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Chapter 18: and

O E+ O H O E

carbonyl H O E+

Enol

18.1: The α-Carbon Atom and its pKa

O "' "

#' !' ! #

126

The inductive effect of the carbonyl causes the α- to be more acidic. The negative charge of the enolate (the conjugate of the or ) is stabilized by delocalization. The pKa of the α-protons of and is in the range of 16-20 (Table 18.1, p. 754) resonance effect ! - inductive O O !+ O + B effect C H C C + H-B !+ C C C

carbonyl Enolate anion

H

C C C C C C O O O

O

H3C CH3 C H3CH2COH H3C CH3 ethane ethanol 127 pKa= 50-60 pKa= 19 pKa= 16

65 O O O O O C C Cl C C C H3C CH3 H3C C H3C C H3C C CH3 H H H H H H

pKa 19 14 16 9

O O + H O C + H3O C 2 H C CH H3C CH3 3 2 acid base conjugate conjugate base acid

pKa 19 -1.7 (weaker acid) (weaker base) (stronger base) (stronger acid)

O O + HO C + H O C H C CH 2 H3C CH3 3 2 acid base conjugate conjugate base acid

pKa 19 15.7 (weaker acid) (weaker base) (stronger base) (stronger acid) 128

O O O O C C + H2O C C + HO H C C CH H C C CH 3 3 3 3 H H H acid base conjugate conjugate base acid

pKa 9 15.7 (stronger acid) (stronger base) (weaker base) (weaker acid)

18.2: The - An enolate of one carbonyl () reacts with the carbonyl carbon () of a second carbonyl compound resulting in the formation of a new C-C bond

O OH O 2 H C C H + HO + HO 3 H3C CH CH2 C H

3-hydroxybutanal (!-hydroxy aldehyde)

129

66 Mechanism of the base-catalyzed aldol condensation (Fig. 18.1)

The position of the equilibrium for the is highly dependent on the reaction conditions, substrates, and steric considerations of the aldol product. Low temperature tends to favor the aldol product. 130

O H O NaOEt HO H aldol reactions involving α-monosubstituted R C C H R C C EtOH C C H aldehydes are generally favorable H H H H R

O H O NaOEt HO H aldol reactions involving α,α-disubstituted R C C H R C C aldehydes are generally unfavorable EtOH C C H R R H R R

O H O NaOEt HO R aldol reactions involving ketones are R C C R R C C generally unfavorable EtOH C C R H H H R H The aldol product can undergo base-catalyzed dehydration to an α,β-unsaturated carbonyl. The dehydration is essentially irreversible. The dehydration is favored at higher temperatures. (mechanism Fig. 18.2)

131

67 18.3: Mixed Aldol Reactions - Aldol reaction between two different carbonyl compounds

Four possible products (not very useful) HO H O HO H O C C C C O O NaOH, H3CH2CH2CH2C C H H3CH2C C H H2O H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C H C H H H H H HO H O HO H O C C C C H3CH2C C H H3CH2CH2CH2C C H H3C H H H3CH2CH2C Aldehydes with no α-protons can only act as the electrophile O HO H O O O NaOH, HO H C C C + H3C C H2O + C C H C H C H H3CH2C C H H H H3C H H3C H

Preferred reactivity

HO H O O O NaOH, C C C C H2O H + C CH3 H3C CH 3 H H

132

Discrete generation of an enolate with lithium diisopropyl amide (LDA) under aprotic

conditions (THF as solvent) THF O

H3C C HO H O O O Li+ C H LDA, THF, -78°C C C H CH CH C C H H 3 2 2 H3CH2CH2C C H3CH2C C H C H C H H then H2O H CH CH C H H H 3 2 2 O

H3CH2CH2C C O O Li+ C H HO H O LDA, THF, -78°C H H C C H3C C H3C C C H C H H3CH2CH2CH2C C H H C H H H H then H2O 3

Lithium diisopropylamide (LDA): a very strong base

O O C + N Li C + N H H3C CH3 H3C CH2

pKa= 19 pKa= 40 (stronger acid) (stronger base) (weaker base) (weaker acid)

+ H CH CH CH C N H + H3CH2CH2CH2C Li N Li 3 2 2 3

133 pKa= 40 pKa= 60

68 18.4: Alkylation of Enolate - enolate anions can react with other such as alkyl halides and tosylates to form a new C-C bonds. The alkylation reaction is an SN2 reaction.

Reaction works best with the discrete generation of the enolate by LDA in THF, then the addition of the alkyl halide

18.5: Enolization and Content : , usually related by a transfer, that are in equilibrium

134

Keto-enol tautomeric equilibrium lies heavily in favor of the keto form. H O O C C H C C

enol keto

C=C ΔH° = 611 KJ/mol C=O ΔH° = 735 KJ/mol C-O 380 C-C 370 O-H 426 C-H 400 ΔH° = -88 KJ/mol

OH O C H H3C C H3C CH3 H

99.9999999 % 0.0000001%

Enolization is acid- and base-catalyzed 135

69 Base-catalyzed mechanism (Figure 18.3, 9.764):

Acid-catalyzed mechanism (Figure 18.4, p. 765):

18.6: Stabilized enols (please read)

136

18.7: α Halogenation of Aldehydes and Ketones- α-proton of aldehydes and ketones can be replaced with a -Cl, -Br, or -I (-X)

through the acid-catalyzed reaction with Cl2 , Br2 , or I2 , (X2) respectively. The reaction proceeds through an enol.

