Named Reactions 186 CHAPTER 6 Named Reactions 6.1. Aldol Condensation Aldehyde containing an -hydrogen atom undergoes a reversible self addition in presence of the dil. acid or usually in alkali to give condensation product -hydroxy aldehyde or ketone. In every case the addition occurs in such a way that -carbon of the first carbonyl compound get attached to the carbonyl carbon of the second. OH OH–/H+ CH3 CHO + CH3CHO CH3 CH CH2 CHO -hydroxy aldehyde CH3 OH–/H+ CH3COCH3 + CH3COCH3 CH3–C–CH2–CO–CH3 OH -hydroxy ketone Note: If an aldehyde and ketone do not contain -H, the self condensation reaction donot occur. e.g. ArCHO, HCHO, (CH3)3C-CHO, Ar-CO-Ar, Ar–C–CR3 can’t undergo self condensation due to absence of H-atom. O Mechanism: (1) Base - Catalysed mechanism (a) Addition Phase : Nucleophilic addition. O O R CH2 C R ' + B R CH C R' R CH C R ' O enolate ion O R' O R CH2 C R ' + R CH C R' R CH2 C CH C R' – (E+ partner) O (Nu partner) O R R' O BH R CH C CH C R' Proton transfer 2 OH R Aldol Proton transfer reactions are always reversible reaction. Named Reactions 187 (b) Dehydration Phase : R' O R' R' O – B E1CB R CH2 C CH C R' R CH C C COR + BH R CH2 C C C R 2 Mech. OH R OH R R -unsaturated aldehyde / ketone In general the aldol reaction is reversible in both acidic and basic condition, but when reaction conditions are favourable to cause dehydration, predominantly in acidic medium the reaction goes to completion. The reaction is unfavourable usually for acyclic ketones this is because - 1. Carbonyl carbon of the ketone is less electrophilic because of the +I effect of the alkyl groups. 2. Due to steric hindrance the probability of nucleophilic attack by enolate or enol is decreased. (2) Acid Catalysed Mechanism : Enol is less nucleophilic than enolate. (a) Addition Phase : O O H OH ' – (i) R CH2 C R + HA R CH2 C R' + A R CH C R' Enol R' O – H (ii) ' R CH2 C R + R CH C R' R CH2 C CH C R' O H O H OH R Protonated E+ Aldol (Better electrophile than the unprotonated aldehyde/ketone) (b) Dehydration Phase : R' O R' O H+ R CH2 C CH C R' R CH2 C CH C R' Proton transfer OH R R OH2 R' H O R' O + – H2O – H R CH C C C R' R CH C C C R' Better L.G. 2 2 E1 Mechanism R R Experimental Evidence : Aldehyde : O O O (1) OH– H C C H CH3CHO CH2 C H CH2 C H + 3 (2) H2O CH3 CH CH2 CHO CH3 CH CH2 CHO OH 45% O Named Reactions 188 Ketone : O O O (1) OH– H3C CO CH3 H2C C CH3 H2C C CH3 + C CH3 (2) H3C CH3 CH3 H2O H3C C CH2 C CH3 H3C C CH2 C CH3 OH O O O Carrying out a reaction with D2O fails to result in the incorporation of any deuterium to the CH3 group of aldehyde to produce D CH2 CHO but it produces D–CH2–COCH3 in case of ketone. This indicates that the step two is faster than reversal of state one in case of aldehyde and slower in case of ketone. The reaction can be made of synthetic importance by : (1) Continuous distillation of the products in a Soxhlet Apparatus (Reaction move forward following Le - Chatelier Principle) using Ba(OH)2 base. (2) Using acid catalysis tendency of dehydration of aldol products is increased producing more stable - unsaturated aldehyde / ketone (3) To stop at the aldol stage the best catalyst are basic ion exchange resin. o E 3o 2 o 1 o (4) A 3 alcohol always undergoes dehydration through E1 mechanism. 