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Home , Cannizzaro reaction, Carbonyl group, Carboxylic acid, Chemical test, Geminal, Thiocarboxylic acid

Preview of Carbonyl O O Kinds of carbonyls C C R H R R' 1. and -al -one O 2. Carboxylic derivatives O O C C C R O carboxylic R OH R OR' R' acid chlorides -oic acid -oate cyclic ester

acid anhydrides O O O C C C R Cl R O R acid chloride acid anhydride -oyl chloride -oic anhydride

O O C R' C R'' R N R N R C N R'' R' -amide cyclic amide -nitrile 132

Carbonyl groups have a significant dipole moment

! - O O O C ! + C C

Aldehyde 2.72 D Ketone 2.88 Carboxylic acid 1.74 Acid chloride 2.72 Ester 1.72 Amide 3.76 Nitrile 3.90

Water 1.85

Carbonyl are electrophilic sites and can be attacked by 133

67 Chapter 19: Aldehydes and Ketones: Reactions

Recall: and reduction

Chapter 20: Carboxylic Acids and Nitriles Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions

O O O + Y: C R Y R Nu R Nu :Nu Y tetrahedral intermediate Y is a : 134 -Cl (acid chloride), -OR (ester), -NR2 (amide) , -O2CR (anhydride)

Chapter 22. Carbonyl Alpha-Substitution Reactions Chapter 23. Carbonyl Condensation Reactions

O O O O C C C C C R' C R' ! C R' C R' H E B: anion E E= halide or carbonyl compound Chapter 24. Chapter 25. : H O

H C OH HO HO C H HO HO O H C OH HO H C OH OH

CH2OH Chapter 26: Biomolecules: Amino Acids, , and

H - H2O + N CO2H H2N H N CO H H N CO H 2 2 2 2 O

Ala Val Ala - Val

Carboxylic acids + amino group amides 135 (peptides & proteins)

68 Chapter 27. Biomolecules: fatty acids, , terpenoids

CO2H

O HO Aracidonic Acid Cholesterol Camphour

Chapter 28: Biomolecules: Heterocycles and Nucleic Acids DNA structure and function, RNA

The central dogma: DNA → mRNA → proteins

136

Chapter 19: Aldehydes and Ketones: Nucleophilic Addition Reactions Aldehydes and ketones are characterized by the the carbonyl (C=O)

19.1 Naming Aldehydes and Ketones Aldehydes are named by replacing the terminal -e of the corresponding name with -al The parent chain must contain the -CHO group The -CHO is numbered as C1 If the -CHO group is attached to a ring, name the ring andd add the suffix carboxaldehyde

O O O

H H H

137 butanal 2-ethyl-4-methylpentanal cyclohexane carboxaldehyde

69 Ketones are named by replacing 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

Non systematic names:

138

Ketones and Aldehydes as The R–C=O as a is an is used with the suffix -yl from the root of the carboxylic acid

The prefix oxo- is used if other functional groups are present and the doubly bonded is labeled as a substituent on a parent chain

139

70 19.2 Preparation of Aldehydes Oxidation of primary with pyridinium chlorochromate (PCC) Chapter 17.8 of an (with at least one =C-H) Chapter 7.8

electrical + 3 O 2 O O _ (O3): 2 discharge 3 O O

O3, CH2Cl2 O R R 1 3 -78 °C O O O O Zn R1 R3 R 1 R3 O + O R1 R3 R R2 R4 2 O R4 R2 R4 R2 R4 molozonide + ZnO

1) O3 2) Zn H + O=CH2

O 1) O3 2) Zn O

H 140 O

Hydroboration of a terminal (Chapter 8.5)

1) BH , THF 3 O 2) H2O2, NaOH R C C H R H

Reduction of an ester with diisobutylaluminum hydride (DIBAH) - not really a reliable reaction. Reduction of a lactone

or nitrile to an aldehyde is much better Al H

O O [H] O [H] C R C OCH3 R CH2OH R OCH3 C H R H fast H iBu O DIBAL Al H O+ O iBu 3 O C R OCH R C OCH C 3 3 R H H

iBu H O+ DIBAL Al iBu 3 O R C N N C C R H R H H 141

71 19.2 Preparation of Ketones Oxidation of alcohols with pyridinium chlorochromate (PCC) or (Ch. 17.8) Ozonolysis of an alkene (Chapter 7.8)

