<<

C H N 129.0 10 11 128.0 127.3 29.2 38.9 11.4

CDCl 135.8 120.7 3 TMS

1.92 3.72 (2H, dq, J=7.4, 7.1) (1H, t, J=7.1) 7.3 1.06 (5H, m) (3H, t, J=7.4)

187

Chapter 20: and

O E+ O H O E

carbonyl H O E+

Enol

20.1: Content and Enolization

O β' β

γ' α' α γ

188

94 : , usually related by a transfer, that are in equilibrium.

Keto-enol tautomeric equilibrium lies heavily in favor of the keto form (see Table 20.1, p. 821).

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% 189

Enolization is - and -catalyzed (p. 823):

Base-catalyzed mechanism:

Acid-catalyzed mechanism:

190

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

Rate= k [/] [H+]

rate dependent on enol formation and not [X2] 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 H+ CH3 CH3 CH3 191

Hell-Volhard-Zelinsky Reaction – α-halogenation of carboxylic : O O Br2, PBr3 H C Br C C OH C OH then H2O

Mechanism of α-halogenation goes through an acid bromide intermediate. An acid bromide enolizes more readily than a . Mechanism is analogous to the α-halogenation of aldehydes and ketones

The α-halo carboxylic acid can undergo substitution to give α-hydroxy and α -amino acids. Br O O K2CO3, H2O HO R C C OH R C C OH Δ H H

O Br H N O NH3, H2O 2 192 R C C OH R C C OH H H

96 20.2: Enolates

Typical pKa’s of the α- carbonyl compounds (Table 20.1, p. 825):

aldehydes 17 O O O ketones 19 C C C H3C H H3C CH3 H3C OCH3 25 O amides 30 C H3C C N H C N(CH ) nitriles 25 3 3 2 Acidity of 1,3- compounds

O O C C H3C OCH3 H3C CH3 esterester! ketone ppKaa == 242254! pKa= 19 O O O O O O C C C C C C H3C C OCH3 H C C CH H3CO C OCH3 3 3 H H H H H H 1,3-diester 1,3-keto 1,3-diketone 193 pKa= 13 pKa= 11 pKa= 9

The inductive effect of the carbonyl causes the α-protons to be more acidic. The negative charge of the enolate (the conjugate base of the carbonyl compound) is stabilized by delocalization. The pKa of the α-protons of aldehydes and ketones is in the range of 16-20 resonance effect δ - inductive O O δ+ O + B effect C H C C + H-B δ+ C C δ+ C

carbonyl Enolate anion

H

C C C C C C O O O

O

H3C CH3 C H3CH2COH H3C CH3 ethane 194 pKa= 50-60 pKa= 19 pKa= 16

97 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) _ 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 15.7 195 (stronger acid) (stronger base) (weaker base) (weaker acid)

Lithium diisopropylamide (LDA): a super strong base

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

diisopropylamine LDA

pKa= 36 pKa= 60

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

pKa= 19 pKa= 36 (stronger acid) (stronger base) (weaker base) (weaker acid)

O O C + N C + N H H3C OCH2CH3 H2C OCH2CH3

pKa= 25 pKa= 36 (stronger acid) (stronger base) (weaker base) (weaker acid)

196

98 Enolate Regiochemistry – deprotonation of unsymmetrical ketones. O O O B: B: H3C H H3C H H3C H H H H H B-H B-H

More substituted enolate: Less substituted enolate: thermodynamically more stable less hindered, formed faster kinetically

The more substituted (thermodynamic) enolate is formed under reversible conditions (tBuO- K+, tBuOH).

The less substituted (kinetic) enolate is formed under irreversible conditions (LDA, THF, -78°C).

197

20.3: 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. Mechanism of the base-catalyzed (Mechanism 20.2, p. 828):

O HO H O 2 + – OH H3C C H H3C C C C H H H 3-hydroxybutanal (β-hydroxyaldehyde)

The position of the equilibrium for the aldol reaction is highly dependent on the reaction conditions, substrates, and steric considerations of the aldol product. Low temperature tends to favor the aldol product. 198

99 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 acid- or base-catalyzed dehydration to an α,β-unsaturated carbonyl. The dehydration is essentially irreversible. The dehydration is favored at higher temperatures. (mechanism, p. 829)

199

20.4: Mixed and Directed Aldol Reactions – Mixed 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 200

100 Directed aldol reaction – Discrete generation of an enolate with lithium diisopropyl amide (LDA) under aprotic conditions (THF as solvent) 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

20.5: Acylation of Enolates: The Reaction. Base-promoted condensation of two esters to give a β-keto-ester product

O Na+ –OEt, EtOH O O 2 C C C H C OEt + 3 then H3O H3C C OEt H H Ethyl 3-oxobutanoate Ethyl acetate () 201

The mechanism of the Claisen condensation (Mechanism 20.3, p. 834) is a base promoted nucleophilic acyl substitution of an ester by an ester enolate and is related to the mechanism of the aldol reaction.

