Chapter 17 Aldehydes and Ketones Chapter 17 Aldehydes and Ketones. Nucleophilic Addition to the Carbonyl Group 1

17.4 Sources of Aldehydes and Ketones 14

Synthesis of Aldehydes and Ketones From alkenes: Ozonolysis (6.20) From alkynes: Hydration via enol (9.12) From arenes: Friedel-Crafts acylation (12.7) From alcohols: Oxidation (15.10) A number of reactions already studied provide efficient synthetic routes to aldehydes and ketones. 17

What about Aldehydes from Carboxylic Acids? OH H C O R RCH2OH 1. LiAlH4 2. H2O PDC, CH2Cl2 18

Benzaldehyde from benzoic acid Example Benzaldehyde from benzoic acid COH O CH O 1. LiAlH4 2. H2O PDC CH2Cl2 CH2OH (81%) (83%) 18

What about Ketones from Aldehydes? C O R H R' C O R PDC, CH2Cl2 1. R'MgX 2. H3O+ RCHR' OH 18

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

Reactions of Aldehydes and Ketones Already covered in earlier chapters: Reduction of C=O to CH2 (12.8) Clemmensen reduction Wolff-Kishner reduction Reduction of C=O to CHOH (15.2) Addition of Grignard and organolithium reagents (14.6-14.7) 2

17.6 Principles of Nucleophilic Addition to Carbonyl Groups: Hydration of Aldehydes and Ketones 4

Hydration of Aldehydes and Ketones C •• O • • H2O HO C O H •• 5

Substituent Effects on Hydration Equilibria OH R R' + H2O C O Compared to H Electronic: Alkyl groups stabilize reactants Steric: Alkyl groups crowd product 6

Equilibrium Constants and Relative Rates of Hydration C=O Hydrate K % Relative rate CH2=O CH2(OH)2 2300 >99.9 2200 CH3CH=O CH3CH(OH)2 1.0 50 1.0 (CH3)3CCH=O (CH3)3CCH(OH)2 0.2 17 0.09 (CH3)2C=O (CH3)2C(OH)2 0.0014 0.14 0.0018 Decreased hydration with greater alkyl substitution due to electron donation and steric crowding. 7

When Does Equilibrium Favor Hydrate? When carbonyl group is destabilized: electron-withdrawing groups destabilize C=O. 8

Substituent Effects on Hydration Equilibria OH O + H2O R C R C R R OH R = CH3: K = 0.000025 R = CF3: K = 22,000 9

Mechanism of Hydration (Base) Step 1: • • O H •• – •• HO C O • • – C •• O • • + 10

Mechanism of Hydration (Base) Step 2: •• HO C O • • – + •• • • O H – HO C OH • • O H •• 10

Mechanism of Hydration (Acid) Step 1: • • H O + C •• O • • + C •• OH • • H O + 10

Mechanism of Hydration (Acid) Step 2: • • H O + • • H O •• C OH + + C OH •• 10

Mechanism of Hydration (Acid) Step 3: • • O H •• C OH + H O •• + • • H O •• C OH 10

17.7 Cyanohydrin Formation

Cyanohydrin Formation •• • • C O H C O N • • •• + HCN 18

Cyanohydrin Formation – N • • •• • • C O 18

Cyanohydrin Formation + O • • Then acidify solution: – O N C •• • • H O • • N C •• 18

2,4-Dichlorobenzaldehyde Example Cl CH O Cl CHCN OH NaCN, water then H2SO4 2,4-Dichlorobenzaldehyde cyanohydrin (100%) 20

Acetone cyanohydrin is used in the synthesis of methacrylonitrile. Example CH3CCH3 O CH3CCH3 OH CN NaCN, water then H2SO4 (77-78%) Acetone cyanohydrin is used in the synthesis of methacrylonitrile. 21

17.8 Acetal Formation 1

Compounds related to imines Enamine formation The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamine formation The Wittig reaction 22

Hemiacetals and Acetals OH H HO HOCH2 O O OCH3 OH HO HOCH2 -D-Glucopyranose (a form of glucose), a hemiacetal Methyl--D-Glucopyranose, an acetal O HOCH2 OH HO Polyoxymethylene, a polyacetal Lactose, an acetal and hemiacetal 5

Recall Hydration of Aldehydes and Ketones HOH C •• O • • HO H R R' 5

Alcohols Under Analogous Reaction with Aldehydes and Ketones R"OH C •• O • • R R' R"O H Product is called a hemiacetal. 5

Hemiacetal Reacts Further in Acid to Yield an Acetal R"O C O H •• R R' Hemiacetal R"OH, H+ R"O C OR" •• R R' Product is called an acetal. 5