1) O3 2) Zn O + O

Oxymercuration of a terminal alkyne (methyl ketone)

+ (Chapter 8.5) HgSO4, H3O O R C C H R CH3

methyl ketone

O + O HgSO4, H3O R C C R R + R1 1 2 2 R2 -or- R1 hydroboration

142

Friedel-Crafts ( ketone) Chapter 16.4

O O C R Cl R

AlCl3

Reaction of an acid chloride with a Gilman reagent (diorganocopper lithium, cuprates) Chapter 10.9

H3C _ + 2 CH3Li + CuI Cu Li + LiI H3C Gilman's reagent (dimethylcuprate, dimethylcopper lithium)

O O C R Cl + (H3C)2CuLi C R CH3

143

72 19.3 Oxidation of Aldehydes and Ketones + Chromic acid (CrO3/H3O ) oxidizes aldehydes to carboxylic acids

Silver , Ag2O, in aqueous (Tollens’ reagent) oxidizes aldehydes to carboxylic acids

O AgO2 O NH4OH, H2O C C + Ag R H R OH

Precipitated Ag(0) forms a silver mirror: chemical test for aldehydes

144

19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones Nucleophiles:

w/ a formal negative charge Neutral: must have a of electrons

OH O H-A O O H-A OH -HOH Nu C C C C C C Nu Nu Nu-H Nu-H Nu: :Nu-H

145

73 19.5 Relative Reactivity of Aldehydes and Ketones aldehydes are more reactive toward nucleophilic addition than ketones.

In general aromatic aldehydes () are less reactive because of with the aromatic ring

19.6 Nucleophilic Addition of H2O: Hydration Water can reversibly add to the carbonyl carbon of aldehydes and ketones to give 1,1- (geminal or gem-diols)

OH O + H2O C C R OH R R R - H2O 146

R= H, H 99.9 % hydrate O + H O OH R= CH3, H 50 % 2 C R C R= (H3C)3C, H 20 % R R OH - H2O R R= CH3, CH3 0.1 %

The rate of hydration is slow, unless catalyzed by acid or Base-catalyzed mechanism (Fig. 19.4): is a better than water

Acid-catalyzed mechanism (Fig. 19.5): protonated carbonyl is a better

Does adding acid or base change the amount of hydrate? 147

74 The hydration is reversible

Hydration is a typical of aldehydes and ketones

148

19.7 Nucleophilic Addition of HCN: Formation Aldehydes and unhindered ketones react with HCN to give (mechanism: p. 694) Equilibrium favors cyanohydrin formation

O H C N OH C R R' pKa ~ 9.2 R C N R'

The nitrile of a cyanohydrin can be reduced to an or + hydrolyzed (with H3O ) to a carboxylic acid (Ch. 20.9)

LiAlH OH 4 OH + OH or B2H6 H3O C R C C OH CH2NH2 R C N R C R' R' R' O 149

75 19.8 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Formation (also see Chapters 17.6 & 17.5) Preparation of alcohols from ketones and aldehydes

MgX MgX OH O H O+ O R-MgX O 3 C C C R ether C R

R: M M OH O O H O+ M-H O 3 C C C C H H

H: Note: the mechanism () is not much different than for the hydration of carbonyls

O O H OH OH + :OH C C C OH OH :OH

H OH2 O OH OH OH + C + H3O C C C OH OH 150 :OH 2 H :OH2

19.9 Nucleophilic Addition of Amines: and Enamine Formation

Primary amines, RNH2, will add to aldehydes and ketones followed by lose of water to give (Schiff bases)

Secondary amines, R2NH, react similarly to give enamines, after lose of water and tauromerization (ene + amine = unsaturated amine)

151

76 Mechanism of Formation of Imines Imines are isoelectronic with a carbonyl Fig. 19.8

O

O H2N NH-opsin H HN

+ retinal G- coupled Lys-opsin receptor N H

+ h! opsin N G-protein Cascade H 152

Chapter 19.15: Please read

Pyridoxal Phosphate (Vitamin B6) Involved in , and catabolism

- R CO2 - R CO2 NH2 H O N Imine - H2O 2 OH () 2 OH O PO O3PO 3 + H2O N N H H

Pyridoxal phosphate dependent L-DOPA decarboxylase HO CO2 HO NH3 NH HO 3 HO CO2 aromatic amino acid HO NH decarboxylase 3 HO NH3

