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Organic Chemistry 2a

A Conceptual Approach to Molecular Understanding


Second Year Course for Chemists, Molecular Life Scientists and General Scientists

Dr. A.J.H. Klunder Department of Organic Chemistry UL 357 Tel. (36)52193 E-mail: ajhk@sci.kun.nl September 2000

Organic Chemistry 2a

Introduction
Organic Chemistry 2a
Place
A

in Curriculum

second years course. The third course in a series of 4. The sequel to prof. Noltes first years courses Organic Chemistry 1a and 1b.

Prerequisite
Good

knowledge of basic (first years) General and Organic Chemistry

Organic Chemistry 2a

Introduction
Organic Chemistry 2a
Book
Maitland

Jones, Jr. Organic Chemistry First Edition, 1997

Subjects
Carbonyl
Amines

Chemistry

chapters 16,18,19,20 chapter 21


Ethers

and Epoxides

chapters 17, 25
Carbohydrates

chapters 24

Organic Chemistry 2a

Introduction
Organic Chemistry 2a

Course Philosophy Conceptual approach! Molecules must be understood to explain their behavior. Avoid memorization! Do it yourself! We can only help you (lectures and workshops - 20 24 hrs; self study - 60 hrs!). Keep up with the course! It is highly repetitive. Losing track means losing time! Work the problems. Use paper and pencil!

Organic Chemistry 2a

Introduction
Organic Chemistry 2a

Course Philosophy Lectures will be highly interactive! Workshops form an essential part of the course and are, therefore, highly recommended. Workshops are given on an individual base. Where necessary computer simulation or visualization will be used or recommended see: www.cmbi.kun.nl/wetche/organic/ Work at home will be inevitable!

Organic Chemistry 2a

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 book Workshops are problem oriented; problems come from the book and exams. Book contains CD which illustrates basic concepts. Useful for home study. Work at home will be inevitable!

Organic Chemistry 2a

Introduction
Organic Chemistry 2a

How to use the book?


Not all information in the book is relevant for this course! There is much more to appreciate. A detailed list of paragraphs containing the required course material will be provided. Watch also the overheads! Of course an interested reader is invited to stroll through neighboring paragraphs. A list of selected problems is provided. These problems are vital to gain the necessary experience to learn the basic properties of organic molecules.

Organic Chemistry 2a

Carbonyl Chemistry
Chapter 16

Carbonyl Chemistry 1: Addition Reactions

Current 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

Organic Chemistry 2a

Carbonyl Chemistry

Carbonyl Chemistry 1: Addition Reactions

Chapter 16

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 and the carbon-hydrogen bonds. Fig. 16.1

Organic Chemistry 2a

Carbonyl Chemistry
16.1 Structure of Carbon-Oxygen Bond (page 754)

10

One orbital picture of the simplest carbonyl compound, formaldehyde. Fig. 16.2

Organic Chemistry 2a

Carbonyl Chemistry
16.1 Structure of Carbon-Oxygen Bond (page 754)

11

A comparison of the structures of formaldehyde, acetaldehyde and ethylene. Fig. 16.3

Organic Chemistry 2a

Carbonyl Chemistry
16.1 Structure of Carbon-Oxygen Bond (page 755)

12

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

Organic Chemistry 2a

Carbonyl Chemistry
16.1 Structure of Carbon-Oxygen Bond (page 755)

13

A resonance formulation of a carbonyl group. Note the polar resonance form. Fig. 16.6

Organic Chemistry 2a

Carbonyl Chemistry
16.2 Nomenclature of carbonyl compounds (pages 756-759)

14

Different substitution patterns for simple carbonyl compounds. Fig. 16.7 + 16.14

Organic Chemistry 2a

Carbonyl Chemistry
16.5 Reactions of Carbonyl Compounds: simple reversible additions (page 763).

15

What is the mechanism of this addition of water to the carbonyl function?


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

Organic Chemistry 2a

Carbonyl Chemistry
16.5 Reactions of Carbonyl Compounds: simple reversible additions (page 763-765).

16

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

Organic Chemistry 2a

Carbonyl Chemistry
16.5 Reactions of Carbonyl Compounds: simple reversible additions (page 767).

17

Acid-catalyzed hydration of a carbonyl compound Fig. 16.26

Organic Chemistry 2a

Carbonyl Chemistry
16.5 Reactions of Carbonyl Compounds: simple reversible additions (page 767).

18

+ -

Base-catalyzed hydration of a carbonyl compound Fig. 16.27

Organic Chemistry 2a

Carbonyl Chemistry
16.7 Other addition reactions: additions of cyanide and bisulfite (page 772).

19

A dynamic example 16_99

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

Organic Chemistry 2a

Carbonyl Chemistry

20

16.11 Irreversible addition reactions to carbonyl compounds (page 767).


+ + - + -

Organometallic reagents are strong enough nucleophiles to add to carbonyl compounds. When water is added in the second step, alcohols are produced. Fig. 16.69

Organic Chemistry 2a

Carbonyl Chemistry

21

General scheme for addition reactions to carbonyl compounds

Addition of nucleophiles to carbonyl compounds Fig. 18.1

Organic Chemistry 2a

Carbonyl Chemistry

22

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

Organic Chemistry 2a

Carbonyl Chemistry

23

Carbonyl Chemistry 2: Reactions at the -Position

Chapter 18

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 878)

Carbonyl compounds bearing hydrogen at the -position are weak acids, with pKa values in the high teens. Fig. 18.2

Organic Chemistry 2a

Carbonyl Chemistry
18.1 Aldehydes and Ketones are weak Brnsted Acids (page 879)

24

Carbonyl compound CH 3CH 2COCH2CH 3 CH 3COC H3 PhCOC H3 PhCH 2COC H3 PhCH2COCH 3 Cyclohexanone CH3CHO

Pka 19,9 18,9 17,7 18,3 15,9 17,8 16,5

Some pKa values for simple ketones and aldehydes Table 18.1

Organic Chemistry 2a

Carbonyl Chemistry
Carbonyl Chemistry 2: Reactions at the -Position

25

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 879)

Why?

Organic Chemistry 2a

Carbonyl Chemistry

26

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 carbonhydrogen bond. Fig. 18.3

Organic Chemistry 2a

Carbonyl Chemistry
18.1 (page 879)

27

The dipole in the carbon-oxygen bond will stabilize an adjacent anion more than a more distant anion. Fig. 18.4

Organic Chemistry 2a

Carbonyl Chemistry

28

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 880)

Loss of the -hydrogen leads to a resonance-stabilized enolate anion. Fig. 18.5

Organic Chemistry 2a

Carbonyl Chemistry

29

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 880)

problem 18.1*
Write a mechanism for the base-catalyzed equilibration of the carbonyl and enol forms of acetone.

Organic Chemistry 2a

Carbonyl Chemistry

30

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 881)

Stabilization by orbital overlap. Fig. 18.7

Organic Chemistry 2a

Carbonyl Chemistry

31

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 881)

A comparison of the enolate and allyl anions Fig. 18.7

Organic Chemistry 2a

Carbonyl Chemistry

32

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

Organic Chemistry 2a

Carbonyl Chemistry

33

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 882)

Problem 18.2* Propionaldehyde (propanal) can form two enols. What are they?

Organic Chemistry 2a

Carbonyl Chemistry

34

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

Organic Chemistry 2a

Carbonyl Chemistry

35

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

Organic Chemistry 2a

Carbonyl Chemistry

36

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

Organic Chemistry 2a

Carbonyl Chemistry

37

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 883, 884)

Problem 18.3 Explain why the aldehyde hydrogen in acetaldehyde does not exchange in D2O/OD-

Problem 18.4 Explain why the bicyclic ketone in Figure 18.12 exchanges only the two hydrogens shown and not the bridgehead hydrogen, which is also .

Organic Chemistry 2a

Carbonyl Chemistry

38

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 883)

Write a mechanism for this acid-catalyzed H/D exchange Problem 18.5*


Exchange can also be carried out in deuterated acid, D3O+/D2O. Fig. 18.13

Organic Chemistry 2a

Carbonyl Chemistry

39

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

Organic Chemistry 2a

Carbonyl Chemistry

40

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

Organic Chemistry 2a

Carbonyl Chemistry

41

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 885)

A dynamic example 18_129

Reaction of the enol with D3O+ will generate exchanged acetaldehyde. Fig. 18.16

Organic Chemistry 2a

Carbonyl Chemistry

42

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 886)

Where does the equilibrium between carbonyl compound and enol lie? Fig. 18.19

Organic Chemistry 2a

Carbonyl Chemistry

43

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

Organic Chemistry 2a

Carbonyl Chemistry
18.1 Aldehydes and Ketones are weak Brnsted Acids (page 887)

44

Acetone is less enolized than acetaldehyde because of the greater stabilization provided to the keto form by the second methyl group. Fig. 18.21

Organic Chemistry 2a

Carbonyl Chemistry

45

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 887)

-Dicarbonyl compounds are more enolized than are monoketones Fig. 18.22

Organic Chemistry 2a

Carbonyl Chemistry

46

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 -dicarbonyl compounds.