O O H X2, H-X X H H + H-X X= Cl, Br, I

18.8: Mechanism of α Halogenation of Aldehydes and Ketones Acid-catalyzed mechanism (Fig. 18.5, p. 769)

Rate= k [ketone/aldehyde] [H+] 137 rate dependent on enol formation and not [X2]

70 α,β-unsaturated ketones and aldehydes: α -bromination followed by elimination O O O CH3 CH - + 3 Br2, CH3CO2H (H3C)3CO K CH3 Br E2 Why is one enol favored over the other?

OH O OH + CH3 H CH3 CH3

18.9: The Haloform Reaction. Mechanism of the base-promoted α-halogenation of aldehydes and ketones (Fig. 18.6, p. 770)

138

In the base promoted reaction, the product is more reactive toward enolization and resulting in further α-halogenation of the ketone or aldehyde. For methyl ketone, an α, α, α -trihalomethyl ketone is produced. O O O O NaOH, NaOH, H2O X C X 2 C X H2O, X2 C X C X C C C C H H H X X X H pKa ~14 pKa ~12 The α, α, α -trihalomethyl ketone reacts with aquous hydroxide

to give the and haloform (HCX3)

Iodoform reaction: chemical tests for a methyl ketone O O NaOH, H2O + HCI Iodoform: bright yellow C C 3 139 R CH3 I2 R O Iodoform precipitate

71 18.10: Some Chemical and Stereochemical Consequences of Enolization (please read)

O O NaOD, D2O D D -or- D D + D3O

O O O (R) (R) (S) NaOD, D2O + H -or- CH H3C + H3C H H 3 D3O 50 : 50 18.11: Effects of Conjugation in α,β-Unsaturated Aldehydes and Ketones. α,β -Unsaturated carbonyl have a conjugated C=C 1 O "' R= H, α,β-unsaturated aldehyde= enal 3 R 2 4 R≠ H, α,β-unsaturated ketone= enone ! #

Conjugation of the π- of the C=C and C=O is a stabilizing interaction

140

α,β -Unsaturated ketones and aldehydes are prepared by: a. Aldol reactions with dehydration of the aldol b. α-halogenation of a ketone or aldehyde followed by E2 elimination

18.12: Conjugate Addition to α,β-Unsaturated Carbonyl Compounds. The resonance structures of an α,β-unsaturated ketone or aldehyde suggest two sites for ; the carbonyl carbon and the β-carbon

141

72 Organolithium reagents, Grignard reagents and 1 O "' LiAlH4 reaction α,β-unsaturated ketone and 3 R 2 4 aldehydes at the carbonyl carbon. This is referred ! # to as 1,2-addition.

Organocopper reagents, enolates, amines, react at the β-carbon of α,β-unsaturated ketone and aldehydes. This is referred to a 1,4-addition or conjugate addition.

When a reaction can take two possible path, it is said to be under kinetic control when the products are reflective of the path that reacts fastest. The reaction is said to be under thermodynamic control when the most stable product is obtained from the reaction. In the case of 1,2- versus 1,4 addition of an α,β- unsaturated carbonyl, 1,2-addition is kinetically favored and 1,4-addition is thermodynamically favored.

142

1,2 vs 1,4-addition α,β-unsaturated ketone and aldehydes

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

O 1) Nu: :Nu + O Nu 2) H3O Nu: C C C C No Reaction R C R C C H 143

73 18.13: Addition of to α,β-Unsaturated Carbonyl Compounds: The . The conjugate addition of a enolate ion to an α,β-unsaturated carbonyl. The Michael reaction works best with enolates of β-.

EtONa, O O O O H H O EtOH C CH2 + C C C C C H C C 3 EtO C CH3 H3C C C CH3 H H H H H H CO2Et electrophile nucleophile

The product of a Michael reaction is a 1,5- compound, which can undergo a subsequent intramolecular aldol reaction to give a cyclic α,β-unsaturated ketone or aldehyde. This is Known as a .

144

O OH H3C H3C

H H3C H

H H H H HO HO HO O

Lanosterol Cholesterol Estrone Testosterone

O O O H C H3C H3C O Robinson 3 OH O O HO Li(0), NH3 H3C annulation + H+ tBuOH O O O O H O

O O O H C H C 3 O 3 O H3C H3C-I NaBH4 A-B ring precursor of steroids

O HO P-O H H H

O O H3C Robinson annulation O + H3C O H3CO O H3CO 145

74 18.14: Conjugate Addition of Organocopper Reagents to α,β-Unsaturated Carbonyl Compounds Recall from Ch. 14.11 the preparation of organocopper reagents

2 Li(0) R-X R-Li + LiX Dialkylcopper lithium: (H3C)2CuLi pentane Divinylcopper lithium: (H C=CH) CuLi ether 2 2 2 R2Li + CuI R2CuLi + LiI Diarylcopper lithium: Ar CuLi diorganocopper reagent 2 (cuprate, Gilman's reagent)

O H3C O (H3C)2CuLi

C6H13 C6H13 α,β -unsaturated ketones and aldehydes react with diorganocopper O O O O reagents to give 1,4-addition products (H2C=CH)2CuLi

O O (C-C bond forming reaction)

O O

Ph2CuLi

H3C H3C Ph CH3 H3C H3C CH3 146

75