Chapter 17: Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group

17.1: Nomenclature (please read) 17.2: Structure and Bonding: Carbonyl groups have a significant dipole moment

Aldehyde 2.72 D ! - Ketone 2.88 O Carboxylic acid 1.74 C ! + Acid chloride 2.72 Ester 1.72 O O Amide 3.76 C C Nitrile 3.90

Water 1.85

Carbonyl carbons are electrophilic sites and can be attacked by nucleophiles. The carbonyl oxygen is a basic site. 97

17.3: Physical Properties (please read) 17.4: Sources of Aldehydes and Ketones (Table 17.1, p. 708) 1a. Oxidation of 1° and 2° alcohols (15.10)

1b. From carboxylic acids

1c. Ketones from aldehydes

98

50 2. Ozonolysis of alkenes (6.20)

3. Hydration of alkynes (9.12)

4. Friedel-Craft Acylation (12.7) -aryl ketones

5. Hydroformylation of alkenes (please read) 99

17.5: Reactions of Aldehydes and Ketones: A Review and a Preview

Reactions of aldehydes and ketones: Review: 1. Reduction to hydrocarbons a. Clemmenson reduction (Zn-Hg, HCl)

b. Wolff-Kishner (H2NNH2, KOH, Δ)

100

51 2. Reduction to 1° and 2° alcohols (15.2)

3. Addition of Grignard Reagents (14.6-14.7)

101

17.6: Principles of Nucleophilic Addition: Hydration of Aldehydes and Ketones Water can reversibly add to the carbonyl carbon of aldehydes and ketones to give 1,1-diols (geminal or gem-diols) R= H, H 99.9 % hydrate O + H O OH 2 R= CH3, H 50 % C R C R R OH R= (H3C)3C, H 17 % - H2O R R= CH3, CH3 0.14 % R= CF3, CF3 > 99 % The hydration reaction is base and acid catalyzed Base-catalyzed mechanism (Fig. 17.1): hydroxide is a better nucleophile than water

102

52 Acid-catalyzed mechanism (Fig. 17.2): protonated carbonyl is a better electrophile

The hydration is reversible

Does adding acid or base change the amount of hydrate? Does a catalysts affect ΔGo, ΔG‡, both, or neither 103

17.7: Cyanohydrin Formation Addition of H-CN adds to the aldehydes and unhindered ketones. (related to the hydration reaction) The equilibrium favors cyanohydrin formation Mechanism of cyanohydron fromation (Fig. 17.3)

104

53 17.8: Acetal Formation Acetals are geminal diethers- structurally related to hydrates, which are geminal diols.

OH O + H2O C C R R R OH - H2O R hydrate (gem-diol)

O + R'OH OH + R'OH OR' C H C C + H2O R H OR' H OR' - R'OH R - R'OH R aldehyde hemi-acetal acetal (gem-diether)

O + R'OH OH + R'OH OR' C R C C + H O R R OR' R OR' 2 - R'OH R - R'OH R ketone hemi-ketal ketal (gem-diether) 105

Mechanism of acetal (ketal) formation is acid-catalyzed (Fig 17.4)

Dean-Stark Trap

The mechanism for acetal/ketal formation is reversible

How is the direction of the reaction controlled? 106

54 Dioxolanes and dioxanes: cyclic acetal (ketals) from 1,2- and 1,3-diols

+ O H , - H2O + OH O O 1,3-dioxolane C HO R R + R R H3O 1,2-diol

+ O H , - H2O + C HO OH 1,3-dioxane R R O O + 1,3-diol H3O R R

107

17.9: Acetals (Ketals) as Protecting Groups Protecting group: Temporarily convert a functional group that is incompatible with a set of reaction conditions into a new functional group (with the protecting group) that is compatible with the reaction. The protecting group is then removed giving the original functional group (deprotection).

