiral center, the R and
  S enantiomers are formed in equal amounts, and
  the product is a racemic mixture

C

C
C
H
H
H
H
R Enantiomer
S Enantiomer
R Enantiomer
A racemic mixture
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Stereochemistry

• For SN1 reactions at a chiral center
• examples of complete racemization have been
  observed, but
• partial racemization with a slight excess of
  inversion is more common

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Stereochemistry

• For SN2 reactions at a chiral center, there is
  inversion of configuration at the chiral center
• Experiment of Hughes and Ingold
• This is called a Walden inversion.

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Hughes-Ingold Expt

• the reaction is 2nd order, therefore, SN2
• the rate of racemization of enantiomerically pure
  2-iodooctane is twice the rate of incorporation
  of I-131

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D. Structure of RX, Fig. 9-3

• SN1 reactions governed by electronic factors
• the relative stabilities of carbocation
  intermediates
• SN2 reactions governed by steric factors
• the relative ease of approach of a nucleophile to
  the reaction site

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Effect of ?-Branching on SN2, Table 9-9
Alkyl Bromide
b
b
b
b
0
1
2
3
Relative Rate
1.0
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Effect of ?-Branching, Fig. 9-4
Bromoethane
(Ethyl bromide)
1-Bromo-2,2-dimethylpropane
(Neopentyl bromide)
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E. Allylic Halides

• Allylic cations are stabilized by resonance
  delocalization of the positive charge
• a 1 allylic cation is about as stable as a 2
  alkyl cation

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Allylic Cations

• 2 3 allylic cations are even more stable
• as also are benzylic cations
• add these carbocations to those from Section 6.3

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F. The Leaving Group

• The more stable the anion, the better the leaving
  ability
• the most stable anions are the conjugate bases of
  strong acids

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G. The Solvent - SN2

• The most common type of SN2 reaction involves a
  negative Nu and a negative leaving group
• the weaker the solvation of Nu, the less the
  energy required to remove it from its solvation
  shell and the greater the rate of SN2

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The Solvent - SN2, Table 9-10


solvent
Solvent
N
5000
polar aprotic
2800
1300
7
polar protic
1
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The Solvent - SN1

• SN1 reactions involve creation and separation of
  unlike charge in the transition state of the
  rate-determining step
• Rate depends on the ability of the solvent to
  keep these charges separated and to solvate both
  the anion and the cation
• Polar protic solvents (formic acid, water,
  methanol) are the most effective solvents for SN1
  reactions

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The Solvent - SN1, Table 9-11
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H. Rearrangements in SN1

• Rearrangements are common in SN1 reactions if the
  initial carbocation can rearrange to a more
  stable one

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Rearrangements in SN1

• Mechanism of a carbocation rearrangement

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9.5 Summary of SN1 SN2, Table 9-12
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Summary of SN1 SN2 from class

• Nucleophile
• SN1 Strength of nucleophile not important
• SN2 Needs a strong nucleophile
• Substrate
• SN1 3o gt 2o
• SN2 CH3 gt 1o gt 2o
• Solvent
• SN1 Enhanced by more polar solvent
• SN2 Enhanced by less polar solvent

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Summary of SN1 SN2 from class

• Kinetics
• SN1 rate kRX
• SN2 rate kRXNu
• Stereochemistry
• SN1 both inversion and retention (racemic)
• SN2 inversion only
• Rearrangements
• SN1 rearrangements common
• SN2 rearrangements not possible

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SN1/SN2 Problems

• Problem 1 predict the mechanism for this
  reaction, and the stereochemistry of each product
• Problem 2 predict the mechanism of this reaction

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SN1/SN2 Problems

• Problem 3 predict the mechanism of this reaction
  and the configuration of product
• Problem 4 predict the mechanism of this reaction
  and the configuration of the product

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SN1/SN2 Problems

• Problem 5 predict the mechanism of this reaction

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9.6 ?-Elimination

• ?-Elimination a reaction in which a molecule,
  such as HCl, HBr, HI, or HOH, is split out or
  eliminated from adjacent carbons

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?-Elimination

• Zaitsev rule the major product of a
  ?-elimination is the more stable (the more highly
  substituted) alkene

2-Methyl-1-butene

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9.7 ?-Elimination

• There are two limiting mechanisms for
  ?-elimination reactions
• E1 mechanism at one extreme, breaking of the
  R-Lv bond to give a carbocation is complete
  before reaction with base to break the C-H bond
• only R-Lv is involved in the rate-determining
  step
• E2 mechanism at the other extreme, breaking of
  the R-Lv and C-H bonds is concerted
• both R-Lv and base are involved in the
  rate-determining step

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A. E1 Mechanism

• ionization of C-Lv gives a carbocation
  intermediate
• proton transfer from the carbocation intermediate
  to the base (in this case, the solvent) gives the
  alkene

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E1 Mechanism

• Compare the E1 mechanism with slides 12 and 13 on
  SN1.
• In both cases the rate determining step (slow
  step) is formation of the carbocation.
• Where Nu is stronger than B, the reaction
  favors substitution.
• Where B is stronger than Nu, the reaction
  favors elimination.
• Generally, higher temperature favors elimination
  over substitution.

