Named Reactions 186

CHAPTER 6

Named Reactions

6.1. 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 . 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) - 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– E CB R CH C CH C R' 1 2 R CH2 C C COR + BH R CH2 C C C R Mech. OH R OH R R -unsaturated aldehyde / ketone

In general the 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 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 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 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 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. CN– catalyses the reaction because : (i) It is good nucleophile (ii) It is good (iii) It increases the acidity of the C–H bond and stabilises the carbanion that results from the loss of proton from C. 3. Benzoin is a colourless solid (M.P. 157oC) which assumed to tautomerise to ene .

H O OH OH C C C C OH Ene diole Reduction of Benzoin : 2[H] * * Ph CH CH Ph Na/EtOH Hydrobenzoin OH HO (Pinacol)

2[H] Ph CH C Ph Deoxybenzoin Sn/HCl 2 O Ph CH C Ph H OH O [H] KOH/EtOH Ph CH CH Ph Ph CH CH Ph Zn/Hg, HCl E 2 Stilbene OH

4 H2 Ph CH2 CH2 Ph Dibenzyl Ni/H2 Named Reactions 194 Oxidation of Benzoin : CHO COOH

CrO3 +

[O] Ph CH C Ph Ph C C Ph Benzil HNO3 OH O O O [O] Ph C C Ph CuSO4, Py O O 6.4. Birch Reduction Reduction of aromatic ring by means of alkali metals (sodium or lithium) in liquid ammonia or amine with ethanol as proton donor to give mainly conjugated dihydro derivatives. Ethers are sometimes used as a co- solvent to dissolve the aromatic compound. Use of t-butanol fulfils the dual role of proton donor and co solvent. R R R

Na, NH (liq) 3 or where alcohol E.W  electron withdrawing group. E.R.  electron releasing group. where R R is E.W.Group is E.R.Group Mechanism : Solvated electrons are reducing agent. Na (NH ) + 3 Na (NH3)X + e (NH3)X R R R R R H – e ROH – e ROH

H H H H H H H Radical anion Radical anion Product Effect of Substituent on Aromatic Ring (Regioselectivity) : Electronic Factor : Electron withdrawing groups make the ring more susceptible towards reduction and hence increases the rate of reaction on the other hand electron donating groups decrease the rate of reaction. Electron withdrawing groups promote ipso & para reduction whearas electron donating groups promote meta and ortho reduction.

Ipso OCH3 OCH COOH COO Li COOH 3 H Li, NH (l) H Li, NH (l) H+ 3 (i) 3 (ii) H EtOH EtOH H

E+ H H para H HOOC LiOOC o,m-reduction E E Ipso, para-reduction

H+ Named Reactions 195 To Produce Cyclohexanones : H OCH3 O O O H H O+ 3 H+ – CH3OH

Example:

Li/Et2NH + (i) MeNH 80% 20%

CH2OH Li, NH3 (COOH)2 CH2OH (ii) H2O, t-BuOH MeO O

OMe OMe (iii) Li, NH3 N N t-BuOH

HOOC 1) Li, NH3 , EtOH (iv) COOH 2) Br H H

H H OCH 1) Li, NH3 3 + OCH OCH3 H 3 (v) + H C 2) H , H2O H C 3 3 H C H H 3

OMe O O OMe 1) K, NH , t – BuOH Et N 3 (vi) N 2) Et–I OMe OMe 6.5. Cannizzaro Reaction Under the influence of strong and conc. base, aldehyde which has no -H (non enolazable) undergoes self oxidation reduction reaction () to produce corresponding alcohol and acid. This is knwon as Cannizzaro reaction.

e.g. Aldehyde - HCHO, PhCHO, R C– CHO, CHO 3 O Named Reactions 196 which have -H undergo aldol reaction much faster than the cannizzaro reaction.

1) Conc.NaOH 2 PhCHO + Ph COOH + PhCH2OH 2) H3O Benzoic acid Benzyl alcohol (Oxidised) (Reduced)

Disproportionation Mechanism: The mechanism involves intermolecular hydride transfer OH O OH O OH RDS Ph Ph C H Ph C H + C Ph Ph C + C fast Slow H O O H O H – Nu donar E+ acceptor + H3O PhCOOH + PhCH OH Ph C O + 2 acidic work up PhCH2OH O Rate = K[PhCHO]2[OH–] 3rd order reaction Cannizzaro reaction is a third order reaction.

