1. Dr. Wolf's CHM 201 & 202 17- 1 Chapter 17 Aldehydes and Ketones. Nucleophilic Addition to the Carbonyl Group

2. Dr. Wolf's CHM 201 & 202 17- 2 NomenclatureNomenclature

3. Dr. Wolf's CHM 201 & 202 17- 3 IUPAC Nomenclature of Aldehydes HOOH OHCCHCHO Base the name on the chain that contains the carbonyl group and replace the -e ending of the hydrocarbon by -al.

4. Dr. Wolf's CHM 201 & 202 17- 4 4,4-dimethylpentanal 5-hexenal IUPAC Nomenclature of Aldehydes HOOH OHCCHCHO 2-phenylpropanedial (keep the -e ending before -dial)

5. Dr. Wolf's CHM 201 & 202 17- 5 when named as a substituent formyl group carbaldehyde or carboxaldehyde when named as a suffix C HO IUPAC Nomenclature of Aldehydes

6. Dr. Wolf's CHM 201 & 202 17- 6 CH 3 CH 2 CCH 2 CH 2 CH 3 O CH 3 CHCH 2 CCH 3 O CH 3 H3CH3CH3CH3C O Base the name on the chain that contains the carbonyl group and replace -e by -one. Number the chain in the direction that gives the lowest number to the carbonyl carbon. Substitutive IUPAC Nomenclature of Ketones

7. Dr. Wolf's CHM 201 & 202 17- 7 Substitutive IUPAC Nomenclature of Ketones CH 3 CH 2 CCH 2 CH 2 CH 3 O CH 3 CHCH 2 CCH 3 O CH 3 H3CH3CH3CH3C O 3-hexanone 4-methyl-2-pentanone 4-methylcyclohexanone

8. Dr. Wolf's CHM 201 & 202 17- 8 Functional Class IUPAC Nomenclature of Ketones CH 3 CH 2 CCH 2 CH 2 CH 3 OO CH 2 CCH 2 CH 3 CH CH 2 O H2CH2CH2CH2C CHC List the groups attached to the carbonyl separately in alphabetical order, and add the word ketone.

9. Dr. Wolf's CHM 201 & 202 17- 9 CH 3 CH 2 CCH 2 CH 2 CH 3 O ethyl propyl ketone benzyl ethyl ketone divinyl ketone O CH 2 CCH 2 CH 3 CH CH 2 O H2CH2CH2CH2C CHC Functional Class IUPAC Nomenclature of Ketones

10. Dr. Wolf's CHM 201 & 202 17- 10 Structure and Bonding: The Carbonyl Group

11. Dr. Wolf's CHM 201 & 202 17- 11 planar bond angles: close to 120° C=O bond distance: 122 pm Structure of Formaldehyde

12. Dr. Wolf's CHM 201 & 202 17- 12 1-butene propanal The Carbonyl Group O dipole moment = 0.3D dipole moment = 2.5D very polar double bond

13. Dr. Wolf's CHM 201 & 202 17- 13 2475 kJ/mol 2442 kJ/mol Alkyl groups stabilize carbonyl groups the same way they stabilize carbon-carbon double bonds, carbocations, and free radicals. heat of combustion Carbonyl group of a ketone is more stable than that of an aldehyde O OH

14. Dr. Wolf's CHM 201 & 202 17- 14 Heats of combustion of C 4 H 8 isomeric alkenes CH 3 CH 2 CH=CH 2 2717 kJ/mol cis-CH 3 CH=CHCH 3 2710 kJ/mol trans-CH 3 CH=CHCH 3 2707 kJ/mol (CH 3 ) 2 C=CH 2 2700 kJ/mol 2475 kJ/mol 2442 kJ/mol O OH Spread is greater for aldehydes and ketones than for alkenes

15. Dr. Wolf's CHM 201 & 202 17- 15 nucleophiles attack carbon; electrophiles attack oxygen Resonance Description of Carbonyl Group C O C O +–

16. Dr. Wolf's CHM 201 & 202 17- 16 Carbon and oxygen are sp 2 hybridized Bonding in Formaldehyde

17. Dr. Wolf's CHM 201 & 202 17- 17 The half-filled p orbitals on carbon and oxygen overlap to form a  bond Bonding in Formaldehyde

