Download Extra Practice Problems for Sections 22.4-22.7

22.4 Claisen Condensations
• Esters also undergo reversible condensations reactions
• Unlike a ketone or aldehyde, an ester has a leaving
group
Copyright 2012 John Wiley & Sons, Inc.
22-1
22.4 Claisen Condensations
• Esters also undergo reversible condensations reactions
• The resulting doubly-stabilized enolate must be treated
with an acid in a last step. WHY?
• A beta-keto ester is produced
Copyright 2012 John Wiley & Sons, Inc.
22-2
22.4 Claisen Condensations
• There are some limitations to the Claisen condensation
1. The starting ester must have 2 alpha protons, because
removal of the second proton by the alkoxide ion is what
drives the equilibrium forward
2. Hydroxide cannot be used as the base to promote Claisen
condensations, because a hydrolysis reaction occurs between
hydroxide and the ester
3. An alkoxide equivalent to the –OR group of the ester is a
good base, because transesterification is avoided
• Practice conceptual checkpoints 22.28 and 22.29
Copyright 2012 John Wiley & Sons, Inc.
22-3
22.4 Claisen Condensations
• Crossed Claisen reactions can also be achieved using the
same strategies employed in crossed aldol reactions
• Practice with conceptual checkpoint 22.30
Copyright 2012 John Wiley & Sons, Inc.
22-4
22.4 Claisen Condensations
• Intramolecular Claisen condensations can also be
achieved
• This Diekmann cyclization proceeds through the
expected 5-membered ring transition state. DRAW it
• Practice with conceptual checkpoints 22.31 and 22.32
Copyright 2012 John Wiley & Sons, Inc.
22-5
22.4 Claisen Condensations
• Give reagents necessary to synthesize the following
molecules
Copyright 2012 John Wiley & Sons, Inc.
22-6
22.5 Alkylation of the Alpha Proton
• The alpha position can be alkylated when an enolate is
treated with an alkyl halide
• The enolate attacks the alkyl halide via an SN2 reaction
Copyright 2012 John Wiley & Sons, Inc.
22-7
22.5 Alkylation of the Alpha Proton
• When 2° or 3° alkyl halides are used, the enolate can act
as a base in an E2 reaction. SHOW a mechanism
• The aldol reaction also competes with the desired
alkylation, so a strong base such as LDA must be used
• Regioselectivity is often an issue when forming enolates
• If the compound below is treated with a strong base,
two enolates can form – see next few slides
Copyright 2012 John Wiley & Sons, Inc.
22-8
22.5 Alkylation of the Alpha Proton
• What is meant by kinetic and thermodynamic enolate?
See next few slides for details
Copyright 2012 John Wiley & Sons, Inc.
22-9
22.5 Alkylation of the Alpha Proton
• For clarity, the kinetic and thermodynamic pathways are
exaggerated below
• Explain the energy
differences below using
steric and stability
arguments
Copyright 2012 John Wiley & Sons, Inc.
22-10
22.5 Alkylation of the Alpha Proton
• LDA is a strong base, and at low temperatures, it will
react effectively in an irreversible manner
• NaH is not quite as strong, and if heat is available, the
system will be reversible
• Practice with
conceptual checkpoints
22.33 and 22.24
Copyright 2012 John Wiley & Sons, Inc.
22-11
22.5 Alkylation of the Alpha Proton
• Give necessary reagents to synthesize the compound
below starting with carbon fragments with 5 carbons or
less
Copyright 2012 John Wiley & Sons, Inc.
22-12
22.5 Alkylation of the Alpha Proton
• The malonic ester synthesis allows a halide to be
converted into a carboxylic acid with two additional
carbons
• Diethyl malonate is first treated with a base to form a
doubly-stabilized enolate
Copyright 2012 John Wiley & Sons, Inc.
22-13
22.5 Alkylation of the Alpha Proton
• The enolate is treated with the alkyl halide
• The resulting diester can be hydrolyzed with acid or
base using heat
Copyright 2012 John Wiley & Sons, Inc.
