1. Chapter 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions
Why this Chapter?
Carboxylic acids are among the most widespread of molecules.
A study of them and their primary reaction “nucleophilic acyl substitution” is fundamental to understanding organic chemistry

2. Carboxylic Compounds
Acyl group (C=O) bonded to X, an electronegative atom or leaving group
X includes: halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates)

3. General Reaction Pattern
Nucleophilic acyl substitution

4. 21.1 Naming Carboxylic Acid Derivatives
Acid Halides, RCOX
Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the
-carboxylic acid ending with –carbonyl and
specifying the halide
Cyclohexanecarboxylic Acid 
Cyclohexanecarbonyl chloride
Acetic Acid 
Acetyl chloride
Benzoic Acid 
Benzoyl bromide

5. Naming Acid Anhydrides, RCO2COR'
If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid
Acetic anhydride
Benzoic anhydride
Succinic anhydride
Unsymmetrical anhydrides - cite the two acids alphabetically
Acetic benzoic anhydride

6. Cyclopentane-carboxamide N,N-Diethylcyclohexanecarboxamide
Naming Amides, RCONH2
With unsubstituted NH2 group. replace
-oic acid or -ic acid with -amide, or by replacing the
-carboxylic acid ending with –carboxamide
Cyclopentane-carboxamide
Acetamide
Hexanamide
If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide
N-Methylpropanamide
N,N-Diethylcyclohexanecarboxamide

7. Cyclohexanecarboxylic acid tert-Butyl cyclohexanecarboxylate
Naming Esters, RCO2R’
Name R’ and then, after a space, the carboxylic acid (RCOOH), replace“-ic acid” with “-ate”
Malonic acid 
Dimethyl malonate
Acetic acid 
Ethyl acetate
Cyclohexanecarboxylic acid 
tert-Butyl cyclohexanecarboxylate

8. Naming Thioesters, RCOSR’
Name like an ester but:
For common names
add “thio” before the acid name “-ate”
Methyl acetate 
Methyl thioacetate
Ethyl butanoate 
Ethyl butanthioate
Methyl cyclohexanecarboxylate 
Methyl cyclohexanecarbothioate
For IUPAC names
Replace “-oate” or “-carboyxlate” with “thioate” or “-carbothioate”

9. Naming Acyl Phosphates
Name Acyl group then add -phosphate:
Benzoyl phosphate
Acetyl adenosyl phosphate
If an alkyl group is attached to a phospate O name it after the acyl group

10. Naming Summary:

11. Learning Check:
Name the following:

12. 4-methylpentanoyl chloride Isopropyl 2-methylpropanoate
Solution:
Name the following:
4-methylpentanoyl chloride
Cyclohexylacetamide
Isopropyl 2-methylpropanoate

13. Learning Check:
Name the following:

14. Isopropyl cyclopenanecarboxylate Cyclopentyl 2-methylpropanoate
Solution:
Name the following:
Benzoic anhydride
Isopropyl cyclopenanecarboxylate
Cyclopentyl 2-methylpropanoate

15. Learning Check:
Name the following:

16. Solution: Name the following: N-Methyl-4-pentenamide
(R)-2-Hydroxypropanoyl phosphate
Ethyl 2,3-dimethyl-2-butenethioate

17. 21.2 Nucleophilic Acyl Substitution
Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave
A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution

18. Nucleophilic Acyl Substitution

19. Relative Reactivity of Carboxylic Acid Derivatives
Nucleophiles react more readily with unhindered carbonyl groups
More electrophilic carbonyl groups are more reactive to addition
(acyl halides are most reactive, amides are least)
The intermediate with the best leaving group decomposes fastest

20. Substitution in Synthesis
More reactive acid derivatives can be readily converted into a less reactive one
Reactions in the opposite sense are possible but require more complex approaches

21. General Reactions of Carboxylic Acid Derivatives
ammonia or an amine  an amide
alcohols  esters
hydride source  an aldehyde or an alcohol
water  carboxylic acid
Grignard reagent  a ketone or an alcohol

22. Complete the following reaction:
Learning Check:
Complete the following reaction:

23. Complete the following reaction:
Solution:
Complete the following reaction:

24. Learning Check:
Rank compounds in the following sets in order of reactivity toward nucleophilic acyl substitution: (#1 = fastest)