Fig. 18.23

Organic Chemistry 2a

Carbonyl Chemistry

47

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 888)

Why?
The equilibrium constant for enolization of cyclohexadienone is estimated to be greater than 1013. Fig. 18.24

Organic Chemistry 2a

Carbonyl Chemistry

48

18.1 Aldehydes and Ketones are weak Brnsted Acids (page 888)

Phenol is aromatic!
The equilibrium constant for enolization of cyclohexadienone is estimated to be greater than 1013. Fig. 18.24

Organic Chemistry 2a

Carbonyl Chemistry
Chapter 18

49

Extended Knowledge of Carbonyl Compounds after 18.1


Carbonyl compounds containing -hydrogens are relatively acidic 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.

18.2 Reactions of Enols and Enolates

Organic Chemistry 2a

Carbonyl Chemistry

50

18.2 Reactions of enols and enolates (page 888) 18.2a Exchange Reactions

Exchange reactions of carbonyl compounds bearing -hydrogens can be either acid or base catalyzed. Fig. 18.25

Organic Chemistry 2a

Carbonyl Chemistry
18.2 Reactions of enols and enolates 18.2b Racemization (page 888) Under acidic conditions!

51

Starting from pure (S)!

Why? Explain!

Optically active carbonyl compounds are racemized in acid or base, as long as an -hydrogen is present on the stereogenic carbon Fig. 18.26

Organic Chemistry 2a

Carbonyl Chemistry

52

18.2 Reactions of enols and enolates 18.2b Racemization (pg 889) Under acidic conditions!
Protonation of the planar enol must result in formation of equal amounts of two enantiomers. An optically active carbonyl compound is racemized on enol formation! Fig. 18.27 From (S) to (R)

Organic Chemistry 2a

Carbonyl Chemistry

53

18.2 Reactions of enols and enolates 18.2b Racemization (pg 889)


From (S) to (S) Protonation of the planar enol must result in formation of equal amounts of two enantiomers. An optically active carbonyl compound is racemized on enol formation! Fig. 18.27

Organic Chemistry 2a

Carbonyl Chemistry

54

18.2 Reactions of enols and enolates 18.2b Racemization (page 890) Under basic conditions!

Resonance-stabilization of the enolate depends on overlap of the 2porbitals 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

Organic Chemistry 2a

Carbonyl Chemistry

55

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, or chlorine in acids leads to -halogenation Fig. 18.30

Organic Chemistry 2a

Carbonyl Chemistry

56

18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 890)

Why? Explain!
Treatment of a ketone containing an -hydrogen with iodine, bromine, or chlorine in acids leads to -halogenation Fig. 18.30

Organic Chemistry 2a

Carbonyl Chemistry

57

18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 890) A dynamic example 18_30

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

Organic Chemistry 2a

Carbonyl Chemistry
18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 891)

58

Under acidic conditions only monohalogenation.

Why?

Organic Chemistry 2a

Carbonyl Chemistry

59

18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 891)

Protonation of the -iodoketone is disfavored by the electronwithdrawing character of the halogen. Fig. 18.32

Organic Chemistry 2a

Carbonyl Chemistry

60

18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 892)

Under basic conditions only polyhalogenation.

Why?

Organic Chemistry 2a

Carbonyl Chemistry

61

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 than the carbonyl compound itself. The introduced iodine makes enolate formation easier. Fig. 18.33

Organic Chemistry 2a

Carbonyl Chemistry

62

18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 892)

All -hydrogens are replaced! Sequential enolate formations and iodinations lead to the , , -triiodo carbonyl compound. Fig. 18.34

Organic Chemistry 2a

Carbonyl Chemistry
18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 893)

63

What is the mechanisme of this reaction?