18. Dr. Wolf's CHM 201 & 202 17- 18 Physical Properties

19. Dr. Wolf's CHM 201 & 202 17- 19 boiling point –6°C 49°C 97°C Aldehydes and ketones have higher boiling than alkenes, but lower boiling points than alcohols. More polar than alkenes, but cannot form intermolecular hydrogen bonds to other carbonyl groups O OH

20. Dr. Wolf's CHM 201 & 202 17- 20 Sources of Aldehydes and Ketones

21. Dr. Wolf's CHM 201 & 202 17- 21 2-heptanone (component of alarm pheromone of bees) O Many aldehydes and ketones occur naturally

22. Dr. Wolf's CHM 201 & 202 17- 22 trans-2-hexenal (alarm pheromone of myrmicine ant) Many aldehydes and ketones occur naturally O H

23. Dr. Wolf's CHM 201 & 202 17- 23 citral (from lemon grass oil) Many aldehydes and ketones occur naturally O H

24. Dr. Wolf's CHM 201 & 202 17- 24 from alkenes ozonolysis from alkynes hydration (via enol) from arenes Friedel-Crafts acylation from alcohols oxidation Synthesis of Aldehydes and Ketones A number of reactions already studied provide efficient synthetic routes to aldehydes and ketones.

25. Dr. Wolf's CHM 201 & 202 17- 25 COR OH aldehydes from carboxylic acids RCH 2 OH 1. LiAlH 4 2. H 2 O PDC, CH 2 Cl 2 H COR What about..?

26. Dr. Wolf's CHM 201 & 202 17- 26 benzaldehyde from benzoic acid COHO CHO 1. LiAlH 4 2. H 2 O PDC CH 2 Cl 2 CH 2 OH (81%) (83%) ExampleExample

27. Dr. Wolf's CHM 201 & 202 17- 27 COR H ketones from aldehydes R' COR PDC, CH 2 Cl 2 1. R'MgX 2. H 3 O + RCHR' OH What about..?

28. Dr. Wolf's CHM 201 & 202 17- 28 C O CH 3 CH 2 H 3-heptanone from propanal H 2 CrO 4 1. CH 3 (CH 2 ) 3 MgX 2. H 3 O + CH 3 CH 2 CH(CH 2 ) 3 CH 3 OH O CH 3 CH 2 C(CH 2 ) 3 CH 3 (57%) ExampleExample

29. Dr. Wolf's CHM 201 & 202 17- 29 Reactions of Aldehydes and Ketones: A Review and a Preview

30. Dr. Wolf's CHM 201 & 202 17- 30 Already covered in earlier chapters: reduction of C=O to CH 2 Clemmensen reduction Wolff-Kishner reduction reduction of C=O to CHOH addition of Grignard and organolithium reagents Reactions of Aldehydes and Ketones

31. Dr. Wolf's CHM 201 & 202 17- 31 Principles of Nucleophilic Addition to Carbonyl Groups: Hydration of Aldehydes and Ketones

32. Dr. Wolf's CHM 201 & 202 17- 32 H2OH2OH2OH2O Hydration of Aldehydes and Ketones C O HO C O H

33. Dr. Wolf's CHM 201 & 202 17- 33 compared to H electronic: alkyl groups stabilize reactants steric: alkyl groups crowd product OHOH R R' + H2OH2OH2OH2O C C R R' O Substituent Effects on Hydration Equilibria

34. Dr. Wolf's CHM 201 & 202 17- 34 C=OhydrateK%Relative rate CH 2 =OCH 2 (OH) 2 2300>99.92200 CH 3 CH=OCH 3 CH(OH) 2 1.0501.0 (CH 3 ) 3 CCH=O(CH 3 ) 3 CCH(OH) 2 0.2170.09 (CH 3 ) 2 C=O(CH 3 ) 2 C(OH) 2 0.00140.140.0018 Equilibrium Constants and Relative Rates of Hydration

35. Dr. Wolf's CHM 201 & 202 17- 35 when carbonyl group is destabilized alkyl groups stabilize C=O electron-withdrawing groups destabilize C=O When does equilibrium favor hydrate?

