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Organic Chemistry2aA Conceptual Approach toMolecular Understanding
Second Year Course for Chemists,Molecular Life Scientists and GeneralScientists
Dr. A.J.H. KlunderDepartment of Organic ChemistryUL 357Tel. (36)52193E-mail: [email protected]
September 2000
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Organic
Chemistry 2a
2
Introduction
Organic Chemistry 2a
Place in CurriculumA second years course. The third
course in a series of 4.The sequel to prof. Noltes firstyears courses Organic Chemistry1a and 1b.
PrerequisiteGood knowledge of basic (first
years) General and OrganicChemistry
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Organic
Chemistry 2a
3
Introduction
Organic Chemistry 2aBook
Maitland Jones, Jr.Organic ChemistryFirst Edition, 1997
SubjectsCarbonyl Chemistry
chapters 16,18,19,20
Amines chapter 21
Ethers and Epoxides chapters 17, 25
Carbohydrates chapters 24
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Organic
Chemistry 2a
4
Introduction
Organic Chemistry 2a
Course PhilosophyConceptual approach! Molecules
must be understood to explain their
behavior.Avoid memorization!
Do it yourself! We can only helpyou (lectures and workshops - 20 -24 hrs; self study - 60 hrs!).
Keep up with the course! It ishighly repetitive. Losing trackmeans losing time!
Work the problems. Use paper andpencil!
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Organic
Chemistry 2a
5
Introduction
Organic Chemistry 2a
Course PhilosophyLectures will be highly interactive!Workshops form an essential part
of the course and are, therefore,highly recommended.
Workshops are given on anindividual base.
Where necessary computersimulation or visualization will beused or recommendedsee:www.cmbi.kun.nl/wetche/organic/
Work at home will be inevitable!
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Organic
Chemistry 2a
6
Introduction
Organic Chemistry 2a Function of Lectures and Book
Lectures explain basic concepts.Overhead sheets are merely
copies of the text figures.More detailed information in the
bookWorkshops are problem oriented;
problems come from the book and
exams.Book contains CD which illustrates
basic concepts. Useful for homestudy. Work at home will beinevitable!
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Organic
Chemistry 2a
7
Introduction
Organic Chemistry 2a How to use the book?
Not all information in the book is relevantfor this course! There is much more toappreciate.
A detailed list of paragraphs containingthe required course material will beprovided. Watch also the overheads!
Of course an interested reader is invitedto stroll through neighboring paragraphs.
A list of selected problems is provided.These problems are vital to gain thenecessary experience to learn the basicproperties of organic molecules.
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Organic
Chemistry 2a
8
Carbonyl Chemistry
Chapter 16 Carbonyl Chemistry 1: Addition
ReactionsCurrent Knowledge
Good: OC1a and OC1b course!
Aldehydes and Ketones, Chapter 12,page 104-120; Chapter 18, page 160-167(carboxylic acids and esters).
Chapter 18 Carbonyl Chemistry 2: Reactions
at the -Position.Current Knowledge
Limited! Some examples in OC1b
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Organic
Chemistry 2a
9
Carbonyl Chemistry
Carbonyl Chemistry 1: AdditionReactions 16.1 Structure of Carbon-Oxygen Bond
(page 753)
A generic carbonyl group has three loci of reactivity:
the nonbonding, or lone-pair electrons; the bond andthe carbon-hydrogen bonds.
Fig. 16.1
Chapter 16
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Organic
Chemistry 2a
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Carbonyl Chemistry 16.1 Structure of Carbon-Oxygen Bond (page
754)
One orbital picture of the simplest carbonyl compound,
formaldehyde.
Fig. 16.2
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Chemistry 2a
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Carbonyl Chemistry 16.1 Structure of Carbon-Oxygen Bond (page
754)
A comparison of the structures of formaldehyde,
acetaldehyde and ethylene.
Fig. 16.3
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Organic
Chemistry 2a
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Carbonyl Chemistry 16.1 Structure of Carbon-Oxygen Bond (page
755)
Carbonyl compounds are polar molecules with
substantial dipole moments. Notice the small bond
dipole arrow that points from the positive end toward
the negative end of the dipole.
Fig. 16.5
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Chemistry 2a
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Carbonyl Chemistry 16.1 Structure of Carbon-Oxygen Bond (page
755)
A resonance formulation of a carbonyl group. Note the
polar resonance form.