The haloform reaction Trihalocarbonyl compounds react in base to give a molecule of a carboxylate anion and a haloform (trihalomethane) Fig. 18.35

Organic Chemistry 2a

Carbonyl Chemistry

64

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

Organic Chemistry 2a

Carbonyl Chemistry

65

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 an sp2 carbon. Fig. 18.37

Organic Chemistry 2a

Carbonyl Chemistry

66

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

Organic Chemistry 2a

Carbonyl Chemistry

67

18.2 Reactions of enols and enolates 18.2c Halogenation in the -position (page 894)

A dynamic example 18_31


The pKa of iodoform is about 14. Iodoform is a strong acid, and the loss of CI3- is a reasonable step. Fig. 18.39

Organic Chemistry 2a

Carbonyl Chemistry

68

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

Prototypes of basic reactions involving enolates (in base) or enols (in acid). Fig. 18.40

Organic Chemistry 2a

Carbonyl Chemistry

69

18.2 Reactions of enols and enolates 18.2d Alkylation Reactions (page 895)

A dynamic example 18_132


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

Organic Chemistry 2a

Carbonyl Chemistry
18.2 Reactions of enols and enolates 18.2d Alkylation Reactions (page 896)

70

In principle, alkylation of the enolate could take place at either carbon or oxygen. Fig. 18.42

Organic Chemistry 2a

Carbonyl Chemistry

71

18.2 Reactions of enols and enolates 18.2d Alkylation Reactions (page 896)

In practice, alkylation generally takes place at carbon. Fig. 18.43

Organic Chemistry 2a

Carbonyl Chemistry

72

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

Organic Chemistry 2a

Carbonyl Chemistry

73

18.2 Reactions of enols and enolates 18.2d Alkylation Reactions (page 897)

Reaction only valuable if a single type of -hydrogens are present!

Strong bases such as LDA or NaH are effective at forming enolates Fig. 18.46

More info on LDA later!

Organic Chemistry 2a

Carbonyl Chemistry

74

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 900)

Under basic conditions!


Two reactions of acetaldehyde with hydroxide ion: addition (hydrate formation) and enolate formation. Fig. 18.50

Organic Chemistry 2a

Carbonyl Chemistry

75

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 900)

Under basic conditions! 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

Organic Chemistry 2a

Carbonyl Chemistry

76

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 900)

Under basic conditions! 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

Organic Chemistry 2a

Carbonyl Chemistry

77

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 901)

A dynamic example 18_133

Under basic conditions!

Protonation of these intermediates gives the hydrate, or, in the enolate case, a compound known as aldol, a -hydroxy aldehyde. Fig. 18.53

Organic Chemistry 2a

Carbonyl Chemistry

78

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 901)

Knowing now the mechanism of the base-catalyzed aldol condensation, suggest a mechanism for its acid-catalyzed counterpart.

Organic Chemistry 2a

Carbonyl Chemistry

79

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 901)

Under acidic conditions!

The acid-catalyzed aldol condensation begins with enol formation. Fig. 18.54

Organic Chemistry 2a

Carbonyl Chemistry
18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 902)

80

Under acidic conditions! 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

Organic Chemistry 2a

Carbonyl Chemistry
18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 902)

81

Problem 18.13*
Write the products of the aldol condensations of the following compounds (fig. 18.56) Write both acid- and base-catalyzed mechanisms for reaction of (b)

Organic Chemistry 2a

Carbonyl Chemistry

82

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 904)

Under acidic conditions!

The acid-catalyzed dehydration of aldol Fig. 18.57

Organic Chemistry 2a

Carbonyl Chemistry

83

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 905)

Under basic conditions!

The base-catalyzed elimination of water from aldol. The reaction mechanism is E1cB. Fig. 18.58

Organic Chemistry 2a

Carbonyl Chemistry
Chapter 18

84

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

Organic Chemistry 2a

Carbonyl Chemistry

85

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 905) 7.13 The E1cB reaction (pg 288)

E1cB constitutes: Elimination, unimolecular (1), conjugate Base

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

Organic Chemistry 2a

Carbonyl Chemistry
18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 902)

86

Problem 18.14
What are the products of dehydration of the condensation products of Problem 18.13 ?

Organic Chemistry 2a

Carbonyl Chemistry

87

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

Organic Chemistry 2a

Carbonyl Chemistry

88

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, 4methyl-3-penten-2-one. Fig. 18.61

Organic Chemistry 2a

Carbonyl Chemistry

89

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

Organic Chemistry 2a

Carbonyl Chemistry

90

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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Carbonyl Chemistry

91

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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Carbonyl Chemistry

92

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

Organic Chemistry 2a

Carbonyl Chemistry

93

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

Organic Chemistry 2a

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94

18.3 Condensation Reactions of Carbonyl Compounds:The Aldol Condensation (pg 909)

Problem 18.16
Write mechanisms for the acid- and basecatalyzed reverse aldol condensation of diacetone alcohol (fig. 18.65)

Organic Chemistry 2a

Carbonyl Chemistry

95

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.

