A Conceptual Approach To Molecular Understanding

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
Introduction
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
Introduction
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
Introduction
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!
Introduction
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!
Introduction
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!
Introduction
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.
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
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
Carbonyl Chemistry
10
One orbital picture of the simplest carbonyl compound, formaldehyde. Fig. 16.2
Carbonyl Chemistry
11
A comparison of the structures of formaldehyde, acetaldehyde and ethylene. Fig. 16.3
Carbonyl Chemistry
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
Carbonyl Chemistry
13
A resonance formulation of a carbonyl group. Note the polar resonance form. Fig. 16.6
Carbonyl Chemistry
16.2 Nomenclature of carbonyl compounds (pages 756-759)
14
Different substitution patterns for simple carbonyl compounds. Fig. 16.7 + 16.14
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
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
Carbonyl Chemistry
17
Acid-catalyzed hydration of a carbonyl compound Fig. 16.26
Carbonyl Chemistry
18
+ -
Base-catalyzed hydration of a carbonyl compound Fig. 16.27
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
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
Carbonyl Chemistry
21
General scheme for addition reactions to carbonyl compounds
Addition of nucleophiles to carbonyl compounds Fig. 18.1
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
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
Carbonyl Chemistry
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
Carbonyl Chemistry
Carbonyl Chemistry 2: Reactions at the -Position
25
Why?
Carbonyl Chemistry
26
There are three possible anions that can be formed from butyraldehyde through breaking an sp3-1s carbonhydrogen bond. Fig. 18.3
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
Carbonyl Chemistry
28
Loss of the -hydrogen leads to a resonance-stabilized enolate anion. Fig. 18.5
Carbonyl Chemistry
29
problem 18.1*
Write a mechanism for the base-catalyzed equilibration of the carbonyl and enol forms of acetone.
Carbonyl Chemistry
30
Stabilization by orbital overlap. Fig. 18.7
Carbonyl Chemistry
31
A comparison of the enolate and allyl anions Fig. 18.7
Carbonyl Chemistry
32
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
Carbonyl Chemistry
33
Problem 18.2* Propionaldehyde (propanal) can form two enols. What are they?
Carbonyl Chemistry
34
In D2O/DO-, the three -hydrogens of acetaldehyde are exchanged for deuterium. Fig. 18.9
Carbonyl Chemistry
35
Enolate formation is an equilibrium reaction, and is endothermic in the case of acetaldehyde. Fig. 18.10
Carbonyl Chemistry
36
The exchange reaction is a catalytic process, with deuteroxide ion (-OD) acting as the catalyst. Fig. 18.10
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 .
Carbonyl Chemistry
38
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
Carbonyl Chemistry
39
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
Carbonyl Chemistry
40
Removal of a proton from carbon generates the neutral enol form. Removal of a deuteron from oxygen regenerates starting material. Fig. 18.15
Carbonyl Chemistry
41
Reaction of the enol with D3O+ will generate exchanged acetaldehyde. Fig. 18.16
Carbonyl Chemistry
42
Where does the equilibrium between carbonyl compound and enol lie? Fig. 18.19
Carbonyl Chemistry
43
For simple aldehydes and ketones, it is the carbonyl form that is favored at equilibrium. Fig. 18.20
Carbonyl Chemistry
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
Carbonyl Chemistry
45
-Dicarbonyl compounds are more enolized than are monoketones Fig. 18.22
Carbonyl Chemistry
46
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
Carbonyl Chemistry
47
Why?
The equilibrium constant for enolization of cyclohexadienone is estimated to be greater than 1013. Fig. 18.24
Carbonyl Chemistry
48
Phenol is aromatic!
The equilibrium constant for enolization of cyclohexadienone is estimated to be greater than 1013. Fig. 18.24
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
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
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
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)
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
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
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
Carbonyl Chemistry
56
Why? Explain!
Treatment of a ketone containing an -hydrogen with iodine, bromine, or chlorine in acids leads to -halogenation Fig. 18.30
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
Carbonyl Chemistry
58
Under acidic conditions only monohalogenation.
Why?
Carbonyl Chemistry
59
Protonation of the -iodoketone is disfavored by the electronwithdrawing character of the halogen. Fig. 18.32
Carbonyl Chemistry
60
Under basic conditions only polyhalogenation.
Why?
Carbonyl Chemistry
61
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
Carbonyl Chemistry
62
All -hydrogens are replaced! Sequential enolate formations and iodinations lead to the , , -triiodo carbonyl compound. Fig. 18.34
Carbonyl Chemistry
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
Carbonyl Chemistry
64
The bond-making and bond-breaking requirements for this reaction Fig. 18.36
Carbonyl Chemistry
65
There is no precedent for this hypothetical SN2 displacement at an sp2 carbon. Fig. 18.37
Carbonyl Chemistry
66
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
Carbonyl Chemistry
67

