1. John E. McMurry http://www.cengage.com/chemistry/mcmurry Richard Morrison University of Georgia, Athens Chapter 14 Aldehydes and Ketones: Nucleophilic Additions Reactions

2. Aldehydes (RCHO) and Ketones (R 2 CO) are among the most widely occurring of all compounds Required by living organisms Pyridoxal phosphate (PLP) is common coenzyme Hydrocortisone is steroid hormone secreted by adrenal glands Solvents and starting materials in chemical industry 1.9 million tons of formaldehyde, H 2 C=O, produced each year for insulation materials and resins 1.5 million tons of acetone, ((CH 3 ) 2 C=O), produced each year for use as industrial solvent Aldehydes and Ketones

3. Aldehydes named by replacing terminal –e of corresponding alkane name with –al Parent chain must contain the –CHO group See Appendix A and Table A.2 for naming polyfunctional organic compounds containing an aldehyde – CHO carbon is numbered as C1 14.1 Naming Aldehydes and Ketones

4. Carbaldehyde suffix is used for cyclic aldehydes Naming Aldehydes and Ketones

6. Ketones named by replacing terminal –e of corresponding alkane name with –one Parent chain is longest chain containing ketone group Numbering begins at end of chain nearer the carbonyl carbon Naming Aldehydes and Ketones

7. Some common names accepted by IUPAC Naming Aldehydes and Ketones

8. If R-C=O is a substituent the name acyl (a-sil) group is used and name ending –yl is attached The prefix oxo- is used if ketone is not highest priority functional group and the carbonyl is considered a substituent on the parent chain See Appendix A and Table A.2 for naming polyfunctional organic compounds containing a ketone Naming Aldehydes and Ketones

9. What is the IUPAC name of the following compound? a. 3-methyl-3-phenylpropanol b. 3-phenylbutanal c. 3-phenyl-1-butanone d. 3-phenylbutanoic acid

10. What is the IUPAC name of the following compound? a. 4-phenylhexan-3-one b. 3-phenylhexan-4-one c. 1,2-diethyl-2-phenylethanal d. 1-methyl-1-phenylbutan-2-one

11. Aldehydes from oxidation of primary alcohols using the Dess- Martin periodinane reagent 14.2 Preparing Aldehydes and Ketones

12. Aldehydes from reduction of carboxylic esters using diisobutylaluminum hydride (DIBAH) Preparing Aldehydes and Ketones

13. Secondary alcohols are oxidized by variety of chromium-based reagents to give ketones Aryl ketones from Friedel-Crafts acylation reactions Preparing Aldehydes and Ketones

14. Ketones are also prepared from carboxylic acid derivatives Preparing Aldehydes and Ketones

15. Aldehydes easily oxidized to carboxylic acids but ketones are relatively inert toward oxidation –CHO hydrogen abstracted during oxidation CrO 3 most common oxidizing agent KMnO 4 and hot HNO 3 occasionally used 14.3 Oxidation of Aldehydes

16. Oxidation of aldehydes proceeds through intermediate 1,1-diols called hydrates Hydrates formed by reversible nucleophilic addition of water to carbonyl group (section 14.5) Oxidation of Aldehydes

17. Nucleophilic addition reaction :Nu – approaches C=O bond at 75° angle and adds to electrophilic C=O carbon Carbonyl carbon rehybridizes to sp 3 Electron pair moves from C=O bond to electronegative oxygen atom producing tetrahedral alkoxide ion intermediate Intermediate is protonated to give neutral alcohol product 14.4Nucleophilic Addition Reactions of Aldehydes and Ketones

18. Nucleophiles can be either negatively charged (:Nu - ) or neutral (:Nu) If neutral, the nucleophile usually carries a hydrogen atom that can be subsequently eliminated Nucleophilic Addition Reactions of Aldehydes and Ketones