Fig. 16.6
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Organic
Chemistry 2a
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Carbonyl Chemistry 16.2 Nomenclature of carbonyl compounds
(pages 756-759)
Different substitution patterns for simple carbonyl
compounds.
Fig. 16.7 + 16.14
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Organic
Chemistry 2a
15
Carbonyl Chemistry 16.5 Reactions of Carbonyl Compounds:
simple reversible additions (page 763).
Addition of water to an alkene to give an alcohol and
addition to a ketone to give a hydrate are analogous
reactions.
Fig. 16.20
What is the mechanism of thisaddition of water to the
carbonyl function?
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Organic
Chemistry 2a
16
Carbonyl Chemistry 16.5 Reactions of Carbonyl Compounds:
simple reversible additions (page 763-765).
+ -
Addition of water occurs at the positive carbonyl carbon which puts the
negative charge on the relatively electronegative oxygen. The hydration
reaction is completed by a series of proton transfers. Fig. 16.24
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Chemistry 2a
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Carbonyl Chemistry 16.5 Reactions of Carbonyl Compounds:
simple reversible additions (page 767).
Acid-catalyzed hydration of a carbonyl compound
Fig. 16.26
+ -
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Organic
Chemistry 2a
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Carbonyl Chemistry 16.5 Reactions of Carbonyl Compounds:
simple reversible additions (page 767).
Base-catalyzed hydration of a carbonyl compound
Fig. 16.27
-+
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Organic
Chemistry 2a
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Carbonyl Chemistry 16.7 Other addition reactions: additions of
cyanide and bisulfite (page 772).
Cyanohydrin formation. The carbonyl is first attacked
by the Lewis base cyanide to give an alkoxide. The
alkoxide is protonated in second step to give the
cyanohydrin
Fig. 16.36
A dynamic example 16_99
+ -
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Chemistry 2a
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Carbonyl Chemistry 16.11 Irreversible addition reactions to
carbonyl compounds (page 767).
-
Organometallic reagents
are strong enough
nucleophiles to add tocarbonyl compounds.
When water is added in
the second step, alcohols
are produced.
Fig. 16.69
++
--
-+
+-
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Organic
Chemistry 2a
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Carbonyl Chemistry General scheme for addition reactions to
carbonyl compounds
Addition of nucleophiles to carbonyl compounds
Fig. 18.1
-
+
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Chemistry 2a
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Carbonyl Chemistry 16.17 Additional Problems(Page 812-813)
Problem 16.32 a,b,c,d,g,h (write a mechanism whenever
possible)
Problem 16.34
a,b,d,e Problem 16.35 Problem 16.36
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Organic
Chemistry 2a
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Carbonyl Chemistry
Carbonyl Chemistry 2:Reactions at the -Position 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 878)
Carbonyl compounds bearing hydrogen at the -positionare weak acids, with pKa values in the high teens.
Fig. 18.2
Chapter 18
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Chemistry 2a
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Carbonyl Chemistry18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 879)
Some pKa values for simple ketones and aldehydes
Table 18.1
CH3CH2COCH2CH3CH3COCH3PhCOCH3PhCH2COCH3PhCH2COCH 3Cyclohexanone
CH3CHO
19,9
18,9
17,7
18,3
15,9
17,8
16,5
Carbonyl compound Pka
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Chemistry 2a
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Carbonyl ChemistryCarbonyl Chemistry 2:
Reactions at the -Position 18.1 Aldehydes and Ketones are weak
Brnsted Acids(page 879)
Why?
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 879)
There are three possible anions that can be formed from
butyraldehyde through breaking an sp3-1s carbon-
hydrogen bond.
Fig. 18.3
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Chemistry 2a
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Carbonyl Chemistry18.1 (page 879)
The dipole in the carbon-oxygen bond will stabilize an
adjacent anion more than a more distant anion.
Fig. 18.4
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 880)
Loss of the -hydrogen leads to a resonance-stabilizedenolate anion.
Fig. 18.5
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 880)
problem 18.1*
Write a mechanism for the base-catalyzedequilibration of the carbonyl and enol forms of
acetone.
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 881)
Stabilization by orbital overlap.
Fig. 18.7
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 881)
A comparison of the enolate and allyl anions
Fig. 18.7
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 882)
The oxygen atom of the enolate plays a crucial role in promoting the
acidity at the -position. Acetaldehyde is much more acidic than propene.Fig. 18.8
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 882)
Problem 18.2*
Propionaldehyde (propanal) can form twoenols. What are they?