25. Solution:
Rank compounds in the following sets in order of reactivity toward nucleophilic acyl substitution: (#1 = fastest) 1 2 3 1 3 2

26. 21.3 Reactions of Carboxylic Acids Nucleophilic Acyl Substitution
Must enhance reactivity
Convert OH into a better leaving group
Specific reagents can produce acid chlorides, anhydrides, esters, amides

27. Carboxylic Acids into Acid Chlorides
Reaction with thionyl chloride, SOCl2

28. Mechanism of Thionyl Chloride Reaction
Nucleophilic acyl substitution pathway
Carboxylic acid is converted into a chlorosulfite which then reacts with chloride

29. Carboxylic Acids into Acid Anhydrides
Acid anhydrides can be derived from two molecules of carboxylic acid by strong heating to remove water

30. Carboxylic Acids into Esters
Methods include reaction of a carboxylate anion with a primary alkyl halide

31. Fischer Esterification
Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid

32. Mechanism of the Fischer Esterification
acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid

33. Mechanism of the Fischer Esterification
When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled

34. Carboxylic Acids into Amides
Amides difficult to prepare.
Carboxylic acids more easily react with amines to make salts.
Reaction with DCC makes better leaving group that will be kicked out by an amine.

35. Carboxylic Acids into Alcohols

36. Carboxylic Acids into Alcohols
Preferred over LiAlH4 due to relative ease and safety.
Selectively reduces Carboxylic acids in presence of nitros

37. 21.4 Chemistry of Acid Halides
Acid chlorides are prepared from carboxylic acids by reaction with SOCl2
Reaction of a carboxylic acid with PBr3 yields the acid bromide

38. Reactions of Acid Halides
Nucleophilic acyl substitutions
Halogen replaced by OH, by OR, or by NH2
Reduction yields a primary alcohol
Grignard reagent yields a tertiary alcohol

39. Hydrolysis: Acid Halides into Acids
Acid chlorides react with water to yield carboxylic acids
HCl is generated during the hydrolysis: a base is added to remove the HCl

40. Acid Halides to Esters
Esters are produced in the reaction of acid chlorides with alcohols in the presence of pyridine or NaOH. This is called Alcoholysis
The reaction is better with less steric bulk

41. Aminolysis: Acid Halides into Amides
Amides result from the reaction of acid chlorides with NH3, primary (RNH2) and secondary amines (R2NH)
HCl produced is neutralized by
the amine or an added base
The reaction with tertiary amines (R3N) gives an unstable species that cannot be isolated

42. Reduction: Acid Chlorides into Alcohols
LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols

43. Acid Chlorides with Organometallic Reagents
Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same

44. Formation of Ketones from Acid Chlorides
Acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu

45. 21.5 Chemistry of Acid Anhydrides
Prepared by nucleophilic acyl substitution of a carboxylate with an acid chloride

46. Reactions of Acid Anhydrides
Similar to acid chlorides in reactivity

47. Acetylation
Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines

48. 21.6 Chemistry of Esters
Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers
Also present in fats and vegetable oils

49. Preparation of Esters
Esters are usually prepared from carboxylic acids

50. Reactions of Esters
Less reactive toward nucleophiles than are acid chlorides or anhydrides
Cyclic esters are called lactones and react similarly to acyclic esters

51. Hydrolysis: Esters into Carboxylic Acids
An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol

52. Mechanism of Ester Hydrolysis: Base catalysed
Hydroxide catalysis via an addition intermediate

53. Mechanism of Ester Hydrolysis: Acid catalysed

54. Aminolysis: Esters into Amides
Ammonia reacts with esters to form amides

55. Reduction: Esters into Alcohols
Reaction with LiAlH4 yields primary alcohols

56. Mechanism of Reduction of Esters
Hydride ion adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde
Reduction of the aldehyde gives the primary alcohol
Use bulky DIBAH to stop at an aldehyde

57. Reaction of Esters with Grignard Reagents
React with 2 equivalents of a Grignard reagent to yield a tertiary alcohol

58. 21.7 Chemistry of Amides
Amides are abundant in all living organisms…proteins, nucleic acids, and other pharmaceuticals have amid functional groups