Organic Chemistry 2a

Carbonyl Chemistry

96

18.4 Reactions Related to The Aldol Condensation (pg 911) 18.4a Intramolecular Aldol Condensations

The mechanism

The mechanism for a base-catalyzed intramolecular aldol condensation. Fig. 18.68

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97

18.4 Reactions Related to The Aldol Condensation (pg 911) 18.4a Intramolecular Aldol Condensations

Examples

Work out a mechanism!

Fig. 18.68

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Carbonyl Chemistry

98

18.4 Reactions Related to The Aldol Condensation (pg 911) 18.4b Crossed Aldol Condensations

What is the problem with this synthesis?


A retrosynthetic analysis suggests that a condensation between diethyl ketone and acetone should give the -hydroxy ketone shown. Fig. 18.70

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Carbonyl Chemistry

99

18.4 Reactions Related to The Aldol Condensation (pg 911) 18.4b Crossed Aldol Condensations

A Mixture!!!

When this synthetic route is attempted, four -hydroxyketones, A, B, C and D are likely to be produced. Fig. 18.71

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Carbonyl Chemistry

100

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, C and D are likely to be produced. Fig. 18.71

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101

18.4 Reactions Related to The Aldol Condensation (pg 913) 18.4b Crossed Aldol Condensations

See next slide for enlarged scheme

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

Organic Chemistry 2a

Carbonyl Chemistry

102

Mistake in the book: in text the substrate is tert-butyl methyl ketone; in the scheme it is acetone.

Fig. 18.72 enlarged!

Organic Chemistry 2a

Carbonyl Chemistry

103

18.4 Reactions Related to The Aldol Condensation (pg 914) 18.4b Crossed Aldol Condensations

Why?
In fact, there is only major product in the aldol condensation of tert-butyl methyl ketone and benzaldehyde. Fig. 18.73

Organic Chemistry 2a

Carbonyl Chemistry

104

18.4 Reactions Related to The Aldol Condensation (pg 914) 18.4b Crossed Aldol Condensations

Why are additions to aldehydes generally more favorable than to ketones?

The carbonyl group of benzaldehyde is more reactive than that of tertbutyl methyl ketone, and equilibrium favors the product in the reaction with benzaldehyde, but not for the reaction with tert-butyl methyl ketone. Fig. 18.74

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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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18.4 Reactions Related to The Aldol Condensation (pg 914) 18.4b Crossed Aldol Condensations

How would you carry out this reaction to avoid any condensation of the ketone?
In fact, there is only major product in the aldol condensation of tert-butyl methyl ketone and benzaldehyde. Fig. 18.73

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18.4 Reactions Related to The Aldol Condensation (pg 914) 18.4b Crossed Aldol Condensations
1. Together in reaction flask and stir. No -hydrogens no enolization no condensation!

Problem 18.20

However!

There is a reaction between benzaldehyde and base (NaOH). What is it, and why does it not interfere with the aldol condensation?

In fact, there is only major product in the aldol condensation of tert-butyl methyl ketone and benzaldehyde. Fig. 18.73

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18.4 Reactions Related to The Aldol Condensation (pg 914) 18.4b Crossed Aldol Condensations
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
In fact, there is only major product in the aldol condensation of tert-butyl methyl ketone and benzaldehyde. Fig. 18.73

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18.4 Reactions Related to The Aldol Condensation (pg 914) 18.4b Crossed Aldol Condensations

Why is LDA such an excellent base for condendations and alkylations?


A crossed aldol condensation with LDA as base Fig. 18.75

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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= 15-25 for 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 intermediate chemoselectivity

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LDA is a very strong base (pKa= 36 for diisopropylamine) and therefore leads to an efficient formation of enolates (pKa= 15-25 for carbonyl compounds). Fig. 18.46

111

Preparation of LDA
See Amines; Fig. 21.31 + 21.32; page 1090

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LDA is a large, sterically encumbered base and removes a proton from the sterically less hindered position regioselectivity reaction occurs preferentially at one of the conceivable positions.

Regioselective depronation using LDA


See 18.7; Fig. 18.114; page 937

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LDA does not add to the carbonyl function as this leads to a highly crowded intermediate chemoselectivity reactions occurs preferentially at one of the conceivable reaction centers.