1 Me O O H+ CH3COCH3 Me C CH COMe Me2C=CH–C–Me Me2C CH C CH CMe2 H O HCl – 2 Mesityl oxide Phorone OH H Example: OH O O OH (i) C CH C O CH3 O O O O O Dowex-50 O (ii) H+ (iii) O H+ (iv) NaOEt C7H15CHO C7H15 CH C CHO C6H13 O O Ba(OH)2 (v) Named Reactions 189 Crossed-Aldol / Mixed Aldol : (Claisen-Schmidt Condensation) When one of the partner in a crossed aldol condensation is benzaldehyde which can only act as a E+ and any other aldehyde or ketone which can form either enol or enolate then this type of mixed condensation is known as Claisen - Schmidt Condensation. O H C H C CH CHO CH3CHO KOH Cinnamaldehyde H C CH C CH3 CH3 CO CH3 HCl O H C CH C Ph CH3COPh O Electron donating groups in benzaldehyde will make the reaction slower and e– withdrawing groups make the reaction faster. O O OH NaOH H2O CH3NO2 NO2 NO2 NaOH Henry Aldol condensation Nitro alcohol Conditions For Crossed Aldol : (i) Only one enolizable component (aldehyde / ketone having -H) (ii) No other compound containing more acidic hydrogens than aldehyde/ketone eg. CH3NO2 (iii) The carbonyl E+ should be more reactive than the compound being enolised) Example: O 1. C CH2 O O O O OH KOH Ph C H C CH2 CH Ph C CH2 CH Ph + MeOH (E cb) O –H2O 1 C C CH Ph H CH3 CH3 O O CH3 O OH O O 2. NaOMe MeOH H CH CH O O O H2O CH 3 O CH O Named Reactions 190 O O OH CH3 CH C H O 3 CH CH CH CH + CH3 CH C Et COEt EtOH COEt 3. CH2OH CH2OH CH2OH (E1 cb) H2O H CH3 C C COEt CH2OH Retro Aldol : Because the aldol reaction is reversible, so when the aldol product is heated with a strong base then it reverse back to an equilibrium mixture which mainly contain initial reactant. OH O O O O OH CH3 C CH2 C CH3 CH3 C CH2 C CH3 CH3 C CH3 + H2C COCH3 CH3 CH3 H2O 5% in equilibrium mixture 2 CH3COCH3 95% in equilibrium mixture PROBLEMS O (i) LDA- 78oC , THF ? 1. Ph O (ii) O OLi LDA Ph Ph Soln. H Li N O Li O O O O H O OH + 2 Ph Ph Ph Aldol O (i) LDA ? 2. (H3C)2HC CH(CH3)2 O (ii) H O O O O + H (H3C)2HC C(CH3)2 (H3C)2HC C CH H3C CH3 O Li Soln. O OH (H3C)H2C C(CH3)2 (H3C)2HC H3C CH3 Named Reactions 191 6.2. Baeyer - Villiger Oxidation Reaction Oxidation of ketone to ester by reacting reactant (ketone) with hydrogen peroxide or peroxy compound or peracid( RCO3H) in presence of acid catalyst. O O O H+ R C R' + R'' COOH R COR' + R''CO2H Mechanism : OH OH OH O O + + R''CO H R" COO – H H 3 R C OR R C OR R C R' R C R' R C R' O O OH C O R C R' R" When unsymmetrical ketones are used, then order of migration of alkyl group, is : tert-alkyl, sec-alkyl > Benzyl, Phenyl > Prim - alkyl > cyclopropyl > methyl. For Benzophenone, p-OCH3 > CH3 > H > Cl > NO2 in para - position. Note: Peroxy trifluoro acetic acid and m-chloro peroxy Benzoic acid can also be used : Examples: O O CH3COOOH (i) O2N C H O2N C O H HOAc, H2SO4 O O O O RCO3H CH3 C O C CH3 (ii) CH3 C C CH3 O O CH3 (iii) m-CPBA O CH2Cl2 CH3 CH3 CH3 C4H9 C4H9 m-CPBA (iv) H2SO4 O O O CH3COOOH O O (v) H+ O O O O (vi) CF3 COOOH H+ O (vii) CF3CO3H O H+ O Named Reactions 192 O CF3COOOH (viii) C O O C CH3 + H3C H Cl Cl CF3COOOH (ix) C CH3 O C CH Cl H+ 3 Cl O O PROBLEMS • O HO• R O O O R R CF3CO3H O C C (i) CF3 O by migration of Ph BnO BnO (ii) m-CPBA O O O O O (iii) Ph Ph O Me Ph Me + OMe Me Me O Me (Major) (Minor) O O (iv) HOAc O O O OAc O m-CPBA, CF SO H (v) 3 3 OAc CH2Cl2, 45 min, 90% 6.3. Benzoin Condensation Condensation of aromatic aldehyde in presence of CN– ion to give condensation products called benzoin, is known as Benzoin Condensation. O CN 2 Ar CHO Ar CH C Ar OH 2 When Ar = Ph, it is called benzoin rate law r K ArCHO CN Named Reactions 193 The reaction involves attack of CN– ion on the carbonyl carbon but in this reaction instead of H– transfer (as that of cannizzaro reaction) it is now a carbanion addition of the one aromatic aldehyde to the carbonyl carbon of the other aromatic aldehyde. The reaction is of 3rd order. O OH O OH Step - 1 Ph C H Step - 2 Ph C H Ph C Ph C CN intramolecular CN H-abstraction C N C N OH O OH O O HO OHO Step - 3 CN Ph C Ph C H Ph C C Ph Ph C C Ph Ph C CH Ph Benzoin C N CN H CN H -hydroxy ketone 1. This reaction is completely reversible, the reversibility indicated by the fact that when benzoin is heated with an another aromatic aldehyde, mixed products are obtained. H KCN ' Ph C C Ph + 2Ar CHO 2 Ph CH C Ar' HO O HO O This reaction is intermolecular mixed product reversible reaction 2.