19. Two products can arise from the tetrahedral alkoxide ion intermediate Protonation by water or acid gives an alcohol The carbonyl oxygen atom can be protonated and then eliminated as HO - or H 2 O to give a product with a C=Nu double bond Nucleophilic Addition Reactions of Aldehydes and Ketones

20. Aldehydes more reactive toward nucleophilic addition than ketones Aldehydes (a) are less sterically hindered than ketones (b) Nucleophilic Addition Reactions of Aldehydes and Ketones

21. Aldehydes are more reactive than ketones due to electronic factors C=O of aldehyde more polarized than C=O of ketone Nucleophilic Addition Reactions of Aldehydes and Ketones

22. Aromatic aldehydes are less reactive in nucleophilic addition reactions than aliphatic aldehydes because the electron- donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic Nucleophilic Addition Reactions of Aldehydes and Ketones

23. Aldehydes and ketones react reversibly with water to give 1,1- diols, or geminal (gem) diols Equilibrium favors carbonyl compound for steric reasons with the exception of formaldehyde 14.5Nucleophilic Addition of H 2 O: Hydration

24. Nucleophilic addition of water to aldehyde or ketone is slow under neutral conditions but catalyzed by both acid and base Base-catalyzed hydration mechanism Hydroxide ion is good nucleophile Nucleophilic Addition of H 2 O: Hydration

25. Acid-catalyzed mechanism Protonated carbonyl oxygen is a better electrophile Nucleophilic Addition of H 2 O: Hydration

26. In general, equilibrium favors the carbonyl-containing aldehyde or ketone reactant for nucleophiles such as H 2 O, CH 3 OH, HCl, HBr, or H 2 SO 4 Nucleophilic Addition of H 2 O: Hydration

27. Many nucleophilic addition reactions of aldehydes and ketones are catalyzed by acid or base. Bases catalyze hydration by: a.making the carbonyl group more electrophilic b.shifting the equilibrium of the reaction c.making the carbonyl group less electrophilic d.converting the water to hydroxide ion, a much better nucleophile

28. Grignard reagent reacts with aldehyde or ketone C=O to give tetrahedral magnesium alkoxide intermediate Intermediate is hydrolyzed to produce neutral alcohol Grignard reagent reacts like a carbon anion, or carbanion Reaction mechanism involves radicals but can be represented as proceeding through a nucleophilic addition of a carbanion to the C=O carbon 14.6Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation

29. Mechanism of Grignard Reaction Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation

30. In an analogous manner the reaction of aldehydes and ketones with hydride reagents may be represented as proceeding through a nucleophilic addition of a hydride ion (:H – ) to the C=O carbon LiAlH 4 and NaBH 4 act as if they are donors of hydride ion Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation

31. Primary amines, RNH 2, add to aldehydes and ketones to yield imines, R 2 C=NR Secondary amines, R 2 NH, add similarly to yield enamines, R 2 N-CR=CR 2 14.7Nucleophilic Addition of Amines: Imine and Enamine Formation

32. Imines are common biological intermediates where they are often called Schiff bases Nucleophilic Addition of Amines: Imine and Enamine Formation

33. Mechanism of imine formation Nucleophilic addition of primary amine to give carbinolamine tetrahedral intermediate Elimination of water to form new C=Nu bond Nucleophilic Addition of Amines: Imine and Enamine Formation

34. Mechanism of enamine formation: Nucleophilic addition of secondary amine to give carbinolamine tetrahedral intermediate Elimination of water yields iminium ion Loss of proton from  -carbon atom yields enamine Nucleophilic Addition of Amines: Imine and Enamine Formation

35. Imine and enamine formations reach maximum rate around pH = 4 to 5 Slow at pH > 5 because there is insufficient H + present in solution to protonate intermediate carbinolamine –OH to yield the better leaving group –OH 2 + Slow at pH < 4 because the basic amine nucleophile is protonated and initial nucleophilic addition cannot occur Nucleophilic Addition of Amines: Imine and Enamine Formation

