Aldehydes and Ketones. Nucleophilic Addi3on Reac3ons

Transcription

1 Aldehydes and Ketones Nucleophilic Addi3on Reac3ons 1

2 Aldehydes and Ketones Aldehydes (RCHO) and ketones (R 2 CO) are characterized by the carbonyl func3onal group (C=O) The compounds occur widely in nature as intermediates in metabolism and biosynthesis 2

3 3

4 Aldehydes and Ketones 4

5 Nomenclature of Aldehydes 5

6 Naming the Aldehyde as a Subs3tuent 6

7 Naming Ketones Replace the terminal - e of the alkane name with one Parent chain is the longest one that contains the ketone group Numbering begins at the end nearer the carbonyl carbon 7

8 Ketones with Common Names IUPAC retains well- used but unsystema3c names for a few ketones 8

9 Nomenclature of Ketones 9

10 Ketones and Aldehydes as Subs3tuents The R C=O as a subs3tuent is an acyl group, used with the suffix - yl from the root of the carboxylic acid CH 3 CO: acetyl; CHO: formyl; C 6 H 5 CO: benzoyl The prefix oxo- is used if other func3onal groups are present and the doubly bonded oxygen is labeled as a subs3tuent on a parent chain 10

11 Reac3vity of Aldehydes and Ketones Electronic Reasoning: An aldehyde has a greater partial positive charge on its carbonyl carbon than does a ketone. Because a hydrogen is more electron withdrawing than an alkyl group. 11

12 Aldehydes are More Reac3ve than Ketone Ketones have greater steric crowding in their transi3on states, so they have less stable transi3on states than do aldehydes. The carbonyl carbon of an aldehyde is more accessible to the nucleophile. Reac3vity of Carbonyl Groups 12

13 Preparing Aldehydes and Ketones From Alkenes (Ozonolysis) From Alkynes Aldehyde from terminal alkyne via Hydrobra3on Ketone from symmetrical alkyne via Hydrobora3on and Mercury 2+ catalyzed hydra3on From Alcohols (Aldehyde and Ketone From Arene (ketones from Friedel- Craas acyla3on) From Carbonyl Chemistry 13

14 From Various Carbonyls O 1) R'Li H OH O O R H 2) H 2 O R R' R R' 14

15 Oxida3on of Aldehydes and Ketones CrO 3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently Silver oxide, Ag 2 O, in aqueous ammonia (Tollens reagent) oxidizes aldehydes 15

16 Ketones Oxidize with Difficulty Undergo slow cleavage with hot, alkaline KMnO 4 C C bond next to C=O is broken to give carboxylic acids Reac3on is prac3cal for cleaving symmetrical ketones 16

17 Oxida3on of Aldehydes and Ketones 17

18 The Baeyer Villiger Oxida3on 18

19 Nucleophilic Addi3on Reac3ons of Aldehydes and Ketones Nucleophiles Nucleophiles can be nega3vely charged ( :Nu - ) or neutral ( :Nu) at the reac3on site Hydride, hydroxide, organolithium, organomagnesium, acetylide, cyanide 19

20 Rela3ve Reac3vity of Aldehydes and Ketones Aldehydes are generally more reac3ve than ketones in nucleophilic addi3on reac3ons The transi3on state for addi3on is less crowded and lower in energy for an aldehyde (a) than for a ketone (b) Aldehydes have one large subs3tuent bonded to the C=O: ketones have two 20

21 Electrophilicity of Aldehydes and Ketones Aldehyde C=O is more polarized than ketone C=O As in carboca3ons, more alkyl groups stabilize + character Ketone has more alkyl groups, stabilizing the C=O carbon induc3vely 21

22 Reac3vity of Aroma3c Aldehydes Less reac3ve in nucleophilic addi3on reac3ons than alipha3c aldehydes Electron- dona3ng resonance effect of aroma3c ring makes C=O less reac3ve electrophile than the carbonyl group of an alipha3c aldehyde 22

