Chapter 7 Alkyl Halides

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Chapter 7 Alkyl Halides and Nu Substitution
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Characteristics of RX
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RX are classified as shown below
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Practice ( see lecture notes)
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RX with X near a pi bond
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Naming RX
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Use the nomenclature rules for naming alkanes
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Name these compounds.
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Common Names
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Practice (see lecture notes)
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Occurrence of Selected RX
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Chloromethane is produced by giant kelp and
algae and also found in emissions of volcanoes
such as Hawaiis Kilauea.
Dichloromethane (or methylene chloride) is an
important solvent, once used to decaffeinate
coffee.
Halothane is a safe general anesthetic
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Physical Properties of RX
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The C-X bond is polar.
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RX and Nu Substitution
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Recall RX undergo a Nu substitution rxn due to
the ? charge on the C of the C-X bond.
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An example of a one step SN reaction
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An RX SN rxn with a neutral Nu.
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RX and the Leaving Group
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Recall the leaving group is the negatively
charge ion that separates from the carbon atom
during SN
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Which is a better leaving group H2O or OH- ?
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Conjugate Bases of Strong Acids Are Good LGs
HCl ______ H3O ________ HF
______ HCN ______ HBr ________ H2O
______
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Conjugate Bases of Strong Acids Are Good LGs
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Conjugate Bases of Weak Acids Are Poor LGs
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RX and the Nucleophile
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Nucleophilicity and basicity are related but are
fundamentally different. Basicity How much?
Ka or pKa thermodynamic property. Nucleophil
icity .. How fast? rate constant, k, a
kinetic property.
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Alkyl Halides and Nucleophilic Substitution
The Nucleophile
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The Nucleophile and Solvent Effects
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Two principal types of solvents used in organic
chemistry. Protic - solvents that are polar
but also possess a hydrogen bond Aprotic -
solvents that are polar but have no hygrogen bond
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These are examples of protic solvents (Fig 7.6)
H2O, CH3OH, CH3CH2OH, (CH3)3COH, and CH3COOH
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These are examples of aprotic solvents (Fig 7.7)
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Effect of Protic Solvents on Nucleophilicity
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Effect of Aprotic Solvents on Nucleophilicity
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The Nucleophile and Steric Effects
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Large R groups on a Nu will always make it less
nucleophilic.. ..however large R groups do not
affect the basicity.
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The SN2 Mechanism
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Energy Diagram for the SN2 Rxn
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Key Characteristics of the SN2 Mechanism

• A one step 2? order rxn
• Nu attacks from the opposite side
• of the LG
• 3. Reactant undergoes inversion of
• configuration

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Key Characteristics of the SN2 Mechanism
(continued)

• Mechanism affected by steric hindrance
• (i.e. bulky or large R groups)
• 5. Mechanism is best in polar aprotic
• solvents

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Stereochemistry in the SN2 Mechanism
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Inversion of configuration is known as the Walden
inversion.
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Draw the product of each rxn to include the
correct stereochemistry.
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SN2 Effect of Steric Hindrance
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Larger R groups will decrease the rate constant
of SN2 rxns
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Compare the T.S. for a methyl RX and a 2? RX.
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The SN2 Mechanism Summary
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How would you prepare tert-butanol from
tert-butyl bromide?
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Lets look at two possibilities
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The SN1 Mechanism
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Key Characteristics of the SN1 Mechanism

• A two step 1? order rxn
• Nu attacks from the top and bottom sides
• of the C intermediate.
• 3. Reactant undergoes racemization

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Key Characteristics of the SN1 Mechanism
(continued)

• Mechanism favored by stable
• carbocations
• 5. Mechanism is best in polar protic
• solvents

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Why does the reaction below occur with a weaker
nucleophile and a protic solvent?
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To answer this kind of a question we return to
the mechanism of a rxn and its energy diagram.
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This is an Energy Diagram for an SN1 Rxn
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Stereochemistry of SN1
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The stereochemistry of SN1 is determined by the
structure of the C intermediate.
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Stereochemistry of SN1
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Examples of racemization in SN1
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Effect of Carbocation Stability on the Reactivity
of SN1 Reactions
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Which RX in each pair reacts faster in an SN1
reaction?
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Reactivity of RX in SN1 Rxns
Note Methyl and primary RX do not undergo SN1
rxns
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What is the explanation for this trend in SN1
reactivity among RX?
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To answer this question we again return to the
mechanism and the energy diagram, in particular
the T.S. of the r.d.s.
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Carbocation stability affects the T.S. of the
r.d.s.
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Two questions (1) Why does the stability of C
increase with more R groups? (2) Why does the
C affect the T.S.?
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Carbocation stability is determined by (1)
inductive effects and (2) hyperconjugation.
Lets look at the inductive effect argument first
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More positive charge at C a more unstable C
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Carbocation Stability and Hyperconjugation
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Delocalization of the positive charge on C
increased carbocation stability
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Now lets look at the second question.s (2)
Why does the C affect the T.S.? (1) Why
does the stability of C increase with more R
groups?
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The Hammond Postulate
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We cant see or measure the T.S. directly.
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However, we can see or measure the reactant or
product on either side of the T.S.
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The T.S. should resemble the side which
best approximates its energy.
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The Hammond postulate states that the T.S.
resembles the product in an endothermic rxn
while the opposite is true in an exothermic
rxn. .
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Now lets look at the second question.s (2)
Why does the C affect the T.S.? (1) Why
does the stability of C increase with more R
groups?
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Summary of SN1 Mechanism
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Alkyl Halides and Nucleophilic Substitution
The Hammond Postulate

• The Hammond postulate relates reaction rate to
  stability. It provides a quantitative estimate of
  the energy of a transition state.
• The Hammond postulate states that the transition
  state of a reaction resembles the structure of
  the species (reactant or product) to which it is
  closer in energy.