36. Dr. Wolf's CHM 201 & 202 17- 36 OH OH R R + H2OH2OH2OH2O C C R RO Substituent Effects on Hydration Equilibria R = CH 3 : K = 0.000025 R = CF 3 : K = 22,000

37. Dr. Wolf's CHM 201 & 202 17- 37 Mechanism of Hydration (base) C O O H – Step 1: + HO C O –

38. Dr. Wolf's CHM 201 & 202 17- 38 Mechanism of Hydration (base) Step 2: O HH HO C O – + O H – HO C OHOHOHOH

39. Dr. Wolf's CHM 201 & 202 17- 39 Mechanism of Hydration (acid) C O Step 1: + HOH H + + C OHOHOHOH + H O H

40. Dr. Wolf's CHM 201 & 202 17- 40 Mechanism of Hydration (acid) Step 2: C OHOHOHOH + + HO H C OHOHOHOH HO H +

41. Dr. Wolf's CHM 201 & 202 17- 41 Mechanism of Hydration (acid) Step 3: + HO H C OHOHOHOH H OH O H C OHOHOHOH + H H OH +

42. Dr. Wolf's CHM 201 & 202 17- 42 Cyanohydrin Formation

43. Dr. Wolf's CHM 201 & 202 17- 43 + Cyanohydrin Formation CO HCN H C O NC

44. Dr. Wolf's CHM 201 & 202 17- 44 Cyanohydrin Formation CO C–N

45. Dr. Wolf's CHM 201 & 202 17- 45 Cyanohydrin Formation – O NC C HH H + O H H O O NC C H

46. Dr. Wolf's CHM 201 & 202 17- 46 2,4-Dichlorobenzaldehyde cyanohydrin (100%) ExampleExampleClCl CH OClCl CHCN OH NaCN, water then H 2 SO 4

47. Dr. Wolf's CHM 201 & 202 17- 47 ExampleExample CH 3 CCH 3 O NaCN, water then H 2 SO 4 CH 3 CCH 3 OHCN (77-78%)

48. Dr. Wolf's CHM 201 & 202 17- 48 Acetal Formation

49. Dr. Wolf's CHM 201 & 202 17- 49 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Enamine formation Compounds related to imines The Wittig reaction

50. Dr. Wolf's CHM 201 & 202 17- 50 Recall Hydration of Aldehydes and Ketones HOH C O HO C O H RR' R R'

51. Dr. Wolf's CHM 201 & 202 17- 51 Alcohols Under Analogous Reaction with Aldehydes and Ketones R"OH C O RR' R"O C O H R R' Product is called a hemiacetal.

52. Dr. Wolf's CHM 201 & 202 17- 52 Product is called a hemiacetal. ROH, H + Hemiacetal reacts further in acid to yield an acetal R"O C O H RR' R"O C OR RR' Product is called an acetal.

53. Dr. Wolf's CHM 201 & 202 17- 53 HCl 2CH 3 CH 2 OH + + H 2 O Benzaldehyde diethyl acetal (66%) ExampleExample CHO CH(OCH 2 CH 3 ) 2

54. Dr. Wolf's CHM 201 & 202 17- 54 HOCH 2 CH 2 OH + CH 3 (CH 2 ) 5 CH O p-toluenesulfonic acid benzene + H2OH2OH2OH2O (81%) H (CH 2 ) 5 CH 3 H2CH2CH2CH2C CH 2 O O C Diols Form Cyclic Acetals

55. Dr. Wolf's CHM 201 & 202 17- 55 In general: Position of equilibrium is usually unfavorable for acetal formation from ketones. Important exception: Cyclic acetals can be prepared from ketones.

56. Dr. Wolf's CHM 201 & 202 17- 56 HOCH 2 CH 2 OH +O p-toluenesulfonic acid benzene + H2OH2OH2OH2O H2CH2CH2CH2C CH 2 O O C (78%) C 6 H 5 CH 2 CCH 3 CH 3 C 6 H 5 CH 2 ExampleExample

57. Dr. Wolf's CHM 201 & 202 17- 57 First stage is analogous to hydration and leads to hemiacetal acid-catalyzed nucleophilic addition of alcohol to C=O Mechanism of Acetal Formation

58. Dr. Wolf's CHM 201 & 202 17- 58 MechanismMechanism C O HH R + O

59. Dr. Wolf's CHM 201 & 202 17- 59 MechanismMechanism C O H R O H +

60. Dr. Wolf's CHM 201 & 202 17- 60 MechanismMechanism C O H +RH O

61. Dr. Wolf's CHM 201 & 202 17- 61 MechanismMechanism C O O H + R H O RH

62. Dr. Wolf's CHM 201 & 202 17- 62 MechanismMechanism +HO RH C O O H R

63. Dr. Wolf's CHM 201 & 202 17- 63 Second stage is hemiacetal-to-acetal conversion involves carbocation chemistry Mechanism of Acetal Formation

