1. Dr. Wolf's CHM 201 & 202 20-1 20.10 Ester Hydrolysis in Base: Saponification

2. Dr. Wolf's CHM 201 & 202 20-2 is called saponification is irreversible, because of strong stabilization of carboxylate ion if carboxylic acid is desired product, saponification is followed by a separate acidification step (simply a pH adjustment) Ester Hydrolysis in Aqueous Base RCO – O+ R'OH RCOR' O+ HO –

3. Dr. Wolf's CHM 201 & 202 20-3 Example water-methanol, heat (95-97%) CH 2 OCCH 3 CH 3 O+ NaOH CH 2 OH CH 3 O CH 3 CONa +

4. Dr. Wolf's CHM 201 & 202 20-4 Example (87%) + CCOH CH 3 O H2CH2CH2CH2C 1. NaOH, H 2 O, heat 2. H 2 SO 4 CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C

5. Dr. Wolf's CHM 201 & 202 20-5 Soap-Making CH 3 (CH 2 ) y COCH CH 2 OC(CH 2 ) x CH 3 O CH 2 OC(CH 2 ) z CH 3 O O Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids. These salts are soaps. K 2 CO 3, H 2 O, heat CH 3 (CH 2 ) x COK O CH 3 (CH 2 ) y COK O CH 3 (CH 2 ) z COK O

6. Dr. Wolf's CHM 201 & 202 20-6 Which bond is broken when esters are hydrolyzed in base? RCO O + R' – OHOHOHOH RCO O + R'OH – One possibility is an S N 2 attack by hydroxide on the alkyl group of the ester. Carboxylate is the leaving group.

7. Dr. Wolf's CHM 201 & 202 20-7 Which bond is broken when esters are hydrolyzed in base? + –OH RC O OR'OR'OR'OR' + OR' – A second possibility is nucleophilic acyl substitution. RC O OH

8. Dr. Wolf's CHM 201 & 202 20-8 18 O Labeling gives the answer 18 O retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution. CH 3 CH 2 COCH 2 CH 3 ONaOH + CH 3 CH 2 CONa O CH 3 CH 2 OH +

9. Dr. Wolf's CHM 201 & 202 20-9 Stereochemistry gives the same answer alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution not S N 2 CH 3 COK O+ CH 3 C O C OH C6H5C6H5C6H5C6H5 CH 3 C HOHOHOHOH C6H5C6H5C6H5C6H5 KOH, H 2 O

10. Dr. Wolf's CHM 201 & 202 20-10 Does it proceed via a tetrahedral intermediate? + –OH RC O OR'OR'OR'OR' + OR' – Does nucleophilic acyl substitution proceed in a single step, or is a tetrahedral intermediate involved? RC O OH

11. Dr. Wolf's CHM 201 & 202 20-11 18 O Labeling Studies + H2OH2OH2OH2O COCH 2 CH 3 O O+ H2OH2OH2OH2O Ethyl benzoate, labeled with 18 O at the carbonyl oxygen, was subjected to hydrolysis in base. Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18 O label. This observation is consistent with a tetrahedral intermediate. HO –

12. Dr. Wolf's CHM 201 & 202 20-12 18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 + H2OH2OH2OH2O COCH 2 CH 3 O HO – COCH 2 CH 3 O+ H2OH2OH2OH2O HO –

13. Dr. Wolf's CHM 201 & 202 20-13 Involves two stages: 1)formation of tetrahedral intermediate 2)dissociation of tetrahedral intermediate Mechanism of Ester Hydrolysis in Base

14. Dr. Wolf's CHM 201 & 202 20-14 First stage: formation of tetrahedral intermediate RCOHOH OR' + H2OH2OH2OH2O RCOR' O 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. Dr. Wolf's CHM 201 & 202 20-15 Second stage: cleavage of tetrahedral intermediate RCOHOH OR' + R'OH RCOHO HO –

16. Dr. Wolf's CHM 201 & 202 20-16 Mechanism of formation of tetrahedral intermediate

17. Dr. Wolf's CHM 201 & 202 20-17 Step 1 RC O OR' RC O OR' O H – O H –

18. Dr. Wolf's CHM 201 & 202 20-18 Step 2 RC O OR' O H – HO H RC O OR' O H H – O H

19. Dr. Wolf's CHM 201 & 202 20-19 Dissociation of tetrahedral intermediate

20. Dr. Wolf's CHM 201 & 202 20-20 Step 3 RC O OR' O H H – O H HO H OR' – RC O O H

21. Dr. Wolf's CHM 201 & 202 20-21 Step 4 OR' – RC O O H HO – RC O O – H OR' H2OH2OH2OH2O

22. Dr. Wolf's CHM 201 & 202 20-22 Nucleophilic addition of hydroxide ion to carbonyl group in first step Tetrahedral intermediate formed in first stage Hydroxide-induced dissociation of tetrahedral intermediate in second stage Key Features of Mechanism

23. Dr. Wolf's CHM 201 & 202 20-23 20.11 Reactions of Esters with Ammonia and Amines

24. Dr. Wolf's CHM 201 & 202 20-24 RCOR'O RCNR' 2 O RCO – O Reactions of Esters

25. Dr. Wolf's CHM 201 & 202 20-25 Reactions of Esters + RCNR' 2 O+ Esters react with ammonia and amines to give amides: R' 2 NH RCOR' O R'OH via: C R O OR' NR' 2 H

26. Dr. Wolf's CHM 201 & 202 20-26 Example (75%) + CCNH 2 CH 3 O H2CH2CH2CH2C CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C + NH3NH3NH3NH3 H2OH2OH2OH2O

27. Dr. Wolf's CHM 201 & 202 20-27 Example (61%) + FCH 2 COCH 2 CH 3 O NH2NH2NH2NH2 + CH 3 CH 2 OH FCH 2 CNH Oheat

28. Dr. Wolf's CHM 201 & 202 20-28 20.12 Amides

29. Dr. Wolf's CHM 201 & 202 20-29 Physical Properties of Amides Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives.

30. Dr. Wolf's CHM 201 & 202 20-30 Physical Properties of Amides Amides are capable of hydrogen bonding.

31. Dr. Wolf's CHM 201 & 202 20-31 Physical Properties of Amides Amides are less acidic than carboxylic acids. Nitrogen is less electronegative than oxygen.

32. Dr. Wolf's CHM 201 & 202 20-32 acyl chlorides (Table 20.1) anhydrides (Table 20.2) esters (Table 20.5) Preparation of Amides Amides are prepared from amines by acylation with:

33. Dr. Wolf's CHM 201 & 202 20-33 Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOHO+ R'NH 2 RCOO+ R'NH 3 + – If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating.

34. Dr. Wolf's CHM 201 & 202 20-34 Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOHO+ R'NH 2 RCOO+ R'NH 3 + – heat RCNHR' O+ H2OH2OH2OH2O

35. Dr. Wolf's CHM 201 & 202 20-35 Example COHO+ H2NH2NH2NH2N 225°C + H2OH2OH2OH2O (80-84%) CNHCNHCNHCNHO