N N H H Serotonin 153

77 Related C=N derivatives

NO2 H NO2 N H OH NH2 N N O N H2NOH O2N NO2 2,4-dinitrohydrazine

-H2O -H2O 2,4-dinitrophenylhydrazone

Enamine Formation: Mechanism (Fig. 19.10)

154

19.10 Nucleophilic Addition of : The Wolff–Kishner Reaction

Reduction of aldehydes and ketones to a (CH2) with hydrazine (H2NNH2) and base (NaOH)

NH2 H H N O H H -N H2N-NH2, 2 NaOH H2, Pd/C

H2O

General reduction of ketones Chapter 16.11

and aldehydes to -CH2 Limited to aryl ketones

O H2N-NH2, NaOH, H2O

H3CO H3CO H N-NH , O 2 2 NaOH, H2O H

H2N-NH2, O NaOH, H2O

HO2C CO2H HO2C CO2H

155 Mechanism: Fig 19.11 (p. 702), please read

78 19.11 Nucleophilic Addition of Alcohols: Formation

O + CH3OH, H H3CO OCH3 C C + H2O R R' R R' ketone ketal aldehyde acetal Mechanism of acetal/ketal formation (Fig. 19.12)

The mechanism for acetal/ketal formation is reversible How is the direction of the reaction controlled? 156

OH O cannot be NaBH4 O OCH3 done directly OCH3 OH

O O Chapter 17.5 keto-ester + HOCH2CH2OH, - HOCH2CH2OH H3O - H2O HCl, C6H6

O O LiAlH4, ether O O OCH3 OH

O 1,3- ketal or an ketal

Dean-Stark 1 + O OH trap O H H+ 3 2 O O O OH O 2 4 6 6 2 4 6 1 3 7 5 1 3 7 5 4 O 8 5 8 8 9 9 9 7 Brevicomin

157

79 19.12 Nucleophilic Addition of Phosphorus : The 1979 Nobel Prize: Georg Wittig- Wittig Reaction H.C. Brown- Hydroboration The synthesis of an alkene from the reaction of an aldehyde or ketone and a phosphorus (Wittig reagent)

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 an ylide, a dipolar intermediate with formal opposite charges on adjacent (overall charge neutral). A phosphorane is a neutral resonance structure of the ylide. 158

Wittig reaction O CH2 Ph3P CH3 Br + Ph3P=O H3CLi, THF

Accepted Mechanism: (Fig. 19.13) Please read

+ + Ph3P O Ph3P O O PPh3 + C C C C C C R4 R2 R R R R R 4 R2 1 2 3 4 R R1 3 R3 R1 betaine oxaphosphetane ketone or (never onserved) aldehyde

R4 R2 C C + Ph3P=O

R3 R1

Predicting the geometry (E/Z) of the alkene product is complex and is dependent upon the nature of the ylide.

159

80 The Wittig reaction gives C=C in a defined location, based on the location of the (C=O) The Wittig reaction is highly selective for ketones and aldehydes; esters, , nitriles and amides will not react but are tolerated in the substrate. Acidic groups (alcohols, amine and carboxylic acids) are not tolerated.

CH CH3 O CH 2 1) CH3MgBr, THF + 2 Ph P CH + 2) POCl3 3 2 THF 1 : 9

O + O PPh O H + 3 O O O O CHO + O O + Ph P OCH3 3 OCH O 3 O 160

19.13 The : Biological Reductions (please read)- not a particularly useful reaction, but mechanistically important

O O NaOH A reaction between 2 C + C + PhCH2OH Ph H OH Ph OH two aldehydes catayzed by a strong base H OH O O OH + The aldehyde -H is a source of hydride C C Ph H Ph H (carbon hydride); most hydride sources are metal

Nicotinamide coenzyme: Natures (carbon) hydride source

H H H N O O 2 N H2N N O O O O N N O O P O P O O N NH2 N N O O P O P O O N NH2 N OH OH N OH OH O OH HO OH O OH HO OH R R reduced form oxidized form R= H NADH, NAD+ + 2- + 161 R PO3 NADPH, NADP