OH O cannot be NaBH4 O OCH3 done directly OCH3 OH

O O keto-ester

108

55 The reaction cannot be done directly, as shown. Why?

a) NaNH2 O O b) H3C-I

CH3

17.10: Reaction with Primary Amines: Imines (Schiff base)

O + R'OH OH + R'OH OR' C R C C + H2O R R OR' R OR' - R'OH R - R'OH R Aldehyde hemi-acetal acetal or ketone or hemi-ketal or ketal

O + R'NH OH 2 + R'NH2 NHR' C C C + H O R NHR' R 2 R R R NHR' - R'NH2 - R'NH2 R Aldehyde carbinolamine or ketone

R' N 109 imine C + H2O R R

Mechanism of imine formation (Fig. 17.5):

See Table 17.4 for the related carbonyl derivative, oximes, hydrazone and semicarbazides (please read) O

H2NOH C6H2NHNH2 H2NHNCONH2 O N N N OH N-C6H5 N NH2 H 110 oxime phenylhydrazone semicarbazide

56 17.11: Reaction with Secondary Amines: Enamines O OH R'NH2 - H2O R' C C N 1° amine: R R R NHR' Imine R C R R

R' R' + OH _ O N R' R' 2° amine: H C R' - HO N C R N Iminium ion R R R C R' R R

R' R' + N OH _ R' R' R' R' O - HO N + N ketone with H R C R' - H R C N R C R C R H R R α-protons H R' H H R H H H iminium ion enamine Mechanism of enamine formation (Fig 17.6)

111

17.12: The Wittig Reaction 1979 Nobel Prize in Chemistry: Georg Wittig (Wittig Reaction) and H.C. Brown (Hydroboration)

The synthesis of an alkene from the reaction of an aldehyde or ketone and a phosphorus ylide (Wittig reagent), a dipolar intermediate with formal opposite charges on adjacent atoms (overall charge neutral). R R 1 R 2 R4 + 4 C O + + Ph P=O Ph3P C C C 3 R 2 R3 R1 R3 triphenylphosphonium aldehyde alkene triphenylphosphine ylide (Wittig reagent) or ketone oxide Accepted mechanism (Fig. 17.7) (please read)

112

57 The Wittig reaction gives C=C in a defined location, based on the location of the carbonyl group (C=O)

CH CH3 O CH 2 1) CH3MgBr, THF 2 Ph P CH + 2) POCl3 3 2 THF 1 : 9 The Wittig reaction is highly selective for ketones and aldehydes; esters, lactones, nitriles and amides will not react but are tolerated in the substrate. Acidic groups (alcohols, amine and carboxylic acids) are not tolerated. O O PPh O H + 3 O O O O CHO O O + Ph P OCH3 3 OCH O 3 O Predicting the geometry (E/Z) of the alkene product is complex

and is dependent upon the nature of the ylide. 113

17.13: Planning an Alkene Synthesis via the Wittig Reaction A Wittig reagent is prepared from the reaction of an alkyl halide

with triphenylphosphine (Ph3P:) to give a phosphonium salt. The protons on the carbon adjacent to phosphorous are acidic.

H3CLi Ph P H C Br Ph P CH 3 3 3 3 Ph3P CH2 Ph3P CH2 THF Br ylide phosphorane Phosphonium salt

Deprotonation of the phosphonium salt with a strong base gives the ylide. A phosphorane is a neutral resonance structure of the ylide.

114

58 • There will be two possible Wittig routes to an alkene. • Analyze the structure retrosynthetically, i.e., work the synthesis out backworks • Disconnect (break the bond of the target that can be formed by a known reaction) the doubly bonded carbons. One becomes the aldehyde or ketone, the other the ylide

Disconnect this bond

R2 R4 C C R1 R3

R R4 R2 R4 2 + O C C O + Ph3P C - OR - C PPh3 R R3 R1 R3 1

CH CH CH 3 2 2 CH2CH3 C C CH H 3 115

17.14: Stereoselective Addition to Carbonyl Groups (please read) 17.15: Oxidation of Aldehydes

Increasing oxidation state

C C C C C C

Cl Cl Cl C Cl C Cl C Cl C Cl Cl Cl Cl

O C OH C O C CO2 OR

C NH2 C NH C N

116

59 PCC H2Cr2O7 CHO CH Cl + CO2H 2 2 OH H3O , acetone

Aldehyde 1° alcohol Carboxylic Acid

O H2O HO OH H2Cr2O7 H Cr O O RCH -OH 2 2 7 2 + H3O , R H hydration R H H O+, 1° alcohol 3 R OH acetone acetone

