1. Chapter 22 Carboxylic Acid Derivatives
Organic Chemistry, 6th Edition L. G. Wade, Jr.
Chapter 22 Carboxylic Acid Derivatives

2. Carboxylic Acid Derivatives
STRUCTURE AND PROPERTIES
PREPARATIONS OF CARBOXYLIC ACID DERIVATIVES
REACTIONS
ENOLATE REACTIONS

3. Sec 1 Acid Derivatives
All can be converted to the carboxylic acid by acidic or basic hydrolysis.
Esters and amides common in nature.

4. Acid Halides
More reactive than acids; the halogen withdraws e- density from carbonyl.
Named by replacing -ic acid with -yl halide.
3-bromobutanoyl bromide
-bromobutyryl bromide
benzoyl chloride

5. 1,2-benzenedicarboxylic anhydride
Anhydrides
The word acid is replaced with anhydride.
For a mixed anhydride, name both acids.
Diacids may form anhydrides if a 5- or 6-membered ring is the product.
ethanoic anhydride
acetic anhydride
1,2-benzenedicarboxylic anhydride
phthalic anhydride

6. 2-methylpropyl ethanoate
Naming Esters
Esters are named as alkyl carboxylates.
Alkyl from the alcohol, carboxylate from the carboxylic acid precursor.
ethanol
ethyl alcohol
ethanoic acid
acetic acid
ethyl ethanoate
ethyl acetate
Name These
isobutyl acetate
2-methylpropyl ethanoate
benzyl formate
benzyl methanoate

7. Cyclic Esters
Reaction of —OH and —COOH on same molecule produces a cyclic ester called lactone.
To name, add the word lactone to the IUPAC acid name or
replace the -ic acid of common name with -olactone. 7

8. (g-butyrolactone)
g －丁内酯
(d-valerolactone)
d －戊内酯
(g-valerolactone)
g －戊内酯

9. Amides
Not basic because the lone pair on nitrogen is delocalized by resonance. The C—N bond has double-bond character.
Classes of Amides
1 amide ; 2 amide or N-substituted amide has two C-N bonds (one N-H); 3 amide or N,N-disubstituted amide has three C-N bonds (no N-H).
Bond angles around N are close to 120.

10. Protonation of Amides
Under acidic conditions, the double-bonded oxygen will get protonated. 10

11. N-ethyl-N,2-dimethylpropanamide 4-aminopentanoic acid lactam
Naming Amides
For 1 amide, drop -ic or -oic acid from the carboxylic acid name, add -amide.
For 2 and 3 amides, the alkyl groups bonded to nitrogen are named with N- to indicate their position.
Cyclic Amides
Reaction of -NH2 and -COOH on same molecule produces a cyclic amide, lactam.
To name, add word lactam to the IUPAC acid name or replace the -ic acid of common name with -olactam.
N-ethyl-N,2-dimethylpropanamide
N-ethyl-N-methylisobutyramide
4-aminopentanoic acid lactam
-valerolactam

12. 丙酰胺
N-甲基乙酰胺
N,N－二甲基甲酰胺

13. (g-butyrolactam)
丁内酰胺
(d-valerolactam)
d-戊内酰胺
(g-valerolactam)
g-戊内酰胺
Succinimide
丁二酰亚胺
Maleimide
丁烯二酰亚胺
Phthalimide
邻苯二甲酰亚胺

14. Boiling Points

15. Intermolecular Forces of Amides
Even 3 amides have
strong attractions. 15

16. Melting Points Amides have very high melting points.
Melting points increase with increasing number of N-H bonds.
m.p. -61C
m.p. 28C
m.p. 79C

17. Solubility
Acid chlorides and anhydrides are too reactive to be used with water or alcohol.
Esters, 3 amides, and nitriles are good polar aprotic solvents.
Solvents commonly used in organic reactions:
Ethyl acetate
Dimethylformamide (DMF)
Acetonitrile

19. Sec 2 Interconversion of Acid Derivatives
Nucleophile adds to the carbonyl to form a tetrahedral intermediate.
Leaving group leaves and C=O regenerates.

20. Reactivity
Reactivity decreases as leaving group becomes more basic.

21. Interconversion of Derivatives
More reactive derivatives can be converted to less reactive derivatives.

22. 1. Acid Chloride 羧酸衍生物的三解反应 水解、醇解、氨解
w/ R2CuLi or 2
w/ LiAlH(t-OBu)3
w/ LiAlH4

23. Acid Chloride Reactions (1)
ester
amide
acid anhydride

24. Acid Chloride Reactions (2)
3° alcohol
ketone
1° alcohol
aldehyde
acylbenzene
AlCl3

25. Acid Chloride to Anhydride
Acid or carboxylate ion attacks the C=O.
Tetrahedral intermediate forms.
Chloride ion leaves, C=O is restored, H+ is abstracted.

26. Acid Chloride to Ester Alcohol attacks the C=O.
Tetrahedral intermediate forms.
Chloride ion leaves, C=O is restored, H+ is abstracted.