Benzaldehyde diethyl acetal (66%) Example CH O + 2CH3CH2OH HCl CH(OCH2CH3)2 + H2O Benzaldehyde diethyl acetal (66%) 6

Diols Form Cyclic Acetals CH3(CH2)5CH + HOCH2CH2OH p-toluenesulfonic acid, benzene H (CH2)5CH3 H2C CH2 O C + H2O (81%) 7

Important exception: Cyclic acetals can be prepared from ketones. In General: Position of equilibrium is usually unfavorable for acetal formation from ketones. Important exception: Cyclic acetals can be prepared from ketones. 8

p-toluenesulfonic acid, Example O C6H5CH2CCH3 + HOCH2CH2OH p-toluenesulfonic acid, benzene H2C CH2 O O + H2O (78%) C C6H5CH2 CH3 7

Mechanism of Acetal Formation First stage is analogous to hydration and leads to hemiacetal: Acid-catalyzed nucleophilic addition of alcohol to C=O. 10

Mechanism H R + O • • C O •• • • 10

Mechanism H •• + C O O • • • • H R 10

Mechanism R H O • • •• + C O H 10

Mechanism R •• •• O C O O R H •• • • + H H 10

Mechanism C O •• • • H R + H O R •• 10

Mechanism of Acetal Formation Second stage is hemiacetal-to-acetal conversion: Involves carbocation chemistry. 15

Hemiacetal-to-Acetal Stage R + O • • C O •• • • H R 16

Hemiacetal-to-Acetal Stage R O • • C O •• H R + 16

Hemiacetal-to-Acetal Stage •• H R + C 16

Hemiacetal-to-Acetal Stage •• R + O •• H • • 16

Hemiacetal-to-Acetal Stage •• R + C O R •• + Carbocation is stabilized by delocalization of unshared electron pair of oxygen. 16

Hemiacetal-to-Acetal Stage •• R + O •• H R • • 16

Hemiacetal-to-Acetal Stage •• R + H O •• H R • • 16

Hemiacetal-to-Acetal Stage •• R + H O •• R 16

Reverse of acetal formation; hemiacetal is intermediate. Hydrolysis of Acetals OR" R R' C + H2O C R R' O 2R"OH + Mechanism: Reverse of acetal formation; hemiacetal is intermediate. Application: Aldehydes and ketones can be "protected" as acetals. 26

17.9 Acetals as Protecting Groups 28

The conversion shown cannot be carried out directly... Example The conversion shown cannot be carried out directly... CH CH3CCH2CH2C O 1. NaNH2 2. CH3I CCH3 CH3CCH2CH2C O 29

Because the carbonyl group and the carbanion are incompatible functional groups. CH3CCH2CH2C O – 31

Strategy 1) Protect C=O 2) Alkylate 3) Restore C=O 32

Example: Protect O + CH3CCH2CH2C CH HOCH2CH2OH H2C CH2 O C CH2CH2C CH p-toluenesulfonic acid, benzene H2C CH2 O C CH3 CH2CH2C CH 7

Example: Alkylate H2C CH2 O C CH2CH2C CCH3 CH3 H2C CH2 1. NaNH2 2. CH3I CH2CH2C CH 7

Example: Deprotect H2C CH2 O C CH3 CH2CH2C CCH3 H2O HCl CCH3 CH3CCH2CH2C O + HOCH2CH2OH (96%) 7

17.10 Reaction with Primary Amines: Imines 2

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Imine (Schiff's Base) Formation H2N R C O •• + • • H Carbinolamine intermediate C O HN R •• Primary amine •• N C + H2O R Imine 3

N-Benzylidenemethylamine (70%) Example CH O Methylamine + CH3NH2 Benzaldehyde CH=NCH3 + H2O N-Benzylidenemethylamine (70%) 4

N-Benzylidenemethylamine (70%) Example Carbinolamine intermediate CH O + CH3NH2 CH OH NHCH3 CH=NCH3 + H2O N-Benzylidenemethylamine (70%) 4

N-Cyclohexylideneisobutylamine (79%) Example O + (CH3)2CHCH2NH2 Isobutylamine Cyclohexanone NCH2CH(CH3)2 + H2O N-Cyclohexylideneisobutylamine (79%) 5

N-Cyclohexylideneisobutylamine (79%) Example O + (CH3)2CHCH2NH2 Carbinolamine intermediate OH NHCH2CH(CH3)2 NCH2CH(CH3)2 + H2O N-Cyclohexylideneisobutylamine (79%) 5

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Reaction with Derivatives of Ammonia H2N G + R2C O NG H2O H2N OH R2C NOH Hydroxylamine Oxime 14

Example CH3(CH2)5CH + H2NOH O Hydroxylamine Heptanal CH3(CH2)5CH + H2O Heptanal oxime (81-93%) 15

