Download Klein, 2e

Organic Chemistry
Second Edition
David Klein
Chapter 7
Substitution Reactions
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
7.1 Substitution reactions
• One group of atoms is replaced with another
– Generic example
– Specific example
• Label the nucleophile and electrophile
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7-1
Klein, Organic Chemistry 2e
7.1 Substitution reactions
• Which side do you think will be favored in the dynamic
equilibrium? WHY?
• Draw a reaction coordinate diagram that illustrates
your equilibrium prediction
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
7-2
Klein, Organic Chemistry 2e
7.1 Substitution reactions
• During the substitution, one group ATTACKS and one
group LEAVES. Can you label them in the reaction?
• A leaving group always takes a pair of electrons with it.
• In the reaction below, fill in arrows to show the
mechanism and label the leaving group.
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7-3
Klein, Organic Chemistry 2e
7.1 Substitution reactions
To encourage substitution a good leaving group must
fulfill two criteria:
1. The electronegative leaving group creates a partial charge
on the site of attack to attract the negative charge of the
nucleophile
2. The Leaving Group must be able to stabilize the electrons it
leaves with
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7-4
Klein, Organic Chemistry 2e
7.1 Substitution reactions
Can you give some examples of groups of atoms that
qualify as good leaving groups according to the two key
criteria?
1. Create a positive charge to attract the nucleophile.
2. Be able to stabilize the electrons it leaves with
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7-5
Klein, Organic Chemistry 2e
7.2 Alkyl Halides
• Alkyl halides are compounds where a carbon group
(alkyl) is bonded to a halide (F, Cl, Br, or I)
• Recall from section 4.2 the steps we use to name a
molecule
1.
2.
3.
4.
•
Identify and name the parent chain
Identify the name of the substituents
Assign a locant (number) to each substituents
Assemble the name alphabetically
The halide group is the key substituent we will name
and locate
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7-6
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Nomenclature
• For each of these examples, convince yourself that
they are numbered in the most appropriate way.
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7-7
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Nomenclature
• Some simple molecules are also recognized by their
common names.
– the alkyl group is named
as the substituent, and
the halide is treated as
the parent name
Methylene chloride is a
commonly used organic
solvent
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7-8
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Nomenclature
• Give reasonable names for the following molecules
• Try more examples with conceptual checkpoint 7.1
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7-9
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Structure
• Greek letters are often used to label the carbons of the
alkyl group attached to the halide
– Substitutions occur at the alpha carbon
WHY?
• The amount of branching at the alpha carbon affects
the reaction mechanism. There are three types of
alkyl halides
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7-10
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Structure
• Some alkyl halides are used as insecticides. For the
insecticides below…
– Label each halide as either primary, secondary, or tertiary
– For the circled atoms, label all of the alpha, beta, gamma,
and delta carbons.
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7-11
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Structure
• Halides appear in a wide variety of natural products
and synthetic compounds
• The structure of the molecule determines its function,
and functions include…
–
–
–
–
–
Insecticides (DDT, etc.)
Dyes (tyrian purple, etc.)
Drugs (anticancer, antidepressants, antimicrobial, etc.)
Food additives (Splenda, etc.)
Many more
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7-12
Klein, Organic Chemistry 2e
7.2 Alkyl Halide Structure
HOW does a molecule’s structure affect its function and
properties?
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7-13
Klein, Organic Chemistry 2e
7.3 Substitution Mechanisms
• Recall from chapter 6 the FOUR arrow pushing
patterns for ionic processes
1.
2.
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7-14
Klein, Organic Chemistry 2e
7.3 Substitution Mechanisms
• Recall from chapter 6 the arrow pushing patterns for
ionic processes
3.
4.
