a conceptual approach to molecular understanding

8/3/2019 A Conceptual Approach to Molecular Understanding

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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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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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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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Chemistry 2a

4

Introduction


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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Introduction


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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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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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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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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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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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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754)

A comparison of the structures of formaldehyde,

acetaldehyde and ethylene.

Fig. 16.3


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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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755)

A resonance formulation of a carbonyl group. Note the

polar resonance form.

Fig. 16.6


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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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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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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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Acid-catalyzed hydration of a carbonyl compound

Fig. 16.26

+ -


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Base-catalyzed hydration of a carbonyl compound

Fig. 16.27

-+


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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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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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Carbonyl Chemistry General scheme for addition reactions to

carbonyl compounds

Addition of nucleophiles to carbonyl compounds

Fig. 18.1

-

+


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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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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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Carbonyl Chemistry18.1 Aldehydes and Ketones are weak


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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Carbonyl ChemistryCarbonyl Chemistry 2:

Reactions at the -Position 18.1 Aldehydes and Ketones are weak

Brnsted Acids(page 879)

Why?


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Carbonyl Chemistry 18.1 Aldehydes and Ketones are weak


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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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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Loss of the -hydrogen leads to a resonance-stabilizedenolate anion.

Fig. 18.5


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problem 18.1*

Write a mechanism for the base-catalyzedequilibration of the carbonyl and enol forms of

acetone.


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Stabilization by orbital overlap.

Fig. 18.7


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A comparison of the enolate and allyl anions

Fig. 18.7


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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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Problem 18.2*

Propionaldehyde (propanal) can form twoenols. What are they?


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In D2O/DO-, the three -hydrogens of acetaldehyde are exchanged for

deuterium.

Fig. 18.9


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Enolate formation is an equilibrium reaction, and is endothermic in the

case of acetaldehyde.

Fig. 18.10


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The exchange reaction is a catalytic process, with deuteroxide ion (-OD)

acting as the catalyst.

Fig. 18.10


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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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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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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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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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Reaction of the enol with D3O+ will generate exchanged acetaldehyde.

Fig. 18.16

A dynamic example18_129

42


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Where does the equilibrium between carbonyl compound and enol lie?

Fig. 18.19

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For simple aldehydes and ketones, it is the carbonyl form that is favored

at equilibrium.

Fig. 18.20

44


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Carbonyl Chemistry18.1 Aldehydes and Ketones are weak


Acetone is less enolized than acetaldehyde because of the greater

stabilization provided to the keto form by the second methyl group.

Fig. 18.21

45


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-Dicarbonyl compounds are more enolized than are monoketonesFig. 18.22

46


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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

47


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The equilibrium constant for enolization of cyclohexadienone is estimated

to be greater than 1013.

Fig. 18.24

Why?

48


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The equilibrium constant for enolization of cyclohexadienone is estimated

to be greater than 1013.

Fig. 18.24

Phenol is

aromatic!

49


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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)


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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!

55


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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



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


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


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Under acidic conditions only monohalogenation.

Why?

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Protonation of the -iodoketone is disfavored by the electron-withdrawing character of the halogen.

Fig. 18.32

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Under basic conditions only polyhalogenation.

Why?

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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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Sequential enolate formations and iodinations lead to the , , -triiodocarbonyl compound.

Fig. 18.34

All -hydrogens are replaced!

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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?

O i64


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The bond-making and bond-breaking requirements for this reaction

Fig. 18.36

O i65


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There is no precedent for this hypothetical SN2 displacement at ansp2

carbon.

Fig. 18.37

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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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The pKa of iodoform is about 14. Iodoform is a strong acid, and the loss of

CI3- is a reasonable step.

Fig. 18.39


O i68

C C


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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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C b l Ch i


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Organic


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


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C b l Ch i t


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Organic



In principle, alkylation of the enolate could take place at either carbon or

oxygen.

Fig. 18.42

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C b l Ch i t


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In practice, alkylation generally takes place at carbon.

Fig. 18.43

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C b l Ch i t


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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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C b l Ch i t


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Organic



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!