27. Acid Chloride to Amide Ammonia yields a 1 amide
A 1 amine yields a 2 amide
A 2 amine yields a 3 amide

28. 2. Anhydrides
( low T)
w/ Na2Fe(CO)4
w/ LiAlH4

29. Anhydride Reactions
acid
ester
amide
acylbenzene
AlCl3

30. Anhydride vs. Acid Chloride
Acetic anhydride is cheaper, gives a better yield than acetyl chloride.
Use acetic formic anhydride to produce formate esters and formamides.
Use cyclic anhydrides to produce a difunctional molecule.

31. Anhydride to Ester Alcohol attacks one C=O of anhydride.
Tetrahedral intermediate forms.
Carboxylate ion leaves, C=O is restored, H+ is abstracted.

33. Anhydride to Amide Ammonia yields a 1 amide
A 1 amine yields a 2 amide
A 2 amine yields a 3 amide

34. 3. Esters
Prepared by
The nucleophilic substitution of acid chlorides or acid anhydrides with alcohols,
The nucleophilic substitution of carboxylic acids with alcohol in the presence of a catalytic amount of mineral acid,
The SN2 nucleophilic substitution of an alkyl halide with a carboxylate ion,
The reaction of carboxylic acids with diazomethane to give methyl esters.

35. Synthesis of Esters
acid
acid chloride
acid anhydride
methyl ester

36. Lactones Formation favored for five- and six-membered rings.
For larger rings, remove water to shift equilibrium toward products

37. Polyesters
Dacron® thread
Mylar® tape
Glyptal resin
PET bottles

38. Reactions of Esters
( low T)
w/ DIBAH;
LiAlH2(i-Bu)2
w/ LiAlH4

39. Reactions of Esters
acid
ester
amide
1° alcohol
3° alcohol

40. Organometallic Reagents
Grignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.

41. Organometallic Reagents
Grignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.

42. Ester to Amide Nucleophile must be NH3 or 1 amine.
Prolonged heating required.
Surprise!

43. Transesterification
One alkoxy group can be replaced by another with acid or base catalyst.
Use large excess of preferred alcohol.

44. Hydrolysis of Acid Chlorides and Anhydrides
Hydrolysis occurs quickly, even in moist air with no acid or base catalyst.
Reagents must be protected from moisture.

45. Acid Hydrolysis of Esters
Reverse of Fischer esterification.
Reaches equilibrium.
Use a large excess of water.

46. Saponification Base-catalyzed hydrolysis of ester.
“Saponification” means “soap-making.”
Soaps are made by heating NaOH with a fat (triester of glycerol) to produce the sodium salt of a fatty acid - a soap.
One example of a soap is sodium stearate, Na+ -OOC(CH2)16CH3.

47. Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40% aqueous NaOH is required.

48. 4. Amides Synthesis of Amides
acid
acid chloride
acid anhydride
ester
nitrile

49. Reactions of Amides
acid and amine
amine
1° amine
nitrile

50. Hofmann 重排

51. Questions

52. 缩二脲反应

53. Lactam Formation
Five- and six-membered rings can be formed by heating - and -amino acids.
Smaller or larger rings do not form readily.

54. -Lactams Highly reactive, 4-membered ring.
Found in antibiotics isolated from fungi.
Amide  ester !!

55. Polyamides
Nylon 6.6

56. Sec 3 羧酸衍生物的还原

58. Summary of Reactions of Derivatives of Acids
Derivative H2O ROH NH [H] RMgX
Acid Chloride acid ester amide (ald)/alc (ket)/alc
Anhydride acid ester amide (ald)/alc (ket)/alc
Ester acid ester amide (ald)/alc (ket)/alc
Amide acid (NR) (NR) amine (NR)
Nitrile amide ester (NR) amine/ket/acid (ald)

59. Reduction to Alcohols
Lithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols.

60. Reduction to Aldehydes
Acid chlorides will react with a weaker reducing agent to yield an aldehyde.

61. Reduction to Amines
Lithium aluminum hydride reduces amides and nitriles to amines.
Nitriles and 1 amides reduce to 1 amines.
A 2 amide reduces to a 2 amine.
A 3 amide reduces to a 3 amine.

62. Reduction to Alcohols
Lithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols.

63. Reduction to Aldehydes
Acid chlorides will react with a weaker reducing agent to yield an aldehyde.

64. Reduction to Amines
Lithium aluminum hydride reduces amides and nitriles to amines.
Nitriles and 1 amides reduce to 1 amines.
A 2 amide reduces to a 2 amine.
A 3 amide reduces to a 3 amine.

65. Grignard Reagents and Nitriles
A Grignard reagent or organolithium reagent attacks the cyano group to yield an imine which is hydrolyzed to a ketone.

66. Sec 4 ENOLATE REACTIONS
Enolates
Alkylations
Claisen condensation

67. Enolate ion formation

70. 乙酰乙酸乙酯的性质 互变异构现象 一般性质： 酮式： 烯 醇式： 羰基试剂 FeCl3显色 氯代 Na 酯水解 溴水褪色
酮式： 烯 醇式：
羰基试剂 FeCl3显色
氯代 Na
酯水解 溴水褪色
碘仿反应？XXXXX

71. Alkylations

72. Claisen Condensation缩合

74. 酸式、酮式分解

75. －负碳的反应

76. 三乙合成应用

77. The End Of Chap 22
P762: 22-19(a-f)