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7-15
Klein, Organic Chemistry 2e
7.3 Substitution Mechanisms
• EVERY nucleophilic substitution reaction will involve
nucleophilic attack and the loss of a leaving group
• The order that these steps occur can vary
• The inclusion of a proton transfer or rearrangement
can also vary
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7-16
Klein, Organic Chemistry 2e
7.3 Substitution Mechanisms
• Draw mechanisms for each possibility and critique
their likelihood
1. Nucleophilic attack first then loss of leaving group.
2. Loss of leaving group first then nucleophilic attack
3. Both happen simultaneously
• Practice arrow pushing with SkillBuilder 7.1
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7-17
Klein, Organic Chemistry 2e
7.4 SN2 – a concerted mechanism
• How might you write a rate law for this reaction?
• How would you design a laboratory experiment to test
this mechanism?
• Test yourself with conceptual checkpoint 7.6
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7-18
Klein, Organic Chemistry 2e
7.4 SN2 – stereochemistry
• What do S, N, and 2 stand for in the SN2 name?
• How might we use stereochemistry to support the SN2
mechanism for the following reaction?
• Practice drawing SN2 reactions with SkillBuilder 7.2
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7-19
Klein, Organic Chemistry 2e
7.4 SN2 – backside attack
• The nucleophile attacks from the back-side
– Electron density repels the attacking nucleophile from the
front-side
– The nucleophile must approach the back-side to allow
electrons to flow from the HOMO of the nucleophile to the
LUMO of the electrophile.
– Proper orbital overlap cannot
occur with front-side attack
because there is a node on
the front-side of the LUMO
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7-20
Klein, Organic Chemistry 2e
7.4 SN2 – backside attack
• Draw the transition state for the following reaction.
Use extended dotted lines to represent bonds breaking
and forming
Transition state symbol
• Practice drawing transition states with
SkillBuilder 7.3
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7-21
Klein, Organic Chemistry 2e
7.4 SN2 kinetics
• Less sterically hindered electrophiles react more
readily under SN2 conditions.
• To explain this trend, we must examine the
reaction coordinate diagram
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7-22
Klein, Organic Chemistry 2e
7.4 SN2 – Rationalizing kinetic data
• How do we use the
diagram to make a
kinetic argument?
• How do we use the
diagram to make a
thermodynamic
argument?
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7-23
Klein, Organic Chemistry 2e
7.4 SN2 – Rationalizing kinetic data
• Which reaction will have the fastest rate of reaction?
• WHY?
• 3° substrates react too slowly to measure.
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7-24
Klein, Organic Chemistry 2e
7.4 SN2 – Rationalizing kinetic data
• An example to consider: neopentyl bromide
• Draw the structure of neopentyl bromide
• Is neopentyl bromide a primary, secondary, or tertiary
alkyl bromide?
• Should neopentyl bromide react by an SN2 reaction
relatively quickly or relatively slowly? WHY?
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7-25
Klein, Organic Chemistry 2e
7.4 SN2 – Rationalizing kinetic data
• If you memorize rules, you will probably miss questions
about exceptions to rules
• It is better to understand the concepts than to
memorize rules
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7-26
Klein, Organic Chemistry 2e
7.5 SN1 – a step-wise mechanism
• If kinetic experiments were performed to determine
the rate law, you would find that…
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7-27
Klein, Organic Chemistry 2e
7.5 SN1 – reaction coordinate
• A two-step mechanism gives a diagram with two
transitions states. Where on the diagram is the
intermediate?
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7-28
Klein, Organic Chemistry 2e
7.5 SN1 – reaction coordinate
• What is happening to the molecule in each transition
state?
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7-29
Klein, Organic Chemistry 2e
7.5 SN1 – reaction coordinate
• Which step is the
RDS and WHY?
• Why does the
rate depend only
on [electrophile]
and NOT
[nucleophile]?
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7-30
Klein, Organic Chemistry 2e
7.5 SN1 – a step-wise mechanism
• What do the S, N, and 1 stand for in the SN1 name?
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7-31
Klein, Organic Chemistry 2e
7.5 SN1 – SN2 Comparison
• Consider the following generic SN2 reaction:
• If [Nuc:-] were tripled, how would the rate be affected?
WHY?
• Consider the following generic SN1 reaction:
• If [Nuc:-] were tripled, how would the rate be affected?
WHY?
