Chapter 19: Carbonyl Compounds III
Learning Objectives:
1. Write the mechanism for keto-enol tautomerization and explain the consequence of such tautomerizarion in the optical chiral of compound. 2. Remember the approximate p Ka value for the α-hydrogen of a carbonyl group. 3. Provide appropriate bases for the formation of enolate and use such enolate for halogenation and alkylation. 4. Be able to write the general electron-pushing (arrow-pushing) mechanisms of Aldol reaction, Michael reaction, Claisen condensation, and Dieckmann condensation. 5. Be able to write the general electron-pushing (arrow-pushing) mechanisms for decarboxylation of 3-oxocarboxylic acids 6. Be able to employ the above-mentioned reaction for the formation of new carbon-carbon bond
Sections:
19.1 Acidity of α-hydrogens* 19.2 Keto-Enol Tautomerism* 19.3 How Enols and Enolate Ions React* 19.4 Halogenation of the α-Carbon of Aldehydes and Ketones* 19.5 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ) Reaction 19.6 α-Halogenated Carbonyl Compounds in Synthesis* 19.7 Using LDA to form an Enolate* 19.8 Alkylation of the α-Carbon of Carbonyl Compounds* 19.9 Alkylation and Acylation of the α-Carbon via an Enamine Intermediate 19.10 Alkylation of the β-Carbon: the Michael Reaction* 19.11 The Aldol Reaction* 19.12 Dehydration of Aldol Addition Products: Formation of α,β -Unsaturated Aldehydes and Ketones* 19.13 The Mixed Aldol Reaction 19.14 The Claisen Condensation* 19.15 The Mixed Claisen Condensation 19.16 Intramolecular Condensation and Addition Reactions* 19.17 Decarboxylation of 3-Oxocarboxylic Acids* 19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids 19.19 The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones 19.20 Designing a Synthesis VI: Making New Carbon-Carbon Bonds 19.21 Reactions at the α-carbon in Biological Systems #
* Sections that will be focused # Sections that will be skipped
Recommended additional problems
19.44 – 19.52, 19.54 – 19.64, 19.66 – 19.80
1 Class Note
19.1 Acidity of α-hydrogens
A. pKa of α-hydrogen of carbonyl derivatives
O O O O R' α R' R' R' NHR OR R H H H H H
O O O O O O
R' OR R' R R' H H H H
B. Resonance effect
2 19.2 Keto-Enol Tautomerism
O OH R' R R' R H
A. Mechanism in acidic condition
B. Mechanism in basic condition
3 19.3 How Enols and Enolate Ions React
A. Analysis of enols and enolates
4 19.4 Halogenation of the α-Carbon of Aldehydes and Ketones
A. Acid-catalyzed halogenation
O O X2 (Cl2, Br2, I2) + H3O CH3 CH2 X
5 B. Base-promoted halogenation
O X2 (Cl2, Br2, I2) O (excess) R HO- R CH2 CX2
C. Haloform reaction
O X2 (Cl2, Br2, I2) O (excess) HO- CH O 3 + CHX3
6 19.5 Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ) Reaction
1) PBr , Br O 3 2 O 2) H2O R R OH OH Br
7 19.6 α-Halogenated Carbonyl Compounds in Synthesis
A. Analysis of α-halogenated carbonyl Compounds
B. Examples
8 19.7 Using LDA to form an Enolate
N
lithium diisopropylamide (LDA)
19.8 Alkylation of the α-Carbon of Carbonyl Compounds
A. Analysis of the reaction
9 B. Examples
(i) 1) LDA, THF OCH3 2) CH3I
O
(ii) 1) LDA, THF 2) CH3CH2I CN
10 C. Potential problem in alkylation of the α-carbon of carbonyl compounds
O 1) LDA, THF CH3 2) CH3I
11 19.9 Alkylation and Acylation of the α-Carbon via an Enamine Intermediate
O N catalytic H+
+ N H2O H + pyrrolidine enamine
A. Examples 1) catalytic H+
O N H
2) CH3Br + 3) H2O, H
12 19.10 Alkylation of the β-Carbon: the Michael Reaction
A. Michael reaction
O O O - CH3O + CH CH 3 H3C 3
13 B. Examples
(i) O O O base (?)
+ H3CO OCH3
(ii) O O base (?) CN OCH CH + 2 3 H3C
14 C. Stork enamine reaction
O N HCl H2O + CH3
15 19.11 The Aldol Reaction
OH O O base R R H H R
A. Mechanism
16 19.12 Dehydration of Aldol Addition Products: Formation of α,β -Unsaturated Aldehydes and Ketones
B. Examples
(i) O O - H MeO + H MeOH
(ii) O EtO- Na+
EtOH
17 19.13 The Mixed Aldol Reaction
A. Potential problem in aldol reaction
(i) O EtO- Na+
EtOH
(ii) O O MeO- Na+ + MeOH H
18 B. Solution
(i) O O - + H MeO Na + H MeOH
19 19.14 The Claisen Condensation and 19.15 The Mixed Claisen Condensation
O O O base R R OR' + HOR' OR' R
A. Mechanism
20 B. Examples
(i) O base (?) OCH2CH3
(ii) O O base (?) OCH3 + OCH2CH3
21 19.16 Intramolecular Condensation and Addition Reactions
A. Intramolecular Claisen reaction (Dieckmann condensation)
(i) H3CO OCH3 MeO- Na+ MeOH O O
(ii) O
EtO- Na+ H3CH2CO OCH2CH3 EtOH
O
22 B. Intramolecular aldol reaction
(i) H3C CH3 MeO- Na+ MeOH O O
(ii) O
EtO- Na+ H3C CH3 EtOH
O
23 (iii) O
EtO- Na+ H3C H EtOH
O
(iv) Robinson annulation
O O + base H , heat + + H2O CH3 O
24 19.17 Decarboxylation of 3-Oxocarboxylic Acids
A. Easier in acidic condition: mechanism
O O O O
R OH R O
B. Examples of compounds containing 3-oxocarboxylic acid
O O O O
HO OH OH
R R
25 19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids and 19.19 The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones
O O O ? R H3CH2CO OCH2CH3 OH
26 A. Examples:
O O O
OH OH OH
27 19.20 Designing a Synthesis VI: Making New Carbon-Carbon Bonds
O O CO2H synthesis of from H3CO OCH3
28