Chapter 22. Carbonyl Alpha-Substitution Reactions O "' " #' !' ! # O E+ O H Enolate O E carbonyl H O E+ Enol 228 Tautomers: isomers, usually related by a proton transfer, that are in equilibrium 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 376 O-H 436 C-H 420 ΔH° = -104 KJ/mol 229 116 Keto-enol tautomerism is catalyzed by both acid and base 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 Enols: The Mechanism of Alpha-Substitution Reactions H O OH C C C C nucleophile Enol General mechanism for acid-catalzyed α-substitution of carbonyls (Figure 22.3) 231 117 22.3: Alpha Halogenation of Aldehydes and Ketones 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 [ketone/aldehyde] [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 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 233 118 Mechanism (p. 828, please read) α-bromo carboxylic acids, esters, and amides 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 Hydrogen 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 oxygen H C C C C C C O O O O H3C CH3 C H3CH2COH H3C CH3 ethane acetone ethanol 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 nitriles 25 H3C N(CH3)2 238 Acidity of 1,3-dicarbonyl compounds O O C C H C OCH H3C CH3 3 3 ketone ester 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. Enolates 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 Haloform Reaction 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 alkyl 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 hydrolysis to the malonic acid (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-dicarboxylic acid (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 ethyl acetoacetate 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.