1. Dr. Wolf's CHM 201 & 202 20-1 20.4 Nucleophilic Substitution in Acyl Chlorides

2. Dr. Wolf's CHM 201 & 202 20-2 Preparation of Acyl Chlorides from carboxylic acids and thionyl chloride (Section 12.7) (CH 3 ) 2 CHCOH O SOCl 2 heat (CH 3 ) 2 CHCCl O+ SO 2 + HCl (90%)

3. Dr. Wolf's CHM 201 & 202 20-3 RCOCR'OO RCCl O RCOR'O RCNR' 2 O RCO – O Reactions of Acyl Chlorides

4. Dr. Wolf's CHM 201 & 202 20-4 RCCl O Reactions of Acyl Chlorides + R'COH O RCOCR' OO+ HCl Acyl chlorides react with carboxylic acids to give acid anhydrides: via: C R O Cl OCR' HO

5. Dr. Wolf's CHM 201 & 202 20-5 CH 3 (CH 2 ) 5 CCl OExample + CH 3 (CH 2 ) 5 COH Opyridine CH 3 (CH 2 ) 5 COC(CH 2 ) 5 CH 3 OO(78-83%)

6. Dr. Wolf's CHM 201 & 202 20-6 RCCl O Reactions of Acyl Chlorides + RCOR' O+ HCl Acyl chlorides react with alcohols to give esters: R'OH via: C R O Cl OR' H

7. Dr. Wolf's CHM 201 & 202 20-7 Example C 6 H 5 CCl O+ (CH 3 ) 3 COH pyridine (80%) C 6 H 5 COC(CH 3 ) 3 O

8. Dr. Wolf's CHM 201 & 202 20-8 RCCl O Reactions of Acyl Chlorides + RCNR' 2 O+ H2OH2OH2OH2O Acyl chlorides react with ammonia and amines to give amides: R' 2 NH + HO – + Cl – via: C R O Cl NR' 2 H

9. Dr. Wolf's CHM 201 & 202 20-9 Example C 6 H 5 CCl O+ NaOH (87-91%) H2OH2OH2OH2O HNHNHNHN C6H5CNC6H5CNC6H5CNC6H5CNO

10. Dr. Wolf's CHM 201 & 202 20-10 RCCl O Reactions of Acyl Chlorides + RCOH O+ HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O RCCl O+ RCO – O+ Cl – 2HO – + H2OH2OH2OH2O

11. Dr. Wolf's CHM 201 & 202 20-11 RCCl O Reactions of Acyl Chlorides + RCOH O+ HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O via: C R O Cl OHOHOHOHH

12. Dr. Wolf's CHM 201 & 202 20-12 Example C 6 H 5 CH 2 CCl O+ H2OH2OH2OH2O C 6 H 5 CH 2 COH O+ HCl

13. Dr. Wolf's CHM 201 & 202 20-13 Reactivity C 6 H 5 CCl O C 6 H 5 CH 2 Cl Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. Relative rates of hydrolysis (25°C) 1,0001

14. Dr. Wolf's CHM 201 & 202 20-14 20.5 Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides Anhydrides can be prepared from acyl chlorides as described in Table 20.1

15. Dr. Wolf's CHM 201 & 202 20-15 Some anhydrides are industrial chemicals CH 3 COCCH 3 OO Acetic anhydride OO OOO O Phthalic anhydride Maleic anhydride

16. Dr. Wolf's CHM 201 & 202 20-16 From dicarboxylic acids Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids C C H HCOH COHOO OO O H H tetrachloroethane130°C (89%) + H 2 O

17. Dr. Wolf's CHM 201 & 202 20-17 RCOCR'OO RCOR'O RCNR' 2 O RCO – O Reactions of Anhydrides

18. Dr. Wolf's CHM 201 & 202 20-18 Reactions of Acid Anhydrides + RCOR' O+ Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOCR OORCOHO normally, symmetrical anhydrides are used (both R groups the same) reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids

19. Dr. Wolf's CHM 201 & 202 20-19 Reactions of Acid Anhydrides + RCOR' O+ Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOCR OORCOHOvia: C R O OCR OR' HO

20. Dr. Wolf's CHM 201 & 202 20-20 Example (60%) H 2 SO 4 + CH 3 COCCH 3 OO CH 3 CHCH 2 CH 3 OHOHOHOH CH 3 COCHCH 2 CH 3 O CH 3

21. Dr. Wolf's CHM 201 & 202 20-21 Reactions of Acid Anhydrides + RCNR' 2 O+ Acid anhydrides react with ammonia and amines to give amides: 2R' 2 NH RCOCR OO RCO – O R' 2 NH 2 + via: C R O OCR NR' 2 HO

22. Dr. Wolf's CHM 201 & 202 20-22 Example (98%) + CH 3 COCCH 3 OO H2NH2NH2NH2N CH(CH 3 ) 2 O CH 3 CNH CH(CH 3 ) 2

23. Dr. Wolf's CHM 201 & 202 20-23 Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O + 2RCO – O+ 2HO – H2OH2OH2OH2O RCOCR OO OO

24. Dr. Wolf's CHM 201 & 202 20-24 Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O RCOCR OO C R O OCR OHHO

25. Dr. Wolf's CHM 201 & 202 20-25 Example + H2OH2OH2OH2OOO O COHOCOH O

26. Dr. Wolf's CHM 201 & 202 20-26 20.6 Sources of Esters

27. Dr. Wolf's CHM 201 & 202 20-27 CH 3 COCH 2 CH 2 CH(CH 3 ) 2 O Esters are very common natural products 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate” contributes to characteristic odor of bananas

