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Modified from sides of William Tam & Phillis Chang Ch. 16 - 1 Chapter 16 Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group.

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Presentation on theme: "Modified from sides of William Tam & Phillis Chang Ch. 16 - 1 Chapter 16 Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group."— Presentation transcript:

1 Modified from sides of William Tam & Phillis Chang Ch Chapter 16 Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group

2 Ch About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3 Ch Introduction  Carbonyl compounds

4 Ch Nomenclature of Aldehydes & Ketones  Rules ●Aldehyde as parent (suffix)  Ending with “al”; ●Ketone as parent (suffix)  Ending with “one” ●Number the longest carbon chain containing the carbonyl carbon and starting at the carbonyl carbon

5 Ch  Examples

6 Ch  group as a prefix: methanoyl or formyl group  group as a prefix: ethanoyl or acetyl group (Ac)  groups as a prefix: alkanoyl or acyl groups

7 Ch

8 Ch Physical Properties

9 Ch Synthesis of Aldehydes 4A.Aldehydes by Oxidation of 1 o Alcohols

10 Ch  e.g.

11 Ch B.Aldehydes by Ozonolysis of Alkenes

12 Ch  e.g.

13 Ch C.Aldehydes by Reduction of Acyl Chlorides, Esters, and Nitriles

14 Ch  LiAlH 4 is a very powerful reducing agent, and aldehydes are easily reduced ●Usually reduced all the way to the corresponding 1 o alcohol ●Difficult to stop at the aldehyde stage  Not a good method to synthesize aldehydes using LiAlH 4

15 Ch  Two derivatives of aluminum hydride that are less reactive than LAH

16 Ch

17 Ch  Aldehydes from acyl chlorides: RCOCl  RCHO  e.g.

18 Ch  Reduction of an Acyl Chloride to an Aldehyde

19 Ch  Aldehydes from esters and nitriles: RCO 2 R’  RCHO RC≡N  RCHO ●Both esters and nitriles can be reduced to aldehydes by DIBAL-H

20 Ch  Reduction of an ester to an aldehyde

21 Ch  Reduction of a nitrile to an aldehyde

22 Ch  Examples

23 Ch Synthesis of Ketones 5A.Ketones from Alkenes, Arenes, and 2 o Alcohols  Ketones (and aldehydes) by ozonolysis of alkenes

24 Ch  Examples

25 Ch  Ketones from arenes by Friedel–Crafts acylations

26 Ch  Ketones from secondary alcohols by oxidation

27 Ch B.Ketones from Nitriles

28 Ch  Examples

29 Ch  Suggest synthesis of from and

30 Ch  Retrosynthetic analysis need to add one carbon 5 carbons here4 carbons here 

31 Ch  Retrosynthetic analysis disconnectio n

32 Ch  Synthesis

33 Ch  Suggest synthesis of from and

34 Ch  Retrosynthetic analysis no need to add carbon 5 carbons here 

35 Ch  Retrosynthetic analysis disconnectio n

36 Ch  Synthesis

37 Ch Nucleophilic Addition to the Carbon–Oxygen Double Bond  Structure ●Carbonyl carbon: sp 2 hybridized ●Trigonal planar structure Nu ⊖

38 Ch  Polarization and resonance structure ●Nucleophiles will attack the nucleophilic carbonyl carbon ●Note: nucleophiles usually do not attack non-polarized C=C bond

39 Ch  With a strong nucleophile:

40 Ch  Also would expect nucleophilic addition reactions of carbonyl compounds to be catalyzed by acid (or Lewis acid) ●Note: full positive charge on the carbonyl carbon in one of the resonance forms  Nucleophiles readily attack

41 Ch  Mechanism

42 Ch  Mechanism

43 Ch A.Reversibility of Nucleophilic Additions to the Carbon – Oxygen Double Bond  Many nucleophilic additions to carbon– oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of an equilibrium

44 Ch B.Relative Reactivity: Aldehydes vs. Ketones

45 Ch large smal l  Steric factors

46 Ch  Electronic factors (positive inductive effect from only one R group) (positive inductive effect from both R & R' groups)  carbonyl carbon less  + (less nucleophilic)

47 Ch The Addition of Alcohols: Hemiacetals and Acetals  Acetal & Ketal Formation: Addition of Alcohols to Aldehydes Catalyzed by acid

48 Ch  Mechanism

49 Ch  Mechanism (Cont’d)

50 Ch  Mechanism (Cont’d)

51 Ch  Note:All steps are reversible. In the presence of a large excess of anhydrous alcohol and catalytic amount of acid, the equilibrium strongly favors the formation of acetal (from aldehyde) or ketal (from ketone)  On the other hand, in the presence of a large excess of H 2 O and a catalytic amount of acid, acetal or ketal will hydrolyze back to aldehyde or ketone. This process is called hydrolysis