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E1 Mechanism, Fig. 9-5
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B. E2 Mechanism, Fig. 9-6
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9.8 A. Kinetics of E1 and E2

• E1 mechanism
• reaction occurs in two steps
• the rate-determining step is carbocation
  formation
• the reaction is 1st order in RLv and zero order
  is base
• E2 mechanism
• reaction occurs in one step
• reaction is 2nd order first order in RLv and 1st
  order in base

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B. Regioselectivity of E1/E2

• E1 major product is the more stable alkene
• E2 with strong base, the major product is the
  more stable (more substituted) alkene
• double bond character is highly developed in the
  transition state
• thus, the transition state of lowest energy is
  that leading to the most stable (the most highly
  substituted) alkene
• E2 with a strong, sterically hindered base such
  as tert-butoxide, the major product is often the
  less stable (less substituted) alkene

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C. Stereoselectivity of E2

• E2 is most favorable (lowest activation energy)
  when H and Lv are oriented anti and coplanar

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Stereochemistry of E2

• Consider E2 of these stereoisomers

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Stereochemistry of E2

• in the more stable chair of the cis isomer, the
  larger isopropyl is equatorial and chlorine is
  axial

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Stereochemistry of E2

• in the more stable chair of the trans isomer,
  there is no H anti and coplanar with Lv, but
  there is one in the less stable chair

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Stereochemistry of E2

• it is only the less stable chair conformation of
  this isomer that can undergo an E2 reaction

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Stereochemistry of E2

• Problem account for the fact that E2 reaction
  of the meso-dibromide gives only the E alkene

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Summary of E2 vs E1, Table 9-13
Alkyl halide
E1
E2
Primary
E2 is favored.
Secondary
Tertiary
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Summary of E1 E2 from class

• Base
• E1 Strength of base not important
• E2 Needs a strong base
• Substrate
• E1 3o gt 2ogt 1o (1o does not form easily)
• E2 3o gt 2ogt 1o
• Solvent
• E1 Enhanced by more polar solvent
• E2 Solvent effects may vary, not as important

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Summary of E1 E2 from class

• Kinetics
• E1 rate kRX
• E2 rate kRXB
• Regioselectivity
• E1 Zaitsev elimination (most substituted alkene)
• E2 Zaitsev elimination (most substituted alkene)
• Stereochemistry
• E1 No requirement
• E2 Anti, coplanar arrangement necessary
• Rearrangements
• E1 rearrangements common
• E2 rearrangements not possible

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9.9 SN vs E

• Many nucleophiles are also strong bases (OH- and
  RO-) and SN and E reactions often compete.
• The ratio of SN/E products depends on the
  relative rates of the two reactions.
• Generally, lower temperature favors substitution
  and a higher temperature favors elimination.

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SN vs E, Table 9-14
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SN vs E, Table 9-14(contd)
The main reaction with bases/nucleophiles where
Secondary
E2
Tertiary
E2
because of the extreme crowding around the 3
carbon.
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9.10 Phase-Transfer Catalysis

• A substance that transfers ions from an aqueous
  phase to an organic phase
• An effective phase-transfer catalyst must have
  sufficient
• hydrophilic character to dissolve in water and
  form an ion pair with the ion to be transported
• hydrophobic character to dissolve in the organic
  phase and transport the ion into it
• The following salt is an effective phase-transfer
  catalysts for the transport of anions

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Phase-Transfer Catalysis, Fig. 9-7
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9.11 Neighboring Groups

• In an SN2 reaction, departure of the leaving
  group is assisted by Nu in an SN1 reaction, it
  is not
• These two types of reactions are distinguished by
  their order of reaction SN2 reactions are 2nd
  order, and SN1 reactions are 1st order
• But some substitution reactions are 1st order and
  yet involve two successive SN2 reactions

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Mustard Gases

• Mustard gases
• contain either S-C-C-X or N-C-C-X
• what is unusual about the mustard gases is that
  they undergo hydrolysis so rapidly in water, a
  very poor nucleophile

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Mustard Gases

• the reason is neighboring group participation by
  the adjacent heteroatom
• proton transfer to solvent completes the reaction

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Nucleophilic Substitution and ?-Elimination
End Chapter 9