Functional Derivatives of Carboxylic Acids

1. Functional Derivatives of Carboxylic Acids Chapter 18

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. 18.1 A.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. B. Acid Anhydrides • The functional group of an acid anhydride has 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. ethanoic anhydride

6. Succinic Phthalic M aleic anhydride anhydride anhydride Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived. O O O O O O O O O

7. - - O - P - O - P - O H O - P - O - P - O H - - O O O H O H Diphosphoric acid Diphosphate ion (Pyrophosphoric acid) (Pyrophosphate ion) - - O - P - O - P - O - P - O H O - P - O - P - O - P - O H - - - - - - O O O O O O Phosphoric Anhydrides • A phosphoric anhydride contains two phosphoryl groups bonded to an oxygen atom. O O O O O O O O O O Triphosphoric acid Triphosphate ion

8. C. 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 • Cyclic esters are called lactones. • name the parent carboxylic acid, drop the suffix -ic acid and add –olactone. 4-hydroxybutanoic acid lactone

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. D. Amides • The functional group of an amide is an acyl group bonded to a nitrogen atom. • IUPAC: drop -oic acidfrom the name of the parent acid 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 • 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. E. 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. Naming Summary • Open chain Cyclic • pentanoic acid cyclopentanecarboxylic acid • pentanoyl chloride cyclopentanecarbonyl chloride • pentanoic anhydride cyclopentanecarboxylic acid • ethanoic methanoic anhydride butandioic anhydride • ethyl pentanoate ethyl cyclopentanecarboxylate • pentanamide cyclopentanecarboxamide • pentanenitrile cyclopentanecarbonitrile 4-aminopentanoic acid lactam 4-hydroxypentanoic acid lactone

18. 18.2 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.

19. Acidity of N-H bonds • Imides are more acidic than amides because. 1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond, and 2. the imide anion is stabilized by resonance delocalization of the negative charge.

20. - + N H N a O H N N a H O 2 pK 8.3 pK 15.7 a a (stronger (stronger (weaker (weaker acid) base) base) acid) Acidity of N-H • imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts. O O + + O O

21. 18.3 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. 18.4 A. 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. B. Reaction with H2O - Anhydrides • low-molecular-weight acid anhydrides react readily with water to give two molecules of carboxylic acid. • higher-molecular-weight acid anhydrides also react with water, but less readily.

26. C H - C - O - C - C H C H - C - O - C - C H C H - C - O - C - C H H - O - H 3 3 3 3 3 3 O - H O - H T e t r a h e d r a l c a r b o n y l a d d i t i o n i n t e r m e d i a t e Reaction with H2O - Anhydrides • Step 1: addition of H2O to give a TCAI. • Step 2: protonation followed collapse of the TCAI. H + H O H O O O O O + + + O H O H H H H H

27. C. 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.

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

29. Reaction with H2O - Esters • Hydrolysis of an esters in aqueous base is often called saponification. • 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.

30. 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.

31. D. Reaction with H2O - Amides • Hydrolysis of an amide in aqueous acid requires 1 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.

32. Reaction with H2O - Amides • Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide. • reaction is driven to completion by the irreversible formation of the carboxylate sale.

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

34. Reaction with H2O - Amides • Step 2: addition of water (a nucleophile) to the carbonyl carbon (an electrophile) followed by proton transfer gives a TCAI. • Step 3: collapse of the TCAI and proton transfer.

35. O H + H H O R - C R - C N H R - C - N H 2 2 A n i m i d i c a c i d A n a m i d e ( e n o l o f a n a m i d e ) E. 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. O N +

36. 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.

37. Reaction with H2O - Nitriles • hydrolysis of nitriles is a valuable route to carboxylic acids.

38. 18.5 A.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. • where the alcohol or resulting ester is sensitive to HCl, reaction is carried out in the presence of a 3° amine to neutralize the acid.

39. Reaction with Alcohols • sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride (Section 18.1A) with an alcohol or phenol. • the key point here is that OH- (a poor leaving group) is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.

40. C H C O C C H H O C H C H C H C O C H C H C H C O H 3 3 2 3 3 2 3 3 A c e t i c a n h y d r i d e E t h a n o l E t h y l a c e t a t e A c e t i c a c i d B. Reaction with Alcohols • Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid. • cyclic anhydrides react with alcohols to give one ester group and one carboxyl group. O O O O + +

41. C O O H O H C H C O C C H 3 3 A cetic 2-Hydroxybenzoic anhydride acid C O O H (Salicylic acid) C H 3 C H C O H 3 Acetylsalicylic acid (Aspirin) Reaction with Alcohols • aspirin is synthesized by treating salicylic acid with acetic anhydride. O O + O O + O Acetic acid

42. H C l H O O C H 3 Methyl propenoate 1-Butanol (Methyl acrylate) (bp 117°C) (bp 81°C) C H O H 3 Butyl propenoate Methanol (Butyl acrylate) (bp 65°C) (bp 147°C) C. Reaction with Alcohols • Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification. O + O O + D. Amides are the least reactive acid derivatives

43. 18.6 A.Reaction with Ammonia, etc. • Acid halides react with ammonia, 1° amines, and 2° amines to form amides. • 2 moles of the amine are required per mole of acid chloride.

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

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

46. POCl3 N C N H 2 P h P h D. Reaction of Amides • An unsubstituted amide can be converted into a nitrile using POCl3. • POCl3 is a dehydrating agent that removes water from the amide. O + heat 2-Phenylbutanamide 2-Phenylbutanenitrile

47. 18.7 Acid Chlorides with Salts • Acid chlorides react with salts of carboxylic acids to give anhydrides. • most commonly used are sodium or potassium salts.

48. 18.8 Interconversions, Fig. 18.1

49. 18.9 A.Reaction with Grignard Reagents • treating a formic ester with 2 moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol.

50. Reaction with Grignard Reagents • treating an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol.