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Chapter 19

Chapter 19. Aldehydes & Ketones Nucleophilic Addition Reactions. Aldehyde Nomenclature. Find the longest chain that contains the aldehyde. The suffix –al replaces the –e of the corresponding alkane. The carbonyl carbon receives the lowest number.

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Chapter 19

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  1. Chapter 19 Aldehydes & Ketones Nucleophilic Addition Reactions Farshid Zand

  2. Aldehyde Nomenclature • Find the longest chain that contains the aldehyde. • The suffix –al replaces the –e of the corresponding alkane. • The carbonyl carbon receives the lowest number. • Branches are named using the IUPAC system • Complex aldehydes (-CHO is attached to a ring) use the suffix: -carbaldehyde Farshid Zand

  3. Examples 2-Ethyl-4-methylpentanal Farshid Zand

  4. Common Names of Aldehydes Farshid Zand

  5. Ketone Nomenclature • Find the longest chain that contains the ketone (it MUST NOT BE at the end) • Use the base hydrocarbon name; drop the –e and replace with –one. • The carbonyl group has to be assigned the lowest possible number. • In complex molecules, the carbonyl group can be named as a prefix with the term oxo- Farshid Zand

  6. Refering as Subsituents • RCO- = Acyl • CH3CO- = Acetyl • -CHO = Formyl • C6H5CO- = Benzoyl In complex molecules, the carbonyl group can be named as a prefix with the term oxo- methyl 3-oxohexanoate Farshid Zand

  7. Ketone Nomenclature Examples 3-Hexanone 4-Hexen-2-one 2,4 Hexanedione Farshid Zand

  8. Common Names of Some Ketones Acetone Acetophenone Benzophenone Farshid Zand

  9. Synthesis of Aldehydes • Oxidation of 1˚ alcohols Farshid Zand

  10. Synthesis of Aldehydes • Oxidative cleavage of alkenes w/ O3, Zn, CH3COOH Farshid Zand

  11. Synthesis of Aldehydes • Partial reduction of certain carboxylic acid derivatives Farshid Zand

  12. Synthesis of Ketones • Oxidation of 2° alcohols w/ PCC and base Farshid Zand

  13. Synthesis of Ketones • Ozonolysis of alkenes, if one of the unsaturated carbon atoms is disubstituted. Farshid Zand

  14. Synthesis of Ketones • Friedel-Crafts acylation aryl ketones Farshid Zand

  15. Synthesis of Ketones • Hydration of terminal alkynes methyl ketones Farshid Zand

  16. Synthesis of Ketones continue… Farshid Zand

  17. Synthesis of Ketones • From certain carboxylic acid derivatives… using a Gilman reagent (R’2Cu-Li+) Farshid Zand

  18. Oxidation of Aldehydes and Ketones • aldehydes- readily oxidized to form carboxylic acids • Ketones-inert but can be with hot alkaline KMnO4 REASON: aldehydes have a –CHO proton that can be removed during oxidation; ketones don’t. • Oxidizing agents: KMnO4 HNO3 CrO3 in acidic conditions Tollens reagent (Ag2O) in aqueous ammonia Farshid Zand

  19. Aldehyde Oxidation • Occur through intermediate 1,1-diols, or hydrates. H2O An aldehyde A hydrate A carboxylic acid Farshid Zand

  20. Mechanism of Aldehyde Oxidation Farshid Zand

  21. Mechanism of Aldehyde Oxidation continue… Farshid Zand

  22. Ketone Oxidation • Inert to most oxidizing agents • Ketones undergo slow cleavage when treated with hot alkaline KMnO4 1. 2. Farshid Zand

  23. Nucleophilic Addition Rxns of Aldehydes and Ketones • Nucleophile attacks the electrophilic C=O carbon from a direction ~45˚ to the plane of the carbonyl group. • At the same time: Rehybridization of the carbonyl carbon from sp2 to sp3 occurs, an electron pair from the carbon-oxygen double bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced. Farshid Zand

  24. Attacking Nucleophiles • Can be negatively charged or neutral at the reaction site Negatively charged Nucleophiles • HO- (hydroxide ion) • H- (hydride ion) • R3C- (a carbanion) • RO- (an alkoxide ion) • CN- (cyanide ion) Neutral Nucleophiles • H2O (water) • ROH (an alcohol) • H3N (ammonia) • RNH2 (an amine) Farshid Zand

  25. Nucleophilic Addition Rxns of Aldehydes and Ketones • Formation of an alcohol Farshid Zand

  26. Nucleophilic Addition Rxns of Aldehydes and Ketones • Elimination of the carbonyl oxygen atom at HO- or H2O to give a product with C=Nu double bond. Farshid Zand

  27. Relative Reactivity of Aldehydes and Ketones • Reactivity in nucleophilic addition rxns Aldehydes >>> ketones aliphatic aldehydes >>>aromatic aldehydes Farshid Zand

  28. Steric Reason why Aldehydes are More Reactive than Ketones • nucleophile is able to approach aldehydes more readily because it only has 1 large substituent bonded to the C=O carbon, vs. 2 in ketones. • transition state for the aldehyde rxn is therefore less crowded and has lower energy. aldehydeketone Farshid Zand

  29. Electronic Reason why Aldehydes are More Reactive than Ketones • greater polarization of aldehyde carbonyl group • aldehyde is more electrophilic and more reactive than ketones. 2˚carbocation (more stable, less reactive) Ketone (more stabilization of ς+, less reactive) 1˚ carbocation (less stable, more reactive) Aldehyde (less stabilization of ς+, more reactive) ς- ς- ς+ ς+ Farshid Zand

  30. Why: aromatic aldehydes >>> aliphatic aldehydes • The electon-donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic than the carbonyl group of the aliphatic aldehyde. Farshid Zand