36. Show the products you would obtain by acid-catalyzed reaction of pentan-3-one with methylamine, CH 3 NH 2, and with dimethylamine, (CH 3 ) 2 NH Worked Example 14.1 Predicting the Product of Reaction between a Ketone and an Amine

37. Strategy An aldehyde or ketone reacts with a primary amine, RNH 2, to yield an imine, in which the carbonyl oxygen atom has been replaced by the =N-R group of the amine Reaction of the same aldehyde or ketone with a secondary amine, R 2 NH, yields an enamine, in which the oxygen atom has been replaced by the –NR 2 group of the amine and the double bond has moved to a position between the former carbonyl carbon and the neighboring carbon Worked Example 14.1 Predicting the Product of Reaction between a Ketone and an Amine

39. Aldehydes and ketones react reversibly with two equivalents of an alcohol in the presence of an acid catalyst to yield acetals, R 2 C(OR′) 2, sometimes called ketals if derived from a ketone 14.8Nucleophilic Addition of Alcohols: Acetal Formation

40. Mechanism of acetal formation : Acetal formation is acid- catalyzed Reversible nucleophilic addition of alcohol to the carbonyl group yields a hemiacetal Hemiacetal is a hydroxy ether analogous to gem diol formed by water addition Acid catalyst protonates hydroxyl group forming better leaving group, –OH 2 + Nucleophilic Addition of Alcohols: Acetal Formation

41. Mechanism of acetal formation: Loss of –OH 2 + leads to an oxonium ion, R 2 C=OR + Nucleophilic addition of second alcohol gives protonated acetal Deprotonation of protonated acetal yields neutral acetal Nucleophilic Addition of Alcohols: Acetal Formation

42. One equivalent of diol such as ethylene glycol yields a cyclic acetal Cyclic acetals are protecting groups for aldehydes and ketones Nucleophilic Addition of Alcohols: Acetal Formation

43. Reduction of the ester group of ethyl 4-oxopentanoate is complicated by the presence of the ketone group Protection of the ketone group as a cyclic acetal allows the ester group to be selectively reduced Nucleophilic Addition of Alcohols: Acetal Formation

44. Acetal and hemiacetal groups are common in carbohydrate chemistry Glucose, a polyhydroxy aldehyde, undergoes intramolecular nucleophilic addition Exists primarily as a cyclic hemiacetal Nucleophilic Addition of Alcohols: Acetal Formation

45. Show the structure of the acetal you would obtain by acid-catalyzed reaction of pentan-2-one with propane-1,3-diol Worked Example 14.2 Predicting the Product of Reaction between a Ketone and an Alcohol

46. Strategy Acid-catalyzed reaction of an aldehyde or ketone with 2 equivalents of a monoalcohol or 1 equivalent of a diol yields an acetal, in which the carbonyl oxygen atom is replaced by two –OR groups from the alcohol Worked Example 14.2 Predicting the Product of Reaction between a Ketone and an Alcohol

47. Solution Worked Example 14.2 Predicting the Product of Reaction between a Ketone and an Alcohol

48. The substance formed on addition of water to an aldehyde or ketone is called a hydrate or a: a.vicinal diol b.geminal diol c.acetal d.ketal Ch. 14.5

49. Many nucleophilic addition reactions of aldehydes and ketones are catalyzed by acid or base. Bases catalyze hydration by: a.making the carbonyl group more electrophilic b.shifting the equilibrium of the reaction c.making the carbonyl group less electrophilic d.converting the water to hydroxide ion, a much better nucleophile Ch. 14.5

50. The reaction of an aldehyde with hydrogen cyanide is an example of ________ reaction. a.a nucleophilic substitution b.an electrophilic addition c.an electrophilic substitution d.a nucleophilic addition Ch. 14.4

51. The product of this reaction is called: a.an ylide b.an acetal c.a gem diol d.a hydrate Ch. 14.8

52. © 2006 Thomson Higher Education The Nucleophile in this reaction is: a. A b. B c. C d. D