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 882)
In D2O/DO-, the three -hydrogens of acetaldehyde are exchanged for
deuterium.
Fig. 18.9
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 883)
Enolate formation is an equilibrium reaction, and is endothermic in the
case of acetaldehyde.
Fig. 18.10
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 883)
The exchange reaction is a catalytic process, with deuteroxide ion (-OD)
acting as the catalyst.
Fig. 18.10
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 883, 884)
Problem 18.3
Explain why the aldehyde hydrogen inacetaldehyde does not exchange in
D2O/OD-
Problem 18.4
Explain why the bicyclic ketone in Figure18.12 exchanges only the two -hydrogens shown and not the bridgeheadhydrogen, which is also .
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 883)
Exchange can also be carried out in deuterated acid, D3O+/D2O.
Fig. 18.13
Write a mechanism for this acid-catalyzed H/D exchangeProblem 18.5*
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 884)
The first step in the acid-catalyzed exchange is addition of a D+ to the
carbonyl oxygen. A resonance stabilized cation results.
Fig. 18.14
40
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 885)
Removal of a proton from carbon generates the neutral enol form.
Removal of a deuteron from oxygen regenerates starting material.
Fig. 18.15
41
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 885)
Reaction of the enol with D3O+ will generate exchanged acetaldehyde.
Fig. 18.16
A dynamic example18_129
42
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 886)
Where does the equilibrium between carbonyl compound and enol lie?
Fig. 18.19
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 886)
For simple aldehydes and ketones, it is the carbonyl form that is favored
at equilibrium.
Fig. 18.20
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Chemistry 2a
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Carbonyl Chemistry18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 887)
Acetone is less enolized than acetaldehyde because of the greater
stabilization provided to the keto form by the second methyl group.
Fig. 18.21
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 887)
-Dicarbonyl compounds are more enolized than are monoketonesFig. 18.22
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 888)
The formation of an intramolecular hydrogen bond, as well as
conjugation between the carbon-carbon double bond and the carbonyl
group, contributes to the increased stability of the enols in -dicarbonylcompounds.
Fig. 18.23
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Chemistry 2a
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 888)
The equilibrium constant for enolization of cyclohexadienone is estimated
to be greater than 1013.
Fig. 18.24
Why?
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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak
Brnsted Acids (page 888)
The equilibrium constant for enolization of cyclohexadienone is estimated
to be greater than 1013.
Fig. 18.24
Phenol is
aromatic!
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Carbonyl ChemistryChapter 18
Carbonyl compounds containing -hydrogens are relativelyacidic and we know why.We know the basics of enols and enolates.
Carbonyl compounds are in equilibrium with their
enolates; at least in principle.
Carbonyl/enol equilibrium is directly related to their
structural features.
Extended Knowledge of Carbonyl Compounds
after 18.1
18.2 Reactions of Enols and Enolates
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Carbonyl Chemistry18.2 Reactions of enols and enolates (page 888)
18.2a Exchange Reactions
Exchange reactions of carbonyl compounds bearing -hydrogens can beeither acid or base catalyzed.
Fig. 18.25
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Carbonyl Chemistry18.2 Reactions of enols and enolates
18.2b Racemization (page 888)
Optically active carbonyl compounds are racemized in acid or base, as
long as an -hydrogen is present on the stereogenic carbonFig. 18.26
Why? Explain!
Starting from pure (S)!
Under acidic conditions!
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Carbonyl Chemistry
Protonation of the planar enol must
result in formation of equal amountsof two enantiomers. An optically active
carbonyl compound is racemized on
enol formation!
Fig. 18.27
18.2 Reactions of enols and enolates18.2b Racemization (pg 889)
From (S) to (R)
Under acidic conditions!
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Carbonyl Chemistry
Protonation of the planar enol must
result in formation of equal amountsof two enantiomers. An optically active
carbonyl compound is racemized on
enol formation!
Fig. 18.27
18.2 Reactions of enols and enolates18.2b Racemization (pg 889)
From (S) to (S)
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Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2b Racemization (page 890)
Resonance-stabilization of the enolate depends on overlap of the 2p-
orbitals on carbon and oxygen. Maximum overlap requires planarity, and
the planar enolate is necessarily achiral. Racemization has been
accomplished at the enolate stage.