202

101 The Dieckmann Cyclization: An intramolecular Claisen Condensation. The Dieckmann Cyclization works best with 1,6- diesters, to give a 5-membered cyclic β-keto ester product, and 1,7-diesters to give 6-membered cyclic β-keto ester product.

O OEt O O EtONa, EtOH OEt EtONa, EtOH O CO Et CO2Et 2 O OEt OEt O Mechanism: same as the Claisen Condensation

203

Mixed Claisen Condensations. Similar restrictions as the mixed aldol condensation. Four possible products:

O O O O C C C C O O EtONa, H3CH2CH2CH2C C OEt H3CH2C C OEt EtOH H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C OEt C OEt + H H H H then H3O O O O O C C C C C 5 C3 H3CH2C C OEt H3CH2CH2CH2C C OEt H3C H H H3CH2CH2C Esters with no α-protons can only act as the electrophile O O O EtONa, O EtOH C C C + H3C C OEt C OEt C OEt + H C H H H then H3O 3 Discrete (in situ) generation of an ester enolate with LDA O

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

H3CH2CH2C C O O Li+ C OEt O O LDA, THF, -78°C H C C H H C C 3 H3C C H CH CH CH C C OEt C OEt C OEt 3 2 2 2 204 + H C H H H H then H3O 3

102 Acylation of Ketones with Esters. An alternative to the Claisen condensations and Dieckmann cyclization.

b) O O O O a) LDA, THF, -78° C O C H3CO OCH3 OCH3

- + H3CO Na , H3COH

O Equivalent to a mixed O OR + C H C Claisen condensation 3 OCH3

O O b) O O O a) LDA, THF, -78° C C H CO OCH 3 3 OCH3

- + H3CO Na , H3COH Equivalent to a O O Dieckmann cyclization H3CO OCH3 205

20.6: Alkylation of Enolates: The Acetoacetic Ester and Malonic Ester Syntheses – enolate anions of aldehydes, ketones, and esters 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 206

103 Acetoacetic Ester Synthesis: The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2). The product, a β-keto ester, is then hydrolyzed to the β-keto acid and decarboxylated to the ketone. (Ch. 18.16).

O O + O O EtO Na HCl, Δ C CO Et - CO2! C CH R C CO2Et + RH2C-X 2 C CO2H 2 H C C H C C H C C H3C C 3 EtOH 3 3 H H RH C H RH C H H H alkyl 2 2 ethyl acetoacetate halide _ ketone EtO Na+, R'H2C-X EtOH O O - CO O O O HCl, C C 2! Δ C CH R H3C C OH 2 C C H3C C H3C C OEt R'H2C CH2R H CH2R' R'H2C CH2R

An acetoacetic ester can undergo one or two alkylations to give an α-substituted or α,α-disubstituted acetoacetic ester

The enolates of acetoacetic esters are synthetic equivalents to ketone enolates 207

O O + H CO + H COH H C 3 H C 3 C CH3 C CH3 pKa= 16 H H H acetoaacetonecetic es ter pK = 19 pKaa= 19

O O O O + H CO + H COH C C 3 C C 3 H3C C OCH3 H3C C OCH3 pKa= 16 H H H acetoacetic ester pKa= 11 β-Keto esters other than ethyl acetoacetate may be used. The products of a Claisen condensation or Dieckmann cyclization are acetoacetic esters (β-keto esters) O O EtONa, O O H O+ EtONa, EtOH EtOH 3 OEt CO Et CO Et 2 2 Δ O Br then H O+ 3 acetoacetic OEt ester Dieckmann cyclization EtONa, NaOEt O O EtOH O O + O H O H3O H3CH2C C HC C OEt Br H CH C C C C OEt H3CH2C C C CH2CH=CH2 2 H3CH2C C OEt EtOH 3 2 Δ + CH CH CH3 then H3O 3 3 acetoacetic Claisen condensation 208 ester

104 The Malonic Acid Synthesis:

+ CO2Et EtO Na HCl, Δ -CO2 + RH2C-X EtO C CO Et HO2C CO2H 2 2 C RH2C-CH2-CO2H EtOH C CO2Et RH C H alkyl RH2C H 2 carboxylic diethyl halide acid malonate + EtO Na , R'H2C-X Et= ethyl EtOH CH2R HCl, Δ -CO2 HO2C CO2H CH CO2H EtO2C CO2Et C C CH R' RH2C CH2R' 2 RH2C CH2R' carboxylic acid

O O H C + EtO H C + EtOH C OEt C OEt pKa= 16 H H H ethyl acetate pKa= 25

O O O O C C + EtO + EtOH EtO C OEt C C EtO C OEt pKa= 16 H H H pKa= 13 209

Summary: Acetoacetic ester synthesis: equivalent to the alkylation of an ketone (acetone) enolate Malonic ester synthesis: equivalent to the alkylation of a carboxylic (acetic) acid enolate

20.7: The Haloform Reaction – Carbonyls undergo α-halo- genation through base promoted enolate formation (Ch. 20.1).

