1. In this chapter, we focus on four classes of organic compounds derived from carboxylic acids. Under the general formula of each is a drawing to show how it is related to the carboxyl group. Functional Derivatives of Carboxylic Acids

2. Parent Names of Carboxylic Derivatives

3. Acid Chlorides The functional group of an acid halide is an acyl group bonded to a halogen. The most widely used are the acid chlorides. To name, change the suffix -ic acid to -yl chloride. Note this rule works for both IUPAC names and common names.

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

5. 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 (instead of a hydrogen) followed by the name of the acid. Change the suffix -ic acid to -ate.

6. Lactones Lactone: a cyclic ester IUPAC: name the parent carboxylic acid, drop the suffix -oic acid, and add -olactone. The location of the oxygen atom on the carbon chain is commonly indicated by a Greek letter.

7. Amides The functional group of an amide is an acyl group bonded to a trivalent nitrogen. IUPAC: drop -oic acid from 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-. (IUPAC: ethanamide)

8. Lactams Lactam: a cyclic amide. Name the parent carboxylic acid, drop the suffix ‑ oic acid and add -olactam. The connection to the nitrogen atom in the ring is commonly indicated by a Greek letter, , , etc. 6-hexanolactam is an intermediate in the synthesis of nylon 6.

9. The penicillins and cephalosporins are two families of  -lactam antibiotics.

10. The nitrile group is an sp carbon triply bonded to a nitrogen. Applications Nitriles are very polar; therefore, they are excellent polar aprotic solvents. Nitriles are also a component of many rubber materials including hypoallergenic gloves. Even though nitriles contain nitrogen, they are very poor bases. Nitriles

11. Nomenclature Nitriles are carboxylic acid derivatives; therefore, their names are based on the name of the corresponding carboxylic acid. Nitriles are named by replacing the suffix “oic acid” with “enitrile”. The prefix for functional group is cyano-. butanenitrile Common name: acetonitrile2-cyanopentane

12. Nucleophilic acyl substitution: an addition- elimination sequence resulting in substitution of one nucleophile for another. The reaction depends on having a suitable leaving group (Y) bonded to the acyl carbon to complete the elimination. Nucleophilic Acyl Substitution

13. In the general reaction, the nucleophile does not need to be an anion. Neutral molecules such as water, alcohols, ammonia, and amines can also serve as nucleophiles. Remember! The weaker the base, the better the leaving group.

14. Halide ion is the weakest base and the best leaving group. Acid halides are, therefore, the most reactive toward nucleophilic acyl substitution. Amide ion is the strongest base and the poorest leaving group; amides, therefore, are the least reactive toward nucleophilic acyl substitution.

15. Nucleophilic Acyl Substitution

16. Reactivity of Carbonyls to A N  Most reactive least reactive

17. Reaction Summary Hydrolysis Acid chlorides, acid anhydrides, esters, amides, nitriles Alcoholysis Acid chlorides, acid anhydrides, esters Aminolysis Acid chlorides, acid anhydrides, esters Esterification with Grignard reagent Metal hydride reduction Esters, amides

18. Hydrolysis - Acid Chlorides Low-molecular-weight acid chlorides react rapidly with water to form a carboxylic acid and HCl. Higher molecular-weight acid chlorides react less readily.

19. Hydrolysis - Acid 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.

20. Hydrolysis - Esters Esters are hydrolyzed only slowly, even in boiling water. Hydrolysis becomes more rapid if they are heated with either aqueous acid or aqueous base. Hydrolysis in aqueous acid is the reverse of Fischer esterification. The key step in the mechanism of hydrolysis is formation of a tetrahedral carbonyl addition intermediate followed by its collapse (see the next screen for details).

21. Mechanism for the Acid-Catalyzed Hydrolysis of Esters 1)Addition of a proton increases the electrophilic character of the carbonyl carbon. 2)Reaction of a nucleophile with an electrophile to form a new covalent bond 3)proton transfer 4)collapse of the TCAI to eliminate a leaving group.

22. Hydrolysis of an ester 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. Base-promoted ester hydrolysis involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse.

23. Step 1: Reaction of a nucleophile and an electrophile to form a new covalent bond. Step 2: Collapse of the tetrahedral carbonyl addition intermediate to eliminate a leaving group. Mechanism for the Base-Catalyzed Hydrolysis of Esters

24. Step 3: Proton transfer completes the reaction.

25. There are two major differences between acid- catalyzed and base-promoted ester hydrolysis. 1.For acid-catalyzed hydrolysis, acid is required in only catalytic amounts; for base-promoted hydrolysis, equimolar amounts of ester and base are required. 2.Hydrolysis of an ester in aqueous acid is reversible; base-promoted hydrolysis is irreversible because a carboxylate anion is not susceptible to nucleophilic attack.

26. Hydrolysis - Amides Hydrolysis of an amide requires much more vigorous conditions than hydrolysis of an ester. Hydrolysis in aqueous acid requires 1 mole of acid for each mole of amide. The products are a carboxylic acid and an ammonium salt.

27. Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide. The products are a carboxylate salt and an amine.

28. Summary of Hydrolysis Reactions

29. Preparation and Hydrolysis of Nitriles When a 1° or 2° alkyl halide is treated with a cyanide ion, the CN - acts as a nucleophile in an S N 2 reaction. Hydrolysis occurs with a strong acid or strong base.

30. Reaction with Alcohols (Alcoholysis) Acid chlorides react with alcohols and phenols to give an ester and HCl.

31. Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid. Aspirin is prepared via alcoholysis by the following reaction:

32. Esters undergo an exchange reaction called transesterification. The exchange is acid catalyzed. The original -OR group is exchanged for a new -OR group.

33. Amides do not react with alcohols under any conditions.

34. Acid halides react with ammonia, 1° and 2° amines to form amides. Two moles of the amine are required per mole of acid chloride; one to form the amide and one to neutralize the HCl byproduct. Reaction with Amines (Aminolysis)

35. Acid anhydrides react with ammonia, 1° and 2° amines to form amides. Two moles of ammonia or amine are required; one to form the amide and one to neutralize the carboxylic acid byproduct.

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

37. Summary of Reactions with NH 3 & Amines

38. Interconversion of functional groups. Reactivity of Carbonyls to A N 

39. Esters with Grignard Reagents Reaction of a formic ester with two moles of Grignard reagent followed by hydrolysis gives a 2° alcohol. Reaction of an ester other than a formic ester with a Grignard reagent gives a 3° alcohol.

40. Mechanism of Reaction of Esters with Grignard Reagents Step 1: Reaction of a nucleophile and an electrophile to form a new covalent bond.

41. Step 2: Collapse of the carbonyl addition intermediate to eject a leaving group and regenerate the carbonyl group.

42. Step 3: Reaction of a nucleophile with an electrophile to form a new covalent bond.

43. Step 4: Add a proton. Proton transfer completes the reaction.

44. Metal Hydride Reduction Esters are reduced by LiAlH 4 to two alcohols. The alcohol derived from the carbonyl group is primary.

45. NaBH 4 does not normally reduce esters, but it does reduce aldehydes and ketones.

46. LiAlH 4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide.

47. Some Interconversions