22-14
22.5 Alkylation of the Alpha Proton
• One of the resulting carboxylic acid groups can be
decarboxylated with heat through a pericyclic reaction
• Why isn’t the second carboxylic acid group removed?
Copyright 2012 John Wiley & Sons, Inc.
22-15
22.5 Alkylation of the Alpha Proton
• Here is an example of the overall synthesis
Copyright 2012 John Wiley & Sons, Inc.
22-16
22.5 Alkylation of the Alpha Proton
• Double alkylation can also be achieved
• Practice with SkillBuilder 22.5
• The acetoacetic ester synthesis is a very similar process
Copyright 2012 John Wiley & Sons, Inc.
22-17
22.5 Alkylation of the Alpha Proton
• Give a complete mechanism for the process below
• Practice with SkillBuilder 22.6
Copyright 2012 John Wiley & Sons, Inc.
22-18
22.6 Conjugate Addition Reactions
• Recall that α,β-unsaturated carbonyls can be made
easily through aldol condensations
• α,β-unsaturated carbonyls have three resonance
contributors
• Which contributors are electrophilic?
Copyright 2012 John Wiley & Sons, Inc.
22-19
22.6 Conjugate Addition Reactions
• Grignard reagents generally attack the carbonyl position
of α,β-unsaturated carbonyls yielding a 1,2 addition
• In contrast, Gilman reagents generally attacks the beta
position giving 1,4 addition or conjugate addition
Copyright 2012 John Wiley & Sons, Inc.
22-20
22.6 Conjugate Addition Reactions
• Conjugate addition of α,β-unsaturated carbonyls starts
with attack at the beta position
• WHY is the
nucleophile
generally favored
to attack the beta
position?
Copyright 2012 John Wiley & Sons, Inc.
22-21
22.6 Conjugate Addition Reactions
• More reactive nucleophiles (e.g. Grignard) are more
likely to attack the carbonyl directly. WHY?
• Enolates are generally less reactive than Grignards but
more reactive than Gilman reagents, so enolates often
give a mixture of 1,2- and 1,4- addition products
• Doubly-stabilized enolates are stable enough to react
primarily at the beta position
Copyright 2012 John Wiley & Sons, Inc.
22-22
22.6 Conjugate Addition Reactions
• When an enolate attacks a beta carbon, the process is
called a Michael addition
Copyright 2012 John Wiley & Sons, Inc.
22-23
22.6 Conjugate Addition Reactions
• Give a mechanism showing the reaction between the
two compounds shown below
• Practice with conceptual checkpoints 22.44 through
22.46
Copyright 2012 John Wiley & Sons, Inc.
22-24
22.6 Conjugate Addition Reactions
• Because singly-stabilized enolates do not give high
yielding Michael additions, Gilbert Stork developed a
synthesis using an enamine intermediate
• Recall the enamine synthesis from chapter 20
Copyright 2012 John Wiley & Sons, Inc.
22-25
22.6 Conjugate Addition Reactions
• Enolates and enamines have reactivity in common
• The enamine is less nucleophilic and more likely to act
as a Michael donor
Copyright 2012 John Wiley & Sons, Inc.
22-26
22.6 Conjugate Addition Reactions
• Water hydrolyzes the imine and
tautomerizes and protonates the enol
Copyright 2012 John Wiley & Sons, Inc.
22-27
22.6 Conjugate Addition Reactions
• Give reagents necessary to synthesize the molecule
below using the Stork enamine synthesis
• Practice with SkillBuilder 22.7
Copyright 2012 John Wiley & Sons, Inc.
22-28
22.6 Conjugate Addition Reactions
• The Robinson Annulation utilizes the a Michael addition
followed by an aldol condensation
• Practice checkpoints 22.49 and 22.50
Copyright 2012 John Wiley & Sons, Inc.
22-29
22.7 Synthetic Strategies
• Most of the reactions in this chapter are C-C bond
forming
• Three of the reactions yield a product with two
functional groups
• The positions of the functional groups in the product
can be used to design necessary reagents in the
synthesis – see next few slides
• Practice with SkillBuilder 22.8
Copyright 2012 John Wiley & Sons, Inc.
22-30
22.7 Synthetic Strategies
• Stork enamine synthesis  1,5-dicarbonyl compounds
• Aldol and Claisen  1,3-difunctional compounds
Copyright 2012 John Wiley & Sons, Inc.
22-31
22.7 Synthetic Strategies
• We have learned two methods of alkylation
1. The alpha position of an enolate attacks an alkyl halide
2. A Michael donor attacks the beta position of a Michael
acceptor
• These two reactions can also be combined
• Give a reasonable mechanism
• Practice with SkillBuilder 22.9
Copyright 2012 John Wiley & Sons, Inc.
22-32
22.7 Synthetic Strategies
• Give reagents necessary for the following synthesis
Copyright 2012 John Wiley & Sons, Inc.
22-33
Study Guide for Sections 22.4-22.7
DAY 25, Terms to know:
Sections 22.4-22.7 Claisen Condensations, alkylation, malonic ester synthesis, beta position,
conjugate addition, Michael addition
DAY 25, Specific outcomes and skills that may be tested on exam 4:
Sections 22.4-22.7
•Given a desired product, be able to describe ideal reaction conditions and reagents for
reactions discussed including crossed or mixed aldol, Claisen Condensations, alkylation of
alpha position, malonic ester synthesis, including ring-closing reactions
•Be able to predict products and give a complete mechanism for any of the reactions we
discussed including crossed or mixed aldol, Claisen Condensation, alkylation of alpha position,
malonic ester synthesis, including ring closing reactions
•Be able to describe and fully explain how to achieve either kinetic or thermodynamic control
over alkylation of alpha position reactions
•Given a desired product, be able to describe ideal reaction conditions and reagents for
reactions discussed where a nucleophile attacks either the carbonyl carbon or the beta carbon
of an α,β-unsaturated carbonyl
•Be able to predict products and give a complete mechanism for any of the reactions we
discussed where a nucleophile attacks either the carbonyl carbon or the beta carbon of an α,βunsaturated carbonyl
•Be able to solve syntheses with up to 3 steps including setting the syntheses up
retrosynthetically
•Be able to fill in blank reagents, intermediates, or products in a synthesis involving any of the
reactions discussed in this chapter
Extra Practice Problems for Sections 22.4-22.7
Complete these problems outside of class until you are confident you have
learned the SKILLS in this section outlined on the study guide and we will
review some of them next class period. 22.28 22.29 22.30 22.31 22.32
22.77 22.33 22.34 22.35 22.37 22.38 22.39 22.41 22.42 22.44 22.45
22.46 22.47 22.49 22.51 22.52 22.54 22.56 22.90 22.92 22.93 22.94
Prep for Day 26
Must Watch videos:
https://www.youtube.com/watch?v=STIamn93rds (naming amines, Leah)
https://www.youtube.com/watch?v=nvJHBQZoOBw (properties of amines, JP McCormick)
https://www.youtube.com/watch?v=qwFH8EYZxvg (primary amine synthesis, Organic Chemistry
Tutor)
https://www.youtube.com/watch?v=Cu1D6Y9AvIg (Gabriel synthesis, Organic Chemistry Tutor)
Other helpful videos:
https://www.youtube.com/watch?v=Kpov3GS6tjM and
https://www.youtube.com/watch?v=CJzuu_k9Nv0 (naming amines, Khan)
https://www.youtube.com/watch?v=_1gf6b7FyIo&index=21&list=PLqOZ6FD_RQ7nqVjmYjBSZOkjln
_K31ATj (properties of amines, UC-Irvine)
https://www.youtube.com/watch?v=Wi9P3h_lTFY&index=22&list=PLqOZ6FD_RQ7nqVjmYjBSZOkjl
n_K31ATj (preparation of amines, UC-Irvine) watch first 24 minutes
https://www.youtube.com/watch?v=NR_jnYvZC_0 (amines, UC-Irvine) watch first 42 minutes
Read Sections 23.1-23.5