Organic%20Chemistry

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Organic Chemistry

• William H. Brown Christopher S. Foote

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Nucleophilic Substitution and ?-Elimination
Chapter 8

• Chapter 8

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Nucleophilic Substitution

• Nucleophilic substitution any reaction in which
  one nucleophile is substituted 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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Nucleophilic Substitution

• An important reaction of alkyl halides

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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
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Aprotic Solvents
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Mechanisms

• Chemists propose two limiting mechanisms for
  nucleophilic displacement
• 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
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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 with methanol
  gives an oxonium ion. Attack occurs with equal
  probability from either face of the planar
  carbocation
• Step 3 proton transfer completes the reaction

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Mechanism - SN1
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Evidence of SN reactions

• 1. What is the rate of an SN reaction affected
  by
• the structure of Nu?
• the structure of RX?
• the structure of the leaving group?
• the solvent?
• 2. What is the stereochemistry of the product if
  the Nu attacks at a stereocenter?
• 3. When and how does rearrangement occur?

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Kinetics

• For an SN1 reaction, the rate of reaction is
  first order in haloalkane and zero order in
  nucleophile

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Kinetics

• For an SN2 reaction, the rate is first order in
  haloalkane and first order in nucleophile

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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
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Nucleophilicity

• 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?

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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-

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Nucleophilicity

• Generalizations
• within a period, nucleophilicity increases from
  left to right that is, it increases with basicity

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Nucleophilicity

• Generalizations
• in a series of reagents with the same
  nucleophilic atom, anionic reagents are stronger
  nucleophiles than neutral reagents

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Nucleophilicity

• 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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Stereochemistry

• For an SN1 reaction at a stereocenter, the
  product is almost completely racemized

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Stereochemistry

• For SN1 reactions at a stereocenter
• 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 stereocenter, there is
  inversion of configuration at the stereocenter
• Experiment of Hughes and Ingold

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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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Structure of RX

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

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Effect of ?-Branching
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Effect of ?-Branching
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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

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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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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
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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
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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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Summary of SN1 SN2
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Neighboring Groups

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

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SN1/SN2 Problems

• Problem 5 predict the mechanism of this reaction

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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
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?-Elimination

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

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?-Elimination

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

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?-Elimination

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

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E1 Mechanism

• ionization of C-X 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
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E2 Mechanism
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Kinetics of E1 and E2

• E1 is a 1st order reaction 1st order in RX and
  zero order is base
• E2 is a 2nd order reaction 1st order in base and
  1st order in RX

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Regioselectivity of E1/E2

• E1 major product is the more stable alkene
• E2 with strong base, the major product is the
  more stable 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

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Stereoselectivity of E2

• E2 is most favorable (lowest activation energy)
  when H and X 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 X, 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
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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

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SN vs E
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SN vs E (contd)
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Prob 8.9

• Draw a structural formula for the most stable
  carbocation of each molecular formula.

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Prob 8.11

• From each pair, select the stronger
  nucleophile.

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Prob 8.12

• Draw a structural formula for the product of
  each SN2 reaction.

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Prob 8.12 (contd)
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Prob 8.14

• Account for the fact that the rate of this
  reaction is 1000 times faster in DMSO than it is
  in ethanol.

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Prob 8.15

• The following reaction involves two
  successive SN2 reactions. Propose a structural
  formula for the product.

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Prob 8.16

• Which member of each pair shows the greater
  rate of SN2 reaction with KI in acetone?

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Prob 8.17

• Which member of each pair gives the greater
  rate of SN2 reaction with KN3 in acetone?

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Prob 8.19

• Limiting yourself to a single 1,2-shift,
  suggest a structural formula for a more stable
  carbocation.

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Prob 8.21

• Draw a structural formula for the product of
  each SN1 reaction.

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Prob 8.24

• From each pair, select the compound that
  undergoes SN1 solvolysis in ethanol more rapidly.

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Prob 8.25

• Account for the following relative rates on
  solvolysis under SN1 conditions.

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Prob 8.26

• Explain why the following compound is very
  unreactive under SN1 conditions.

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Prob 8.27

• Propose a synthesis for each compound from a
  haloalkane and a nucleophile.

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Prob 8.29

• Propose a mechanism for the formation of each
  product.

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Prob 8.30

• Propose a mechanism for the formation of this
  product. If the configuration of the starting
  material is S, what is the configuration of the
  product?

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Prob 8.31

• Propose a mechanism for the formation of the
  products of this solvolysis reaction.

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Prob 8.32

• Propose a mechanism for the formation of each
  product.

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Prob 8.33

• Which compound in each set undergoes more
  rapid solvolysis when refluxed in ethanol?

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Prob 8.34

• Account for these relative rates of
  solvolysis in acetic acid.

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Prob 8.35

• On SN1 solvolysis in acetic acid, (1) reacts
  1011 times faster than (2). Furthermore,
  solvolysis of (1) occurs with complete retention
  of configuration. Draw structural formulas for
  the products of each solvolysis and account for
  the difference in rates.

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Prob 8.36

• Draw structural formulas for the alkene(s)
  formed on treatment of each compound with sodium
  ethoxide in ethanol. Assume reaction by an E2
  mechanism.

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Prob 8.37

• Draw structural for all chloroalkanes that
  undergo dehydrohalogenation when treated with KOH
  to give each alkene as the major product.

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Prob 8.38

• On treatment with sodium ethoxide in ethanol,
  each compound gives 3,4-dimethyl-3-hexene. One
  compound gives an E alkene, the other gives a Z
  alkene. Which compound gives which alkene?

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Prob 8.39

• On treatment with sodium ethoxide in ethanol,
  this compound gives a single stereoisomer.
  Predict whether the alkene has the E or Z
  configuration.

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Prob 8.40

• Elimination of HBr from 2-bromonorbornane
  gives only 2-norbornene. Account for the
  regiospecificity of this elimination reaction.

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Prob 8.43

• Arrange these haloalkanes in order of
  increasing ratio of E2 to SN2 products on
  reaction of each with sodium ethoxide in ethanol.

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Prob 8.44

• Draw a structural formula for the major
  product of each reaction and specify the most
  likely mechanism for its formation.

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Prob 8.44 (contd)
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Prob 8.45

• Propose a mechanism for the formation of each
  product.

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Prob 8.46

• Show how to bring about each conversion.

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Prob 8.46 (contd)

• Show how to bring about each conversion.

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Prob 8.47

• Which reaction gives the tert-butyl ether in
  good yield? What is the product of the other
  reaction?

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Prob 8.48

• Each ether can, in principle, by synthesized
  by a Williamson ether synthesis forming bond (1)
  or bond (2). Which combination gives the better
  yield?

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Prob 8.49

• Propose a mechanism for this reaction.

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Prob 8.50

• Each compound can be synthesized by an SN2
  reaction. Propose a combination of haloalkane and
  nucleophile that will give each product.

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Prob 8.50 (contd)
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Nucleophilic Substitution and ?-Elimination
End Chapter 8