The pKa of iodoform is about 14. Iodoform is a strong acid, and the loss of CI3- is a reasonable step. Fig. 18.39
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
Carbonyl Chemistry
69
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
Carbonyl Chemistry
70
In principle, alkylation of the enolate could take place at either carbon or oxygen. Fig. 18.42
Carbonyl Chemistry
71
In practice, alkylation generally takes place at carbon. Fig. 18.43
Carbonyl Chemistry
72
For many ketones there are at least two possible enolates, and therefore mixtures are obtained in the alkylation reaction. Fig. 18.44
Carbonyl Chemistry
73
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!
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
Carbonyl Chemistry
75
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
Carbonyl Chemistry
76
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
Carbonyl Chemistry
77
Protonation of these intermediates gives the hydrate, or, in the enolate case, a compound known as aldol, a -hydroxy aldehyde. Fig. 18.53
Carbonyl Chemistry
78
Knowing now the mechanism of the base-catalyzed aldol condensation, suggest a mechanism for its acid-catalyzed counterpart.
Carbonyl Chemistry
79
Under acidic conditions!
The acid-catalyzed aldol condensation begins with enol formation. Fig. 18.54
Carbonyl Chemistry
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
Carbonyl Chemistry
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)
Carbonyl Chemistry
82
Under acidic conditions!
The acid-catalyzed dehydration of aldol Fig. 18.57
Carbonyl Chemistry
83
The base-catalyzed elimination of water from aldol. The reaction mechanism is E1cB. Fig. 18.58
Carbonyl Chemistry
Chapter 18
84
What is the E1cB mechanism?

See Chapter 7 on Substitution and Elimination Reactions: The SN2, SN1, E2 and E1 Reactions. 7.13, page 288
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
Carbonyl Chemistry
86
Problem 18.14
What are the products of dehydration of the condensation products of Problem 18.13 ?
Carbonyl Chemistry
87
The base-catalyzed aldol condensationof acetone (as an example for the aldol condensation of ketones). Fig. 18.60
Carbonyl Chemistry
88
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
Carbonyl Chemistry
89
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
Carbonyl Chemistry
90
The operation of a Soxhlet extractor in the aldol condensation Fig. 18.63
Carbonyl Chemistry
91
The operation of a Soxhlet extractor in the aldol condensation Fig. 18.63
Carbonyl Chemistry
92
A retrosynthetic analysis for the product of an aldol condensation followed by hydration Fig. 18.64
Carbonyl Chemistry
93
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
Carbonyl Chemistry
94
Problem 18.16
Write mechanisms for the acid- and basecatalyzed reverse aldol condensation of diacetone alcohol (fig. 18.65)
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.
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
Carbonyl Chemistry
97
18.4 Reactions Related to The Aldol Condensation (pg 911) 18.4a Intramolecular Aldol Condensations
Examples
Work out a mechanism!
Fig. 18.68
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
Carbonyl Chemistry
99
A Mixture!!!
When this synthetic route is attempted, four -hydroxyketones, A, B, C and D are likely to be produced. Fig. 18.71
Carbonyl Chemistry
100
When this synthetic route is attempted, four -hydroxyketones, A, B, C and D are likely to be produced. Fig. 18.71
Carbonyl Chemistry
101
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
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!
Carbonyl Chemistry
103
Why?
In fact, there is only major product in the aldol condensation of tert-butyl methyl ketone and benzaldehyde. Fig. 18.73
Carbonyl Chemistry
104
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
Carbonyl Chemistry
105
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
Carbonyl Chemistry
106
How would you carry out this reaction to avoid any condensation of the ketone?
Carbonyl Chemistry
107
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?
Carbonyl Chemistry
108
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
Carbonyl Chemistry
109
Why is LDA such an excellent base for condendations and alkylations?