6.6. Clemmensen Reduction: Ketone and aldehyde on reduction with zinc amalgam and hydrochloric acid give the corresponding hydrocarbon i.e, is converted into methylene group. O H2 Zn/Hg C C R R' HCl R R' The mechanism of Clemmensen reduction is uncertain. The following expected reaction pathway involve the transfer of electron from the metal surface to the carbon atom of the protonated carbonyl group. Transfer of 4e– from Zn to one molecule is expected to occur. Mechanism :

O OH + OH H Zn, Cl H+ C R C R' C e– transfer R C R' R R' R R' – H2O ZnCl ZnCl

2Zn

+ + H H + H R C R' R C R' + 2Zn ZnCl2 + R CH2 R' ZnCl ZnCl Special Features: (i) The acid should be conc. (aq. phase should be low) to prevent the bimolecular condensation reaction of carbonyl compound. (ii) The reduction fail with acid sensitive and high molecular weight substrate. (iii) Certain types of aldehyde and ketones do not give the normal reduction products alone.

C.R. (a) CH3 C CH2 C CH3 CH3 C CH CH3 O O O CH3 Named Reactions 197 Mechanism : Through Rearrangement

H+ Zn H+ O O O HO OH HO OH HO OH OH2 H

CH3 [H] – H2O H3C C CH O CH3 O O CH3

O O + O O NH NH /KOH O O H3O Zn-Hg (b) 2 2 ethylene HCl glycol

This ring is stable in basic medium. In acidic medium it will be broken.

Application : (1) To reduce keto acid : O CH CH CH COOH Zn-Hg 2 2 2 C CH CH COOH 2 2 HCl

(2) To prepare naphthalene : O C CH 1) Zn-Hg, HCl Zn-Hg 2 AlCl3 Se CH2 2) SOCl2 HCl  COOH Cl O O Example: Ph C C H C.R. (i) 3 7 Ph CH2 C3H7 O (ii) C.R. CH3(CH2)7 CHO CH3(CH2)7 CH3

2) Cl 1) AlCl3 Zn-Hg Se (iii) HCl O  O O C.R. (iv) Ph Ph 14 14 OH OH O OCH3 OH OH Zn/Hg OCH3 C(CH2)5CH3 CH2 (CH2)5CH3 (v) HCl (vi) HCl Zn(Hg) CH O CH3 (81– 86)% (60 – 67)% Named Reactions 198

O O Zn(Hg) (vii) C C CH2 CH2 HCl

CH3 CH3 Zn(Hg)

(viii) HCl O H H 6.7. Cope eliminations: (Thermally syn elimination of N-oxide to less substituted Olefins as major) The formation of an Olifin and a hydroxylamine by thermal decomposition of tertiary amine oxide is known as cope elimination. The N-oxide derivatives are prepared by the oxidation of corresponding tertiary aliphatic or aromatic amines with aqueous hydrogen peroxide or m-chloroperbenzoic acid.

O R3 R OH H N  2 + R R N 3 1 R1 R2 R R The reaction takes place at much lower temperature (120–150ºC). It has been found in general with aliphatic , xanthates or amine oxide which could form either a Z or E-alkene on pyrolysis that the more stable E isomers is formed in larger amount. There is syn elimination therefore the threo isomer of the amine oxide gives the Z-alkene while the erythro isomer gives the E-alkene.  CH3CH2CHCH3 CH3CH=CHCH3 + CH3CH2CH=CH2 Z = 12% 67% O N(CH3)2 E = 21%

Mechanism:

O

N R R3 OH  R3 + N H Ei R1 R2 2 R R R1 EXAMPLES

N m-CPBA + O rt, 100% N (i) CN O OH CN

O

N(CH3)2  (ii) N(CH3)2

O Named Reactions 199

H H i-Pr 100–180ºC (iii) Me Me i-Pr Me i-Pr NMe2 + H O H H 65 % 35 %

H H i-Pr 90–160ºC (iv) Me H Me i-Pr H H NMe2 O 6.8. Crossed Cannizzaro Reaction Reaction between different aldehyde Conc. PhCHO + HCHO PhCH OH H COO– NaOH 2 +

1. When undergoes a cannizzaro reaction with other aldehyde without a -H, then it is observed that the formaldehyde is oxidised and other is reduced. This is because the nucleophilic attack occurs on formaldehyde much easily than on any other aldehyde.

