1. FUNCTIONAL DERIVATIVES OF CARBOXYLIC ACIDS
Chapter 21
FUNCTIONAL DERIVATIVES OF CARBOXYLIC ACIDS

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

3. Structure: Acid Halides
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 acid to -yl halide.

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

5. Acid Anhydrides
The functional group of an carboxylic 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. Carboxylic Esters
The functional group of a carboxylic 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 or -oic acid and add -olactone.
The location of the oxygen atom is indicated by a number if the IUPAC name of the acid is used, or by a Greek letter  and so forth if the common name of the acid is used.

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
The functional group of an amide is an acyl group bonded to a nitrogen atom.
IUPAC: drop -oic acid from the name of the parent acid and add -amide.
Common name, drop -ic of the parent name and add amide.
If the amide nitrogen is bonded to alkyl or aryl groups, name the group and show its location on nitrogen by N-.

12. Amides Lactam: A cyclic amide.
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 and Nitriles
The functional group of an imide is two acyl groups bonded to nitrogen.
Both succinimide and phthalimide are cyclic imides.
The functional group of a nitrile is a cyano group.
IUPAC names: name as an alkanenitrile.
Common names: drop -ic acid and add –onitrile.

16. 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.

17. Acidity of N-H bonds
Imides (pKa 8-10) 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. O N A r e s o n a c - t b i l z d

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

19. 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 a water-soluble salt. The ammonium salt is used to make liquid Saccharin. Saccharin in solid form is the Ca2+ salt.

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

21. Characteristic Reactions
The four carboxylic acid derivatives we focus on in this chapter have the following relative reactivity toward nucleophilic acyl substitution.
One effect leading to this trend is relative leaving ability. The weakest base in the series is the best leaving group (Figure 18.1).

22. 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.

23. Hydrolysis of 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.
Acid chlorides are so reactive that hydrolysis does not require acid or base catalysis.

24. Hydrolysis of Acid Chlorides
Step 1: Make a new bond between a nucleophile and an electrophile. Water attacks the carbonyl carbon directly to give a tetrahedral carbonyl addition intermediate.

25. Hydrolysis of Acid Chlorides
Step 2: Take a proton away. Proton transfer is rapid and reversible.

26. Hydrolysis of Acid Chlorides
Step 3: Break a bond to give stable molecules or ions. Collapse of the tetrahedral intermediate and expulsion of chloride ion gives the carboxylic acid.

27. Hydrolysis of Acid 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.
As with hydrolysis of acid chlorides, the hydrolysis of acid anhydrides will occur without an added acid or base catalyst.

28. Hydrolysis of an Ester
Esters are hydrolyzed very only slowly at neutral pH, even when heated to reflux.
Hydrolysis is considerably more rapid when heated with either 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.

29. Acid-catalyzed Ester Hydrolysis
Step 1: Add a proton. Protonation of the carbonyl oxygen of A gives structure B.

30. Acid-catalyzed Ester Hydrolysis
Step 2: Make a new bond between a nucleophile and an electrophile. Attack of a water molecule on the carbonyl carbon gives a tetrahedral carbonyl addition intermediate.

31. Acid-catalyzed Ester Hydrolysis
Step 3: Take a proton away.

32. Acid-catalyzed Ester Hydrolysis
Step 4: Add a proton. Protonation of the –OR’ group converts it to a better leaving group.

33. Acid-catalyzed Ester Hydrolysis
Step 5: Break a bond to give stable molecules or ions. R’-OH leaves.

34. Acid-catalyzed Ester Hydrolysis
Step 6: Take a proton away. Proton transfer to H2O gives the carboxylic acid and regenerates the acid catalyst.

35. Microscopic Reversibility
Principle of microscopic reversibility: A principle that states that for any reversible reaction, the sequence of intermediates and transition states must be the same but in reverse order for the backward versus the forward reaction. (Review Section 10.6).
The reverse of Add a Proton is Take a Proton Away.
The reverse of nucleophilic attack (Make a new bond between a nucleophile and an electrophile) is leaving group departure (Break a bond to give stable molecules or ions).

36. Hydrolysis of Esters in Aqueous Base
Saponification: The hydrolysis of an ester 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.