28. Dr. Wolf's CHM 201 & 202 20-28 Esters of Glycerol R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or "triglycerides" fats and oils are mixtures of glyceryl triesters RCOCH CH 2 OCR' O CH 2 OCR" OO

29. Dr. Wolf's CHM 201 & 202 20-29 Esters of Glycerol CH 3 (CH 2 ) 16 COCH CH 2 OC(CH 2 ) 16 CH 3 O OO Tristearin: found in many animal and vegetable fats

30. Dr. Wolf's CHM 201 & 202 20-30 Cyclic Esters (Lactones) (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) OO H H CH 2 (CH 2 ) 6 CH 3

31. Dr. Wolf's CHM 201 & 202 20-31 Fischer esterification (Sections 15.8 and 19.14) from acyl chlorides (Sections 15.8 and 20.4) from carboxylic acid anhydrides (Sections 15.8 and 20.6) Baeyer-Villiger oxidation of ketones (Section 17.16) Preparation of Esters

32. Dr. Wolf's CHM 201 & 202 20-32 20.7 Physical Properties of Esters

33. Dr. Wolf's CHM 201 & 202 20-33 Boiling Points Esters have higher boiling points than alkanes because they are more polar. Esters cannot form hydrogen bonds to other ester molecules, so have lower boiling points than alcohols. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH28°C 57°C 99°C boiling point

34. Dr. Wolf's CHM 201 & 202 20-34 Solubility in Water Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH~0 33 12.5 Solubility (g/100 g)

35. Dr. Wolf's CHM 201 & 202 20-35 20.8 Reactions of Esters: A Review and a Preview

36. Dr. Wolf's CHM 201 & 202 20-36 with Grignard reagents (Section 14.10) reduction with LiAlH 4 (Section 15.3) with ammonia and amines (Sections 20.12) hydrolysis (Sections 20.10 and 20.11) Reactions of Esters

37. Dr. Wolf's CHM 201 & 202 20-37 20.9 Acid-Catalyzed Ester Hydrolysis

38. Dr. Wolf's CHM 201 & 202 20-38 maximize conversion to ester by removing water maximize ester hydrolysis by having large excess of water equilibrium is closely balanced because carbonyl group of ester and of carboxylic acid are comparably stabilized Acid-Catalyzed Ester Hydrolysis RCOH O+ R'OH RCOR' O+ H2OH2OH2OH2O H+H+H+H+ is the reverse of Fischer esterification

39. Dr. Wolf's CHM 201 & 202 20-39 Example HCl, heat + H2OH2OH2OH2OO CHCOCH 2 CH 3 Cl + CH 3 CH 2 OH OCHCOH Cl (80-82%)

40. Dr. Wolf's CHM 201 & 202 20-40 Is the reverse of the mechanism for acid- catalyzed esterification. Like the mechanism of esterification, it involves two stages: 1)formation of tetrahedral intermediate (3 steps) 2)dissociation of tetrahedral intermediate (3 steps) Mechanism of Acid-Catalyzed Ester Hydrolysis

41. Dr. Wolf's CHM 201 & 202 20-41 First stage: formation of tetrahedral intermediate RCOHOH OR' + H2OH2OH2OH2O RCOR' O H+H+H+H+ water adds to the carbonyl group of the ester this stage is analogous to the acid- catalyzed addition of water to a ketone

42. Dr. Wolf's CHM 201 & 202 20-42 Second stage: cleavage of tetrahedral intermediate RCOHOH OR' + R'OH H+H+H+H+ RCOHO

43. Dr. Wolf's CHM 201 & 202 20-43 Mechanism of formation of tetrahedral intermediate

44. Dr. Wolf's CHM 201 & 202 20-44 Step 1 RC O OR' O + HHH RC O OR' + H O H H

45. Dr. Wolf's CHM 201 & 202 20-45 Step 1 RC O OR' + H carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O OR' + H

46. Dr. Wolf's CHM 201 & 202 20-46 Step 2 O H H RC O OR' + H RC OH OR' O + H H

47. Dr. Wolf's CHM 201 & 202 20-47 Step 3 O HH RC OH OR' O H H + O H H H + RC OH OR' O H

48. Dr. Wolf's CHM 201 & 202 20-48 Cleavage of tetrahedral intermediate

49. Dr. Wolf's CHM 201 & 202 20-49 Step 4 O HH H + RC OH O OH R' RC OH O OH R' H + O H H

50. Dr. Wolf's CHM 201 & 202 20-50 Step 5 RC OH O OH R' H + O R' H + RC OH OH +

51. Dr. Wolf's CHM 201 & 202 20-51 Step 5 RC OHOH + RC OH OH +

52. Dr. Wolf's CHM 201 & 202 20-52 Step 6 RC OOH + H O H H + O H HH RC O OH

53. Dr. Wolf's CHM 201 & 202 20-53 Activation of carbonyl group by protonation of carbonyl oxygen Nucleophilic addition of water to carbonyl group forms tetrahedral intermediate Elimination of alcohol from tetrahedral intermediate restores carbonyl group Key Features of Mechanism

54. Dr. Wolf's CHM 201 & 202 20-54 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 acid- catalyzed hydrolysis. Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18 O label. This observation is consistent with a tetrahedral intermediate. H+H+H+H+

55. Dr. Wolf's CHM 201 & 202 20-55 18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 COCH 2 CH 3 O H+H+H+H+ + H2OH2OH2OH2O + H2OH2OH2OH2O O H+H+H+H+