CHO CH2OH O NaOH + C H + HCOO H

OCH3 OCH3 2. When HCHO reacts with other aldehyde with -H then first the cross aldol reaction takes place followed by cross-cannizzaro reaction. O CH3 CH2OH CH2OH crossed OH– CH CH + HCHO (H3C)2C (H C) C Aldol HCHO 3 2 + HCOO H C CHO 3 CH2OH Crossed Cannizzaro Example: CH OH CH OH 2 HCHO 2 CH C CHO (i) 3 CH3 C CH2OH + HCOO CH2OH CH2OH

CH2OH CH2OH (ii) CH CHO 3HCHO HCHO 3 CH2OH C CHO CH2OH C CH2OH + HCOO

CH2OH CH2OH Named Reactions 200

CHO NaOH CH2 OH COO (iii) 2  + COOH COO COO Intramolecular Cannizaro Reaction: Dialdehyde and-keto aldehyde undergo suitable I.C.R.

O O OH OH– O HO OH O H C C O H C O Proton transfer C H C C O H C C O Glyoxal H H H H

CHO nd rate = K OH 2 order reaction CHO Hence, intramolecular cannizzaro is a second order reaction. Normal Cannizzaro : 3rd Order Reaction: Cannizaro in strongly basic medium 4th order Internal cannizaro - 2nd order

O OH OH Ph C CHO Ph C C O O H OH O O OH proton transfer Ph C C O Ph C C O H H H– ions come from aldehyde

6.9. Dakin Reaction Aromatic carbonyl compounds having a hydroxy or amino group in either ortho or para position can be converted to phenols on treatment with alkaline hydrogen peroxide. CHO OH

OH – OH H2O2/OH + HCOO

Mechanism:

O O O O H OH O C OH C H O C H O H OH OH OH HOO OH OH

OH O OH O OH HCOO + H C OH + Named Reactions 201 Examples:

O CH3 C OH – H2O2/OH (i) + CH3COO

NH2 NH2

O

C OH

– H2O2/OH (ii) + C6H5COO

OH OH 6.10. Darzens Reaction The Darzens reaction is the condensation of a carbonyl compound with an   haloester having atleast one  -hydrogen in the presence of a base to form an ,   epoxy ester.. O O O KO t-Bu R' CO2R'" + X R R' OR'" t-BuOH R R" R' Mechanism: The first step in this reaction is addition of enolate of the   haloester to the carbonyl compound. After this oxygen formed in the addition does nucleophilic attack, displacing the halide and forming ,   epoxy ester(also called glycidic ester) O O O O O O R C C C R R HC OC H R2C CH OC2H5 OC2H5 2 5 R H Cl Cl O O O O O Cl OtBu Cl Cl OEt Cl OEt O OEt -tBuOH OEt syn H H Cl H + O O Cl OEt anti Cl In the subsequent step, an intramolecular SN2 reaction form the epoxide.

O O O O O OEt –Cl– OEt CO Et trans 2 anti Cl Cl

O O O OEt O O –Cl– CO Et Cl 2 OEt cis

syn Cl Named Reactions 202 PROBLEMS

O CO2C2H5 KOC(Me)3 1. O + ClCH2CO2C2H5 H O H CO2C2H5 2. KOC(Me)3 PhHC O + PhCHCO2C2H5 Ph Ph 75% Cl O O O H3C CO2C2H5 Ph CO2C2H5 KOC(Me)3 PhCCH3 + ClCHCO2C2H5 + 3. Ph H H3C H (1:1 mixture of isomers) O 1. LiHMDS H3C CO2C2H5 4. CH3CH2CHCO2C2H5 2. O Br Ph CH2CH3 C H3C Ph

6.11. Dienone-Phenol rearrangement: Acid-promoted rearrengement of 4, 4 disubstituted cyclohexadienones to 3, 4-disubstituted phenols.

O OH

H+

R R R R Mechanism:

O H O OH OH

+ H+ 1, 2 alkyl –H H shift H R R R R R R R R EXAMPLES

O O

O O 50% aq. H2SO4 (i) reflux, 80% HO O