59. Preparation of Amides
Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines

60. Reactions of Amides
Heating in either aqueous acid or aqueous base produces a carboxylic acid and amine
Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia

61. Basic Hydrolysis: Amides  Acids
Addition of hydroxide and loss of amide ion

62. Reduction: Amides into Amines
Reduced by LiAlH4 to an amine rather than an alcohol
Converts C=O  CH2

63. Mechanism of Reduction
Addition of hydride to carbonyl group
Loss of the oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine

64. Uses of Reduction of Amides
Works with cyclic and acyclic
Good route to cyclic amines

65. 21.8 Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives
Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate
Acetyl CoA’s are most common thioesters in nature

66. 21.9 Polyamides and Polyesters: Step-Growth Polymers
Reactions occur in distinct linear steps, not as chain reactions
Reaction of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide
A diol with a diacid leads to a polyester

67. Polyamides (Nylons)
Heating a diamine with a diacid produces a polyamide called Nylon®
Nylon 66® is from adipic acid and hexamethylene-diamine at 280°C

68. Polyesters
The polyester from dimethyl terephthalate and ethylene glycol is called Dacron® and Mylar® to make fibers

71. Biodegradable Polymers

72. 21.10 Spectroscopy of Carboxylic Acid Derivatives
Infrared Spectroscopy
Acid chlorides absorb near 1800 cm1
Acid anhydrides absorb at 1820 cm1 and also at cm1
Esters absorb at 1735 cm1, higher than aldehydes or ketones
Amides absorb near the low end of the carbonyl region

74. Nuclear Magnetic Resonance Spectroscopy
Hydrogens on the carbon next to a C=O are near 2 in the 1H NMR spectrum.
All acid derivatives absorb in the same range so NMR does not distinguish them from each other

75. 13C NMR
13C NMR is useful for determining the presence or absence of a carbonyl group in a molecule of unknown structure
Carbonyl carbon atoms of the various acid derivatives absorb from 160 to 180

76. Which of the following is not an acyl derivative?
Learning Check:
Which of the following is not an acyl derivative? 1. 2. 3. 4. 5. 1 2 3 4 5

77. Which of the following is not an acyl derivative?
Solution:
Which of the following is not an acyl derivative? 1. 2. 3. 4. 5. 1 2 3 4 5

78. Which of the following is not an ester?
Learning Check:
Which of the following is not an ester? 1. 2. 4. 3. 1 2 3 4

79. Which of the following is not an ester?
Solution:
Which of the following is not an ester? 1. 2. 4. 3. 1 2 3 4

80. All lactams can be classified as amides and vice versa.
Learning Check:
All lactams can be classified as amides and vice versa.
True
False

81. All lactams can be classified as amides and vice versa.
Solution:
All lactams can be classified as amides and vice versa.
True
False

82. Learning Check: Name the following: ethyl-N-2-butylmethylamide
N-(2-methylbutyl)propanamide
N-methylbutylpropane amide
N-(2-methylbutyl)propane amide
N-(2-methylbutylethyl) amide
3,4-dimethylphenyl pentanoate
3,4-dimethylpentyl benzenoate
3,4-dimethylpentyl benzoate
benzyl 3,4-dimethylpentanoate
phenyl 3,4-dimethylpentanoate

83. Solution: Name the following: ethyl-N-2-butylmethylamide
N-(2-methylbutyl)propanamide
N-methylbutylpropane amide
N-(2-methylbutyl)propane amide
N-(2-methylbutylethyl) amide
3,4-dimethylphenyl pentanoate
3,4-dimethylpentyl benzenoate
3,4-dimethylpentyl benzoate
benzyl 3,4-dimethylpentanoate
phenyl 3,4-dimethylpentanoate

84. Learning Check: Name the following: 3-ethyl-3-phenylpropanoyl bromide
3-phenyl-3-ethylpropanoyl bromide
1-ethyl-1-phenylpropanoyl bromide
1-phenyl-1-ethylpropanoyl bromide
3-phenylpentanoyl bromide

85. Solution: Name the following: 3-ethyl-3-phenylpropanoyl bromide
3-phenyl-3-ethylpropanoyl bromide
1-ethyl-1-phenylpropanoyl bromide
1-phenyl-1-ethylpropanoyl bromide
3-phenylpentanoyl bromide

86. Learning Check:
Which of the following is true concerning the given two carboxylic acid derivatives?
Only molecule A can be hydrolyzed.
Only molecule B can be hydrolyzed.
Both molecules can be hydrolyzed, but A will react faster than B.
Both molecules can be hydrolyzed, but B will react faster than A.
A and B can be hydrolyzed at roughly the same rate.

