hapter 22. arbonyl Alpha-Substitution eactions "' " #'!'! # Enolate E + E carbonyl 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. enol = Δ = 611 KJ/mol - 380-436 Δ = -104 KJ/mol keto = Δ = 735 KJ/mol - 376-420 229 116
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 the acidity of the α-protons 230 22.2: eactivity of Enols: The Mechanism of Alpha-Substitution eactions Enol nucleophile General mechanism for acid-catalzyed α-substitution of carbonyls (Figure 22.3) 231 117
22.3: Alpha alogenation of Aldehydes and Ketones an α-proton of aldehydes and ketones can be replaced with a -l, -, or -I (-X) through the acid-catalyzed reaction with l 2, 2, or I 2, (X 2 ) respectively. X 2, + X= l,, I X Mechanism of the acid-catalyzed α-halogenation (Fig. 22.4) ate= k [ketone/aldehyde] [ + ] rate dependent on enol formation 232 α,β-unsaturated ketones and aldehydes: α -bromination followed by elimination 3 2, 3 2 3 ( 3 ) 3 - K + 3 E 2 Why is one enol favored over the other? 3 3 3 22.4: Alpha omination of arboxylic Acids: The ell Volhard Zelinskii (VZ) eaction α-bromination of a carboxylic acid 2, P 3, Ac then 2 233 118
Mechanism (p. 828, please read) α-bromo carboxylic acids, esters, and amides 2, P 3, Ac then 2 2 3 2 3 2 2 3 3 234 α,β-unsaturated ketones and aldehydes: α -bromination followed by elimination 3 2, 3 2 3 ( 3 ) 3 - K + 3 E 2 Why is one enol favored over the other? 3 3 3 22.4: Alpha omination of arboxylic Acids: The ell Volhard Zelinskii (VZ) eaction α-bromination of a carboxylic acid 2, P 3, Ac then 2 235 119
22.5: Acidity of Alpha ydrogen Atoms: Enolate Ion Formation Base induced enolate formation B Enolate anion The negative charge of the enolate ion (the conjugate base of the aldehyde or ketone) is stabilized by delocalization onto the oxygen 3 3 3 2 3 3 ethane acetone ethanol pk a = 60 pk a = 19 pk a = 16 236 Base induced enolate formation 3 3 + 3 2 3 2 + 3 2 acetone ethoxide enolate ethanol pk a = 19 pk a = 16 (weaker acid) (weaker base) (stronger base) (stronger acid) Lithium diisopropylamide (LDA): a very strong base Li diisopropylamine pk a = 40 LDA is used to generate enolate ions from carbonyl by abstraction of α-protons 3 3 + [( 3 ) 2 ] 2 pk a = 19 pk a = 40 (stronger acid) (stronger base) (weaker base) (weaker acid) 3 2 + [( 3 ) 2 ] 2 237 120
TF + 3 2 2 2 Li Li + 3 2 2 3 pk a = 40 pk a = 60 α-deprotonation of a carbonyl compound by LDA occurs rapidly in TF at -78. Typical pk a s of carbonyl compounds (α-protons): aldehydes 17 ketones 19 3 3 3 esters 25 amides 30 nitriles 25 3 ( 3 ) 2 3 3 3 238 Acidity of 1,3-dicarbonyl compounds 3 3 3 ketone pk a = 19 3 1,3-diketone pk a = 9 3 3 3 3 3 ester pk a = 25 3 1,3-diester pk a = 13 3 3 Meldrum's acid pk a = 5 1,3-keto ester pk a = 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 3 3 3 3 3 3 pk a = 9 3 3 3 3 3 3 pk a = 11 3 3 3 3 3 3 pk a = 13 Enolate formation for a 1,3-dicarbonyl is very favorable 3 3 acetoacetic ester pk a = 11 + 3 3 3 + 3 pk a = 16 240 22.6: eactivity 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 E E E E 241 122
