Chapter 18 Carboxylic Acid Derivatives

1. Chapter 18 Carboxylic Acid Derivatives Lecture 24 Chem 30B

2. Carboxyl Derivatives • In this chapter, we study five classes of organic compounds. • Under the structural formula of each is a drawing to help you see its relationship to the carboxyl group.

3. Structure: Acid Chlorides • The functional group of an acid halide is an acyl group bonded to a halogen. • The most common are the acid chlorides. • To name, change the suffix -ic acidto -yl halide.

4. Sulfonyl Chlorides • Replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride.

5. Acid Anhydrides • The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom. • The anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups). • To name, replace acid of the parent acid by anhydride.

6. Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.

7. Phosphoric Anhydrides • A phosphoric anhydride contains two phosphoryl groups bonded to an oxygen atom.

8. Esters • The functional group of an ester is an acyl group bonded to -OR or -OAr. • Name the alkyl or aryl group bonded to oxygen followed by the name of the acid. • Change the suffix -ic acid to -ate.

9. Esters • Lactone: A cyclic ester. • name the parent carboxylic acid, drop the suffix -ic acid and add -olactone.

10. Esters of Phosphoric Acid • Phosphoric acid forms mono-, di-, and triesters. • Name by giving the name of the alkyl or aryl group(s) bonded to oxygen followed by the word phosphate. • In more complex phosphoric esters, it is common to name the organic molecule and then indicate the presence of the phosphoric ester by the word phosphate or the prefix phospho-.

11. Amides • IUPAC: drop -oic acidfrom the name of the parent acid and add -amide. For the common name, drop -ic of the parent name and add -amide. • if the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by N-.

12. Amides • Lactams: A cyclic amides are called lactams. • Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam.

13. Penicillins • The penicillins are a family of -lactam antibiotics.

14. Cephalosporins • The cephalosporins are also -lactam antibiotics.

15. Imides • The functional group of an imide is two acyl groups bonded to nitrogen. • Both succinimide and phthalimide are cyclic imides.

16. Nitriles • The functional group of a nitrile is a cyano group • IUPAC names: name as an alkanenitrile. • common names: drop the -ic acidand add -onitrile.

17. Acidity of N-H bonds • Amides are comparable in acidity to alcohols. • Water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water-soluble salts. • Sulfonamides and imides are more acidic than amides.

18. Acidity of N-H bonds • Imides are more acidic than amides because • the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond 2. the imide anion is stabilized by resonance delocalization of the negative charge.

19. Acidity of N-H • Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.

20. Acidity of N-H • Saccharin, an artificial sweetener, is an imide. The imide is sufficiently acidic that it reacts with NaOH and aqueous NH3 to form water-soluble salts. The ammonium salt is used to make liquid Saccharin. Saccharin in solid form is the Ca2+ salt.

21. Characteristic Reactions • Nucleophilic acyl substitution:An addition-elimination sequence resulting in substitution of one nucleophile for another.

22. Characteristic Reactions • In the general reaction, we showed the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group.

23. Characteristic Reactions • Halide ion is the weakest base and the best leaving group; acid halides are the most reactive toward nucleophilic acyl substitution. • Amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution.

24. Reaction with H2O - Acid Chlorides • Low-molecular-weight acid chlorides react rapidly with water. • Higher molecular-weight acid chlorides are less soluble in water and react less readily.

25. Reaction with H2O - Anhydrides • Low-molecular-weight anhydrides react readily with water to give two molecules of carboxylic acid. • Higher-molecular-weight anhydrides also react with water, but less readily.

26. Reaction with H2O - Anhydrides • Step 1: Addition of H2O to give a TCAI.

27. Reaction with H2O - Anhydrides • Step 2: Protonation followed collapse of the TCAI.

28. Reaction with H2O - Esters • Esters are hydrolyzed only slowly, even in boiling water. • Hydrolysis becomes more rapid if they are heated with either aqueous acid or base. • Hydrolysis in aqueous acid is the reverse of Fischer esterification. • The role of the acid catalyst is to protonate the carbonyl oxygen and increase its electrophilic character toward attack by water (a weak nucleophile) to form a tetrahedral carbonyl addition intermediate. • Collapse of this intermediate gives the carboxylic acid and alcohol.

29. Reaction with H2O - Esters • Acid-catalyzed ester hydrolysis

30. Reaction with H2O - Esters • Saponification: The hydrolysis of an esters in aqueous base. • Each mole of ester hydrolyzed requires 1 mole of base • For this reason, ester hydrolysis in aqueous base is said to be base promoted. • Hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer.

31. Reaction with H2O - Esters • Step 1: Attack of hydroxide ion (a nucleophile) on the carbonyl carbon (an electrophile). • Step 2: Collapse of the TCAI. • Step 3: Proton transfer to the alkoxide ion; this step is irreversible and drives saponification to completion.

32. Reaction with H2O - Amides • Hydrolysis of an amide in aqueous acid requires one mole of acid per mole of amide. • Reaction is driven to completion by the acid-base reaction between the amine or ammonia and the acid.

33. Reaction with H2O - Amides • Hydrolysis of an amide in aqueous base requires one mole of base per mole of amide. • Reaction is driven to completion by the irreversible formation of the carboxylate salt.

34. Reaction with H2O - Amides • Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.

35. Reaction with H2O - Amides • Step 2: Addition of water to the carbonyl carbon followed by proton transfer gives a TCAI. • Step 3: Collapse of the TCAI and proton transfer.

36. Reaction with H2O - Nitriles • The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion. • Protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid. • Keto-enol tautomerism gives the amide.

37. Reaction with H2O - Nitriles • Hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid.

38. Reaction with H2O - Nitriles Hydrolysis of nitriles is a valuable route to carboxylic acids.

39. Chapter 18 Carboxylic Acid Derivatives Lecture 25 Chem 30B

40. Reaction with Alcohols • Acid halides react with alcohols to give esters. • Acid halides are so reactive toward even weak nucleophiles such as alcohols that no catalyst is necessary. • If the alcohol or resulting ester is sensitive to HCl, the reaction is carried out in the presence of a 3° amine to neutralize the acid.

41. Reaction with Alcohols • Sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol. • The key point here is that OH- is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.

42. Reaction with Alcohols • Acid anhydrides react with alcohols to give one mole of ester and one mole of a carboxylic acid. • Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group.

43. Reaction with Alcohols • Aspirin is synthesized by treating salicylic acid with acetic anhydride.

44. Reaction with Alcohols • Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification.

45. Reaction with Ammonia, etc. • Acid halides react with ammonia, 1° amines, and 2° amines to form amides. • Two moles of the amine are required per mole of acid chloride.

46. Reaction with Ammonia, etc. • Acid anhydrides react with ammonia, and 1° and 2° amines to form amides. • Two moles of ammonia or amine are required.

47. Reaction with Ammonia, etc. • Esters react with ammonia and with 1° and 2° amines to form amides. • Esters are less reactive than either acid halides or acid anhydrides. • Amides do not react with ammonia or with 1° or 2° amines.

48. Acid Chlorides with Salts • Acid chlorides react with salts of carboxylic acids to give anhydrides. • Most commonly used are sodium or potassium salts.

49. Chapter 18 Carboxylic Acid Derivatives Lecture 26 Chem 30B

50. Interconversions of Acid Derivatives