Chapter 12 Nucleophilic Addition and Substitution at Carbonyl Groups

1. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Nucleophilic Addition to a Carbonyl Group • Nucleophilic Addition of Hydrogen to Carbonyl groups • Oxygen Nucleophiles • Nitrogen Nucleophiles • Nucleophilic Acyl Substitution of Carboxylic Acids and Derivatives • Derivatives of Sulfonic and Phosphoric Acids • Carbon Nucleophiles • Synthetic Applications • Spectroscopy

2. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Nucleophilic Addition to a Carbonyl Group • The Carbonyl Group • 3 Loci of Reactivity, Structure of C=O • Characteristics: bond length, hybridization, pKa, Dipole, Bond angle, resonance structures, molecular orbitals, physical properties, H-bonds • Possible Reactions of a Nucleophile with a Carbonyl Group • Nucleophilic Addition (with heteroatom or carbon nucleophile) • Nucleophilic Substitution (by heteroatom or carbon nucleophile) • Anions as Nucleophiles • Lewis base anions and neutral Lewis bases as Nucleophiles • Nucleophilicity • NH3 > H2O >HF (same row) • Iodide ion > Bromide > Chloride > Fluoride (same column)

3. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Group • Nucleophilic Addition of Hydrogen to Carbonyl groups • Complex Metal Hydride Reductions • LiAlH4, LiBH4 and NaBH4 • Aldehydes and Ketones reduced to primary and secondary R-OH • Esters reduced to R-CH2-OH • pri-, sec-, tert-Amides reduced to pri-, sec-, tert-amine • Thiol Ester reduced to mercaptan • Carboxylic Acid to primary Alcohol • Relative Reactivity of Carbonyl Compounds toward Hydride Reducing Agents • Aldehyde > Ketone > Thiol ester > Ester > Amide > Carboxylate • use NaBH4 with Aldehyde and Ketone, LiAlH4 on all above

4. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Oxygen Nucleophiles • Addition of Water; Hydrate Formation • Base Catalyzed (2 steps: addition, followed by protonation) • Acid Catalyzed (3 steps: protonation, addition, deprotonation) • Generalized for oxygen and nitrogen nucleophiles • Equilibrium of carbonyls and hydrates • Addition of Hydroxide Ion: The Cannizzaro Reaction and Hydride Transfer • Aromatic aldehydes and aldehydes lacking alpha hydrogen • Addition of Alcohols • Aldehydes form hemiacetals and acetals • Ketones form hemiketals and ketals • Acetals and Ketals as protecting groups

5. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Nitrogen Nucleophiles • Amines • Primary amines and carbonyls form Imines (also called Schiff base) • examples include, hydrazones, phenylhydrazones, 2,4-dinitrophenylhydrazones, semicarbazones, tosylhydrazones, oximes • Secondary amines and carbonyls form Enamines • mechanism involves an immonium ion (also called iminium ion) lacking a hydrogen on the nitrogen atom • Other Nitrogen Nucleophiles • Formation of derivatives shown under primary amines above • used for identification of ketone or aldehyde

6. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Nucleophilic Acyl Substitution of Carboxylic Acids and Derivatives • Relative Stability of Carboxylic Acid Derivatives • General RCO-X converted to RCO-Y • Reactivity acid chloride > thiol ester = anhydride > ester > carboxylic acid > amide > carboxylate anion • Interconverison of Carboxylic Acid Derivatives • Thiol Esters acid catalyzed hydrolysis to Acid (by Base to RCO2 ion) • Ester acid catalyzed hydrolysis to Acid (reverse reaction in ROH) • Transesterification • Amides hydrolyzed to Acid • Carboxylic Acid Chlorides • Preparation from thionyl chloride • with H2O forms acid, with ROH forms ester, with amine forms amide, with LiAlH4 forms alcohol • Reactions of Acid Anhydrides • Hydrolysis of Nitriles to Carboxylic Acids

7. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Derivatives of Sulfonic and Phosphoric Acids • Sulfonic Acid Derivatives • Formation of sulfonyl chloride (RSO2Cl) • Nucleophilic substitution with alcohols to form tosylates • Nucleophilic SN2 displacement of tosylates • Relative Rates of Displacement of various Leaving Groups • Nucleophilic substitution with amines to form sulfonamides • Phosphoric Acid Derivatives • Similar reactions as sulfonic acid derivatives

8. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Carbon Nucleophiles • Cyanide Ion • Cyanohydrin formation • Strecker synthesis to form -amino acids • Grignard Reagents • with Ketones to form 3 alcohols • with Esters to form 3 alcohols • with carbon dioxide to form carboxylic acid • Organolithium Reagents • with formaldehyde, aldehydes, ketones to 1 , 2 , 3 alcohol, respectively • The Wittig Reaction • ylide formation from Ph3P, alkyl halide and Base • ylide and carbonyl reaction to form alkenes

9. Chapter 12Nucleophilic Addition and Substitution at Carbonyl Groups • Synthetic Applications • Review Table 12.2 p 643ff • Using Nucleophilic Additions and Substitutions (and Related Reactions) to Make Various Functional Groups • Spectroscopy • Review of Reactions • Summary

10. Chapter 12 Summary • Nucleophilic Substitution and Addition to C=O • Order of Reactivity towards Nucleophiles is aldehydes > ketones > esters > amides > carboxylate anions • Addition takes place if a poor leaving group is bonded to C=O, as in aldehydes and ketones • Substitution takes place if a good leaving group is bonded to C=O, as in acid chlorides, anhydrides, esters, amides and nitrides • Nucelophile reactivity C > N > O • Leaving group stability O > N > C

11. Chapter 12 Summary • Addition of water to C=O occurs rapidly, reversibly with acid or base catalysis • Addition of alcohols yields ketals or acetals • Nitrogen nucleophiles add to C=O to from imines from primary alcohols and enamines from secondary amines • Hydrazine or substitutes derivatives form hydrazones • Carboxylic acids derivatives interconverted by Nucleophilic acyl substitution • Reactivity acid chloride > thiol ester = anhydride > ester > carboxylic acid > amide > carboxylate anion • Carbon nucleophiles: nitriles, Grignard, organolithium and wittig reactions