1. Chapter 18
Functional
Derivatives of
Carboxylic Acids

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

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

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 acid and add -onitrile

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

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

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. 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 C H 3 O + H O C 2 3 C H 3 O 2 + C H 3 O A c e t i a n h y d r E t h a n o l E t h y l a c e A c e t i a d

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

42. C. Reaction with Alcohols
Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification. O H C l + O C H 3 H O
Methyl propenoate
(Methyl acrylate)
(bp 81°C)
1-Butanol
(bp 117°C) O O + C H 3 O
Butyl propenoate
(Butyl acrylate)
(bp 147°C)
Methanol
(bp 65°C)
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. 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
C N +
POCl3 N H 2
heat P h P h
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.

51. Reaction with Grignard Reagents
1. addition of 1 mole of RMgX to the carbonyl carbon gives a TCAI.
2. collapse of the TCAI gives a ketone (an aldehyde from a formic ester).

52. Reaction with Grignard Reagents
3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI.
4. treatment with aqueous acid gives the alcohol.

53. B. 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.

54. C. Gilman Reagents
Acid chlorides at -78°C react with Gilman reagents to give ketones.
under these conditions, the TCAI is stable, and it is not until acid hydrolysis that the ketone is liberated.
See Chapter 15 for formation of Gilman reagent. O O 1 . ( C H 3 ) 2 u L i , e t h r - 7 8 C l 2 . H O
2-Hexanone
Pentanoyl chloride

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

56. 18.10 Reduction: RCOCl by LiAlH4
Most reductions of carbonyl compounds now use hydride reducing agents.
Acid chlorides are reduced by LiAlH4 alcohols. O P h 1 . L i A l H 4 , e t h r O H P h Cl 2 . H O , C l
2-Phenyl-1-
propanol
Methyl 2-phenyl-
propanoate

57. 18.10 Reduction: using Li(tBuO)3AlH
Specialized hydride reagents can provide specific reductions.
an acid chloride is reduced by Li(tBuO)3AlH to an aldehyde. O P h
CHO 1 . L i
(tBuO)AlH, Et2O P h Cl 2 . H O , C l
2-Phenyl-1-
propanol
Methyl 2-phenyl-
propanoate

58. 18.10 A. Reduction: Esters by LiAlH4
Esters are reduced by LiAlH4 to two alcohols.
The alcohol derived from the carbonyl group is primary. O P h 1 . L i A l H 4 , e t h r O H + C H 3 O P h O C H 3 2 . H O , C l
2-Phenyl-1-
propanol M
ethanol
Methyl 2-phenyl-
propanoate

59. Reduction: Esters by LiAlH4
Reduction occurs in three steps plus workup.
Steps 1 and 2 reduce the ester to an aldehyde.
Step 3 reduction of the aldehyde followed by work up gives a 1° alcohol.

60. 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.

61. Reduction: Esters by DIBAlH
Diisobutylaluminum hydride (DIBAlH) at -78°C selectively reduces an ester to an aldehyde.
at -78°C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated.

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

63. Reduction: Amides by LiAlH4
The mechanism is divided into 4 steps.
Step 2: a Lewis acid-base reaction and formation of an oxygen-aluminum bond.
Step 1: transfer of a hydride ion to the carbonyl carbon.

64. Reduction: Amides by LiAlH4
Step 3: redistribution of electrons and ejection of H3AlO- gives an iminium ion.
Step 4: transfer of a second hydride ion to the iminium ion completes the reduction to the amine.

65. Interconversions
Problem: show reagents and experimental conditions to bring about each reaction.

66. C. Reduction - Nitriles by LiAlH4
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine.

67. IR Spectroscopy

68. Derivatives of
Carboxylic Acids
End Chapter 18