Fig. 18.28
Under basic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 890)
Treatment of a ketone containing an -hydrogen with iodine, bromine, orchlorine in acids leads to -halogenation
Fig. 18.30
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 890)
Treatment of a ketone containing an -hydrogen with iodine, bromine, orchlorine in acids leads to -halogenation
Fig. 18.30
Why? Explain!
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Organic
Chemistry 2a Carbonyl Chemistry18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 890)
Under acidic conditions the enol is formed, and then reacts with iodine to
give the open, resonance stabilized cation. Deprotonation leads to the -iodide.
Fig. 18.31
A dynamic example 18_30
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Chemistry 2a Carbonyl Chemistry18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 891)
Under acidic conditions only monohalogenation.
Why?
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 891)
Protonation of the -iodoketone is disfavored by the electron-withdrawing character of the halogen.
Fig. 18.32
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 892)
Under basic conditions only polyhalogenation.
Why?
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 892)
The initially formed -iodo carbonyl compound is a stronger acid thanthe carbonyl compound itself. The introduced iodine makes enolate
formation easier.
Fig. 18.33
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 892)
Sequential enolate formations and iodinations lead to the , , -triiodocarbonyl compound.
Fig. 18.34
All -hydrogens are replaced!
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Organic
Chemistry 2a Carbonyl Chemistry18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 893)
Trihalocarbonyl compounds react in base to give a molecule of a
carboxylate anion and a haloform (trihalomethane)
Fig. 18.35
The haloform reaction
What is the mechanisme of
this reaction?
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Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 893)
The bond-making and bond-breaking requirements for this reaction
Fig. 18.36
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 893)
There is no precedent for this hypothetical SN2 displacement at ansp2
carbon.
Fig. 18.37
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 894)
Addition of hydroxide to the carbonyl group leads to a tetrahedral
intermediate that can lose triiodomethide anion to generate the carboxylic
acid. Transfer of a proton completes the reaction.
Fig. 18.38
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2c Halogenation in the -position(page 894)
The pKa of iodoform is about 14. Iodoform is a strong acid, and the loss of
CI3- is a reasonable step.
Fig. 18.39
A dynamic example 18_31
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Chemistry 2a Carbonyl Chemistry
Prototypes of basic reactions involving enolates (in base) or enols (in
acid).
Fig. 18.40
18.2 Reactions of enols and enolates (page 895)
Summary
Problem 18.9
All rates of these 3
reactions are
identical. Explain!
Use an Energy versus
Progress diagram
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Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2d Alkylation Reactions (page 895)
If the enolate could act as a nucleophile in the SN2 reaction, we might
have a way of alkylating at the -position.Fig. 18.41
A dynamic example 18_132
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Chemistry 2a Carbonyl Chemistry18.2 Reactions of enols and enolates
18.2d Alkylation Reactions (page 896)
In principle, alkylation of the enolate could take place at either carbon or
oxygen.
Fig. 18.42
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Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2d Alkylation Reactions (page 896)
In practice, alkylation generally takes place at carbon.
Fig. 18.43
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Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2d Alkylation Reactions (page 897)
For many ketones there are at least two possible enolates, and therefore
mixtures are obtained in the alkylation reaction.
Fig. 18.44
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Organic
Chemistry 2a Carbonyl Chemistry 18.2 Reactions of enols and enolates
18.2d Alkylation Reactions (page 897)
Strong bases such as LDA or NaH are effective at forming enolates
Fig. 18.46
Reaction only valuable if asingle type of -hydrogens are
present!
More info on LDA later!
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 900)
Two reactions of acetaldehyde with hydroxide ion: addition (hydrate
formation) and enolate formation.
Fig. 18.50
Under basic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 900)
The enolate can be reprotonated at either carbon or oxygen. Reaction at
oxygen usually dominates, but the resulting enol equilibrates with the
more stable carbonyl form
Fig. 18.51
Under basic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 900)
Addition of hydroxide and the enolate anion to the carbonyl group are
simply two examples of the addition reaction of nucleophiles to carbonyl
groups.
Fig. 18.52
Under basic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 901)
Protonation of these intermediates gives the hydrate, or, in the enolate
case, a compound known as aldol, a -hydroxy aldehyde.Fig. 18.53
Under basic conditions!
A dynamic example 18_133
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 901)
Knowing now the mechanism of
the base-catalyzed aldolcondensation, suggest a
mechanism for its acid-catalyzed
counterpart.
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 901)
The acid-catalyzed aldol condensation begins with enol formation.
