1. Organic
Chemistry
William H. Brown &
Christopher S. Foote

2. Carboxyl
Derivatives

3. 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

4. Carboxyl Derivatives
an amide is formally related to a carboxyl group by loss of -OH from the carboxyl and -H from ammonia
loss of -OH and -H from an amide gives a nitrile

5. Structure: Acid Chlorides
The functional group of an acid halide is an acyl group bonded to a halogen
to name, change the suffix -ic acid to -yl halide

6. Acid Chlorides
replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride

7. 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

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

9. Acid Anhydrides
A phosphoric acid anhydride contains two phosphoryl groups bonded to an oxygen atom

10. 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

11. Esters Cyclic esters are called lactones
name the parent carboxylic acid, drop the suffix -ic acid, and add -olactone

12. 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-

13. Amides Cyclic amides are called lactams
Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam

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

15. Penicillins
Amoxicillin

16. Cephalosporins
The cephalosporins are also -lactam antibiotics

17. Cefetamet

18. Nitriles The functional group of a nitrile is a cyano group
IUPAC: name as an alkanenitrile
Common: drop the -ic acid and add -onitrile

19. 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

20. 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

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

22. IR Spectroscopy

23. NMR Spectroscopy 1H-NMR 13C-NMR
H on the -carbon to a C=O group are slightly deshielded and come into resonance at 
H on the carbon of the ester oxygen are more strongly deshielded and come into resonance at 
13C-NMR
the carbonyl carbons of esters show characteristic resonance at 

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

25. Characteristic Reactions
in this general reaction, we have shown the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group

26. 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

27. Rexn with H2O - RCOCl
low-molecular-weight acid chlorides react rapidly with water
higher molecular-weight acid chlorides are less soluble in water and react less readily

28. Rexn with H2O - RCO2OR
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

29. Rexn 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 to form a tetrahedral carbonyl addition intermediate
collapse of this intermediate gives the carboxylic acid and alcohol

30. Rexn with H2O - Esters
Acid-catalyzed ester hydrolysis

31. Rexn 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

32. Rexn with H2O - Amides
Hydrolysis of an amide in aqueous acid requires 1 mole of acid per mole of amide

33. Rexn with H2O - Amides
Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide

34. Rexn with H2O - Nitriles
The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion

35. Rexn with H2O - Nitriles
protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid
keto-enol tautomerism of the imidic acid gives the amide

36. Rexn 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. Rexn with H2O - Nitriles
Hydrolysis of nitriles is a valuable route to carboxylic acids

38. Rexn 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. Rexn with Alcohols
sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol

40. Rexn with Alcohols
Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid

41. Rexn with Alcohols
cyclic anhydrides react with alcohols to give one ester group and one carboxyl group

42. Rexn with Alcohols
aspirin is synthesized by treatment of salicylic acid with acetic anhydride

43. Rexn with Alcohols
Esters react with alcohols in the presence of an acid catalyst in a reaction called transesterification, an equilibrium reaction

44. Rexn 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

45. Rexn with Ammonia, etc.
Acid anhydrides react with ammonia, and 1° and 2° amines to form amides.
2 moles of ammonia or amine are required

46. Rexn 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
Amides do not react with ammonia, or 1° or 2° amines

47. Interconversions

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. Rexns with Grignards
treatment of a formic ester with 2 moles of Grignard reagent followed by hydrolysis with aqueous acid gives a 2° alcohol

50. Rexn with Grignards
treatment of an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol

51. Rexns with Grignards
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 Grignards
3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI
4. treatment with aqueous acid gives the alcohol

53. Rexns 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. 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

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. Redn - 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

57. Redn - Esters by LiAlH4
Reduction occurs in three steps plus workup

58. Redn - Esters by LiAlH4
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

59. Redn - 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

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

61. Redn - Amides by LiAlH4 The mechanism is divided into 4 steps
Step 1: transfer of a hydride ion to the carbonyl carbon
Step 2: formation of an oxygen-aluminum bond

62. Redn - Amides by LiAlH4
Step 3: redistribution of electrons gives an iminium ion
Step 4: transfer of a second hydride ion completes the reduction to the amine

63. Redn - Nitriles by LiAlH4
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine

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

65. Hofmann Rearrangement
When a 1° amide is treated with bromine or chlorine in aqueous NaOH or KOH,
the carbonyl carbon is lost as carbonate ion, and
the amide is converted to an amine of one fewer carbon atoms

66. Hofmann Rearrangement
Stage 1: acid-base reaction gives an amide anion, which reacts as a nucleophile with Br2
Stage 2: a 2nd acid-base reaction followed by elimination of Br- gives a nitrene, an electron-deficient species, that rearranges to an isocyanate

67. Hofmann Rearrangement
Stage 3: reaction of the isocyanate with water gives a carbamic acid
Stage 4: decarboxylation of the carbamic acid gives the primary amine

68. Prob 18.19
Propose a structural formula for each compound.

69. Prob (cont’d)
Propose a structural formula for each compound.

70. Prob 18.20
Draw a structural formula for the product formed on treatment of benzoyl chloride with each reagent.

71. Prob 18.26
Draw a structural formula for the product of treating this a,b-unsaturated ketone with each reagent.

72. Prob 18.28
Draw a structural formula for the product of treating this anhydride with each reagent.

73. Prob 18.31
Show how to bring about each step in this conversion of nicotinic acid to nicotinamide.

74. Prob 18.32
Complete these reactions.

75. Prob 18.35
Draw structural formulas for the products of complete hydrolysis of each compound in hot aqueous acid.

76. Prob 18.36
Show reagents to bring about each step in this synthesis of anthranilic acid.

77. Prob 18.37
Propose a mechanism for each step in this sequence.

78. Prob 18.38
Propose a mechanism for each step in this sequence.

79. Prob 18.39
Show how to prepare the insect repellent DEET from 3-methyltoluic acid.

80. Prob 18.40
Show how to prepare isoniazid from 4-pyridinecarboxylic acid.

81. Prob 18.41
Show how to bring about this conversion.

82. Prob 18.42
Propose a mechanism for the formation of this bromolactone, and account for the observed stereochemistry of each substituent on the cyclohexane ring.

83. Prob 18.43
Propose a mechanism for this reaction.

84. Prob 18.44
Propose a synthesis of this b-chloroamine from anthranilic acid.

85. Prob 18.45
Show reagents for the synthesis of 5-nonanone from 1-bromobutane as the only organic starting material.

86. Prob 18.46
Describe a synthesis of procaine from the three named starting materials.

87. Prob 18.47
The following sequence converts (R)-2-octanol to (S)-2-octanol. Propose structural formulas for A and B, and specify the configuration of each.

88. Prob 18.48
Propose a mechanism for this reaction.

89. Prob 18.49
Propose a mechanism for this reaction.

90. Prob 18.50
Show how each hypoglycemic drug can be synthesized by converting an appropriate amine to a carbamate ester, and then treating its sodium salt with a substituted benzenesufonamide.

91. Prob 18.51
Propose a mechanism for Step 1, and reagents for Step 2 in the synthesis of the antiviral agent amantadine.

92. Prob 18.52
Propose structural formulas for intermediates A-F and for the configuration of the bromoepoxide.

93. Prob 18.53
Show reagents for the synthesis of (S)-Metolachlor from the named starting materials

94. Derivatives of
Carboxylic Acids
End Chapter 18