1. Chapter 21 Carboxylic Acid Derivatives
Organic Chemistry, 5th Edition L. G. Wade, Jr.
Chapter 21 Carboxylic Acid Derivatives
Jo Blackburn
Richland College, Dallas, TX
Dallas County Community College District
ã 2003, Prentice Hall

2. Acid Derivatives
All can be converted to the carboxylic acid by acidic or basic hydrolysis.
Esters and amides common in nature.
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3. 2-methylpropyl ethanoate
Naming Esters
Esters are named as alkyl carboxylates.
Alkyl from the alcohol, carboxylate from the carboxylic acid precursor.
isobutyl acetate
2-methylpropyl ethanoate
benzyl formate
benzyl methanoate
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4. Cyclic Esters
Reaction of -OH and -COOH on same molecule produces a cyclic ester, lactone.
To name, add word lactone to the IUPAC acid name or replace the -ic acid of common name with -olactone.
4-hydroxy-2-methylpentanoic acid lactone
-methyl--valerolactone
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5. Amides
Product of the reaction of a carboxylic acid and ammonia or an amine.
Not basic because the lone pair on nitrogen is delocalized by resonance.
Bond angles around N
are close to 120 =>
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6. Classes of Amides 1 amide has one C-N bond (two N-H).
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) =>
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7. 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.
N-ethyl-N,2-dimethylpropanamide
N-ethyl-N-methylisobutyramide
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8. 4-aminopentanoic acid lactam
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.
4-aminopentanoic acid lactam
-valerolactam
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9. Nitriles
-CN can be hydrolyzed to carboxylic acid, so nitriles are acid derivatives.
Nitrogen is sp hybridized, lone pair tightly held, so not very basic. (pKb about 24).
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10. Naming Nitriles For IUPAC names, add -nitrile to the alkane name.
Common names come from the carboxylic acid. Replace -ic acid with -onitrile.
5-bromohexanenitrile
-bromocapronitrile
Cyclohexanecarbonitrile =>
Chapter 21

11. 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
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12. Acid Anhydrides
Two molecules of acid combine with the loss of water to form the anhydride.
Anhydrides are more reactive than acids, but less reactive than acid chlorides.
A carboxylate ion is the leaving group in nucleophilic acyl substitution reactions.
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13. 1,2-benzenedicarboxylic anhydride
Naming 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
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14. Multifunctional Compounds
The functional group with the highest priority determines the parent name.
Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne.
ethyl o-cyanobenzoate
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15. Boiling Points Even 3 amides have strong attractions. =>
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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
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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 =>
Chapter 21

18. IR Spectroscopy
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19. 1H NMR Spectroscopy
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20. 13C NMR Spectroscopy
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21. Interconversion of Acid Derivatives
Nucleophile adds to the carbonyl to form a tetrahedral intermediate.
Leaving group leaves and C=O regenerates.
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22. Reactivity Reactivity decreases as leaving group becomes more basic.
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23. Interconversion of Derivatives
More reactive derivatives can be converted to less reactive derivatives.
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24. 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 =>
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25. Acid Chloride to Ester Alcohol attacks the C=O.
Tetrahedral intermediate forms.
Chloride ion leaves, C=O is restored, H+ is abstracted =>
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26. Acid Chloride to Amide Ammonia yields a 1 amide
A 1 amine yields a 2 amide
A 2 amine yields a 3 amide
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27. Anhydride to Ester Alcohol attacks one C=O of anhydride.
Tetrahedral intermediate forms.
Carboxylate ion leaves, C=O is restored, H+ is abstracted =>
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28. Anhydride to Amide Ammonia yields a 1 amide
A 1 amine yields a 2 amide
A 2 amine yields a 3 amide
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29. Ester to Amide Nucleophile must be NH3 or 1 amine.
Prolonged heating required.
Surprise!
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30. Leaving Groups
A strong base is not usually a leaving group unless it’s in an exothermic step.
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31. Transesterification
One alkoxy group can be replaced by another with acid or base catalyst.
Use large excess of preferred alcohol.
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32. 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.
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33. Acid Hydrolysis of Esters
Reverse of Fischer esterification.
Reaches equilibrium.
Use a large excess of water.
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34. 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)16CH =>
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35. Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40% aqueous NaOH is required.
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36. Hydrolysis of Nitriles
Under mild conditions, nitriles hydrolyze to an amide.
Heating with aqueous acid or base will hydrolyze a nitrile to an acid.
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37. Reduction to Alcohols
Lithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols.
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38. Reduction to Aldehydes
Acid chlorides will react with a weaker reducing agent to yield an aldehyde.
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39. 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.
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40. Organometallic Reagents
Grignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.
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41. Grignard Reagents and Nitriles
A Grignard reagent or organolithium reagent attacks the cyano group to yield an imine which is hydrolyzed to a ketone.
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42. Acid Chloride Synthesis
Use thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2.
Other products are gases.
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43. Acid Chloride Reactions (1)
ester
amide
acid anhydride
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44. Acid Chloride Reactions (2)
3° alcohol
ketone
1° alcohol
aldehyde
acylbenzene
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45. Industrial Synthesis of Acetic Anhydride
Four billion pounds/year produced.
Use high heat (750°C) and triethyl phosphate catalyst to produce ketene.
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46. Lab Synthesis of Anhydrides
React acid chloride with carboxylic acid or carboxylate ion.
Heat dicarboxylic acids to form cyclic anhydrides.
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47. Anhydride Reactions
acid
ester
amide
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acylbenzene
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48. 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.
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49. Synthesis of Esters acid acid chloride acid anhydride =>
methyl ester
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50. Reactions of Esters acid ester amide 1° alcohol 3° alcohol =>
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51. Lactones Formation favored for five- and six-membered rings.
For larger rings, remove water to shift equilibrium toward products
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52. Synthesis of Amides acid acid chloride acid anhydride ester nitrile
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53. Reactions of Amides acid and amine amine 1° amine nitrile =>
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54. Lactam Formation
Five- and six-membered rings can be formed by heating - and -amino acids.
Smaller or larger rings do not form readily =>
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55. -Lactams Highly reactive, 4-membered ring.
Found in antibiotics isolated from fungi.
Amide  ester !!
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56. Synthesis of Nitriles 1° amide alkyl halide diazonium salt
aldehyde or ketone
cyanohydrin
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57. Reactions of Nitriles
amide
acid
1° amine
ketone
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58. Thioesters More reactive than esters because:
-S-R is a better leaving group than -O-R
Resonance overlap is not as effective.
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59. Carbonic Acid Esters CO2 in water contains some H2CO3.
Diesters are stable.
Synthesized from phosgene.
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60. Urea and Urethanes Urea is the diamide of carbonic acid.
Urethanes are esters of a monoamide of carbonic acid.
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61. Polymers Polycarbonates are long-chain esters of carbonic acid.
Polyurethanes are formed when a diol reacts with a diisocyanate.
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62. End of Chapter 21
Chapter 21