Chapter 17: Carbonyl Compounds II Learning Objectives: 1. 2. 3. 4. 5. 6. 7. Recognize and assign names to aldehydes and ketones. 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. Be able to explain the relative reactivity of carbonyl compounds toward nucleophilic addition. Be able to describe the concept of employing protecting groups. Predict the products of the reactions of carbonyl compounds with Grignard reagents, hydride ion donors, sulfur nucleophiles, and with phosphonium ylides (the Wittig reaction). Be able to recognize Re and Si faces of carbonyl compounds, and the stereochemistry outcomes from a nucleophilic addition. Predict the products of addition reactions to -unsaturated carbonyl compounds. Sections: 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 17.10 17.11 17.12 17.13 17.14 17.15 17.16 17.17 17.18 Nomenclature of Aldehydes and Ketones Relative Reactivities of Carbonyl Compounds* How Aldehydes and Ketones React* Reaction of Carbonyl Compounds with Grignard Reagents* Reaction of Carbonyl Compounds with Acetylide Inos Reaction of Carbonyl Compounds with Hydride Ion* Reaction of Aldehydes and Ketones with Hydrogen Cyanide Reaction of Aldehydes and Ketones with Amines and Derivatives of Amines* Reaction of Aldehydes and Ketones with Water Reaction of Aldehydes and Ketones with Alcohol* Protecting Groups* Addition of Sulfur Nucleophiles The Wittig Reaction Forms an Alkene* Stereochemistry of Nucleophilic Addition Reactions: Re and Si Faces# Designing a Synthesis VI: Disconnections, Synthones, and Synthetic Equivalents Nucleophilic Addition to -Unsaturated Aldehydes and Ketones* Nucleophilic Addition to -Unsaturated Carboxylic Acid Derivatives Enzyme-catalyzed Additions to -Unsaturated Carbonyl Compounds# * Sections that will be focused # Sections that will be skipped Recommended additional problems 17.45 – 17.65, 17.67 – 17.70, 17.73 – 17.77, 17.79 – 17.82, 17.84 1 Class Note 17.1 Nomenclature of Aldehydes and Ketones O O H H O O H H O H H HO O H O H O Cl H OCH2CH3 O OCH2CH3 O CHO 2 O H H O O O O O O O O O O O CH3 3 17.2 Relative Reactivities of Carbonyl Compounds* Nucleophilic addition 17.3 How Aldehydes and Ketones React* A. In basic condition O O R H (R) Nu R H(R) tetrahedral intermediate Nu ( Z) 4 O H R Nu H(R) B. In acidic condition H B + B H O R O H (R) H R H (R) 5 O H R B H(R) 17.4 Reaction of Carbonyl Compounds with Grignard Reagents* 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 17.5 Reaction of Carbonyl Compounds with Acetylide Inos (i) pKa of R CH2 CH2 H R CH CH (ii) Mechanism 8 H R C C H 17.7 Reaction of Aldehydes and Ketones with Hydrogen Cyanide (i) pKa of H-CN (ii) Mechanism (iii) Synthesis of -hydroxy carboxylic acid 9 17.6 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 17.8 Reaction of Aldehydes and Ketones with Amines and Derivatives of Amines* 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 17.9 Reaction of Aldehydes and Ketones with Water A. Addition of water (formation of hydrate, gem-diol, geminal diol) O HO R OH H (R) R H2O (i) Consideration of pKa (ii) Stability consideration 17 H(R) 17.10 Reaction of Aldehydes and Ketones with Alcohol* A. Addition of alcohol (formation of hemiacetal, acetal, hemiketal, and ketal) O R'O R'O R OR' OH H R R H H HOR' (2 equivalents) H2O O R'O R'O R OR' OH R R R R R HOR' (2 equivalents) H2O 18 C. Mechanism 19 17.11 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 17.12 Addition of Sulfur Nucleophiles 17.13 The Wittig Reaction Forms an Alkene* A. Wittig reagents (C6H5)3P CH2 (C6H5)3P phosphonium ylide B. Formation of Wittig reagents 22 CH2 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 17.15 Designing a Synthesis VI: Disconnections, Synthones, and Synthetic Equivalents A. Retrosynthetic analysis Example OH synthesis of 26 OH from 17.16 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 2) H2O, H+ O H (vi) O 1) CH3MgBr 2) H2O, H+ 29 (vii) O 17.17 1) (CH3)2CuLi 2) H2O, H+ Nucleophilic Addition to -Unsaturated Carboxylic Acid Derivatives O Cl + HOCH3 O NHCH3 + O HOCH3 1) LiAlH4 2) H2O, H+ OCH3 O + NH3 (excess) Cl 30