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Chapter 22. Carbonyl Alpha-Substitution Reactions

O "' "

#' !' ! #

O E+ O H O E

carbonyl H O E+

Enol

228

Tautomers: isomers, usually related by a proton transfer, that are in equilibrium Keto- 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 376 O-H 436 C-H 420 ΔH° = -104 KJ/mol

229

116 Keto-enol tautomerism is catalyzed by both and

Acid-catalyzed mechanism (Figure 22.1):

Base-catalyzed mechanism (Figure 22.2):

The carbonyl significantly increases H H O H H C C C the acidity of the α-protons C C 230 H H H H

22.2: Reactivity of : The Mechanism of Alpha-Substitution Reactions H O OH C C C C

Enol

General mechanism for acid-catalzyed α-substitution of carbonyls (Figure 22.3)

231

117 22.3: Alpha Halogenation of and an 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.

O + O X2, H C H C X C C X= Cl, Br, I Mechanism of the acid-catalyzed α-halogenation (Fig. 22.4)

Rate= k [/] [H+] rate dependent on enol formation 232

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 CH3 CH3

22.4: Alpha Bromination of Carboxylic : The Hell–Volhard–Zelinskii (HVZ) Reaction

α-bromination of a

O O Br , PBr , AcOH H C 2 3 Br C C OH C OH then H2O 233

118 Mechanism (p. 828, please read)

α-bromo carboxylic acids, , and

O O Br2, PBr3, AcOH OH then H2O Br Br H3CNH2 H2O CH3CH2OH

O O O

OH CH3 OCH2CH3 N Br H Br Br 234

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 CH3 CH3

22.4: Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii (HVZ) Reaction

α-bromination of a carboxylic acid

O O Br , PBr , AcOH H C 2 3 Br C C OH C OH then H2O 235

119 22.5: Acidity of Alpha Atoms: Enolate Ion Formation Base induced enolate formation

B O O O C H C C C C C

Enolate anion The negative charge of the enolate ion (the conjugate base of the aldehyde or ketone) is stabilized by delocalization onto the

H

C C C C C C O O O

O

H3C CH3 C H3CH2COH H3C CH3

ethane acetone 236 pKa= 60 pKa= 19 pKa= 16

Base induced enolate formation

O O H CH CO C + 3 2 C + H3CH2COH H3C CH3 H3C CH2

acetone ethoxide enolate ethanol pKa= 19 pKa= 16 (weaker acid) (weaker base) (stronger base) (stronger acid)

Lithium diisopropylamide (LDA): a very strong base

diisopropylamine N Li N H pKa= 40

LDA is used to generate enolate ions from carbonyl by abstraction of α-protons O O

C + [(H3C)2CH]2N C + [(H3C)2CH]2NH H3C CH3 H3C CH2

pKa= 19 pKa= 40 (stronger acid) (stronger base) (weaker base) (weaker acid) 237

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

pKa= 40 pKa= 60

α-deprotonation of a carbonyl compound by LDA occurs rapidly in THF at -78° C.

Typical pKa’s of carbonyl compounds (α-protons): aldehydes 17 O O O ketones 19 C C C H C H H C CH H C OCH esters 25 3 3 3 3 3 amides 30 O C H3C C N 25 H3C N(CH3)2

238

Acidity of 1,3- compounds

O O C C H C OCH H3C CH3 3 3 ketone pKa= 19 pKa= 25 H H O O O C O O O C C C C C C H3C C CH3 O O H3CO C OCH3 C H H H H H3C CH3 1,3-diketone 1,3-diester Meldrum's acid pKa= 9 pKa= 13 pKa= 5 O O C C H3C C OCH3 H H

