11' Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

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11. Reactions of Alkyl Halides Nucleophilic
Substitutions and Eliminations
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Topics to discuss

• Alkyl halide reactions with nucleophiles and
  bases
• Two general reaction pathways
• Importance of Mechanisms
• Nucleophilic Substitutions
• Eliminations
• Summary

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Introduction

• Alkyl halides are easily converted to other
  functional groups.
• Halogen atom can leave with its bonding pair of
  electrons to form a stable halide ion.
• When another atom/ion replaces the halide ion,
  the reaction is called a SUBSITUTION.
• When the halide leaves with another atom/ion
  (typically a H), the reaction is called an
  ELIMINATION.

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Remember the Types of Organic Reactions

• Q What occurs? How does it happen?
• 4 Common patterns
• Addition reactions
• Elimination reactions
• Substitution
• Rearrangement reactions

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Alkyl Halides React with Nucleophiles and Bases

• Alkyl halides are polarized at the carbon-halide
  bond, making the carbon
• Nucleophiles will replace the halide in C-X bonds
  of many alkyl halides
• Nucleophiles that are Brønsted bases produce

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Acids and Bases The Lewis Definition

• Lewis acid
• electron pair acceptors
• Lewis base
• electron pair donors
• Brønsted acids are not Lewis acids because they
  cannot accept an electron pair directly (only a
  proton would be a Lewis acid)

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Some Lewis Acids

• Neutral proton donors
• H2O, HCl, HBr, HNO3, H2SO4
• Carboxylic acids, phenols, alcohols
• Some cations
• Li, Mg2, Br
• Some metal compounds
• Group 3A elements, such as BF3 and AlCl3
• Transition-metal compounds, such as TiCl4, FeCl3,
  ZnCl2, and SnCl4

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Some Lewis Bases

• Most oxygen- and nitrogen-containing organic
  compounds (have lone e-)
• Some compounds can act as both acids and bases,
  depending on the reaction

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Two General Reaction Pathways

• SUBSTITUTION
• ELIMINATION

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Substitutions and Eliminations

• The four types of reactions, SN1, SN2, E1 E2
  are closely related to one another.
• Substitution vs. Elimination are like the two
  sides of the same coin.
• They are challenging because

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Mechanisms

• Q Why do they occur at the same time?
• Q Why are they important?

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Substitution Elimination Mechanisms

• Each reaction involves a
• Even though two of the mechanisms involve bases
  _______ and two involve nucleophiles _________,
  nucleophiles can act as bases and vice versa.

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Bases vs. Nucleophiles

• Base
• Nucleophile
• Because of this, whether we call something a base
  or a nucleophile depends on

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Substitutions SN2 vs. SN1

• Depends on the rate equation of the reaction.
• SN2 substitution, nucleophilic, bimolecular.
• SN1 substitution, nucleophilic, unimolecular.

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Comparing the Mechanisms

• SN1 vs. SN2

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SN2 Mechanism and Stereochemistry

• In the case where a stereocenter is present, it
  is important to note that SN2 mechanisms lead to
  an _____________________ about the stereocenter.
• This occurs b/c
• The nucleophile cant
• The nucleophile will

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SN2 Mechanism and Stereochemistry

• Nucleophile attacks the stereogenic carbon from
  the opposite side of the leaving group.
• Transition state forms where the bond to the
  nucleophile begins to form, and the bond to the
  leaving group begins to break.
• The stereogenic carbon inverts its
  stereochemistry as the product is formed.

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SN2 Reactions of Alkyl Halides
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Eliminations E2 vs. E1

• Depends on the rate equation of the reaction.
• E2 elimination, nucleophilic, bimolecular.
• E1 elimination, nucleophilic, unimolecular.

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Comparing the Mechanisms

• E1 vs. E2

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Major Products

• Even though all 4 reactions occur simultaneously,
  there is often a ________________.
• In order to identify the major product, you must
  learn to identify

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Predicting Major Products

• Q How do we know which is the predominant
  mechanism?
• Q What are the 5 factors to consider?

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How to learn this

• You will try to memorize the conditions. DONT
  DO IT! Instead, you will learn that the
  mechanisms lead to a rate equation.
• The rate equation, along with a fundamental
  understanding of what drives the mechanism, will
  allow you to LEARN how to use the 5 factors to
  determine the predominant mechanism, so you dont
  have to MEMORIZE them.