53. © 2006 Thomson Higher Education The catalyst in this reaction is : a. A b. B c. C d. D

54. Choose the BEST reagent for carrying out each of the following conversions. A. LiAlH 4, THF B. NaBH 4, ethanol C. 1. DIBAH, toluene 2. H 3 O + D. All of the above work well

55. Wittig reaction Converts aldehydes and ketones into alkenes Phosphorus ylide, R 2 C–P(C 6 H 5 ) 3, adds to aldehyde or ketone to yield dipolar, alkoxide ion intermediate Ylide (pronounced ill-id) is a neutral, dipolar compound with adjacent positive and negative charges Also called a phosphorane and written in the resonance form R 2 C=P(C 6 H 5 ) 3 Dipolar intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph) 3 P=O Wittig reaction results in replacement of carbonyl oxygen with R 2 C= group of original phosphorane + 14.9Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

56. Wittig reaction mechanism Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

57. Phosphorus ylides are prepared by S N 2 reaction of primary and some secondary alkyl halides with triphenylphosphine, (Ph) 3 P, followed by treatment with base Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

58. Wittig reaction yields a single, pure alkene of defined structure Grignard reaction yields two products Most-substituted double bond is the major product Wittig reaction yields only one product Less-substituted double bond is the sole product Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

59. Wittig reactions used commercially to synthesize numerous pharmaceuticals Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

60. What carbonyl compound and what phosphorus ylide might you use to prepare 3-ethylpent-2-ene? Worked Example 14.3 Synthesizing an Alkene Using a Wittig Reaction

61. Strategy An aldehyde or ketone reacts with a phosphorus ylide to yield an alkene in which the oxygen atom of the carbonyl reactant is replaced by the =CR 2 of the ylide Preparation of the phosphorus ylide itself usually involves S N 2 reaction of a primary alkyl halide with triphenylphosphine, so the ylide is typically primary, RCH=P(Ph) 3 Disubstituted alkene carbon in product comes from carbonyl reactant, while the monosubstituted alkene carbon comes from the ylide Worked Example 14.3 Synthesizing an Alkene Using a Wittig Reaction

62. Solution Worked Example 14.3 Synthesizing an Alkene Using a Wittig Reaction

63. Choose the BEST reagent for carrying out each of the following conversions A. 1. PhMgBr, ether B. 1. PhCH 2 MgBr, ether 2. H 3 O + C. (C 6 H 5 ) 3 P=CHC 6 H 5, THF D. Li(C 6 H 5 ) 2 Cu, ether

64. Nucleophilic addition reactions are characteristic of aldehydes and ketones Tetrahedral intermediate produced by addition of nucleophile cannot expel a stable leaving group 14.10 Biological Reductions

65. Cannizzaro reaction is a nucleophilic acyl substitution reaction of aldehydes and ketones OH ¯ adds to aldehyde to give tetrahedral intermediate H: ¯ ion is transferred to a second aldehyde The aldehyde accepting the H: ¯ ion is reduced and the aldehyde transferring the H: ¯ is oxidized Biological Reductions

66. Cannizzaro reaction mechanism is analogous to biological reduction in living organisms by nicotinamide adenine dinucleotide, NADH NADH donates H: ¯ to aldehydes and ketones, similar to tetrahedral alkoxide intermediate in Cannizzaro reaction Biological Reductions

67. Choose the BEST reagent for carrying out each of the following conversions A. NaBH 4, ethanol, H 3 O + B. 1. LiAlH 4, ether 2. H 3 O + C. NaOH, H 2 O D. All of the above Ch. 14.10

68. Nucleophiles can add directly to carbonyl group of aldehydes and ketones, called 1,2-addition Nucleophiles can also add to conjugated C=C bond adjacent to carbonyl group of aldehydes and ketones, called conjugate addition or 1,4- addition Carbon atom adjacent to carbonyl carbon is the  carbon atom and the next one is the  carbon atom Initial product of conjugate addition is a resonance-stabilized enolate ion 14.11 Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