• Practice with Conceptual Checkpoint 7.13
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7-32
Klein, Organic Chemistry 2e
7.5 SN1 kinetics
• The structure-rate relationship for SN1 is the opposite
of what it was for SN2.
• To explain this trend, we must examine the mechanism
and the reaction coordinate diagram
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7-33
Klein, Organic Chemistry 2e
7.5 SN1 – Rationalizing Kinetic Data
• A carbocation forms during the mechanism.
• Recall that if a carbocation is more substituted with
carbon groups, it should be more stable.
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7-34
Klein, Organic Chemistry 2e
7.5 SN1 – Rationalizing Kinetic Data
• HOW do carbon groups stabilize a carbocation?
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7-35
Klein, Organic Chemistry 2e
7.5 SN1 – Rationalizing kinetic data
• To explain why the 3° substrate will have a faster rate,
draw the relevant transition states and intermediates.
• Primary substrates react too slowly to measure.
• Practice with SkillBuilder 7.4
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7-36
Klein, Organic Chemistry 2e
7.5 SN1 – stereochemistry
• For the pure SN1 reaction below, predict the
product(s). Pay close attention to stereochemistry.
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7-37
Klein, Organic Chemistry 2e
7.5 SN1 – stereochemistry
• The formation of
ion pairs can
cause inversion
to occur slightly
more often than
retention
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7-38
Klein, Organic Chemistry 2e
7.5 SN – stereochemistry
• Consider the following reaction
• What accounts for the 35%/65% product ratio?
• Is the reaction reacting more by SN1 or SN2?
• What happened to the Cl atom?
• Practice with SkillBuilder 7.5
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7-39
Klein, Organic Chemistry 2e
7.5 SN – summary
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7-40
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• In SN1, proton transfer steps often occur before the
substitution process.
• Why would a proton transfer sometimes be necessary
before the substitution reaction? For example…
• If the OH is protonated first though…
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7-41
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• Would it also be helpful to protonate an OH
group in an SN2 substitution?
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7-42
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• Lets look at the complete mechanism.
• Practice with conceptual checkpoint 7.18
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7-43
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• In SN1, proton transfer steps often occur after the
substitution process. Examine the following example
• The leaving group is
good, but what
about the nucleophile?
• Draw a complete mechanism. Each step is an
equilibrium. Which side will the equilibrium favor?
• If the nucleophile were used as the solvent (a
solvolysis reaction), would that shift the equilibrium
one way or the other?
• Practice with Conceptual Checkpoint 7.19
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7-44
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• Rearrangements sometimes occur In SN1 reactions
• Example:
• After the leaving group
leaves, the resulting
carbocation may rearrange. What type of
rearrangements are likely? WHY?
• Predict the product(s), and explain why the
carbocation rearrangement is likely to occur before the
nucleophile has a chance to attack.
• Check your work with Conceptual Checkpoint 7.20
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7-45
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
Summary of considerations to make
• Will proton transfers be necessary?
– look at the quality of the leaving group
– Look at the stability of the final product
• Will the mechanism be SN1 or SN2?
– look at how crowded the electrophilic site is
– Look at how stable the resulting carbocation would be
• Are rearrangements likely?
– look for ways to improve the stability of the carbocation
• Will the product have inversion or racemization?
– SN1=racemization while SN2=inversion
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7-46
Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• Use the considerations from the previous slide to solve
this problem
1. Predict the reagents necessary to complete this
substitution.
2. Draw a complete mechanism
3. Draw a complete reaction coordinate diagram
including drawings for all transition states.
• Practice more with SkillBuilder 7.6
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7-47
Klein, Organic Chemistry 2e
7.7 SN2 Complete Mechanisms
• Proton transfer steps occur often in SN2 reactions for the
same reasons they occur in SN1 reactions.
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7-48
Klein, Organic Chemistry 2e
7.7 SN2 Complete Mechanisms
• Proton transfer steps occur often in SN2 reactions for the
same reasons they occur in SN1 reactions.
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7-49
Klein, Organic Chemistry 2e
7.7 SN2 Complete Mechanisms
• This reaction would be much slower without the proton
transfers. WHY?
