Chapter 18: Carbonyl Compounds II
Learning Objectives:
1. Recognize and assign names to aldehydes and ketones. 2. Write the mechanism for nucleophilic addition and nucleophilic addition-elimination reactions of aldehydes and ketones, and be able to predict the products of such reactions. 3. Be able to explain the relative reactivity of carbonyl compounds toward nucleophilic addition. 4. Be able to describe the concept of employing protecting groups. 5. Predict the products of the reactions of carbonyl compounds with Grignard reagents, hydride ion donors, sulfur nucleophiles, and with phosphonium ylides (the Wittig reaction). 6. Be able to recognize Re and Si faces of carbonyl compounds, and the stereochemistry outcomes from a nucleophilic addition. 7. Predict the products of addition reactions to -unsaturated carbonyl compounds.
Sections:
18.1 Nomenclature 18.2 Relative Reactivities of Carbonyl Compounds* 18.3 How Aldehydes and Ketones React* 18.4 Reaction of Carbonyl Compounds with Carbon Nucleophiles* 18.5 Reaction of Carbonyl Compounds with Hydride Ion* 18.6 Reaction of Aldehydes and Ketones with Nitrogen Nucleophiles* 18.7 Reaction of Aldehydes and Ketones with Oxygen Nucleophiles* 18.8 Protecting Groups* 18.9 Addition of Sulfur Nucleophiles 18.10 The Wittig Reaction* 18.11 Stereochemistry of Nucleophilic Addition Reactions: Re and Si Faces# 18.12 Designing a Synthesis V: Disconnections, Synthones, and Synthetic Equivalents 18.13 Nucleophilic Addition to -Unsaturated Aldehydes and Ketones* 18.14 Nucleophilic Addition to -Unsaturated Carboxylic Acid Derivatives 18.15 Enzyme-catalyzed Additions to -Unsaturated Carbonyl Compounds#
* Sections that will be focused # Sections that will be skipped
Recommended additional problems
8.40 – 8.55, 8.58 – 8.61, 8.63 – 8.67, 8.69 – 8.72, 8.74
1 Class Note
18.1 Nomenclature
O O O O
H H H H
O
H H HO O H
O O H
Cl
H OCH2CH3 OCH2CH3
O O CHO O
2 H H
O O O O
O O O O
O O O
CH3
3 18.2 Relative Reactivities of Carbonyl Compounds
Nucleophilic addition
18.3 How Aldehydes and Ketones React
A. In basic condition
O O Nu H O Nu
R H (R) R H(R) R H(R)
tetrahedral intermediate Nu ( Z)
4 B. In acidic condition
H B B + H
H O O H O B
R H(R) R H (R) R H (R)
5 18.4 Reaction of Carbonyl Compounds with Carbon Nucleophiles
A. Carbon nucleophile (basic or acidic?)
B. Reaction of aldehydes and ketones with Grignard reagent
6 C. Reactions of ester and carboxylic acid with Grignard reagent
7 D. Reactions of aldehydes and ketones with acetylide ions
(i) pKa of
R CH2 CH2 H R CH CH H R C C H
(ii) Mechanism
8 E. Reactions of aldehydes and ketones with hydrogen cyanide
(i) pKa of H-CN
(ii) Mechanism
(iii) Synthesis of -hydroxy carboxylic acid
9 18.5 Reaction of Carbonyl Compounds with Hydride Ion
A. Source of hydride
B. Reduction of aldehydes and ketones
10 C. Reduction of esters
11 D. Reduction of carboxylic acids
12 E. Reduction of amides
13 18.6 Reaction of Aldehydes and Ketones with Nitrogen Nucleophiles
A. pKa of amines
B. Addition of primary amines
14 C. Addition of secondary amines
D. Addition of hydrazine, hydroxyamine
15 E. Mechanism of Wolff-Kishner reduction
16 18.7 Reaction of Aldehydes and Ketones with Oxygen Nucleophiles
A. Addition of water (formation of hydrate, gem-diol, geminal diol)
O
HO OH R H (R)
R H(R)
H2O
(i) Consideration of pKa
(ii) Stability consideration
17 B. Addition of alcohol (formation of hemiacetal, acetal, hemiketal, and ketal)
O R'O OR' R'O OH R H R H R H
HOR' H2O (2 equivalents)
O R'O OR' R'O OH R R R R R R
HOR' H2O (2 equivalents)
18 C. Mechanism
19 18.8 Protecting Groups
A. Stability of acetals and ketals
B. Example
O O O
+ HOCH2CH2OH + H2O
(i)
O O O ?
OCH3 OH
20 C. More examples
(i) NH2 NH2 ?
NO2
(ii)
NH2 NH2 ?
CO2H
21 18.9 Addition of Sulfur Nucleophiles
18.10 The Wittig Reaction
A. Wittig reagents
(C6H5)3P CH2 (C6H5)3P CH2 phosphonium ylide
B. Formation of Wittig reagents
22 C. Reactions
(i) Synthesis of
(ii) Synthesis of
23 D. Stereoselectivity (E vs. Z)
E. Arbuzov (Perkow) reaction and Horner-Emmons reaction
(i) Horner-Emmons reaction
24 (ii) Arbuzov (Perkow) reaction
25 18.12 Designing a Synthesis V: Disconnections, Synthones, and Synthetic Equivalents
A. Retrosynthetic analysis
Example OH OH synthesis of from
26 18.13 Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
A. Analysis of -unsaturated aldehydes and ketones
O
R
B. Direct addition (1,2-addition) and conjugate addition (1,4-addition)
27 C. Examples
(i) O 1) CN 2) HCl
(ii) O
+ HSCH3
(iii) O
+ (CH3)2NH CH3
28 (iv) O 1) NaBH4, CeCl3 + 2) H2O, H
(v) 1) CH3MgBr O + 2) H2O, H
H
(vi) O 1) CH3MgBr + 2) H2O, H
29 (vii) O 1) (CH3)2CuLi + 2) H2O, H
18.14 Nucleophilic Addition to -Unsaturated Carboxylic Acid Derivatives
O
Cl + HOCH3
O
NHCH3 + HOCH3
O 1) LiAlH4 + 2) H2O, H
OCH3
O
+ NH3 (excess) Cl
30