69. Comparison of direct and conjugate additions Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

70. Conjugate addition occurs because the nucleophile can add to either one of two electrophilic carbons of the ,  -unsaturated aldehyde or ketone Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

71. Conjugated double bond of ,  -unsaturated carbonyl is activated by carbonyl group of the aldehyde or ketone C=C double bond is not activated for addition in absence of carbonyl group Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

72. Primary and secondary amines add to ,  -unsaturated aldehydes and ketones to yield  -amino aldehydes and ketones Both 1,2- and 1,4-addition occur Additions are reversible More stable conjugate addition product accumulates Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

73. Related biological addition of water to an ,  -unsaturated carboxylic acid in citric acid cycle Cis-aconitate is converted to isocitrate Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

74. Conjugate addition of an alkyl or other organic group to an  - unsaturated ketone (but not aldehyde) is a useful 1,4- addition reaction Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

75. Conjugate addition of alkyl groups to an  -unsaturated ketone (not aldehyde) is accomplished with a lithium diorganocopper reagent, R 2 CuLi (Gilman reagent) Lithium diorganocopper reagent is prepared by reaction of 1 equivalent of copper(I) iodide and 2 equivalents of an organolithium reagent, RLi Organolithium reagent is prepared by reaction of lithium metal with an organohalide Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

76. Primary, secondary, and even tertiary alkyl groups undergo conjugate addition Alkynyl groups react poorly Grignard reagents and organolithium reagents normally give direct carbonyl addition to  -unsaturated ketones Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

77. Mechanism of conjugate addition is thought to involve nucleophilic addition of the diorganocopper anion, R 2 Cu- R 2 Cu- adds to the unsaturated ketone to give copper- containing intermediate R group is transferred from copper to carbon Subsequent elimination of a neutral copper species gives product Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

78. How might you use a conjugate addition reaction to prepare 2-methyl-3-propylcyclopentanone? Worked Example 14.4 Using a Conjugate Addition Reaction

79. Strategy A ketone with a substituent group in its  position might be prepared by a conjugate addition of that group to an  -unsaturated ketone Propyl substituent on the  carbon might be prepared from 2-methylcyclopenten-2-one by reaction with lithium dipropylcopper Worked Example 14.4 Using a Conjugate Addition Reaction

80. Solution Worked Example 14.4 Using a Conjugate Addition Reaction

81. This reaction is called a _________ reaction. a.conjugate addition. b.electrophilic addition. c.direct addition d.1,2-addition. Ch. 14.11

82. Choose the BEST reagent for carrying out each of the following conversions A. NaBH 4, ethanol B. 1. LiAlH 4, ether 2. H 3 O + C. HCHO, NaOH, H 2 O D. All of the above Ch. 14.10

83. C=O bond absorption in IR region from 1660 to 1770 cm -1 is diagnostic of the nature of the carbonyl group Aldehydes show two characteristic C-H absorptions in the range 2720 to 2820 cm -1 14.12 Spectroscopy of Aldehydes and Ketones

84. Spectroscopy of Aldehydes and Ketones

85. Aldehyde protons (RCHO) absorb near 10  in the 1 H NMR Aldehyde proton shows spin-spin coupling with protons on the neighboring carbon, with coupling constant J ≈ 3 Hz Hydrogens on carbon next to a carbonyl group are slightly deshielded and absorb near to 2.0 to 2.3  Spectroscopy of Aldehydes and Ketones

86. Carbonyl-group carbon atoms of aldehydes and ketones have characteristic 13 C NMR resonances in the range of 190 to 215  Spectroscopy of Aldehydes and Ketones

87. Aldehydes and ketones with (  carbon atoms undergo McLafferty rearrangement Aldehydes and ketones also fragment by  cleavage Spectroscopy of Aldehydes and Ketones