Organic74

C b l Ch i t


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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


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C b l Ch i t


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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


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C b l Ch i t


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Organic



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


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C b l Ch i t


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Protonation of these intermediates gives the hydrate, or, in the enolate

case, a compound known as aldol, a -hydroxy aldehyde.Fig. 18.53



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C b l Ch i t


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Knowing now the mechanism of

the base-catalyzed aldolcondensation, suggest a

mechanism for its acid-catalyzed

counterpart.

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C b l Ch i t


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Organic



The acid-catalyzed aldol condensation begins with enol formation.

Fig. 18.54


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C b l Ch i t


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Organic

Chemistry 2a Carbonyl Chemistry18.3 Condensation Reactions of Carbonyl


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


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C b l Ch i t


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Organic


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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Carbon l Chemistr


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The acid-catalyzed dehydration of aldol

Fig. 18.57


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Carbonyl Chemistry


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The base-catalyzed elimination of water from aldol. The reaction

mechanism is E1cB.

Fig. 18.58


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Carbonyl Chemistry


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Organic

Chemistry 2a Carbonyl ChemistryChapter 18 18.3 Condensation Reactions of Carbonyl


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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Carbonyl Chemistry


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Organic


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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Carbonyl Chemistry


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O ga c



Problem 18.14

What are the products of dehydration of the

condensation products of Problem 18.13?

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Carbonyl Chemistry


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g



The base-catalyzed aldol condensationof acetone (as an example for the

aldol condensation of ketones).

Fig. 18.60

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Carbonyl Chemistry


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g



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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Carbonyl Chemistry


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g



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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Carbonyl Chemistry


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g



The operation of a Soxhlet extractor in the aldol condensation

Fig. 18.63

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Carbonyl Chemistry


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g



The operation of a Soxhlet extractor in the aldol condensation

Fig. 18.63

Organic92

Carbonyl Chemistry


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g



A retrosynthetic analysis for the product of an aldol condensation

followed by hydration

Fig. 18.64

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Carbonyl Chemistry


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g



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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Carbonyl Chemistry


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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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Carbonyl Chemistry


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Problem 18.17

Perform retrosynthetic analyses on the three

molecules of fig. 18.65.

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Carbonyl Chemistry


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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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Carbonyl Chemistry


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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!

Organic98

Carbonyl Chemistry


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(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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Carbonyl Chemistry


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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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When this synthetic route is attempted, four -hydroxyketones,A, B, Cand D are likely to be produced.

Fig. 18.71

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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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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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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?

Organic

Ch i 2

105

Carbonyl Chemistry


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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

Organic

Ch i 2

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Fig. 18.73

How would you carry out this

reaction to avoid any condensation of

the ketone?

Organic

Ch i 2

107

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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!

Organic

Ch i t 2

108

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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

Organic

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A crossed aldol condensation with LDA as base

Fig. 18.75

Why is LDA such

an excellent basefor condendations

and alkylations?

Organic

Ch i t 2

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Carbonyl Chemistry


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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

Organic

Ch i t 2

111

Carbonyl Chemistry


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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

Organic

Chemistr 2a

112

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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.

Organic

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Carbonyl Chemistry


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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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(pg 916)

18.4c Knoevenagel Condensations andRelated Reactions.

The Knoevenagel condensation (The general case)

Fig. 18.76

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(pg 916)


The Knoevenagel condensation (Specific examples)

Fig. 18.76

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(pg 915)


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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(pg 915)


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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(pg 917)


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)


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)


Any double bond is the formal result of a condensation reaction followed

by dehydration

Fig. 18.78

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(pg 917)


Problem 18.22

Propose syntheses for the molecules in fig.18.79.

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(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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(pg 918)


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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(pg 918)


By contrast, additions to ,-unsaturated carbonyls are common. Notice theresonance stabilization of the resulting enolate anion.

Fig. 18.81

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(pg 918)


Two Michael additions

Fig. 18.82

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(pg 918)


Also Acid Catalyzed!!!

What would be the

mechanism?

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(pg 918)


Two acid-catalyzed Michael reactions (the general case)

Fig. 18.83

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(pg 919)


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)


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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(pg 921)


Two irreversible addition reactions to the carbonyl group of an ,-unsaturatedcarbonyl compound.

Fig. 18.85

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(pg 922)


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


New Concepts

Reactions of enolates and enols with various Lewis acids.

Fig. 18.122

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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

a conceptual approach to molecular understanding

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