1. Carboxylic acids - Nucleofilic acyl substitution reaction Dr AKM Shafiqul Islam School of Bioprocess Engineering

2. Mechanism of the Fischer Esterification  Step One – Protonation of the carbonyl oxygen:

3. Mechanism of the Fischer Esterification  Step One – Protonation of the carbonyl oxygen:

4. Mechanism of the Fischer Esterification  Step One – Protonation of the carbonyl oxygen:

5. Mechanism of the Fischer Esterification  Step Two – Nucleophilic addition of the alcohol to form an oxonium ion intermediate:

6. Mechanism of the Fischer Esterification  Step Two – Nucleophilic addition of the alcohol to form an oxonium ion intermediate:

7. Mechanism of the Fischer Esterification  Step Two – Nucleophilic addition of the alcohol to form an oxonium ion intermediate:

8. Mechanism of the Fischer Esterification  Step Three – Proton reorganization to give a new oxonium ion intermediate:

9. Mechanism of the Fischer Esterification  Step Three – Proton reorganization to give a new oxonium ion intermediate:

10. Mechanism of the Fischer Esterification  Step Four – Elimination of water:

11. Mechanism of the Fischer Esterification  Step Four – Elimination of water:

12. Mechanism of the Fischer Esterification  Step Five – Deprotonation to give the ester:

13. Mechanism of the Fischer Esterification  Step Five – Deprotonation to give the ester:

14. Mechanism of the Fischer Esterification  Step Five – Deprotonation to give the ester: Note that only a catalytic amount of acid is needed

15. Preparation of Esters  Reaction of an acid chloride with an alcohol An alcohol reacts with an acid chloride with elimination of HCl. Sometimes an amine base is added to precipitate the HCl that is formed.

16. Preparation of Esters  Reaction of an acid chloride with an alcohol An alcohol reacts with an acid chloride with elimination of HCl. Sometimes an amine base is added to precipitate the HCl that is formed.

17. Preparation of Esters  Reaction of an acid chloride with an alcohol An alcohol reacts with an acid chloride with elimination of HCl. Sometimes an amine base is added to precipitate the HCl that is formed.

18. Esterification Mechanism  Step One – Nucleophilic addition of alcohol to acid chloride:

19. Esterification Mechanism  Step One – Nucleophilic addition of alcohol to acid chloride:

20. Esterification Mechanism  Step Two – Deprotonation of the tetrahedral intermediate:

21. Esterification Mechanism  Step Two – Deprotonation of the tetrahedral intermediate:

22. Esterification Mechanism  Step Three – Elimination of chloride anion:

23. Esterification Mechanism  Step Three – Elimination of chloride anion:

24. Reactions of Esters  Hydrolysis Esters are normally unreactive with water. However, in the presence of either aqueous acid (aq. HCl or H 2 SO 4 ) or aqueous base (NaOH or KOH), they can be hydrolyzed.

25. Acid-Catalyzed Hydrolysis  The reverse of the Fischer esterification

26. Base-Promoted Hydrolysis (Saponification)  This reaction is used to make soap

27. Mechanism of Saponification  Step One – Nucleophilic addition of hydroxide anion:

28. Mechanism of Saponification  Step One – Nucleophilic addition of hydroxide anion:

29. Mechanism of Saponification  Step Two – Elimination of alkoxide anion:

30. Mechanism of Saponification  Step Two – Elimination of alkoxide anion:

31. Mechanism of Saponification  Step Three – Proton reorganization (acid– base reaction):

32. Mechanism of Saponification  Step Three – Proton reorganization (acid– base reaction):

33. Reactions of Anhydrides  Esterification (Alcoholysis) Anhydrides react with alcohols to give one molecule of ester and one molecule of carboxylic acid—a useful method for the preparation of esters.

34. Example of Esterification  Preparation of aspirin:

35. Example of Esterification  Preparation of aspirin:

36. Reactions of Anhydrides  Reaction with Ammonia and Amines – Formation of Amides Anhydrides react with ammonia, as well as 1 o or 2 o amines, to form amides. Note that two moles of amine are required (one forms the amide, the other acts as a base).

37. Example of Amide Formation  Preparation of acetamide

38. Example of Amide Formation  Preparation of acetamide

39. Example of Amide Formation  Preparation of acetaminophen