20.10 Ester Hydrolysis in Base: Saponification

1. 20.10Ester Hydrolysis in Base:Saponification

2. O O + RCOR' HO– RCO– Ester Hydrolysis in Aqueous Base • is called saponification • is irreversible, because of strong stabilization of carboxylateion • if carboxylic acid is desired product, saponification is followedby a separate acidification step (simply a pH adjustment) + R'OH

3. O CH2OCCH3 CH3 O CH2OH CH3CONa CH3 Example + NaOH water-methanol, heat + (95-97%)

4. O H2C CCOCH3 CH3 1. NaOH, H2O, heat 2. H2SO4 O H2C CCOH CH3 Example + CH3OH (87%)

5. O CH2OC(CH2)xCH3 O CH3(CH2)yCOCH CH2OC(CH2)zCH3 O O O O Soap-Making • Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids. • These salts are soaps. K2CO3, H2O, heat CH3(CH2)xCOK CH3(CH2)yCOK CH3(CH2)zCOK

6. •• •• O O •• •• – – •• •• •• •• + RCO + R' OH R'OH RCO •• •• •• •• •• •• Which bond is broken when esters arehydrolyzed in base? • One possibility is an SN2 attack by hydroxide on the alkyl group of the ester. Carboxylate is the leaving group.

7. •• •• O O •• •• – – •• •• •• •• RC OR' OH OR' RC OH •• •• •• •• •• •• Which bond is broken when esters arehydrolyzed in base? • A second possibility is nucleophilic acyl substitution. + +

8. O + CH3CH2COCH2CH3 NaOH O + CH3CH2CONa CH3CH2OH 18O Labeling gives the answer • 18O retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution.

9. H O C6H5 CH3C C O CH3 H O C6H5 CH3COK C HO CH3 Stereochemistry gives the same answer • alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution • not SN2 KOH, H2O +

10. •• •• O O •• •• – – •• •• •• •• RC OR' OH OR' RC OH •• •• •• •• •• •• Does it proceed via a tetrahedral intermediate? • Does nucleophilic acyl substitution proceed in a single step, or is a tetrahedral intermediate involved? + +

11. O COCH2CH3 O COCH2CH3 18O Labeling Studies + H2O • Ethyl benzoate, labeled with 18O at the carbonyl oxygen, was subjected to hydrolysis in base. • Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18O label. • This observation is consistent with a tetrahedral intermediate. HO– + H2O

12. O COCH2CH3 OH OCH2CH3 C OH O COCH2CH3 18O Labeling Studies + H2O HO– HO– + H2O

13. Mechanism of Ester Hydrolysisin Base • Involves two stages: • 1) formation of tetrahedral intermediate2) dissociation of tetrahedral intermediate

14. O + RCOR' H2O OH OR' RC OH First stage: formation of tetrahedral intermediate • water adds to the carbonyl group of the ester • this stage is analogous to the base-catalyzed addition of water to a ketone HO–

15. O RCOH OH OR' RC OH Second stage: cleavage of tetrahedralintermediate + R'OH HO–

16. Mechanism of formationoftetrahedral intermediate

17. •• O •• H RC O •• •• – •• OR' •• •• – •• O H •• •• RC O •• •• OR' •• •• Step 1

18. •• O H H •• – •• O RC O •• •• •• •• H OR' •• •• – •• •• O H O •• H •• •• H RC O •• •• OR' •• •• Step 2

19. Dissociation oftetrahedral intermediate

20. •• O H H •• – •• O RC O •• •• •• •• H OR' •• •• •• •• O H O •• •• H RC – •• OR' O H •• •• •• •• Step 3

21. •• O •• RC – O •• •• •• •• OR' H •• •• HO– O •• RC – •• OR' O H •• •• •• •• Step 4 H2O

22. Key Features of Mechanism • Nucleophilic addition of hydroxide ion to carbonylgroup in first step • Tetrahedral intermediate formed in first stage • Hydroxide-induced dissociation of tetrahedralintermediate in second stage

23. 20.11Reactions of Esterswith Ammonia and Amines

24. O RCOR' O RCNR'2 O RCO– Reactions of Esters

25. O O RCNR'2 H O via: R NR'2 C OR' Reactions of Esters Esters react with ammonia and aminesto give amides: + + R'2NH R'OH RCOR'

26. O + NH3 H2C CCOCH3 CH3 O H2C CCNH2 CH3 Example H2O + CH3OH (75%)

27. O + FCH2COCH2CH3 NH2 O + FCH2CNH CH3CH2OH Example heat (61%)

28. 20.12Amides

29. Physical Properties of Amides Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives.

30. Physical Properties of Amides Amides are capable of hydrogen bonding.

31. Physical Properties of Amides Amides are less acidic than carboxylic acids. Nitrogen is less electronegative than oxygen.

32. Preparation of Amides Amides are prepared from amines by acylationwith: • acyl chlorides (Table 20.1) • anhydrides (Table 20.2) • esters (Table 20.5)

33. O O RCO RCOH Preparation of Amides Amines do not react with carboxylic acids to giveamides. The reaction that occurs is proton-transfer(acid-base). • If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating. + – + R'NH3 + R'NH2

34. O O RCO RCOH O RCNHR' Preparation of Amides Amines do not react with carboxylic acids to giveamides. The reaction that occurs is proton-transfer(acid-base). + – + R'NH3 + R'NH2 heat + H2O

35. O H2N COH O CNH Example + 225°C + H2O (80-84%)