Addition of amines to carbonyl function


Sterically much more hindered than starting carbonyl compound! Does not occur with LDA!

See 16.9; Fig. 16.48; page 780

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18.4 Reactions Related to The Aldol Condensation (pg 916) 18.4c Knoevenagel Condensations and Related Reactions.

The Knoevenagel condensation (The general case) Fig. 18.76

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18.4 Reactions Related to The Aldol Condensation (pg 916) 18.4c Knoevenagel Condensations and Related Reactions.

The Knoevenagel condensation (Specific examples) Fig. 18.76

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Why are these bifunctional compounds so acidic?

18.4 Reactions Related to The Aldol Condensation (pg 915) 18.4c Knoevenagel Condensations and Related Reactions.
pKa O EtO NC O H3C O OEt CN O OEt 10,7 H 13,3 11 H3C O Ph O O H 5 O CH3 8,5 O O CH3 8,9 pKa

Diketones and similar compounds with strong carbanion stabilizing groups are in particular suitable for this reaction! Table 18.2

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18.4 Reactions Related to The Aldol Condensation (pg 915) 18.4c Knoevenagel Condensations and Related Reactions.
O O CH3 H + HOR (pKa 17) EtO H O O CH3 EtO H O O CH3

O EtO

O CH3 EtO

H H

pKa 10 OR doubly hydrogens

We will get back to this in Chapter 20 (20.10)


The removal of a doubly proton is an exothermic reaction. Figure 20.64

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18.4 Reactions Related to The Aldol Condensation (pg 917) 18.4c Knoevenagel Condensations and Related Reactions.

O + H3C CH3 NaOCH2CH3/C2H5OH

CH3 CH3

Not only acidic carbonyl compounds are suitable for this reaction!

Propose a mechanism for this condensation reaction.


A condendation reaction leading to fulvenes Fig. 18.77

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The answer:

18.4 Reactions Related to The Aldol Condensation (pg 917) 18.4c Knoevenagel Condensations and Related Reactions.

A condendation reaction leading to fulvenes Fig. 18.77

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18.4 Reactions Related to The Aldol Condensation (pg 917) 18.4c Knoevenagel Condensations and Related Reactions.

Any double bond is the formal result of a condensation reaction followed by dehydration Fig. 18.78

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18.4 Reactions Related to The Aldol Condensation (pg 917) 18.4c Knoevenagel Condensations and Related Reactions. Problem 18.22

Propose syntheses for the molecules in fig. 18.79.

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18.4 Reactions Related to The Aldol Condensation (pg 918) 18.4d More Related Condensations: The Michael 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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18.4 Reactions Related to The Aldol Condensation (pg 918) 18.4d More Related Condensations: The Michael 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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18.4 Reactions Related to The Aldol Condensation (pg 918) 18.4d More Related Condensations: The Michael Reaction

By contrast, additions to ,-unsaturated carbonyls are common. Notice the resonance stabilization of the resulting enolate anion. Fig. 18.81

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18.4 Reactions Related to The Aldol Condensation (pg 918) 18.4d More Related Condensations: The Michael Reaction

Two Michael additions Fig. 18.82

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18.4 Reactions Related to The Aldol Condensation (pg 918) 18.4d More Related Condensations: The Michael Reaction

Also Acid Catalyzed!!! What would be the mechanism?

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18.4 Reactions Related to The Aldol Condensation (pg 918) 18.4d More Related Condensations: The Michael Reaction

Two acid-catalyzed Michael reactions (the general case) Fig. 18.83

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18.4 Reactions Related to The Aldol Condensation (pg 919) 18.4d More Related Condensations: The Michael Reaction

Two acid-catalyzed Michael reactions (specific examples) Fig. 18.83

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18.4 Reactions Related to The Aldol Condensation (pg 921) 18.4d More Related Condensations: The Michael Reaction

The two possible reactions 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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18.4 Reactions Related to The Aldol Condensation (pg 921) 18.4d More Related Condensations: The Michael Reaction

Two irreversible addition reactions to the carbonyl group of an ,-unsaturated carbonyl compound. Fig. 18.85

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18.4 Reactions Related to The Aldol Condensation (pg 922) 18.4d More Related Condensations: The Michael Reaction

Cuprates (and often Grignard reagents) add in Michael fashion to ,-unsaturated carbonyl compounds. Fig. 18.86

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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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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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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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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