  31. Why: aromatic aldehydes >>> aliphatic aldehydes…example • Comparing electrostatic potential maps of formaldehyde and benzaldehyde, shows that the carbonyl carbon atom is less positive in the aromatic aldehyde formaldehydebenzaldehyde Farshid Zand

  32. Nucleophilic Addition of H2O: Hydration • Aldehydes and ketones react with water to yield a geminal diol. This hydration process is reversible. • Nucleophilic addition of water is catalyzed by acid and base. • Base-catalyzed • Acid-catalyzed Farshid Zand

  33. Nucleophilic Addition of HCN: Cyanohydrin Formation • Aldehydes and unhindered ketones react with HCN to yield cyanohydrins. This formation is reversible and base-catalyzed. • Cyanohydrins formation is unusual due to the addition of protic acid to a carbonyl group, but useful because of further chemistry. • Reduced with LiAlH4, yielding primary amine. • Hydrolyzed with hot aqueous acid, yielding carboxylic acid. Farshid Zand

  34. Nucleophilic Addition of Grignard & Hydride Reagents: Alcohol Formation • Grignard reagents R-MgX, strongly polarized reacts with an acid-base behavior. Nucleophilic addition of a carbanion to an aldehyde or ketone, followed by protonation of alkoxide intermediate, yields an alcohol. • Addition of hydride ion, from LiAlH4 or NaBH4, and water or aqueous acid yields an alcohol. Farshid Zand

  35. Nucleophilic Addition of Amines:Imine and Enamine Formation • Difference between imine and enamine is the C=N bond and C=C bond. Farshid Zand

  36. Nucleophilic Addition of Amines:Mechanism of 1º amines forming Imine Farshid Zand

  37. Nucleophilic Addition of Amines:Mechanism of 2º amines forming Enamine Farshid Zand

  38. Nucleophilic Addition of Hydrazine:Wolff-Kishner Reaction • Addition of hydrazine converts aldehyde/ketone to an alkane. An intermediate hydrazone forms, followed by base catalyzed double bond migration, loss of N2 gas, finally protonation yields an alkane. Farshid Zand

  39. Nucleophilic Addition of Alcohols: Acetal Formation • Acetals and Ketals are formed by reacting two equivalents of an alcohol with an aldehyde or ketone, in the presence of an acid catalyst. • Hemiacetals and Hemiketals are formed by reacting only one equivalent of alcohol with the aldehyde or ketone in the presence of an acid catalyst. Further reaction with a second alcohol forms the acetal or ketal. • A diol, with two –OH groups on the same molecule, can be used to form cyclic acetals. • All steps in acetal/ketal formation are reversible. Farshid Zand

  40. Acetal Ketal Hemiacetal Hemiketal Farshid Zand

  41. Mechanism of Acetal Formation: Farshid Zand

  42. Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction • Converts an aldehyde/ketone into an alkene. • A phosphorus ylide(aka phosphorane), , acts as the nucleophile to attack the carbonyl carbon and yields a four-membered ring, dipolar intermediate called the betaine. • The betaine decomposes spontaneously to yield an alkene and a triphenylphosphine oxide. • Can produce monosubstituted, disubstituted, and trisubstituted alkenes. Farshid Zand

  43. Mechanism of the Witting Reaction: Farshid Zand

  44. The Canizzaro Reaction • Requires two equivalents of an aldehyde and a heated aqueous base. • Produces a 1:1 mixture of carboxylic acid and alcohol. • Limited to aldehydes such as formaldehyde and benzaldehyde, which have no hydrogens on carbon next to carbonyl. • Results in simultaneous oxidation and reduction, disproportionation. • Steps: 1. Nucleophillic addition of OH- to first aldehyde forms a tetrahedral intermediate. 2. Tetrahedral intermediate then expels the hydride ion as a leaving group. 3. The second aldehyde picks up the hydride ion. 4. Oxidation of second product yields the acid while reduction of the first product yields an alcohol. Farshid Zand

  45. Mechanism of Cannizzaro Reaction: Farshid Zand

  46. Conjugate Nucleophilic Addition to alpha,beta-Unsaturated Aldehydes and Ketones • Direct addition (aka 1,2 addition) occurs when a nucleophile attacks the carbon in the carbonyl directly. • Conjugate addition (aka 1,4 addition) occurs when the nucleophile attacks the carbonyl indirectly by attacking the second carbon away from the carbonyl group, called the beta carbon, in an unsaturated aldehyde or ketone. • Conjugate addition reactions form an initial product called an enolate, which is protonated on the carbon next to the carbonyl, the alpha carbon, to give the final saturated aldehyde/ketone product. • Conjugate addition can be carried out with nucleophiles such as primary amines, secondary amines, and even alkyl groups like in organocopper reactions. • It is the carbonyl that activates the conjugated C=C double bond for addition which would otherwise not react. Farshid Zand

  47. Conjugate (1,4) addition mechanism: Farshid Zand

  48. Living organisms use nucleophilic addition reactions involving aldehydes and ketones in nature. Examples: -In Metabolism: Breakdown of alanine -In Defense: Secretion of poison by the millipede Some Biological Nucleophilic Addition Reactions Farshid Zand

  49. A Nucleophilic Addition Reaction: Metabolism • The human body uses the amino acid alanine to react with pyridoxal phosphate, an aldehyde, in a metabolic reaction to produce an imine. Farshid Zand

  50. A Nucleophilic Addition Reaction: Defense • Apheloria corrugata, a millipede, discharges poisonous HCN at attackers. • The millipede secretes the mandelonitrile molecule and another enzyme that breaks it down into benzaldeyde and HCN. Farshid Zand

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