87. Solution:
Which of the following is true concerning the given two carboxylic acid derivatives?
Only molecule A can be hydrolyzed.
Only molecule B can be hydrolyzed.
Both molecules can be hydrolyzed, but A will react faster than B.
Both molecules can be hydrolyzed, but B will react faster than A.
A and B can be hydrolyzed at roughly the same rate.

88. Determine the product of the following:
Learning Check:
Determine the product of the following: 2. 1. 3. 4. 5. 1 2 3 4 5

89. Determine the product of the following:
Solution:
Determine the product of the following: 2. 1. 3. 4. 5. 1 2 3 4 5

90. Which step occurs first in the mechanism of Fischer esterification?
Learning Check:
Which step occurs first in the mechanism of Fischer esterification?
attack of the nucleophile on the carbonyl carbon
protonation of the carbonyl oxygen
loss of water from the tetrahedral carbonyl addition intermediate
protonation of the alcohol oxygen
formation of the tetrahedral carbonyl addition intermediate

91. Which step occurs first in the mechanism of Fischer esterification?
Solution:
Which step occurs first in the mechanism of Fischer esterification?
attack of the nucleophile on the carbonyl carbon
protonation of the carbonyl oxygen
loss of water from the tetrahedral carbonyl addition intermediate
protonation of the alcohol oxygen
formation of the tetrahedral carbonyl addition intermediate

92. Learning Check:
Which of the following is the tetrahedral intermediate that appears in the Fischer esterification of ethanol and benzoic acid? 2. 1. 3. 4. 5. 1 2 3 4 5

93. Solution:
Which of the following is the tetrahedral intermediate that appears in the Fischer esterification of ethanol and benzoic acid? 2. 1. 3. 4. 5. 1 2 3 4 5

94. What is the expected product for the following reaction?
Learning Check:
What is the expected product for the following reaction? 1. 2. 3. 5. 4. 1 2 3 4 5

95. What is the expected product for the following reaction?
Solution:
What is the expected product for the following reaction? 1. 2. 3. 5. 4. 1 2 3 4 5

96. What sequence of reagents will accomplish the following?
Learning Check:
What sequence of reagents will accomplish the following? 1. 2. 3. 4. 5. 1 2 3 4 5

97. What sequence of reagents will accomplish the following?
Solution:
What sequence of reagents will accomplish the following? 1. 2. 3. 4. 5. 1 2 3 4 5

98. Predict the product of the following:
Learning Check:
Predict the product of the following: 1. 2. 3. 4.
none of these 5. 1 2 3 4 5

99. Predict the product of the following:
Solution:
Predict the product of the following: 1. 2. 3. 4.
none of these 5. 1 2 3 4 5

100. What sequence of reagents will accomplish the following?
Learning Check:
What sequence of reagents will accomplish the following? 1. 2. 3. 4. 5. 1 2 3 4 5

101. What sequence of reagents will accomplish the following?
Solution:
What sequence of reagents will accomplish the following? 1. 2. 3. 4. 5. 1 2 3 4 5

102. Predict the product of the following:
Learning Check:
Predict the product of the following: 1. 2. 3. 5. 4. 1 2 3 4 5

103. Predict the product of the following:
Solution:
Predict the product of the following: 1. 2. 3. 5. 4. 1 2 3 4 5

104. Learning Check:
Identify the compound that will react fastest when heated in aqueous NaOH. 1. 2. 3. 4. 5. 1 2 3 4 5

105. Solution:
Identify the compound that will react fastest when heated in aqueous NaOH. 1. 2. 3. 4. 5. 1 2 3 4 5