• Qualitatively,
will the
enthalpy and
entropy
changes favor
the products or
the reactants?
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7-50
Klein, Organic Chemistry 2e
7.7 SN2 Complete Mechanisms
• Another example of proton transfer in SN2
• Qualitatively, will the enthalpy and entropy changes
favor the products or the reactants?
• Are carbocation rearrangements possible in SN2?
• Practice with SkillBuilder 7.7
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7-51
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2
• There are four main factors that determine whether a
substitution reaction is more likely to occur by SN1 or
SN2
• Lets examine them in order of importance
1. The substrate (both sterics and the stability of the
carbocation)
2. The quality of the leaving group
3. The strength of the nucleophile
4. The solvent
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7-52
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2
• Before we can examine carbocation stability, let’s
review some terminology ad learn some new
1. Vinyl
2. Allyl
• Let’s learn some new terminology
1. Benzyl
2. Aryl
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7-53
Klein, Organic Chemistry 2e
7.8 Carbocation Stability
2. The stability of the resulting carbocation
• If a relatively stable carbocation can form when the
leaving group leaves, the mechanism may be SN1
• What factors affect the stability of carbocations?
–
–
INDUCTION – already discussed
RESONANCE – example…
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7-54
Klein, Organic Chemistry 2e
7.8 Carbocation Stability
• The resonance for allylic and benzylic carbocations is
illustrated below
• Are allylic and benzylic halides more likely to undergo
SN1 or SN2?
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7-55
Klein, Organic Chemistry 2e
7.8 Carbocation Stability & Sterics
• Consider whether vinyl and aryl halides are likely to
undergo substitution
• Can you make a steric argument?
• Can you make a carbocation stability argument?
• Practice with Conceptual Checkpoint 7.26
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7-56
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the nucleophile)
3. The quality of the nucleophile
• What makes a nucleophile strong or weak?
– Stability (induction, resonance, solvation)
– Sterics
•
Give some examples of strong nucleophiles and some
examples of weak ones
•
Will a strong nucleophile favor SN1 or SN2? WHY?
•
Practice with Conceptual Checkpoint 7.27
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7-57
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the leaving group)
• What makes a leaving group good or bad?
– Stability once it has left WITH a pair of electrons (induction,
resonance, solvation)
– Solvation
• Give some examples of bad leaving groups and some
examples of good ones (figure 7.28 in the text)
• If the leaving group is too bad, then the substitution
can’t take place by either SN1 or SN2. For example…
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7-58
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the leaving group)
• The most commonly used leaving groups are halides
and sulfonate ions.
• What makes sulfonate ions such good leaving groups?
• Practice with Conceptual Checkpoint 7.28
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7-59
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the nucleophile)
• A stronger nucleophile favors SN2 , although it may
react by SN1 if the substrate and is sterically hindered
and the leaving group is good.
• A weaker nucleophile favors SN1, although it may react
by SN2 if the substrate cannot stabilize a carbocation
effectively, and the leaving group is poor.
• What factors make
nucleophiles strong versus
weak?
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7-60
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the solvent)
4. The solvent
• The solvent surrounds each species in the mechanism
including the transition state. How does that help to
facilitate the reaction? See next slide
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7-61
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the solvent)
4. The solvent ( δ+ δ- ) surrounds each species in the
mechanism including the transition state
δ+ δ-
•
δ+
δ-
δδ+
δδ+
δδ+
δ+
δ-
δ-
δ-
δδ+
δ+
δ-
δ+
δ-
δ+
δ-
δ+ δ-
δ- δ+
δ+ δ-
Consider how the energy diagram would be different
with a polar versus a nonpolar solvent
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7-62
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the solvent)
• To specifically promote SN2, what role should the
solvent play?
– The solvent should facilitate the collision between the
nucleophile and the electrophile.
– Is it possible that the solvent could interfere with that key
collision?
• What type of solvent would you choose to accomplish
this role?
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7-63
Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the solvent)
• Will this reaction be SN1 or SN2?