Fig. 18.54
Under acidic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 902)
Two reactions of the weakly nucleophilic enol with Lewis acids. In the
first case, it is protonated to regenerate acetaldehyde; in the second the
enol adds to the strongly Lewis acidic protonated carbonyl to give aldol
Fig. 18.55
Under acidic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 902)Problem 18.13*
Write the products of the aldolcondensations of the following compounds(fig. 18.56)
Write both acid- and base-catalyzedmechanisms for reaction of (b)
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 904)
The acid-catalyzed dehydration of aldol
Fig. 18.57
Under acidic conditions!
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 905)
The base-catalyzed elimination of water from aldol. The reaction
mechanism is E1cB.
Fig. 18.58
Under basic conditions!
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Organic
Chemistry 2a Carbonyl ChemistryChapter 18 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 905)
What is the E1cB
mechanism?
See Chapter 7 on Substitution and Elimination
Reactions: The SN2, SN1, E2 and E1 Reactions.
7.13, page 288
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Organic
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 905) 7.13 The E1cB reaction (pg 288)
The E1 and E1cB reaction contrasted. In the E1 reaction, the slow step is
ionization to give the carbocation. In the E1cB reaction, a proton is first
removed to give an anion that subsequently eliminates the leaving group.
Fig. 7.97
E1cB constitutes:Elimination,
unimolecular (1),
conjugate Base
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O ga c
Chemistry 2a Carbonyl Chemistry18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 902)
Problem 18.14
What are the products of dehydration of the
condensation products of Problem 18.13?
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g
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 907)
The base-catalyzed aldol condensationof acetone (as an example for the
aldol condensation of ketones).
Fig. 18.60
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g
Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 907)
The acid-catalyzed aldol condensationof acetone. The first product,
diacetone alcohol, is generally dehydrated in acid to give mesityl oxide, 4-
methyl-3-penten-2-one.
Fig. 18.61
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 908)
In the hydration of ketones, the hydrate is usually not favored at the
equilibrium. Similarly, in the aldol condensation of ketones, the product
molecule is not usually favored!
Fig. 18.62
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 908)
The operation of a Soxhlet extractor in the aldol condensation
Fig. 18.63
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 909)
The operation of a Soxhlet extractor in the aldol condensation
Fig. 18.63
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 909)
A retrosynthetic analysis for the product of an aldol condensation
followed by hydration
Fig. 18.64
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 909)
Although equilibrium generally favors the condensation product in the
aldol reaction of aldehydes, the reaction of ketones generally favors
starting material. Special techniques must be used to make the reaction of
ketones practical.
Fig. 18.67
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 909)Problem 18.16
Write mechanisms for the acid- and base-catalyzed reverse aldol condensation of
diacetone alcohol (fig. 18.65)
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Chemistry 2a Carbonyl Chemistry 18.3 Condensation Reactions of Carbonyl
Compounds:The Aldol Condensation (pg 910)
Problem 18.17
Perform retrosynthetic analyses on the three
molecules of fig. 18.65.
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol
Condensation (pg 911) 18.4a Intramolecular Aldol Condensations
The mechanism for a base-catalyzed intramolecular aldol condensation.
Fig. 18.68
The mechanism
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 911) 18.4a Intramolecular Aldol Condensations
Fig. 18.68
Examples
Work out a
mechanism!
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 911) 18.4b Crossed Aldol Condensations
A retrosynthetic analysis suggests that a condensation between diethyl
ketone and acetone should give the -hydroxy ketone shown.Fig. 18.70
What is the problem with thissynthesis?
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 911) 18.4b Crossed Aldol Condensations
When this synthetic route is attempted, four -hydroxyketones,A, B, Cand D are likely to be produced.
Fig. 18.71
A Mixture!!!
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 912) 18.4b Crossed Aldol Condensations
When this synthetic route is attempted, four -hydroxyketones,A, B, Cand D are likely to be produced.
Fig. 18.71
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 913) 18.4b Crossed Aldol Condensations
The crossed aldol reaction of acetone and benzaldehyde can give only two
products. Benzaldehyde has no -hydrogens and cannot form an enolate.Fig. 18.72
See next slide for
enlarged scheme
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Chemistry 2a Carbonyl Chemistry
Fig. 18.72
enlarged!
Mistake in the book: in text
the substrate istert-butyl
methyl ketone; in the schemeit is acetone.