A crossed aldol condensation with LDA as base Fig. 18.75
Carbonyl Chemistry
110
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
Carbonyl Chemistry
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
Carbonyl Chemistry
112
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
Carbonyl Chemistry
113
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
Carbonyl Chemistry
114
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
Carbonyl Chemistry
115
The Knoevenagel condensation (Specific examples) Fig. 18.76
Carbonyl Chemistry
116
Why are these bifunctional compounds so acidic?
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
Carbonyl Chemistry
117
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
Carbonyl Chemistry
118
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
Carbonyl Chemistry
119
The answer:
A condendation reaction leading to fulvenes Fig. 18.77
Carbonyl Chemistry
120
Any double bond is the formal result of a condensation reaction followed by dehydration Fig. 18.78
Carbonyl Chemistry
121
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.
Carbonyl Chemistry
122
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
Carbonyl Chemistry
123
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
Carbonyl Chemistry
124
By contrast, additions to ,-unsaturated carbonyls are common. Notice the resonance stabilization of the resulting enolate anion. Fig. 18.81
Carbonyl Chemistry
125
Two Michael additions Fig. 18.82
Carbonyl Chemistry
126
Also Acid Catalyzed!!! What would be the mechanism?
Carbonyl Chemistry
127
Two acid-catalyzed Michael reactions (the general case) Fig. 18.83
Carbonyl Chemistry
128
Two acid-catalyzed Michael reactions (specific examples) Fig. 18.83
Carbonyl Chemistry
129
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
Carbonyl Chemistry
130
Two irreversible addition reactions to the carbonyl group of an ,-unsaturated carbonyl compound. Fig. 18.85
Carbonyl Chemistry
131
Cuprates (and often Grignard reagents) add in Michael fashion to ,-unsaturated carbonyl compounds. Fig. 18.86
Carbonyl Chemistry
132
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
Carbonyl Chemistry
133
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
Carbonyl Chemistry
134
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
Carbonyl Chemistry
135
Reactions of enolates and enols with various Lewis acids. Fig. 18.122
Carbonyl Chemistry
136
Reactions of enolates and enols with various Lewis acids. Fig. 18.122
Carbonyl Chemistry
137
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

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A Conceptual Approach To Molecular Understanding

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Organic Chemistry 2a

A Conceptual Approach to Molecular Understanding

knowledge of basic (first years) General and Organic Chemistry

Jones, Jr. Organic Chemistry First Edition, 1997

chapters 16,18,19,20 chapter 21

How to use the book?

Carbonyl Chemistry 1: Addition Reactions

Carbonyl Chemistry 2: Reactions at the -Position.

Carbonyl Chemistry 1: Addition Reactions

16.1 Structure of Carbon-Oxygen Bond (page 753)

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

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

Acid-catalyzed hydration of a carbonyl compound Fig. 16.26

Base-catalyzed hydration of a carbonyl compound Fig. 16.27

A dynamic example 16_99

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

General scheme for addition reactions to carbonyl compounds

Addition of nucleophiles to carbonyl compounds Fig. 18.1

16.17 Additional Problems(Page 812-813)

Carbonyl Chemistry 2: Reactions at the -Position

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

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

Stabilization by orbital overlap. Fig. 18.7

A comparison of the enolate and allyl anions Fig. 18.7

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

A dynamic example 18_129

Extended Knowledge of Carbonyl Compounds after 18.1

18.2 Reactions of Enols and Enolates

Starting from pure (S)!

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

Under acidic conditions only monohalogenation.

Under basic conditions only polyhalogenation.

What is the mechanisme of this reaction?

A dynamic example 18_31

18.2 Reactions of enols and enolates (page 895)

A dynamic example 18_132

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

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

More info on LDA later!

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

Under basic conditions!

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

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

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

A dynamic example 18_133

Under basic conditions!

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

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

Under acidic conditions!

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

Under acidic conditions!

The acid-catalyzed dehydration of aldol Fig. 18.57

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

Under basic conditions!

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

What is the E1cB mechanism?

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