1,3-keto ester pKa= 11 Why is Meldrum’s acid more acidic than other dicarbonyl

compounds? 239

121 Delocalization of the negative charge over two carbonyl groups dramatically increases the acidity of the α-protons

O O O O O O C C C C C C pKa= 9 H3C C CH3 H3C C CH3 H3C C CH3 H H H

O O O O O O C C C C C C pKa= 11 H3C C OCH3 H3C C OCH3 H3C C OCH3 H H H

O O O O O O C C C C C C pKa= 13 H3CO C OCH3 H3CO C OCH3 H3CO C OCH3 H H H

Enolate formation for a 1,3-dicarbonyl is very favorable

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 240 pKa= 11

22.6: Reactivity of enolate ions By treating carbonyl compounds with a strong base such as LDA, quantitative α-deprotonation occurs to give an enolate ion. Enolate ions are much more reactive toward electrophiles than enols. can react with electrophiles at two potential sites

B O O O C H C C C C C

E E

E O O C E C C C

241

122 22.7 Halogenation of Enolate Ions: The Carbonyls undergo α-halogenation through base promoted enolate formation

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

Base promoted α-halogenation carbonyls is difficult to control because the product is more acidic than the starting material; mono-, di- and tri-halogenated products are often produced

O O O NaOH, H2O Br Br NaOH, H2O C Br C C Br C C C H H Br H Br

O O Br2 C Br C Br C C Br Br Br 242

Haloform reaction:

O OH O NaOH, H2O O OH C C X C X X C C CH3 2 X X X X

O O C + CX3 + HCX3 OH C O Haloform Iodoform reaction: chemical tests for a methyl ketone

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

243

123 22.8 Alkylation of Enolate Ions Enolates react with halides (and tosylates) to form a new C-C bond (alkylation reaction)

B O O O C X SN2 O C H C C C C C C C C

Reactivity of alkyl halides toward SN2 alkylation: H H H C H H H H H R H X _ >> ~ C > C > C C X H X R X R X

benzylic allylic methyl primary secondary

tosylate ~_ -I > -Br > -Cl

Tertiary, vinyl and aryl halides and tosylates do not

participate in SN2 reactions 244

Malonic Ester Synthesis overall reaction

CO Et 2 EtO Na+, EtOH + RH2C-X RH2C-CH2-CO2H then HCl, ! CO2Et alkyl carboxylic diethyl acid malonate halide Et= ethyl

O O O O C C + EtO + EtOH EtO C OEt C C EtO C OEt pKa= 16 H H H diethyl malonate pKa= 13

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

245

124 A malonic ester can undergo one or two alkylations to give an α-substituted or α-disubstituted malonic ester

Decarboxylation: Treatment of a malonic ester with acid and heat results in to the (β-di-acid). An acid group that is β to a carbonyl will lose CO2 upon heating.

O O O HCl, ! O O - CO2 RH2C C C C C C C OH EtO C OEt HO C OH H CH R H H 2 H CH2R 246

Mechanism of decarboxylation: β- (malonic acid synthesis)

β-keto carboxylic acid (acetoacetic ester synthesis)

247

125 CO Et CO2Et + H CH CH CH C 2 HCl, ! H EtO Na , EtOH 3 2 2 2 H CH CH CH C-H CCO H C + H CH CH CH C-Br C 3 2 2 2 2 2 3 2 2 2 H H CO Et CO2Et 2

+ CO Et CO2Et EtO Na , EtOH H 2 EtO Na+, EtOH H3CH2CH2CH2C C + H CH CH CH C-Br C 3 2 2 2 H H CH C-Br H CO Et 3 2 CO2Et 2

CO2Et HCl, ! H3CH2CH2CH2C H3CH2CH2CH2C CO2H C C H3CH2C CO2Et H3CH2C H

CO2Et + CO2Et H EtO Na , EtOH Br-CH2-CH2-H2C-H2C C Br-CH -CH -H C-H C-Br C H + 2 2 2 2 H CO2Et CO2Et H H H H H H C C CO H EtO Na+, EtOH H C CO2Et HCl, ! H C 2 cyclopentane C C carboxylic acid C H C H C CO2Et C H H H H H H H 248

Acetoacetic ester synthesis

O O EtO Na+, EtOH C CO2Et + RH2C-X RH2C C H3C C then HCl, ! C CH3 H H H H alkyl halide ketone

