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David Klein
Capítulo 7
Reações de Substituição
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
– Exemplo Genérico
– Exemplo Específico
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7.1 Substitution reactions
• Which side do you think will be favored in the dynamic
equilibrium? WHY?
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7.1 Substitution reactions
• During the substitution, one group ATTACKS and one
group LEAVES. Can you label them in the reaction?
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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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 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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7.2 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. Identify and name the parent chain
2. Identify the name of the substituents
3. Assign a locant (number) to each substituents
4. Assemble the name alphabetically
• The halide group is the key substituent we will name
and locate
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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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7.2 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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7.2 Alkyl Halide Nomenclature
• Give reasonable names for the following molecules
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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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 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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7.2 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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7.2 Alkyl Halide Structure
HOW does a molecule’s structure affect its function and
properties?
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7.3 Substitution Mechanisms
• Recall from chapter 6 the FOUR arrow pushing
patterns for ionic processes
1.
2.
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7.3 Substitution Mechanisms
• Recall from chapter 6 the arrow pushing patterns for
ionic processes
3.
4.
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7.3 Substitution Mechanisms
• EVERY nucleophilic substitution reaction will involve
nucleophilic attack and the loss of a leaving group
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7.3 Substitution Mechanisms
• Draw mechanisms for each possibility and critique
their likelihood
1. Nucleophilic attack first then loss of leaving group.
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7.4 SN2 – stereochemistry
• What do S, N, and 2 stand for in the SN2 name?
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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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-23 Klein, Organic Chemistry 2e
7.4 SN2 – Rationalizing kinetic data
• Which reaction will have the fastest rate of reaction?
• WHY?
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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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7.5 SN1 – a step-wise mechanism
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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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7.5 SN1 – reaction coordinate
• What is happening to the molecule in each transition
state?
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7.5 SN1 – reaction coordinate
• Which step is the
RDS and WHY?
• Why does the
rate depend only
on [electrophile]
and NOT
[nucleophile]?
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 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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7.5 SN1 – SN2 Comparison
• Consider the following generic SN2 reaction:
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7.5 SN1 kinetics
• The structure-rate relationship for SN1 is the opposite
of what it was for SN2.
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7.5 SN1 – Rationalizing Kinetic Data
• A carbocation forms during the mechanism.
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7.5 SN1 – Rationalizing Kinetic Data
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7.5 SN1 – Rationalizing kinetic data
• To explain why the 3° substrate will have a faster rate,
draw the relevant transition states and intermediates.
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7.5 SN1 – stereochemistry
• The formation of
ion pairs can
cause inversion
to occur slightly
more often than
retention
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7.5 SN – stereochemistry
• Consider the following reaction
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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…
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 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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7.6 SN1 Complete Mechanisms
• Lets look at the complete mechanism.
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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
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-46 Klein, Organic Chemistry 2e
7.6 SN1 Complete Mechanisms
• Use the considerations from the previous slide to solve
this problem
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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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7.7 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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7.7 SN2 Complete Mechanisms
• Another example of proton transfer in SN2
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7.8 SN1 vs. SN2
• Before we can examine carbocation stability, let’s
review some terminology ad learn some new
1. Vinyl
2. Allyl
2. Aryl
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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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7.8 Carbocation Stability
• The resonance for allylic and benzylic carbocations is
illustrated below
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7.8 Carbocation Stability & Sterics
• Consider whether vinyl and aryl halides are likely to
undergo substitution
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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
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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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7.8 SN1 vs. SN2 (the leaving group)
• The most commonly used leaving groups are halides
and sulfonate ions.
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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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7.8 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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7.8 SN1 vs. SN2 (the solvent)
4. The solvent ( δ+ δ- ) surrounds each species in the
mechanism including the transition state
δ- δ- δ-
δ+
δ+ δ+ δ+
δ-
δ+ δ- δ- δ-
δ+ δ- δ+ δ- δ- δ+ δ+ δ-
δ- δ+ δ+ δ+
δ+ δ- δ- δ-
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-63 Klein, Organic Chemistry 2e
7.8 SN1 vs. SN2 (the solvent)
• Will this reaction be SN1 or SN2?
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7.8 Promoting SN2 (the solvent)
• To promote an SN2, use a
polar, aprotic solvent such
as DMSO or acetonitrile
Ready to
• Polar aprotic solvents can attack!
stabilize the counter-ion of
the nucleophile leaving the
nucleophile mostly naked
and ready to attack the
electrophile.
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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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7.8 Promoting SN1 (the solvent)
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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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7.8 Solvent Effect on Halide
Nucleophiles
• Consider the nucleophiles, F-, Cl-, Br-, and I-
• In a polar, protic solvent, which should be most
reactive? WHY?
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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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7.9 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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7.9 Designing Syntheses
• Some options
and choices:
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7.9 Designing Syntheses
• Design a synthesis for the following molecule starting
from 2-chlorobutane
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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
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Additional Practice Problems
• Give the best set of reaction conditions to promote SN2
for the following substrate.
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Additional Practice Problems
• Give the best set of reaction conditions to promote SN1
for the following substrate.
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Additional Practice Problems
• Propose reaction conditions and give a complete
mechanism for the following substitution reaction
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Additional Practice Problems
• Forneça o mecanismo completo para a seguinte reação
de substituição
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