23 Hydride Addi3on Convert C=O to CH- OH LiAlH 4 and NaBH 4 react as donors of hydride ion Protona3on aaer addi3on yields the alcohol 23

24 Cataly3c Hydrogena3on Reduces Carbon Oxygen Double Bonds 24

25 Nucleophilic Addi3on of Grignard Reagents and Organolithium Reagents: Alcohol Forma3on Treatment of aldehydes or ketones with Grignard reagents yields an alcohol Nucleophilic addi3on of the equivalent of a carbon anion, or carbanion. A carbon magnesium bond is strongly polarized, so a Grignard reagent reacts for all prac3cal purposes as R: - MgX +. 25

26 Nucleophilic Addi3on of HCN: Cyanohydrin Forma3on Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)C N Addi3on of HCN is reversible and base- catalyzed, genera3ng nucleophilic cyanide ion, CN - Addi3on of CN - to C=O yields a tetrahedral intermediate, which is then protonated Equilibrium favors adduct 26

27 Uses of Cyanohydrins The nitrile group ( C N) can be reduced with LiAlH 4 to yield a primary amine (RCH 2 NH 2 ) Can be hydrolyzed by hot acid to yield a carboxylic acid 27

28 Cataly3c Hydrogena3on Reduces Carbon Nitrogen Double and Triple Bonds 28

29 Hydra3on of Aldehydes Aldehyde oxida3ons occur through 1,1- diols ( hydrates ) Reversible addi3on of water to the carbonyl group Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols 29

30 Nucleophilic Addi3on of H 2 O: Hydra3on Aldehydes and ketones react with water to yield 1,1- diols (geminal (gem) diols) Hyrda3on is reversible: a gem diol can eliminate water 30

31 Base- Catalyzed Addi3on of Water Addi3on of water is catalyzed by both acid and base The base- catalyzed hydra3on nucleophile is the hydroxide ion, which is a much stronger nucleophile than water 31

32 Acid- Catalyzed Addi3on of Water Protona3on of C=O makes it more electrophilic 32

33 Nucleophilic Addi3on of Alcohols: Acetal Forma3on Alcohols are weak nucleophiles but acid promotes addi3on forming the conjugate acid of C=O Addi3on yields a hydroxy ether, called a hemiacetal (reversible); further reac3on can occur Protona3on of the OH and loss of water leads to an oxonium ion, R 2 C=OR + to which a second alcohol adds to form the acetal 33

34 Uses of Acetals Acetals can serve as protec3ng groups for aldehydes and ketones It is convenient to use a diol to form a cyclic acetal (the reac3on goes even more readily) 34

35 The Reac3ons of Aldehydes and Ketones with Alcohols 35

36 Acid- Catalyzed Hydrolysis of an Acetal 36

37 The Addi3on of Sulfur Nucleophiles 37

38 Thioacetals are Desulfurized with Hydrogen and Raney Nickel 38

39 Addi3on of H Y to C=O Reac3on of C=O with H- Y, where Y is electronega3ve, gives an addi3on product ( adduct ) Forma3on is readily reversible 39

40 Nucleophilic Addi3on of Amines: Imine and Enamine Forma3on RNH 2 adds to R 2 C=O to form imines, R 2 C=NR (aaer loss of HOH) R 2 NH yields enamines, R 2 N CR=CR 2 (aaer loss of HOH) (ene + amine = unsaturated amine) 40

41 Aldehydes and Ketones Form Imines with Primary Amines 41

42 Mechanism of Forma3on of Imines Primary amine adds to C=O Proton is lost from N and adds to O to yield an amino alcohol (carbinolamine) Protona3on of OH converts it into water as the leaving group Result is iminium ion, which loses proton Acid is required for loss of OH too much acid blocks RNH 2 42

