1 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 α,β-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 α,β-Unsaturated Aldehydes and Ketones* 18.14 Nucleophilic Addition to α,β-Unsaturated Carboxylic Acid Derivatives 18.15 Enzyme-catalyzed Additions to α,β-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, 8.742 Class Note 18.1 Nomenclature OHOHOHOHH HO OOHOHHO H OCH2CH3O OOCH2CH3CHO OCl3 HOOHO O OO OO OCH3OO4 18.2 Relative Reactivities of Carbonyl Compounds Nucleophilic addition 18.3 How Aldehydes and Ketones React A. In basic condition R H (R)OR H(R)O NuNu ( Z)tetrahedral intermediateR H(R)O NuH5 B. In acidic condition H BB+H R H (R)OR H(R)O BHR H (R)OH6 18.4 Reaction of Carbonyl Compounds with Carbon Nucleophiles A. Carbon nucleophile (basic or acidic?) B. Reaction of aldehydes and ketones with Grignard reagent7 C. Reactions of ester and carboxylic acid with Grignard reagent8 D. Reactions of aldehydes and ketones with acetylide ions (i) pKa of CH2CH2HRCH CH HR C C HR (ii) Mechanism9 E. Reactions of aldehydes and ketones with hydrogen cyanide (i) pKa of H-CN (ii) Mechanism (iii) Synthesis of α-hydroxy carboxylic acid10 18.5 Reaction of Carbonyl Compounds with Hydride Ion A. Source of hydride B. Reduction of aldehydes and ketones11 C. Reduction of esters12 D. Reduction of carboxylic acids13 E. Reduction of amides14 18.6 Reaction of Aldehydes and Ketones with Nitrogen Nucleophiles A. pKa of amines B. Addition of primary amines15 C. Addition of secondary amines D. Addition of hydrazine, hydroxyamine16 E. Mechanism of Wolff-Kishner reduction17 18.7 Reaction of Aldehydes and Ketones with Oxygen Nucleophiles A. Addition of water (formation of hydrate, gem-diol, geminal diol) R H (R)OR H(R)HO OHH2O (i) Consideration of pKa (ii) Stability consideration18 B. Addition of alcohol (formation of hemiacetal, acetal, hemiketal, and ketal) R HOR HR'O OR'HOR'R HR'O OH(2 equivalents)H2O R ROR RR'O OR'HOR'R RR'O OH(2 equivalents)H2O19 C. Mechanism20 18.8 Protecting Groups A. Stability of acetals and ketals B. Example OHOCH2CH2OH+OO+H2O (i) OOCH3O?OOH21 C. More examples (i) NH2?NH2NO2 (ii) NH2?NH2CO2H22 18.9 Addition of Sulfur Nucleophiles 18.10 The Wittig Reaction A. Wittig reagents (C6H5)3P CH2phosphonium ylide(C6H5)3P CH2 B. Formation of Wittig reagents23 C. Reactions (i) Synthesis of (ii) Synthesis of24 D. Stereoselectivity (E vs. Z) E. Arbuzov (Perkow) reaction and Horner-Emmons reaction (i) Horner-Emmons reaction25 (ii) Arbuzov (Perkow) reaction26 18.12 Designing a Synthesis V: Disconnections, Synthones, and Synthetic Equivalents A. Retrosynthetic analysis Example OHOHsynthesis offrom27 18.13 Nucleophilic Addition to α,β-Unsaturated Aldehydes and Ketones A. Analysis of α,β-unsaturated aldehydes and ketones ROαβ B. Direct addition (1,2-addition) and conjugate addition (1,4-addition)28 C. Examples (i) O1) CN2) HCl (ii) O+HSCH3 (iii) CH3O+(CH3)2NH29 (iv) O1) NaBH4, CeCl32) H2O, H+ (v) HO1) CH3MgBr2) H2O, H+ (vi) O1) CH3MgBr2) H2O, H+30 (vii) 1) (CH3)2CuLi2) H2O, H+O 18.14 Nucleophilic Addition to α,β-Unsaturated Carboxylic Acid Derivatives ClOHOCH3+ NHCH3OHOCH3+ OCH3O1) LiAlH42) H2O, H+ ClONH3