22.7 alogenation of Enolate Ions: The aloform eaction arbonyls undergo α-halogenation through base promoted enolate formation a, 2 + a 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 a, 2 a, 2 2 242 aloform reaction: 3 a, 2 X 2 X X X X X X + X 3 + X 3 aloform Iodoform reaction: chemical tests for a methyl ketone 3 a, 2 I 2 + I 3 Iodoform Iodoform: bright yellow precipitate 243 123
22.8 Alkylation of Enolate Ions Enolates react with alkyl halides (and tosylates) to form a new - bond (alkylation reaction) B X S 2 eactivity of alkyl halides toward S 2 alkylation: X ~_ > > > > X X X X benzylic allylic methyl primary secondary tosylate ~_ -I > - > -l Tertiary, vinyl and aryl halides and tosylates do not participate in S 2 reactions 244 Malonic Ester Synthesis overall reaction 2 Et 2 Et diethyl malonate Et= ethyl + 2 -X alkyl halide Et a +, Et then l,! 2-2 - 2 carboxylic acid Et Et diethyl malonate pk a = 13 + Et Et Et + Et pk a = 16 Et ethyl acetate pk a = 25 + Et Et + Et pk a = 16 245 124
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 2 upon heating. Et Et 2 l,! 2-2 2 246 Mechanism of decarboxylation: β-dicarboxylic acid (malonic acid synthesis) β-keto carboxylic acid (acetoacetic ester synthesis) 247 125
2 Et 2 Et Et a + 2 Et, Et 3 2 2 2 l,! + 3 2 2 2-2 Et 3 2 2 2-2 2 2 Et 2 Et Et a + 2 Et, Et 3 2 2 2 + 3 2 2 2-2 Et Et a +, Et 3 2-3 2 2 2 3 2 2 Et 2 Et l,! 3 2 2 2 3 2 2 2 Et 2 Et Et + - 2-2 - 2-2 - a +, Et 2 Et 2 Et Et a +, Et l,! - 2-2 - 2-2 2 2 Et 2 Et cyclopentane carboxylic acid 248 Acetoacetic ester synthesis 3 2 Et ethyl acetoacetate + 2 -X alkyl halide Et a +, Et then l,! 2 3 ketone 3 Et diethyl malonate pk a = 11 + Et 3 Et + Et pk a = 16 3 acetone pk a = 19 + Et 3 + Et pk a = 16 249 126
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 Et a 2 Et +, 2 Et Et l,! + 3 2 2 2 3 2 2 2-3 2 2 2-2 3-3 3 2 ethyl acetoacetate Et a 2 Et +, 2 Et Et + 3 2 2 2 3 2 2 2-3 3 ethyl acetoacetate 3 2 2 2 3 2 2 Et 3 l,! 3 2 2 2-2 3 3 2 Et a +, Et 3 2-2 Et Et a +, + Et - 2-2 - 2-2 - 2-2 - 2-2 - 3 ethyl acetoacetate 2 Et l,! 3 3-2 2 Et 3 Et a +, Et 251 127
acetoacetic ester 2 Et Et a +, Et 2 Et 2 Et l,! - 2 Summary: Malonic ester synthesis: equivalent to the alkylation of a carboxylic (acetic) acid enolate 2 Et 2 Et + 2 -X 3-2 base Et a +, Et then l,! 2 2 -X 2-2 - 2 2-2 - 2 Acetoacetic ester synthesis: equivalent to the alkylation of an acetone enolate 3 2 Et 3 3 + 2 -X Et a +, Et 2 then l,! 3 base 2 3 2 -X 2 3 252 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 TF. The resulting enolate is then reacted with alkyl halides to give the α-substitution product. 3 LDA, TF 3 2 -X 3 2 major -78 3 2 -X 2 3 minor 253 128
Ester enolate Et LDA, TF -78 Et 2 -X 2 2 Et LDA, TF -78 2 -X 2 itrile enolate LDA, TF -78 2 -X 2 254 Biological decarboxylation reactions: pyruvate decarboxylase Thiamin Diphosphate (Vitamin B 1 ) PP 2-3 P Pyridoxal Phosphate (Vitamin B 6 ) P 2 + S S 3 P - P - - + Enzyme B PP L-DPA decarboxylase L-DPA P S 3 2 PP 3 Enzyme B S L-DPA decarboxylase Imine formation 2 PP P 2-3 P 3 2 Enzyme B S - Enzyme :B 3 + PP - 2 PP P S Dopamine 3 S 3-255 - 2 + 3 129