64. Dr. Wolf's CHM 201 & 202 17- 64 Hemiacetal-to-acetal Stage C O O H R HH R + O

65. Dr. Wolf's CHM 201 & 202 17- 65 Hemiacetal-to-acetal Stage HR O C O O H R H +

66. Dr. Wolf's CHM 201 & 202 17- 66 Hemiacetal-to-acetal Stage O O H R + H C

67. Dr. Wolf's CHM 201 & 202 17- 67 Hemiacetal-to-acetal Stage C O R + O HH

68. Dr. Wolf's CHM 201 & 202 17- 68 Hemiacetal-to-acetal Stage C O R + Carbocation is stabilized by delocalization of unshared electron pair of oxygen C OR +

69. Dr. Wolf's CHM 201 & 202 17- 69 Hemiacetal-to-acetal Stage C O R + O H R

70. Dr. Wolf's CHM 201 & 202 17- 70 Hemiacetal-to-acetal Stage C O R + O H R O HR

71. Dr. Wolf's CHM 201 & 202 17- 71 Hemiacetal-to-acetal Stage + H O HR C O R O R

72. Dr. Wolf's CHM 201 & 202 17- 72 C R R'O 2R"OH + OR" R R' C + H 2 O mechanism: reverse of acetal formation; hemiacetal is intermediate application: aldehydes and ketones can be "protected" as acetals. Hydrolysis of Acetals

73. Dr. Wolf's CHM 201 & 202 17- 73 Acetals as Protecting Groups

74. Dr. Wolf's CHM 201 & 202 17- 74 The conversion shown cannot be carried out directly... CH CH 3 CCH 2 CH 2 C O CCH 3 CH 3 CCH 2 CH 2 C O 1. NaNH 2 2. CH 3 I ExampleExample

75. Dr. Wolf's CHM 201 & 202 17- 75 because the carbonyl group and the carbanion are incompatible functional groups. C:C:C:C: CH 3 CCH 2 CH 2 C O–

76. Dr. Wolf's CHM 201 & 202 17- 76 1) protect C=O 2) alkylate 3) restore C=O 1) protect C=O 2) alkylate 3) restore C=O StrategyStrategy

77. Dr. Wolf's CHM 201 & 202 17- 77 HOCH 2 CH 2 OH + p-toluenesulfonic acid benzene H2CH2CH2CH2C CH 2 O O C CH 3 CH 3 CCH 2 CH 2 C O CH CH 2 CH 2 C CH Example: Protect

78. Dr. Wolf's CHM 201 & 202 17- 78 H2CH2CH2CH2C CH 2 O O C CH 3 CH 2 CH 2 C CH 1. NaNH 2 2. CH 3 I H2CH2CH2CH2C CH 2 O O C CH 3 CH 2 CH 2 C CCH 3 Example: Alkylate

79. Dr. Wolf's CHM 201 & 202 17- 79 H2CH2CH2CH2C CH 2 O O C CH 3 CH 2 CH 2 C CCH 3 H2OH2OH2OH2O HCl HOCH 2 CH 2 OH (96%) CCH 3 CH 3 CCH 2 CH 2 C O+ Example: Deprotect

80. Dr. Wolf's CHM 201 & 202 17- 80 Reaction with Primary Amines: Imines

81. Dr. Wolf's CHM 201 & 202 17- 81 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

82. Dr. Wolf's CHM 201 & 202 17- 82 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

83. Dr. Wolf's CHM 201 & 202 17- 83 H2NH2NH2NH2N R C O + H a carbinolamine CO HNHNHNHN R N R C + H 2 O (imine) Imine (Schiff's Base) Formation

84. Dr. Wolf's CHM 201 & 202 17- 84 CH 3 NH 2 CHO+ CH=NCH 3 + H 2 O N-Benzylidenemethylamine (70%) ExampleExample

85. Dr. Wolf's CHM 201 & 202 17- 85 CH 3 NH 2 CHO+ CH=NCH 3 + H 2 O N-Benzylidenemethylamine (70%) ExampleExample CH OHOHOHOH NHCH 3