Aldehydes are oxidized by Cr(VI) reagents to carboxylic acids in aqueous acid. The reactions proceeds through the hydrate

117

17.16: Baeyer-Villiger Oxidation of Ketones. Oxidation of ketones with a peroxy acid (mCPBA) to give as esters

O O O OH O O + OH R R' R' + R O

Cl ester Cl

Oxygen insertion occurs between carbonyl carbon and more the substituted α-carbon O mCPBA O CH3 O

O O mCPBA H3C O

H3C 118

60 19.17: Spectroscopic Analysis of Aldehydes and Ketones Infrared Spectroscopy: highly diagnostic for carbonyl groups Carbonyls have a strong C=O absorption peak between 1660 - 1770 cm−1 Aldehydes also have two characteristic C–H absorptions around 2720 - 2820 cm−1

Butanal

O C C-H H 2720, 2815 cm-1 C=O (1730 cm-1)

2-Butanone

C-H

C=O (1720 cm-1) 119

C=O stretches of aliphatic, conjugated, aryl and cyclic carbonyls: O O O H H H aliphatic aldehyde conjugated aldehyde aromatic aldehyde 1730 cm-1 1705 cm-1 1705 cm-1 O O O

CH3 H3C CH3 CH3

aliphatic ketone conjugated ketone aromatic ketone -1 1715 cm 1690 cm-1 1690 cm-1 O O O O

1715 cm-1 1750 cm-1 1780 cm-1 1815 cm-1

Conjugation moves the C=O stretch to lower energy (right, lower cm-1) Ring (angle) strain moves the C=O stretch to higher energy (left, higher cm-1) 120

61 1H NMR Spectra of Aldehydes and Ketones: The 1H chemical shift range for the aldehyde proton is δ 9-10 ppm The aldehyde proton will couple to the protons on the α-carbon with a typical coupling constant of J ≈ 2 Hz A carbonyl will slightly deshield the protons on the α-carbon; typical chemical shift range is δ 2.0 - 2.5 ppm

δ = 1.65, sextet, δ = 2.4, dt, J= 7.0, 2H δ = 1.65, t, J= 1.8, 7.0, 2H J= 7.0, 3H δ = 9.8, t, J= 1.8, 1H

121

O

H3C H2C C CH3

δ= 2.5 (2H, q, J = 7.3) 2.1 (3H, s) 1.1 (3H, t, J = 7.3)

H O C C H3C C CH2CH3 H δ 7.0 -6.0 δ 2.7 - 1.0 δ= 6.8 (1H, dq, J =15, 7.0) 6.1 (1H, d, J = 15) 2.6 (2H, q, J = 7.4) 1.9 (3H, d, J = 7.0 ) 1.1 (3H, t, J = 7.4) 122

62 13C NMR: The intensity of the carbonyl resonance in the 13C spectrum usually weak and sometimes not observed. The chemical shift range is diagnostic for the type of carbonyl

ketones & aldehydes: δ = ~ 190 - 220 ppm carboxylic acids, esters, δ = ~ 165 - 185 ppm and amides

O δ= 220, 38, 23 O H3CH2CH2C C OCH2CH3 δ= 174, 60, 27, 14, 9

carbonyl carbonyl

CDCl3

123

C9H10O2 IR: 1695 cm-1 3H 13 C NMR: 191 2H (t, J= 7.5) 163 2H d, J= 8.5 2H d, J= 8.5 q, J= 7.5 130 1H 128 s 115 65 15

C10H12O

IR: 1710 cm-1 2H 13C NMR: 207 (q, J= 7.3) 3H (t, J= 7.3) 134 130 2H 128 5H 126 52 37 10 124

63 7.3 7.2 2.9 2.7 C9H10O (2H, m) (3H, m) (2H, t, J = 7.7) (2H, dt, J = 7.7, 1.5) 9.8 (1H, t, J =1.5)

δ 9.7 - 9.9 δ 7.0 - 7.8 δ 3.1 - 2.5

129,128, 125

28

45

140 CDCl 201 3

125

64