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Rate Equations-SN2 vs. SN1

• SN2
• SN1

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Rate Equations-E2 vs. E1

• E2
• E1

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Rate Equations-SN2, E2 vs. SN1, E1

• SN2/E2
• SN1/E1

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Factor 1 Strength of Nucleophile/Base

• SN2/E2
• SN1/E1
• Strong nucleophiles/bases favor SN2/E2
• Weak nucleophiles/bases favor SN1/E1

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Factor 1 Strength of Nucleophile/Base

• Strong vs. weak nucleophiles
• Strong vs. weak bases

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Factor 2 Concentration of Nucleophile/Base

• Increase nuc
• Increase base
• Important to note

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Factor 3 Stability of Leaving Group

• More stable the LG
• SN1/E1 are more sensitive to the stability of the
  LG b/c
• SN2/E2 are less sensitive to the stability of the
  LG, b/c

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Factor 3 Stability of Leaving Group

• Good vs. Bad Leaving Groups
• Br- is GOOD b/c
• Cl- is OK
• F- is BAD b/c
• -OH is TERRIBLE b/c

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Factor 3 Stability of Leaving Group

• Note We never see alcohols (R-OH) undergo
  E1/SN1 mechanisms without modification of the
  leaving group to water (as in lab).
• Any LG that would come off as stable or less
  stable than OH would be considered a BAD LG!
• Good LG
• Bad LG

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Factor 3 Stability of Leaving Group

• Making a bad LG a good one
• converting OH- to OH2 or NH2- to NH3 would make
  them good leaving groups b/c

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Factor 4 Alkyl Groups on Substrate-SN2

• SN2

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Factor 4 Alkyl Groups on Substrate-E2

• E2

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Factor 4 Alkyl Groups on Substrate-SN1/E1

• SN1/E1

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Factor 5 Choice of Solvent

• Q What are the two types of solvent?
• Q How does solvent affect the rate?

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Factor 5 Choice of Solvent

• Q How does this affect the major product
  formed?
• Q What about APROTIC solvents?
• Q What does all of this mean?

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Substitution vs. Elimination

• Notice that conditions which favor SN2
• This is b/c strong nucleophiles are
  usually______________.
• If OH reacts with a 1o RX in an aprotic solvent,
  we will see products of _________________.
• This occurs b/c the strong nuc/base will FORCE
  the LG to leave

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Substitution vs. Elimination

• Q Is it possible to promote one over the other?

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Substitution vs. Elimination

• Q What about SN1 over E1?
• Q What conditions favor both SN1 and E1?
• Q How can we manipulate the of E1 vs. SN1
  products?

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Substitution vs. Elimination

• Q Does heat play a role in elimination vs.
  substitution?
• Q Why, you ask?
• Q Is entropy higher in substitution or
  elimination reactions?

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Putting it all together

• Q Predict the products of the following
  reaction, including stereochemistry if
  appropriate.
• Q Where do I begin?

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Putting it all together

• 1. Nucleophile/Base Strength
• Br- is a strong nucleophile
• Br- is a weak base

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Putting it all together

• 2. Concentration of Nucleophile/Base
• Br- is concentrated
• Br- is a weak base

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Putting it all together

• 3. Stability of Leaving Group
• Cl- is an OK leaving group

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Putting it all together

• 4. Alkyl Substituents on Substrate
• CH3CH2CH2Cl is a 1o RX
• 1o RX tend to favor

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Putting it all together

• 5. Solvent Effects
• DMSO Aprotic

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Putting it all together

• Lets tabulate what we know, now.

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Putting it all together

• SN2 is the winner! The table indicates that the
  SN2 mechanism would be favored, so we would get
  mainly SN2 products!
• Now that we have decided what mechanism is
  favored, we can predict the products.
• Remember, we still need to consider
  STEREOCHEMISTRY!

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Putting it all together

• In this case, stereochemistry is not an issue,
  since we dont have a stereocenter.
• Remember, if there IS a stereocenter, SN2
  mechanisms lead to an inversion of
  stereochemistry due to backside attack of the
  substrate by the nucleophile.

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Topics to discuss

• Alkyl halide reactions with nucleophiles and
  bases
• Two general reaction pathways
• Importance of Mechanisms
• Nucleophilic Substitutions
• Eliminations
• Summary