52 Ch  Acetals and ketals are stable in neutral or basic solution, but are readily hydrolyzed in aqueous acid

53 Ch  Aldehyde hydrates: gem-diols

54 Ch  Mechanism

55 Ch Hemiacetal: OH & OR groups bonded to the same carbon 7A.Hemiacetals

56 Ch Hemiacetal: OH & OR groups bonded to the same carbon

57 Ch An acetal A ketal 7B.Acetals

58 Ch  Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an excess of a 1,2-diol and a trace of acid

59 Ch  This reaction, too, can be reversed by treating the acetal with aqueous acid

60 Ch C.Acetals Are Used as Protecting Groups  Although acetals are hydrolyzed to aldehydes and ketones in aqueous acid, acetals are stable in basic solutions  Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions

61 Ch  Example

62 Ch ●Synthetic plan  This route will not work

63 Ch Reason: (a) Intramolecular nucleophilic addition (b) Homodimerization or polymerization

64 Ch  Thus, need to “protect” carbonyl group first

65 Ch D.Thioacetals  Aldehydes & ketones react with thiols to form thioacetals

66 Ch  Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to –CH 2 – groups

67 Ch The Addition of Primary and Secondary Amines  Aldehydes & ketones react with 1 o amines to form imines and with 2 o amines to form enamines From a 1 o amineFrom a 2 o amine

68 Ch A.Imines  Addition of 1 o amines to aldehydes & ketones

69 Ch  Mechanism

70 Ch  Similar to the formation of acetals and ketals, all the steps in the formation of imine are reversible. Using a large excess of the amine will drive the equilibrium to the imine side  Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid

71 Ch B.Oximes and Hydrazones  Imine formation – reaction with a 1 o amine  Oxime formation – reaction with hydroxylamine

72 Ch  Hydrazone formation – reaction with hydrazine  Enamine formation – reaction with a 2 o amine

73 Ch C.Enamines

74 Ch  Mechanism

75 Ch  Mechanism (Cont’d)

76 Ch  Mechanism (Cont’d)

77 Ch The Addition of Hydrogen Cyanide: Cyanohydrins  Addition of HCN to aldehydes & ketones

78 Ch  Mechanism

79 Ch  Slow reaction using HCN since HCN is a weak acid and a poor source of nucleophile  Can accelerate reaction by using NaCN or KCN and slow addition of H 2 SO 4

80 Ch  Synthetic applications

81 Ch The Addition of Ylides: The Wittig Reaction

82 Ch  Phosphorus ylides

83 Ch  Example

84 Ch  Mechanism of the Wittig reaction

85 Ch A. How to Plan a Witting Synthesis  Synthesis of using a Wittig reaction

86 Ch  Retrosynthetic analysis

87 Ch  Synthesis – Route 1

88 Ch  Synthesis – Route 2

89 Ch B. The Horner – Wadsworth – Emmons Reaction

90 Ch

91 Ch  The phosphonate ester is prepared by reaction of a trialkyl phosphite [(RO) 3 P] with an appropriate halide (a process called the Arbuzov reaction)

92 Ch Oxidation of Aldehydes

93 Ch Chemical Analyses for Aldehydes and Ketones 12A. Derivatives of Aldehydes & Ketones

94 Ch B. Tollens ’ Test (Silver Mirror Test)

95 Ch Spectroscopic Properties of Aldehydes and Ketones 13A. IR Spectra of Aldehydes and Ketones

96 Ch  Conjugation of the carbonyl group with a double bond or a benzene ring shifts the C=O absorption to lower frequencies by about 40 cm -1

97 Ch

98 Ch B. NMR Spectra of Aldehydes and Ketones  13 C NMR spectra ●The carbonyl carbon of an aldehyde or ketone gives characteristic NMR signals in the  180–220 ppm region of 13 C spectra

99 Ch  1 H NMR spectra ●An aldehyde proton gives a distinct 1 H NMR signal downfield in the  9–12 ppm region where almost no other protons absorb; therefore, it is easily identified ●Protons on the  carbon are deshielded by the carbonyl group, and their signals generally appear in the  2.0–2.3 ppm region ●Methyl ketones show a characteristic (3H) singlet near  2.1 ppm

100 Ch

101 Ch

102 Ch Summary of Aldehyde and Ketone Addition Reactions

103 Ch  END OF CHAPTER 16 

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