86. Dr. Wolf's CHM 201 & 202 17- 86 (CH 3 ) 2 CHCH 2 NH 2 O + + H 2 O N-Cyclohexylideneisobutylamine (79%) NCH 2 CH(CH 3 ) 2 ExampleExample

87. Dr. Wolf's CHM 201 & 202 17- 87 (CH 3 ) 2 CHCH 2 NH 2 O + + H 2 O N-Cyclohexylideneisobutylamine (79%) NCH 2 CH(CH 3 ) 2 OHOHOHOH NHCH 2 CH(CH 3 ) 2 ExampleExample

88. Dr. Wolf's CHM 201 & 202 17- 88 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

89. Dr. Wolf's CHM 201 & 202 17- 89 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

90. Dr. Wolf's CHM 201 & 202 17- 90 Reaction with Derivatives of Ammonia H2NH2NH2NH2NG + R2CR2CR2CR2C O R2CR2CR2CR2C NGNGNGNG+ H2OH2OH2OH2O H2NH2NH2NH2NOH R2CR2CR2CR2C NOH hydroxylamineoxime

91. Dr. Wolf's CHM 201 & 202 17- 91 CH 3 (CH 2 ) 5 CH + H 2 NOH O CH 3 (CH 2 ) 5 CH + H 2 O NOH (81-93%) ExampleExample

92. Dr. Wolf's CHM 201 & 202 17- 92 Reaction with Derivatives of Ammonia H2NH2NH2NH2NG + R2CR2CR2CR2C O R2CR2CR2CR2C NGNGNGNG+ H2OH2OH2OH2O H2NH2NH2NH2NOH R2CR2CR2CR2C NOH hydroxylamineoxime H2NH2NH2NH2N NH 2 R2CR2CR2CR2C NNH 2 hydrazinehydrazone etc.

93. Dr. Wolf's CHM 201 & 202 17- 93 + H 2 NNH 2 + H 2 O (73%) ExampleExampleOC NNH 2 C

94. Dr. Wolf's CHM 201 & 202 17- 94 CCH 3 ExampleExampleO + H 2 NNH phenylhydrazine + H 2 O CCH 3 NNH a phenylhydrazone (87-91%)

95. Dr. Wolf's CHM 201 & 202 17- 95 CH 3 (CH 2 ) 9 CCH 3 O H 2 NNHCNH 2 O + H2OH2OH2OH2O CH 3 (CH 2 ) 9 CCH 3 NNHCNH 2 O+ ExampleExample semicarbazide a semicarbazone (93%)

96. Dr. Wolf's CHM 201 & 202 17- 96 Reaction with Secondary Amines: Enamines

97. Dr. Wolf's CHM 201 & 202 17- 97 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

98. Dr. Wolf's CHM 201 & 202 17- 98 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

99. Dr. Wolf's CHM 201 & 202 17- 99 R2NHR2NHR2NHR2NH + H 2 O (enamine) C R2NR2NR2NR2N C Enamine Formation C O R2NR2NR2NR2N H H C C O H C

100. Dr. Wolf's CHM 201 & 202 17- 100 + (heat in benzene) ExampleExampleO NHNHNHNH via OHOHOHOH N (80-90%) N

101. Dr. Wolf's CHM 201 & 202 17- 101 The Wittig Reaction

102. Dr. Wolf's CHM 201 & 202 17- 102 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

103. Dr. Wolf's CHM 201 & 202 17- 103 Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

104. Dr. Wolf's CHM 201 & 202 17- 104 The Wittig Reaction Synthetic method for preparing alkenes. One of the reactants is an aldehyde or ketone. The other reactant is a phosphorus ylide. (C 6 H 5 ) 3 P C +AB – (C 6 H 5 ) 3 P CAB A key property of ylides is that they have a negatively polarized carbon and are nucleophilic.

105. Dr. Wolf's CHM 201 & 202 17- 105 Figure 17.12 Charge distribution in a ylide

106. Dr. Wolf's CHM 201 & 202 17- 106 The Wittig Reaction (C 6 H 5 ) 3 P C +AB – + + CC R R' A B (C 6 H 5 ) 3 P O + – CORR'

107. Dr. Wolf's CHM 201 & 202 17- 107 ExampleExample + + (C 6 H 5 ) 3 P O+ – (C 6 H 5 ) 3 P CH 2 +– O DMSO (86%) dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is the customary solvent

108. Dr. Wolf's CHM 201 & 202 17- 108 MechanismMechanism CORR' P(C 6 H 5 ) 3 + CAB – OC C RR' B A Step 1

109. Dr. Wolf's CHM 201 & 202 17- 109 MechanismMechanism OC C P(C 6 H 5 ) 3 RR' B A Step 2 P(C 6 H 5 ) 3 + – O R'RA B C C +

110. Dr. Wolf's CHM 201 & 202 17- 110 Planning an Alkene Synthesis via the Wittig Reaction

111. Dr. Wolf's CHM 201 & 202 17- 111 Retrosynthetic Analysis There will be two possible Wittig routes to an alkene. Analyze the structure retrosynthetically. Disconnect the doubly bonded carbons. One will come from the aldehyde or ketone, the other from the ylide. CCRR' A B

112. Dr. Wolf's CHM 201 & 202 17- 112 Retrosynthetic Analysis of Styrene C 6 H 5 CH CH 2 HCH O + (C 6 H 5 ) 3 P CHC 6 H 5 + – C 6 H 5 CH O+ (C 6 H 5 ) 3 P CH 2 + – Both routes are acceptable.

113. Dr. Wolf's CHM 201 & 202 17- 113 Preparation of Ylides Ylides are prepared from alkyl halides by a two-stage process. The first step is a nucleophilic substitution. Triphenylphosphine is the nucleophile. (C 6 H 5 ) 3 P + CHAB X + (C 6 H 5 ) 3 P CHAB + X–X–X–X–

114. Dr. Wolf's CHM 201 & 202 17- 114 Preparation of Ylides In the second step, the phosphonium salt is treated with a strong base in order to remove a proton from the carbon bonded to phosphorus. (C 6 H 5 ) 3 P CAB + H base – (C 6 H 5 ) 3 P CAB + – H base

115. Dr. Wolf's CHM 201 & 202 17- 115 Preparation of Ylides Typical strong bases include organolithium reagents (RLi), and the conjugate base of dimethyl sulfoxide as its sodium salt [NaCH 2 S(O)CH 3 ]. (C 6 H 5 ) 3 P CAB + H base (C 6 H 5 ) 3 P C A B + – – Hbase

116. Dr. Wolf's CHM 201 & 202 17- 116 Stereoselective Addition to Carbonyl Groups Nucleophilic addition to carbonyl groups sometimes leads to a mixture of stereoisomeric products.

117. Dr. Wolf's CHM 201 & 202 17- 117 20% ExampleExample CH 3 H3CH3CH3CH3CO 80% OHOHOHOH H H3CH3CH3CH3C OHOHOHOH H H3CH3CH3CH3C NaBH 4

118. Dr. Wolf's CHM 201 & 202 17- 118 this methyl group hinders approach of nucleophile from top H 3 B—H – preferred direction of approach is to less hindered (bottom) face of carbonyl group preferred direction of approach is to less hindered (bottom) face of carbonyl group Steric Hindrance to Approach of Reagent

119. Dr. Wolf's CHM 201 & 202 17- 119 Biological reductions are highly stereoselective pyruvic acid  S-(+)-lactic acid O CH 3 CCO 2 H NADH H+H+H+H+ enzyme is lactate dehydrogenase CO 2 H HOHOHOHO H CH 3

120. Dr. Wolf's CHM 201 & 202 17- 120 Figure 17.14 One face of the substrate can bind to the enzyme better than the other.

121. Dr. Wolf's CHM 201 & 202 17- 121 Figure 17.14 Change in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially from one side rather than the other.

122. Dr. Wolf's CHM 201 & 202 17- 122 in aqueous solution RCH RCH RCOHOOH OH H2OH2OH2OH2OO Oxidation of Aldehydes

123. Dr. Wolf's CHM 201 & 202 17- 123 K 2 Cr 2 O 7 H 2 SO 4 H2OH2OH2OH2O O O CH O O COH (75%) via O OH CH OH ExampleExample

124. Dr. Wolf's CHM 201 & 202 17- 124 The Baeyer-Villiger Oxidation of Ketones Oxidation of ketones with peroxy acids gives esters by a novel rearrangement.