81 Alcohols dehydrogenase Enzyme H B :B H H H3C C O H3C C O H H H H CONH CONH2 2 CH3CH2OH

N N CH3CHO R R NAD NADH Glyceraldehyde-3-phosphate Dehydrogenase (G3PDH)

H H H 2- CONH O H CONH2 3- O OPO3 2 Csy S PO4 H OH + H OH + N N CH PO 2- CH PO 2- 2 3 R 2 3 R glyceraldehyde-3-phosphate NAD+ NADH O O P O O H H H CONH2 O CONH2 O S Csy Csy S H + N H OH N H OH R CH PO 2- 2- 2 3 R CH2PO3 NADH 162

19.14: Conjugate Nucleophilic Addition to α,β -Unsaturated Aldehydes and Ketones α,β -Unsaturated carbonyl have a conjugated C=C 1 R= H, -unsaturated aldehyde= enal O "' α,β 3 R≠ H, α,β-unsaturated ketone= enone R 2 4 ! # α,β -unsaturated carbonyls react with nucleophiles at two possible sites: the carbonyl carbon: direct addition or 1,2-addition the β-carbon: conjugate addition, or 1,4-addition

163

82 NOTE: conjugation to the carbonyl activates the β-carbon toward nucleophilic addition. An isolated C=C does not normally react with nucleophiles

O 1) Nu: :Nu + O Nu 2) H3O C C C R C R C H

C Nu: C No Reaction

Conjugate addition of amines: α,β -unsaturated carbonyls react

with primary (RNH2) or secondary (R2NH) amines to give the conjugate addition product

R N O O NHR C C C C + RNH2 C R C R C R C H thermodynamically favored 164

Conjugate addition of organocopper (Gilman) reagents α,β -unsaturated ketones react with Gilman reagents to give conjugate addition products (C-C bond forming reaction) Formation of Gilman reagents, R can be alkyl, vinyl or aryl but not alkynyl.

2 Li(0) R-X R-Li + LiX Dialkylcopper lithium: (H3C)2CuLi pentane

ether Divinylcopper lithium: (H2C=CH)2CuLi 2 R2Li + CuI R2CuLi + LiI Gilman's reagent Diarylcopper lithium: Ar2CuLi (cuprate, organocopper lithium)

Organocopper reagents are primarily used for conjugates addition reactions with α,β-unsaturated ketones; however, they also undergo direct addition to non-conjugated ketones (1,2-additions), aldehydes and will react with alkyl halides and tosylates, and

Mechanism of conjugate addition by organocopper reagents is complex (p. 714, please look over) 165

83 O (H C) CuLi OH O H C O 3 2 3 H (H3C)2CuLi C H H C H 6 13 6 13 CH C H C6H13 3 6 13 !,"-unsaturated aldehyde , -unsaturated aldehydes undergo direct O O O O α β

(H2C=CH)2CuLi (1,2-) addition with Grignard, organolithium, and organocopper reagents O O O OH H3C-MgBr C6H13 C6H13 O O -or- CH3 -unsaturated H3C-Li Ph CuLi !," 2 ketone H3C H3C Ph CH3 H3C H3C CH3 α,β-unsaturated ketones undergo direct (1,2-) addition with Grignard, and organolithium reagents

I O Li+ O

CO2Me Li+ RCu O Si O Si RO O Si

O CO2Me O

CO2H

Si O O HO 166 Si OH PGE2

19.16 of Aldehydes and Ketones

Mass spectrometry (p. 718-9, please read)

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

167

84 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 absorption to lower energy (right) Ring (angle) strain moves the C=O absorption to higher energy (left) 168

1H NMR Spectra of Aldehydes and Ketones

A typical 1H chemical shift for the aldehyde proton is ~ δ 9.8 ppm The aldehyde proton will couple to the protons on the α-carbon with a typical coupling constant of J ≈ 3 Hz A carbonyl will slightly deshield the protons on the α-carbon; typical chemical shift range is δ 2.0 - 2.5 ppm

9.8 2.2 (q, J =2.9 Hz) (d, J =2.9 Hz)

169

85 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) 170

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

carbonyl CDCl3

171

86 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 128 115 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 10 172

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

173

87