37. Hydrolysis of an Ester in Base
Step 1: Make a new bond between a nucleophile and an electrophile. Addition of OH- to the carbonyl group creates a tetrahedral carbonyl addition intermediate.

38. Hydrolysis of an Ester in Base
Step 2: Break a bond to give stable molecules or ions. Collapse of the intermediate gives a carboxylic acid and an alkoxide ion.

39. Hydrolysis of an Ester in Base
Step 3: Take a proton away. Proton transfer from the carboxyl group to alkoxide ion drives the reaction to completion.

40. Hydrolysis of Amides in Aqueous Acid
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.

41. Hydrolysis of an Amide in Aqueous Base
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.
One mole of base is required per mole of amide.

42. Hydrolysis of an Amide in Aqueous Acid
Step1: Add a proton. Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate and increases the electrophilic character of the carbonyl carbon.

43. Hydrolysis of an Amide in Aqueous Acid
Step 2: Make a new bond between a nucleophile and an electrophile. Addition of water to the carbonyl carbon.

44. Hydrolysis of an Amide in Aqueous Acid
Step 3: Take a proton away/add a proton. Proton transfer between O and N gives a tetrahedral carbonyl addition intermediate.

45. Hydrolysis of an Amide in Aqueous Acid
Step 4: Break a bond to make stable molecules or ions. Note that the leaving group is a neutral amine (a weaker base), a far better leaving group than an amide ion (NH2-), a much stronger base.

46. Hydrolysis of an Amide in Aqueous Base
Step 1: Make a bond between a nucleophile and an electrophile. Addition of hydroxide ion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate.

47. Hydrolysis of an Amide in Aqueous Base
Step 2: Take proton away. This step creates a dianionic intermediate, which has enough negative charge to expel the amide anion.

48. Hydrolysis of an Amide in Aqueous Base
Step 3: Break a bond to give stable molecules or ions/add a proton. The amide anion has so little lifetime in water because it is so basic; therefore, it will be instantly protonated by water.

49. Hydrolysis of a Nitrile
The cyano group of a nitrile 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.

50. Hydrolysis of a Nitrile in Aqueous Base
Hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylate anion to the carboxylic acid.

51. Hydrolysis of Nitriles
Hydrolysis of nitriles is a valuable route to carboxylic acids from 1° or 2° haloalkanes and from cyanohydrins (Section 16.5D).

52. Reaction of Acid Halides 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.

53. Reaction of Ar-SO2Cl 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- (a poor leaving group) is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.

54. Reaction of Anhydrides 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.

55. Reaction of Anhydrides with Alcohols
Aspirin is synthesized by treating salicylic acid with acetic anhydride.

56. Reaction of Esters with Alcohols
Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification.
The equilibrium can be driven to completion by control of experimental conditions.

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

58. Reaction of Acid Chlorides with NH3
Step 1: Make a new bond between a nucleophile and an electrophile. The nitrogen nucleophile adds to the carbonyl carbon.

59. Reaction of Acid Chlorides with NH3
Step 2: Take a proton away. Proton transfer gives a tetrahedral carbonyl addition intermediate.

60. Reaction of Acid Chlorides with NH3
Step 3: Beak a bond to give stable molecules or ions. The intermediate collapses to expel chloride as a leaving group.

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

62. Reaction of Esters with Ammonia
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.

63. Reaction of Acid Chlorides with Salts
Acid chlorides react with salts of carboxylic acids to give anhydrides.
Sodium or potassium salts are most commonly used for this purpose.

64. Fig 18.2 Reactivities of Acid Derivatives

65. Reaction with Grignard Reagents
Treating a formic ester with two moles of a Grignard reagent followed by hydrolysis of the magnesium alkoxide in aqueous acid gives a secondary alcohol.

66. Reaction with Grignard Reagents
Treating an ester other than a formate gives a tertiary alcohol in which two of the three groups bonded to the carbon bearing the -OH group are the same.

67. Reaction of Ester + Grignard Reagent
Step 1: Make a new bond between a nucleophile and an electrophile. Reaction of the ester with one mole of Grignard reagent forms a tetrahedral carbonyl addition intermediate.