43 Forma3on of Imine Deriva3ves 43

44 Imine Hydrolysis is Irreversible The amine is protonated in the acidic solution, so it is unable to react with the carbonyl compound. 44

45 Imine Deriva3ves Addi3on of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines For example, hydroxylamine forms oximes and 2,4- dinitrophenylhydrazine readily forms 2,4- dinitrophenylhydrazones These are usually solids and help in characterizing liquid ketones or aldehydes by mel3ng points 45

46 Aldehydes and Ketones Form Enamines with Secondary Amines 46

47 Enamine Forma3on 47

48 Nucleophilic Addi3on of Hydrazine: The Wolff Kishner Reac3on Treatment of an aldehyde or ketone with hydrazine, H 2 NNH 2, and KOH converts the compound to an alkane Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature 48

49 Enamine Hydrolysis is Irreversible The amine is protonated in the acidic solu3on, so it is unable to react with the carbonyl compound. 49

50 Reduc3ve Amina3on The unstable imine formed from ammonia is hydrogenated to an amine. Imines and enamines are reduced to amines with NaBH3CN. 50

51 Nucleophilic Addi3on of Phosphorus Ylides: The Wipg Reac3on The sequence converts C=O to C=C A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine The intermediate spontaneously decomposes through a four- membered ring to yield alkene and triphenylphosphine oxide, (Ph) 3 P=O Forma3on of the ylide is shown below 51

52 Synthesizing Alkenes (The Wipg Reac3on) 52

53 Mechanism of the Wipg Reac3on 53

54 Uses of the Wipg Reac3on Can be used for monosubs3tuted, disubs3tuted, and trisubs3tuted alkenes but not tetrasubs3tuted alkenes The reac3on yields a pure alkene of known structure For comparison, addi3on of CH 3 MgBr to cyclohexanone and dehydra3on with, yields a mixture of two alkenes 54

55 Choosing Partners for the Wipg Reac3on 55

56 Biological Reduc3ons The adduct of an aldehyde and OH - can transfer hydride ion to another aldehyde C=O resul3ng in a simultaneous oxida3on and reduc3on (dispropor2ona2on) 56

57 Direct vs. Conjugate Nucleophilic Addi3on to α,β- Unsaturated Aldehydes and Ketones 57

58 Kine3c and Thermodynamic Control 58

59 Conjugate Addi3on of Amines Primary and secondary amines add to α, β- unsaturated aldehydes and ketones to yield β- amino aldehydes and ketones 59

60 Conjugate Addi3on of Alkyl Groups: Organocopper Reac3ons Reac3on of an α,β- unsaturated ketone with a lithium diorganocopper reagent Diorganocopper (Gilman) reagents form by reac3on of 1 equivalent of cuprous iodide and 2 equivalents of organolithium 1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups 60

61 Mechanism of Alkyl Conjugate Addi3on: Organocopper Reac3ons Conjugate nucleophilic addi3on of a diorganocopper anion, R 2 Cu -, to an enone Transfer of an R group and elimina3on of a neutral organocopper species, RCu 61

62 Spectroscopy of Aldehydes and Ketones Infrared Spectroscopy Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm - 1 aldehydes show two characteris3c C H absorp3ons in the 2720 to 2820 cm - 1 range. 62

63 NMR Spectra of Aldehydes Aldehyde proton signals are near δ 10 in 1 H NMR - dis3nc3ve spin spin coupling with protons on the neighboring carbon, J 3 Hz 63

64 13 C NMR of C=O C=O signal is at δ 190 to δ 215 No other kinds of carbons absorb in this range 64

65 Mass Spectrometry McLafferty Rearrangement Alipha3c aldehydes and ketones that have hydrogens on their gamma (γ) carbon atoms rearrange as shown 65

66 Mass Spectroscopy: α- Cleavage Cleavage of the bond between the carbonyl group and the α carbon Yields a neutral radical and an oxygen- containing ca3on 66