19 hap 19 : Enolate Anions and Enamines 19.1 Formation and eactions of Enolate Anions : An verview α- of aldehydes or ketones : acidic (pk a = 20) 2 : Alkylation by S2 substitution Br a + 2 + a + 2 arbanion Enolate 2 : ucleophilic addition 1st step : - 염기에의한 α-의 abstraction - formation of carbanion and enolate anion (enolate anion이 major) 2nd step : arbanion이친핵체로작용하여 alkylation 혹은 nucleophilic addition 이일어남 new - σ bond formation arbon에서반응이일어나는이유 : i) ucleophilicity : - > - ii) a + 이 - 에단단하게연결되어있어친전자체가접근하기어려움 iii) Alkylation에서생성된 -alkylation 생성물은 -alkylation 생성물보다안정함 - bond strength : = > = 19.2 Aldol eaction α-을갖는 aldehyde 혹은 ketone을염기 [a, Ba() 2, aet] 혹은산촉매하에서반응시켜 β-hydroxy aldehyde 혹은 β-hydroxy ketone을합성하는반응. Aldol = Aldehyde + alcohol
20 A. Mechanism 1) Base-catalyzed aldol reaction 3 + 3 a 3 2 new bond 3-ydroxybutanal ( -hydroxyaldehyde, racemic mixture) 2 + a + pk a 20 arbanion Enolate pk a 15.7 3 3 2 3 2 1st step : emoval of α- by - 2nd step : ucleophilic addition of carbanion to = group of another acetaldehyde 3rd step : - 의 proton ( + ) abstraction 2) Acid-catalyzed aldol reaction 3 A 2 A 2 + A 3 3 2 3 2 1st step : Activation of carbonyl group by A 2nd step : A - 에의한 proton abstraction - formation of enol ate controling step (r.c.s.) 3rd step : 의 nonbonding electron의도움에의하여 =의 π electron이친핵체로작용하여다른 acetaldehyde에 nucleophilic addition 4th step : Transfer of proton
21 Dehydration of aldol product : Aldol 반응이일어나는조건에서도생성된 β-hydroxy aldehyde 혹은 β-hydroxy ketone이탈수를일으킬수도있음. Aldol의탈수는특히산성조건에서잘일어남. Acid-catalyzed dehydration of 3-hydroxybutanal : 3 2 + 3 2-2 3 2 2 3 1st step : 기의 protonation 2nd step : Leaving of 2 ( 2 - good leaving group) 3rd step : 2 가염기로작용하여 + abstraction - E1 elimination α,β-unsaturated aldehyde - conjugation 효과로인하여안정문제 19.2 : B. rossed Aldol eaction ( 교차알돌반응 ) 대개서로다른구조의 aldehyde와 ketone 화합물사이에서일어나는 aldol 반응 i) 대체로한화합물은 α-을갖고, 다른하나는 α-을갖지않을경우에적합 e.g. : 3 3 +, Ph, ( 3 ) 3 - ii) 두화합물이모두 α- 을갖는경우는 acidity 차이가커야함 e.g. : yclohexanone + 3 2 rossed aldol reaction of acetone and benzaldehyde : 3 a 3 2 3-2
22 rossed aldol reaction of nitromethane and cyclohexanone : 1) 3 2 + a 2 2 2) 2 2 + * Intramolecular aldol reaction ( 분자내알돌반응 ) 같은분자내에 enolate 음이온과카보닐기가동시에존재하여첨가반응으로고리가형성되는반응. Formation of ring size : 6 > 5 >> 7 > 4 6-membered ring - o angle strain Aldol reaction of 2,7-octanedione : K - 2 Aldol reaction of 1,5-dione derivative : K - 2. etrosynthetic Analysis 2 +
23 19.3 laisen and Dieckmann ondensations A. laisen ondensation α-을갖는 ester 화합물을염기 (aet or ame) 로처리하였을때축합이일어나 β-keto ester를생성하는반응 3 Et + 3 Et i) aet ii) 3 + 3 2 Et + Et new bond Mechanism : 3 Et + Et 2 Et 2 Et + Et pk a 22 pk a 15.9 3 Et + 2 Et 3 Et 2 Et 3 + Et 2 Et 3 Et + Et 3 Et 3 + 3 2 Et + Et pk a 10.7 pk a 15.9 1st step : aet 염기에의한 ester의 α- abstraction - formation of ester enolate, K < 1 2nd step : Enolate anion의 nucleophilic addition - formation of tetrahedral intermediate 3rd step : 의 anion에의한도움으로 - Et의이탈 4th step : - Et에의한 active methylene의 abstraction K >> 1, 전체평형을오른쪽으로치우치게하여반응을완결시킴 5th step : Acidification of enolate anion - formation of β-keto ester
24 B. Dieckmann ondensation Dicarboxylic ester의분자내 laisen condensation에의하여고리형태의 β-keto ester가생성되는축합반응주로 5원자혹은 6원자고리가생성됨 ondensation of diethyl hexanedioate : Et Et aet Et Et Et. rossed laisen ondensations 서로다른구조의 ester 화합물사이에서일어나는 laisen 축합반응대체로한 ester 화합물은 α-를갖고, 다른 ester 화합물은 α-를갖지않을경우에적합 α-를갖지않는 ester 화합물 : Et Et Et Et Et Et Ethyl formate Diethyl carbonate Ethyl benzoate Diethyl oxalate rossed laisen condensation of methyl benzoate and methyl propanoate : 3 + a + Me 3 3 3 β-keto ester D. etrosynthetis Analysis 2 3
25 E. ydrolysis and Decarboxylation of β-ketoesters Ester 를 laisen condensation 시켜얻어진 β-keto ester 화합물을가수분해한후, decarboxylation (- 2 ) 시키면 ketone 이합성됨. Ethyl propanoate 3-Pentanone : i) aet i) aq a 2 Et ii) aq l Et ii) aq l 문제 19.6 : 19.5 Enamines Enamine : 1) Preparation of enamine 산성촉매하에서 ketone 혹은 aldehyde 와 2 o dialkylamine) 의반응으로생성됨. amine (pyrrolidine, morphorine,
26 eaction of cyclohexanone and pyrrolidine : + 2-2 1st step : Activation of = 2nd step : ucleophilic addition of pyrrolidine and + transfer 3rd step : 의 nonbonding electron의도움에의한 2 의이탈 4th step : 2 에의한 deprotonation - formation of enamine 2) Alkylation of enamine Br Br aq l + l iminium bromide 2-allylcyclohexanone pyrrolinium chloride 1st step : 의 nonbonding electron 의도움에의한 = 의 π electron 이친핵체 로작용하여 alkylation 이일어남 Monoalkylation 2nd step : aq l 에의한 iminium bromide 의 easy hydrolysis B. Acylation of Enamines 3 l l aq l + l 2-Acetylcyclohexanone. etrosynthetic Analysis + + L