Reaction with Derivatives of Ammonia H2N G + R2C O NG H2O OH NOH Hydroxylamine Oxime H2N NH2 R2C NNH2 Hydrazine Hydrazone etc. 14

Benzophenone hydrazone (73%) Example O C + H2NNH2 Hydrazine Benzophenone NNH2 C + H2O Benzophenone hydrazone (73%) 16

Acetophenone phenylhydrazone (87-91%) Example O + H2NNH CCH3 Acetophenone Phenylhydrazine + H2O CCH3 NNH Acetophenone phenylhydrazone (87-91%) 17

2-Dodecanone semicarbazone (93%) Example O O + CH3(CH2)9CCH3 H2NNHCNH2 Semicarbazide 2-Dodecanone H2O CH3(CH2)9CCH3 NNHCNH2 O + 2-Dodecanone semicarbazone (93%) 18

17.11 Reaction with Secondary Amines: Enamines 20

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Enamine Formation C O R2N H Carbinolamine intermediate C O H R2NH •• O R2N H Carbinolamine intermediate C O •• H • • R2NH •• Secondary amine + H2O Secondary enamine C •• R2N 21

Example O N + N H N OH p-toluenesulfonic acid, benzene, heat Cyclopentanone Pyrrolidine OH N via carbinolamine intermediate N-(1-Cyclopentyl)- pyrrolidine (a secondary enamine) (80-90%) 22

Example of the Importance of Imines and Enamines Protonated imine Primary enamine Biochemical reaction catalyzed by acetoacetate decarboxylase 21

17.12 The Wittig Reaction 20

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Compounds related to imines Enamines The Wittig reaction Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction 22

Synthetic method for preparing alkenes. The Wittig Reaction Synthetic method for preparing alkenes. One of the reactants is an aldehyde or ketone. The other reactant is a phosphorus ylide. (C6H5)3P C + A B • • – A key property of ylides is that they have a negatively polarized carbon and are nucleophilic. 22

Charge Distribution in an Ylide 22

The Wittig Reaction C O R R' (C6H5)3P C + A B – + + C R R' A B •• (C6H5)3P C + A B • • – + + C R R' A B (C6H5)3P O • • – •• 22

Example + – O + (C6H5)3P CH2 DMSO + – CH2 + (C6H5)3P O (86%) •• (C6H5)3P CH2 + – •• + DMSO CH2 (C6H5)3P O + • • – •• + (86%) Dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is the customary solvent. 22

Mechanism Step 1 C O R R' O C P(C6H5)3 R R' B A P(C6H5)3 + C A B – •• • • P(C6H5)3 + C A B – •• 22

Mechanism Step 2 O C P(C6H5)3 R R' B A P(C6H5)3 + – O R' R A B C •• •• 22

17.13 Planning an Alkene Synthesis via the Wittig Reaction 20

Retrosynthetic Analysis B 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. 22

Retrosynthetic Analysis of Styrene C6H5CH O + (C6H5)3P CH2 – •• Both routes are acceptable. C6H5CH CH2 HCH O + (C6H5)3P CHC6H5 – •• 22

Ylides are prepared from alkyl halides by a two-stage process. 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. + (C6H5)3P + X– CH A B (C6H5)3P • • + CH A B X 22

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. (C6H5)3P C A B + H base • • – (C6H5)3P C A B + • • – H base 22

Preparation of Ylides Typical strong bases include organolithium reagents (RLi) and the conjugate base of dimethyl sulfoxide as its sodium salt [NaCH2S(O)CH3]. (C6H5)3P C A B + H A + – (C6H5)3P C • • B – H base base • • 22

Section 17.17 Spectroscopic Analysis of Aldehydes and Ketones

Infrared Spectroscopy 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 cm-1 for H—C=O. 6

Infrared Spectrum of Butanal 8

Aldehydes: H—C=O proton is at very low field ( 9-10 ppm). 1H NMR Aldehydes: H—C=O proton is at very low field ( 9-10 ppm). Methyl ketones: CH3 singlet near  2 ppm. More substituted ketones: methylene CH2 around around  2.4 ppm and methine CH around  2.5. 6

2-Butanone CH3 C O CH3CH2 1 Chemical shift (, ppm) 1.0 2.0 3.0 4.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Chemical shift (, ppm) 1

Isobutyraldehyde H C O CH(CH3)2 1 Chemical shift (, ppm) 1.0 2.0 3.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Chemical shift (, ppm) 1

13C NMR Carbonyl carbon is at extremely low field-near  200 ppm. Intensity of carbonyl carbon is usually weak.

3-Heptanone O CH3CH2CCH2CH2CH2CH3 Chemical shift (, ppm) 1 20 40 60 20 40 60 80 100 120 140 160 180 200 Chemical shift (, ppm) 1