O O O O + EtO + EtOH C C C C H3C C OEt H3C C OEt pKa= 16 H H H diethyl malonate pKa= 11

O O H C + EtO H C + EtOH C CH C CH 3 3 pKa= 16 H H H acetone pKa= 19

249

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

Decarboxylation: Treatment of the acetoacetic ester with acid and heat results in hydrolysis to the acetoacetic acid (β-keto acid), which undegoes decarboxylation 250

EtO Na+, O CO2Et CO2Et H EtOH H3CH2CH2CH2C HCl, ! + H CH CH CH C-Br C C C 3 2 2 2 H CH CH CH C-H C CH H H - CO 3 2 2 2 2 3 C CH3 C CH3 2 O O ethyl acetoacetate

+ EtO Na+, EtO Na , CO2Et CO2Et H EtOH H3CH2CH2CH2C EtOH C + H3CH2CH2CH2C-Br C H H H CH C-Br C CH3 C CH3 3 2 O O ethyl acetoacetate O HCl, CO2Et ! H3CH2CH2CH2C H3CH2CH2CH2C C C C - CO CH3 H3CH2C 2 H3CH2C C CH3 H O

+ EtO Na+, EtO Na , CO2Et CO2Et H EtOH Br-CH2-CH2-H2C-H2C EtOH C + Br-CH2-CH2-H2C-H2C-Br C H H C CH3 C CH3 O O ethyl H H H acetoacetate H H H O C H C CO2Et HCl, ! C C H C CH C C 3 H C CH3 C C - CO2 H C H 251 H H H O H H H

127 acetoacetic ester O EtO Na+, O O O EtOH Br HCl, ! CO Et CO2Et 2 CO2Et - CO2 H Summary: Malonic ester synthesis: equivalent to the alkylation of a carboxylic (acetic) acid enolate CO Et 2 EtO Na+, EtOH + RH2C-X RH2C-CH2-CO2H then HCl, ! CO2Et

base O RH2C-X H C-CO H 3 2 C RH2C-CH2-CO2H H2C OH Acetoacetic ester synthesis: equivalent to the alkylation of an acetone enolate O O EtO Na+, EtOH C CO2Et + RH2C-X RH2C C H3C C then HCl, ! C CH3 H H H H O O base O RH C-X 2 RH2C C C C CH3 H3C CH3 C 252 H2C CH3 H H

Direct alkylation of ketones, esters and nitriles α-Deprotonation of ketones, esters and nitriles can be accomplished with a strong bases such as lithium diisopropylamide (LDA) in an aprotic solvent such as THF. The resulting enolate is then reacted with alkyl halides to give the α-substitution product.

O O

H3C RH2C-X H3C CH2R O major H C 3 LDA, THF

O -78° C O RH2C RH2C-X H3C minor H3C

253

128 Ester enolate O O C RH2C-X CH R OEt LDA, THF C 2 OEt -78° C CO2Et

O O O RH C-X LDA, THF 2 CH R O O O 2 -78° C

Nitrile enolate

N N CH2R C LDA, THF C RH2C-X C -78° C N

254

Biological decarboxylation reactions:

O H B O- S O PPO OH H O P O S O - CO P - S 2 O PPO H C C CO H N N -O O 3 2 + N O- N CH3 N R NH2 R

Thiamin Diphosphate (Vitamin B1) Enzyme Enzyme :B H B S PPO OH PPO OH H PPO O S S PPO O + S N H3C C H N N H CH3 CH3 N CH3 R R R R L-DOPA decarboxylase O R R O H O- HO CO 2 L-DOPA OH N N 2- + decarboxylase H - CO2 H O3PO NH3 HO O O N formation PO PO L-DOPA Pyridoxal Phosphate N N H H (Vitamin B6) Enzyme R H B R H H N N O H H H2O H HO NH3 + O O 2- OH PO PO O3PO HO N N N 255 H H Dopamine

129