• What do the highlighted red solvents have in common
that makes them better than the others?
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7-64
Klein, Organic Chemistry 2e
7.8 Promoting SN2 (the solvent)
• To promote an SN2, use a
polar, aprotic solvent such
as DMSO or acetonitrile
Ready to
attack!
• Polar aprotic solvents can
stabilize the counter-ion of
the nucleophile leaving the
nucleophile mostly naked
and ready to attack the
electrophile.
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7-65
Klein, Organic Chemistry 2e
7.8 Promoting SN2 (the solvent)
• Because a polar, aprotic
solvent will not
effectively solvate the
nucleophile, the
nucleophile is less
stable and starts with a
high potential energy
• The activation energy
will be lower and the
reaction faster
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7-66
Klein, Organic Chemistry 2e
7.8 Promoting SN1 (the solvent)
• To promote an SN1, use a
polar, protic solvent
• The protic solvent will
Hydrogen bond with the
nucleophile stabilizing it while
the leaving group leaves first.
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7-67
Klein, Organic Chemistry 2e
7.8 Promoting SN1 (the solvent)
• A polar, protic
solvent will also
stabilize the full
and partial charges
that form during
the SN1 mechanism
• Practice with
Conceptual
Checkpoint 7.29
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7-68
Klein, Organic Chemistry 2e
7.8 Solvent Effect on Halide
Nucleophiles
• Consider the nucleophiles, F-, Cl-, Br-, and I• In a polar, protic solvent, which should be most
reactive? WHY?
• In a polar, aprotic solvent, which should be most
reactive? WHY?
• Why does the size of the halide affect its ability to
attract a polar protic solvent?
• Practice with SkillBuilder 7.8
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7-69
Klein, Organic Chemistry 2e
7.9 Designing Syntheses
• How do we use what we have learned to set up
successful reactions?
– We must choose appropriate substrate, nucleophile, leaving
group, solvent, etc.
• If you are working with a 1° substrate, the reaction will
be SN2, so what are the best conditions?
– Nucleophile?
– Leaving Group?
– Solvent?
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7-70
Klein, Organic Chemistry 2e
7.9 Designing Syntheses
• If you are working with a 3° substrate, the reaction will
be SN1, so what are the best conditions?
– Nucleophile?
– Leaving Group?
– Solvent?
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7-71
Klein, Organic Chemistry 2e
7.9 Designing Syntheses
• If you are working with a 2° substrate, the reaction could
be SN1 or SN2, so what are the best conditions to get the
stereochemistry you want, and WHY?
– Nucleophile?
– Leaving Group?
– Solvent?
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7-72
Klein, Organic Chemistry 2e
7.9 Designing Syntheses
• Some options
and choices:
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7-73
Klein, Organic Chemistry 2e
7.9 Designing Syntheses
•
Design a synthesis for the following molecule starting
from 2-chlorobutane
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7-74
Klein, Organic Chemistry 2e
7.9 Designing Syntheses
•
Sometimes its advantageous to convert a poor –OH
leaving group into a OTs rather than a water. See the
following example and explain why. Describe
appropriate conditions for the following transformation
•
Practice with SkillBuilder 7.9
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7-75
Klein, Organic Chemistry 2e
Additional Practice Problems
• Give reasonable names for the following molecules
• Label each halide as primary, secondary, or tertiary
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7-76
Klein, Organic Chemistry 2e
Additional Practice Problems
• Give the best set of reaction conditions to promote SN2
for the following substrate.
• Describe experiments that could be done to support
the proposed mechanism
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7-77
Klein, Organic Chemistry 2e
Additional Practice Problems
• Give the best set of reaction conditions to promote SN1
for the following substrate.
• Describe experiments that could be done to support
the proposed mechanism
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7-78
Klein, Organic Chemistry 2e
Additional Practice Problems
• Propose reaction conditions and give a complete
mechanism for the following substitution reaction
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7-79
Klein, Organic Chemistry 2e
Additional Practice Problems
• Give a complete mechanism for the following
substitution reaction
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7-80
Klein, Organic Chemistry 2e