68. Reaction of Ester + Grignard Reagent
Step 2: Break a bond to give stable molecules or ions. Collapse of the intermediate and expulsion of alkoxide ion gives a ketone and a magnesium alkoxide.

69. Reaction of Ester + Grignard Reagent
Step 3: Make a new bond between a nucleophile and an electrophile. The ketone reacts with a second mole of Grignard reagent to give a second tetrahedral carbonyl addition intermediate.

70. Reaction of Ester + Grignard Reagent
Step 4: Add a proton. The resulting hydrolysis gives a tertiary alcohol.

71. Reactions with RLi
Organolithium compounds are even more powerful nucleophiles than Grignard reagents.
They react with esters to give the same types of 2° and 3° alcohols as do Grignard reagents.
and often in higher yields.

72. Gilman Reagents
Acid chlorides at -78°C react with Gilman reagents (Section 15.2) to give ketones.
Under these conditions, the tetrahedral carbonyl addition intermediate is stable, and it is not until acid hydrolysis that the ketone is liberated.

73. Gilman Reagents Gilman reagents react only with acid chlorides.
They do not react with acid anhydrides, esters, amides, or nitriles under the conditions described.

74. Reduction of Esters by LiAlH4
Most reductions of carbonyl compounds now use hydride reducing agents.
Esters are reduced by LiAlH4 to two alcohols.
The alcohol derived from the carbonyl group is primary.

75. Reduction - Esters by LiAlH4
Step 1: Make a new bond between a nucleophile and an electrophile. Nucleophilic addition of hydride ion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate.

76. Reduction - Esters by LiAlH4
Step 2: Break a bond to give stable molecules or ions. Collapse of the intermediate gives a new carbonyl-containing compound.

77. Reduction - Esters by LiAlH4
Step 3: Make a new bond between a nucleophile and an electrophile. Nucleophilic addition of a second hydride ion to the newly formed carbonyl group gives an alkoxide ion.

78. Reduction - Esters by LiAlH4
Step 4: Add a proton. Addition of aqueous acid gives a primary alcohol.

79. Reduction of an Ester to an Aldehyde
Reduction of an ester to a primary alcohol involves two successive hydride ion transfers.
A goal has been to modify the structure of the reducing agent so as to be able to reduce an ester to an aldehyde.
A useful modified reducing agent is diisobutyl-aluminum hydride (DIBALH)

80. Reduction of an Ester to an Aldehyde
DIBALH reductions are typically carried out in toluene or hexane at -78°C followed by warming to room temperature and addition of aqueous acid.

81. Reduction - Esters by NaBH4
NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones.
Selective reduction is often possible by the proper choice of reducing agents and experimental conditions.

82. Reduction of Amides by LiAlH4
LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide.

83. Reduction of Amides by LiAlH4
Step 1: Make a new bond between a nucleophile and an electrophile. Addition of hydride ion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate.

84. Reduction of Amides by LiAlH4
Step 2: Make a new bond between a Lewis base and a Lewis acid to create an oxygen-aluminum bond.

85. Reduction of Amides by LiAlH4
Step 3: Break a bond to give stable molecules or ions. Rearrangement of electron pairs generates an iminium ion.

86. Reduction of Amides by LiAlH4
Step 4: Make a new bond between a nucleophile and an electrophile. In this final step the iminium ion adds a second hydride ion to complete the reduction.

87. Reduction of a Nitrile by LiAlH4
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine.
Reduction of a cyano group is useful for the preparation of only primary amines.

88. Interconversions
Problem: Show reagents and experimental conditions to bring about each reaction.

89. Problem 18.38
A step in a synthesis of PGE (prostaglandin E1, alprostadil) is the reaction of a trisubstituted cyclohexene with bromine to form a bromolactone. Propose a mechanism for formation of this bromolactone and account for the observed stereochemistry of each substituent on the cyclohexene ring.

90. Problem 18.38
Step 1: Make a new bond between a nucleophile ( bond) and an electrophile.

91. Problem 18.38
Step 2: Make a bond between a nucleophile and an electrophile.

92. Problem 18.38 Step 3: Take a proton away.
The stereochemistry is fixed by the bicyclic structure. The bromine atom is axial, while the -CHCOOH and methyl groups are equatorial.