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
In fact, there is only major product in the aldol condensation oftert-butyl
methyl ketone and benzaldehyde.
Fig. 18.73
Why?
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
The carbonyl group of benzaldehyde is more reactive than that oftert-
butyl methyl ketone, and equilibrium favors the product in the reaction
with benzaldehyde, but not for the reaction withtert-butyl methyl ketone.
Fig. 18.74
Why are additions to aldehydes
generally more favorable than to
ketones?
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Chemistry 2a Carbonyl Chemistry 16.6 Equilibrium in Addition Reactions (pg 768)
The stability of carbonyl groups depends greatly on the number of alkyl
groups. Like alkenes, more substituted carbonyl groups are more stable
than their less substituted counterparts. In the hydrates, increasing
substitution results in increasing destabilization through steric
interactions.
Fig. 16.29
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
In fact, there is only major product in the aldol condensation oftert-butyl
methyl ketone and benzaldehyde.
Fig. 18.73
How would you carry out this
reaction to avoid any condensation of
the ketone?
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
In fact, there is only major product in the aldol condensation oftert-butyl
methyl ketone and benzaldehyde.
Fig. 18.73
1. Together in reaction flask and stir.
No -hydrogens no enolization no condensation!
Problem 18.20
There is a reaction between benzaldehyde
and base (NaOH). What is it, and why does itnot interfere with the aldol condensation?
However!
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
In fact, there is only major product in the aldol condensation oftert-butyl
methyl ketone and benzaldehyde.
Fig. 18.73
1. Together in reaction flask
2. Add ketone dropwise to mixture and stir for 32 h at room temp low concentration of ketone no self condensation
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
A crossed aldol condensation with LDA as base
Fig. 18.75
Why is LDA such
an excellent basefor condendations
and alkylations?
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 914) 18.4b Crossed Aldol Condensations
LDA is a very strong base (pKa= 36 for
diisopropylamine) and therefore leads to an
efficient formation of enolates (pKa= 15-25for carbonyl compounds). Fig. 18.46
LDA is large sterically encumbered base
and removes a proton from the sterically
less hindered position regioselectivity LDA does not add to the carbonyl function
as this leads to a highly crowded
intermediatechemoselectivity
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Chemistry 2a Carbonyl Chemistry LDA is a very strong base (pKa= 36 for
diisopropylamine) and therefore leadsto an efficient formation of enolates(pKa= 15-25 for carbonyl compounds).Fig. 18.46
See Amines; Fig. 21.31 + 21.32;
page 1090
Preparation of LDA
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Chemistry 2a Carbonyl Chemistry LDA is a large, sterically encumbered
base and removes a proton from thesterically less hindered positionregioselectivity
See 18.7; Fig. 18.114; page 937
Regioselective
depronation using
LDA
reaction occurs preferentially at oneof the conceivable positions.
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Chemistry 2a Carbonyl Chemistry LDA does not add to the carbonyl
function as this leads to a highlycrowded intermediate chemoselectivity
See 16.9; Fig. 16.48; page 780
Addition of amines to carbonyl function
Sterically much more hindered than starting
carbonyl compound! Does not occur with LDA!
reactions occurs preferentially at one ofthe conceivable reaction centers.
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 916)
18.4c Knoevenagel Condensations andRelated Reactions.
The Knoevenagel condensation (The general case)
Fig. 18.76
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 916)
18.4c Knoevenagel Condensations andRelated Reactions.
The Knoevenagel condensation (Specific examples)
Fig. 18.76
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 915)
18.4c Knoevenagel Condensations andRelated Reactions.
Diketones and similar compounds with strongcarbanion stabilizing groups are in particularsuitable for this reaction!
Table 18.2
EtO OEt
O O
NC CN
H3C OEt
O O
H3C CH3
O O
Ph CH3
O O
H H
O O
pKa
13,3
11
10,7
pKa
8,9
8,5
5
Why are
these
bifunctionalcompounds
so acidic?
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 915)
18.4c Knoevenagel Condensations andRelated Reactions.
The removal of a doubly proton is an exothermicreaction.
Figure 20.64
EtO CH3
O O
H H EtO CH3
O O
H EtO CH3
O O
H EtO CH3
O O
H
pKa 10doubly hydrogens
OR + HOR (pKa 17)
We will get back to this in Chapter 20
(20.10)
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Chemistry 2a Carbonyl Chemistry 18.4 Reactions Related to The Aldol Condensation
(pg 917)
18.4c Knoevenagel Condensations andRelated Reactions.
A condendation reaction leading to fulvenes
Fig. 18.77
H3C CH3
O
+CH3
CH3
NaOCH2CH3/C2H5OH
Propose a mechanism for this condensation reaction.
Not only acidic carbonyl compounds are suitable forthis reaction!
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Chemistry 2a Ca bo y C e st y 18.4 Reactions Related to The Aldol Condensation
(pg 917)
18.4c Knoevenagel Condensations andRelated Reactions.
A condendation reaction leading to fulvenes
Fig. 18.77
The answer:
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 917)
18.4c Knoevenagel Condensations andRelated Reactions.
Any double bond is the formal result of a condensation reaction followed
by dehydration
Fig. 18.78
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 917)
18.4c Knoevenagel Condensations andRelated Reactions.
Problem 18.22
Propose syntheses for the molecules in fig.18.79.
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 918)
18.4d More Related Condensations: TheMichael Reaction
The reaction of a nucleophile (Nu-) with an ,-unsaturated carbonyl compound.Michael addition preserves the carbonyl group and is usually favored
thermodynamically.
Fig. 18.84
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 918)
18.4d More Related Condensations: TheMichael Reaction
Addition of a base such as alkoxide to a simple alkene would yield an unstabilized
anion. A measure of the difficulty of this reaction can be gained by examining the
acidity of the related hydrocarbon. Such species are extraordinarily weak bases and
their pKa values are very difficult to determine.
Fig. 18.80
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 918)
18.4d More Related Condensations: TheMichael Reaction
By contrast, additions to ,-unsaturated carbonyls are common. Notice theresonance stabilization of the resulting enolate anion.
Fig. 18.81
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 918)
18.4d More Related Condensations: TheMichael Reaction
Two Michael additions
Fig. 18.82
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 918)
18.4d More Related Condensations: TheMichael Reaction
Also Acid Catalyzed!!!
What would be the
mechanism?
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 918)
18.4d More Related Condensations: TheMichael Reaction
Two acid-catalyzed Michael reactions (the general case)
Fig. 18.83
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Chemistry 2a y y 18.4 Reactions Related to The Aldol Condensation
(pg 919)
18.4d More Related Condensations: TheMichael Reaction
Two acid-catalyzed Michael reactions (specific examples)
Fig. 18.83
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y y y 18.4 Reactions Related to The Aldol Condensation
(pg 921)
18.4d More Related Condensations: TheMichael Reaction
The two possible reactions of a nucleophile (Nu-) with an ,-unsaturated carbonylcompound. Michael addition preserves the carbonyl group and is usually favored
thermodynamically.
Fig. 18.84
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y y y 18.4 Reactions Related to The Aldol Condensation
(pg 921)
18.4d More Related Condensations: TheMichael Reaction
Two irreversible addition reactions to the carbonyl group of an ,-unsaturatedcarbonyl compound.
Fig. 18.85
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y y y 18.4 Reactions Related to The Aldol Condensation
(pg 922)
18.4d More Related Condensations: TheMichael Reaction
Cuprates (and often Grignard reagents) add in Michael fashion to ,-unsaturatedcarbonyl compounds.
Fig. 18.86
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y y y 18.8 Something More: State of the Art Organic
Synthesis (pg 940)
The incredibly complicated molecule, palytoxin carboxylic acid. The box shows a
link forged through an aldol-like reaction.
Fig. 18.119
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y y y 18.8 Something More: State of the Art Organic
Synthesis (pg 941)
A critical aldol-like condensation finishes the sewing together of palytoxin
Fig. 18.120
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y
18.9 Summary (pg 941)
New Concepts
Enolate formation in base and enol formation in acid are typical reactions of
carbonyl compounds bearing -hydrogens.Fig. 18.121
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y
18.9 Summary (pg 942)
New Concepts
Reactions of enolates and enols with various Lewis acids.
Fig. 18.122
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18.9 Summary (pg 942)
New Concepts
Reactions of enolates and enols with various Lewis acids.
Fig. 18.122
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18.11 Additional Problems(Page 946-952)
Enolization: Problems 18.35 t/m 18.39 Carbonyl Synthesis review: Problem 18.41
a,c,d
Enolization, aldol condensations,Knoevenagel reactions and Michael
additions:Problems 18.42 t/m 18.56;Problems 18.61 t/m 18.63