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Alkyl Halides and Nucleophilic Substitution
The Hammond Postulate

• In an endothermic reaction, the transition state
  resembles the products more than the reactants,
  so anything that stabilizes the product
  stabilizes the transition state also. Thus,
  lowering the energy of the transition state
  decreases Ea, which increases the reaction rate.
• If there are two possible products in an
  endothermic reaction, but one is more stable than
  the other, the transition state to form the more
  stable product is lower in energy, so this
  reaction should occur faster.

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Alkyl Halides and Nucleophilic Substitution
The Hammond Postulate

• In the case of an exothermic reaction, the
  transition state resembles the reactants more
  than the products. Thus, lowering the energy of
  the products has little or not effect on the
  energy of the transition state.
• Since Ea is unaffected, the reaction rate is
  unaffected.
• The conclusion is that in an exothermic reaction,
  the more stable product may or may not form
  faster because Ea is similar for both products.

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Alkyl Halides and Nucleophilic Substitution
SN1 Reactions, Nitrosamines and Cancer

• SN1 reactions are thought to play a role in how
  nitrosamines, compounds having the general
  structure R2NNO, act as toxins and carcinogens.

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Alkyl Halides and Nucleophilic Substitution
Predicting the Likely Mechanism of a Substitution
Reaction.

• Four factors are relevant in predicting whether a
  given reaction is likely to proceed by an SN1 or
  an SN2 reactionThe most important is the
  identity of the alkyl halide.

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Alkyl Halides and Nucleophilic Substitution
Predicting the Likely Mechanism of a Substitution
Reaction.

• The nature of the nucleophile is another factor.
• Strong nucleophiles (which usually bear a
  negative charge) present in high concentrations
  favor SN2 reactions.
• Weak nucleophiles, such as H2O and ROH favor SN1
  reactions by decreasing the rate of any competing
  SN2 reaction.
• Let us compare the substitution products formed
  when the 20 alkyl halide A is treated with either
  a strong nucleophile HO or the weak nucleophile
  H2O. Because a 20 alkyl halide can react by
  either mechanism, the strength of the nucleophile
  determines which mechanism takes place.

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Alkyl Halides and Nucleophilic Substitution
Predicting the Likely Mechanism of a Substitution
Reaction.

• The strong nucleophile favors an SN2 reaction.

• The weak nucleophile favors an SN1 reaction.

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Alkyl Halides and Nucleophilic Substitution
Predicting the Likely Mechanism of a Substitution
Reaction.

• A better leaving group increases the rate of both
  SN1 and SN2 reactions.

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Alkyl Halides and Nucleophilic Substitution
Predicting the Likely Mechanism of a Substitution
Reaction.

• The nature of the solvent is a fourth factor.
• Polar protic solvents like H2O and ROH favor SN1
  reactions because the ionic intermediates (both
  cations and anions) are stabilized by solvation.
• Polar aprotic solvents favor SN2 reactions
  because nucleophiles are not well solvated, and
  therefore, are more nucleophilic.

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Alkyl Halides and Nucleophilic Substitution
Predicting the Likely Mechanism of a Substitution
Reaction.
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Alkyl Halides and Nucleophilic Substitution
Vinyl Halides and Aryl Halides.

• Vinyl and aryl halides do not undergo SN1 or SN2
  reactions, because heterolysis of the CX bond
  would form a highly unstable vinyl or aryl cation.

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Alkyl Halides and Nucleophilic Substitution
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Alkyl Halides and Nucleophilic Substitution
Nucleophilic Substitution and Organic Synthesis.

• To carry out the synthesis of a particular
  compound, we must think backwards, and ask
  ourselves What starting material and reagents
  are needed to make it?
• If we are using nucleophilic substitution, we
  must determine what alkyl halide and what
  nucleophile can be used to form a specific
  product.

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Alkyl Halides and Nucleophilic Substitution
Nucleophilic Substitution and Organic Synthesis.

• To determine the two components needed for
  synthesis, remember that the carbon atoms come
  from the organic starting material, in this case,
  a 10 alkyl halide. The functional group comes
  from the nucleophile, HO in this case. With
  these two components, we can fill in the boxes
  to complete the synthesis.

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Alkyl Halides and Nucleophilic Substitution
Mechanisms of Nucleophilic Substitution
The SN2 reaction is a key step in the laboratory
synthesis of many important drugs.
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Alkyl Halides and Nucleophilic Substitution
Mechanisms of Nucleophilic Substitution
Nucleophilic substitution reactions are important
in biological systems as well.
This reaction is called methylation because a CH3
group is transferred from one compound (SAM) to
another (Nu).
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