125. Dr. Wolf's CHM 201 & 202 17- 125 R"COOH O RCR' O + R"COH O + KetoneEster ROCR' O GeneralGeneral

126. Dr. Wolf's CHM 201 & 202 17- 126 C 6 H 5 COOH O (67%) Oxygen insertion occurs between carbonyl carbon and larger group. Methyl ketones give acetate esters. CHCl 3 ExampleExample CCH 3 O OCCH 3 O

127. Dr. Wolf's CHM 201 & 202 17- 127 C 6 H 5 COOH O (66%) Reaction is stereospecific. Oxygen insertion occurs with retention of configuration. CHCl 3 StereochemistryStereochemistry O CCH 3 H3CH3CH3CH3C HH OCCH 3 O H3CH3CH3CH3C HH

128. Dr. Wolf's CHM 201 & 202 17- 128 R"COOH O RCR' O + ROCR' O R"COH O + First step is nucleophilic addition of peroxy acid to the carbonyl group of the ketone. O O C O H R R' OCR" MechanismMechanism

129. Dr. Wolf's CHM 201 & 202 17- 129 R"COOH O RCR' O + ROCR' O R"COH O + O O C OHR R' OCR" Second step is migration of group R from carbon to oxygen. The weak O—O bond breaks in this step. MechanismMechanism

130. Dr. Wolf's CHM 201 & 202 17- 130 Certain bacteria use hydrocarbons as a source of carbon. Oxidation proceeds via ketones, which then undergo oxidation of the Baeyer-Villiger type. Biological Baeyer-Villliger Oxidation O bacterial oxidation O O O 2. cyclohexanone monooxygenase, coenzymes

131. Dr. Wolf's CHM 201 & 202 17- 131 Spectroscopic Analysis of Aldehydes and Ketones

132. Dr. Wolf's CHM 201 & 202 17- 132 Presence of a C=O group is readily apparent in infrared spectrum C=O stretching gives an intense absorption at 1710-1750 cm-1 In addition to peak for C=O, aldehydes give two weak peaks near 2720 and 2820 nm for H—C=O Infrared Spectroscopy

133. Dr. Wolf's CHM 201 & 202 17- 133 Francis A. Carey, Organic Chemistry, Fifth Edition. Copyright © 2003 The McGraw-Hill Companies, Inc. All rights reserved.200035003000250010001500500 Wave number, cm -1 Figure 17.16 Infrared Spectrum of Butanal C=O CH 3 CH 2 CH 2 CH=O H—C=O 2720 cm -1 2820 cm -1 1720 cm -1

134. Dr. Wolf's CHM 201 & 202 17- 134 Aldehydes: H—C=O proton is at very low field (  9-10 ppm). Methyl ketones: CH 3 singlet near  2 ppm. 1 H NMR

135. Dr. Wolf's CHM 201 & 202 17- 135 01.02.03.04.05.06.07.08.09.010.0 Chemical shift ( , ppm) HCO CH(CH 3 ) 2

136. Dr. Wolf's CHM 201 & 202 17- 136 01.02.03.04.05.06.07.08.09.010.0 Chemical shift ( , ppm) CH 3 CO CH 3 CH 2

137. Dr. Wolf's CHM 201 & 202 17- 137 13 C NMR Carbonyl carbon is at extremely low field-near  200 ppm Intensity of carbonyl carbon is usually weak

138. Dr. Wolf's CHM 201 & 202 17- 138 Chemical shift ( , ppm) 020406080100120140160180200 CH 3 CH 2 CCH 2 CH 2 CH 2 CH 3 O

139. Dr. Wolf's CHM 201 & 202 17- 139 UV-VISUV-VIS Aldehydes and ketones have two bands in the UV region:  * and n  *  *: excitation of a bonding  electron to an antibonding  * orbital  *: excitation of a nonbonding electron on oxygen to an antibonding  * orbital

140. Dr. Wolf's CHM 201 & 202 17- 140 UV-VISUV-VIS H3CH3CH3CH3C H3CH3CH3CH3C C O  * max 187 nm n  * max 270 nm

141. Dr. Wolf's CHM 201 & 202 17- 141 Molecular ion fragments to give an acyl cation m/z 86 + m/z 57 Mass Spectrometry CH 2 CH 3 CH 3 CH 2 CCH 2 CH 3 +O CH 3 CH 2 C O +

142. Dr. Wolf's CHM 201 & 202 17- 142 End of Chapter 17