OH O O O NaOH, H2O Br Br C C Br C H C + NaBr C C

The product is more reactive toward enolization, which results 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 210 pKa ~14 pKa ~12

105 The α,α,α -trihalomethyl ketone reacts with aquous hydroxide to give the carboxylic acid and haloform (HCX3) (Mechanism 20.4, p. 842)

Iodoform reaction: chemical tests for a methyl ketone

O O NaOH, H2O Iodoform: bright yellow C C + HCI3 R CH3 I2 R O Iodoform precipitate

211

20.8: Conjugation Efects in α,β–Unsaturated Aldehydes and Ketones – carbonyls that are conjugated C=C.

1 O β' R= H, α,β-unsaturated aldehyde= enal 3 R 2 4 α γ R≠ H, α,β-unsaturated ketone= enone

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

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

212

106 1,2 vs 1,4-addition to α,β-unsaturated ketone and aldehydes – The resonance structures of an α,β-unsaturated ketone or aldehyde suggest two sites for ; the carbonyl carbon and the β-carbon.

1 O β' 3 R 2 4 α γ

Organolithium reagents, Grignard reagents and LiAlH4 react with α,β-unsaturated ketone and aldehydes at the carbonyl carbon. This is referred to as 1,2-addition.

Organocopper reagents, enolates, amines, thiolates, and cyanide react at the β-carbon of α,β-unsaturated ketone and aldehydes. This is referred to a 1,4-addition or conjugate addition. 213

When a reaction can take two possible path, it is said to be under kinetic control when the products are reflective of the fastest reaction. 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.

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

214

107 Preparation of organocopper reagents organocopper reagents(Ch. 14.10)

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 C H C6H13 6 13 α,β -unsaturated ketones and aldehydes react with O O O O

(H2C=CH)2CuLi diorganocopper reagents to

O O give 1,4-addition products (C-C bond forming reaction) O O Ph2CuLi

H3C H3C Ph 215 CH3 H3C H3C CH3

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

This Michael addition product can be decarboxylated.

O H H O + O H H O H3O , Δ C C C C C C H3C C C CH3 - EtOH, H3C C C CH3 -CO2 H H H CO2Et H H H H

216

108 Robinson Annulation – The product of a Michael reaction is a 1,5- dicarbonyl compound, which can undergo a subsequent intramolecular aldol reaction to give a cyclic α,β-unsaturated ketone or aldehyde. annulation: to build a ring onto a reaction substrate

EtONa, CO Et CO2Et CO Et 2 EtOH -H2O 2 + O O O O O

Michael reaction Intramolecular aldol condensation and dehydration

217

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 218

109 Synthetic Applications of ( Ch. 21, p.910). Recall that the reaction of a ketone with a 2° amines gives an (Ch. 17.11, p. 712)

O N N H+ - H+ + N -H2O H ketone Iminium ion Enamine or aldehyde 2° amine w/ α-protons Enamines are reactive equivalents of enols and enolates and can undergo α-substituion reaction with electrophiles. The enamine (iminium ion) is hydrolyzed to the ketone after alkylation.

N N

H H O O

219

Reaction of enamine with α,β-unsaturated ketones (Michael reaction). O O N O + CH 3 then H2O

Enamines react on the less hindered side of unsymmetrical ketones O O O O N CH 3 H C H3C 3 + H3C then H2O N H 220

110

Nu O Grignard Nu OH addition R1 R1 H R2

R1 R1

O 1,4-addition CO2CH3 R1 aldol R H OH O O Wittig 2 reaction Diels- R2 R reaction + R1 -or- 1 R Alder H H 1 R O 1 R R1 1 R aldol 1 CO2CH3 H products R1

R1 H2, Pd/C

O -or- O Wittig α-alkylation + R reaction R R R1 H 1 1 2 X H R1 R1 R1 aldol Grignard reaction addition OH OH O R1 R1 R4 R2 R1 R3 R1

Robert B. Woodward (Harvard): 1965 Nobel Prize in Chemistry 221 "for his outstanding achievements in the art of organic synthesis"

OH

2-ethyl-1-hexanol

O

H O O O OH H H H

two n-C4 units

O

X H

222

111