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Chapter 21Carboxylic Acid Derivatives
Chapter 21 Carboxylic Acids Derivs Slide 21-2
Acid Derivatives
• All can be converted to the carboxylic acid by acidic or basichydrolysis.
• Esters and amides common in nature.
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Chapter 21 Carboxylic Acids Derivs Slide 21-3
Naming Esters
• Esters are named as alkyl carboxylates.• Alkyl from the alcohol, carboxylate from the carboxylic acid
precursor.
CH3CH2 OH HO C
O
CH3
H+
+ + H2OCH3CH2 O C
O
CH3
ethanol
ethyl alcohol
ethanoic acid
acetic acid
ethyl ethanoate
ethyl acetate
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-4
Cyclic Esters: Lactones
• Reaction of -OH and -COOH on same molecule produces acyclic ester, lactone.
• To name, add word lactone to the IUPAC acid name orreplace the -ic acid of common name with -olactone.
O
O
H3C
CH3
4-hydroxy-2-methylpentanoic acid lactoneα-methyl-γ-valerolactone
=>
3
Chapter 21 Carboxylic Acids Derivs Slide 21-5
Amides
• Product of the reaction of a carboxylic acid and ammoniaor an amine.
• Not basic because the lone pair on nitrogen is delocalizedby resonance.
• Good water solubility
H
C
O
N
H
H
H
C
O
N
H
H
_
+
Bond angles around Nare close to 120°. =>
Chapter 21 Carboxylic Acids Derivs Slide 21-6
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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Chapter 21 Carboxylic Acids Derivs Slide 21-7
Naming Amides
• For 1° amide, drop -ic or -oic acid from the carboxylic acidname, add -amide.
• For 2° and 3° amides, the alkyl groups bonded to nitrogen arenamed with N- to indicate their position.
CH3CHC N
O
CH2CH3
CH3
CH3
N-ethyl-N,2-dimethylpropanamideN-ethyl-N-methylisobutyramide
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-8
Cyclic Amides: Lactams
• Reaction of -NH2 and -COOH on same molecule produces acyclic amide, lactam.
• To name, add word lactam to the IUPAC acid name or replacethe -ic acid of common name with -olactam.
N
O
CH3
H4-aminopentanoic acid lactam
γ-valerolactam
=>
5
Chapter 21 Carboxylic Acids Derivs Slide 21-9
Nitriles
• -C≡N can be hydrolyzed to carboxylic acid, so nitriles areacid derivatives.
• Nitrogen is sp hybridized, lone pair tightly held, so not verybasic (pKb about 24).
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-10
Naming Nitriles
• For IUPAC names, add -nitrile to the alkane name.• Common names come from the carboxylic acid. Replace -ic
acid with -onitrile.
CH3CHCH2CH2CH2CN
Br
5-bromohexanenitrile∂-bromocapronitrile
C N
Cyclohexanecarbonitrile =>
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Chapter 21 Carboxylic Acids Derivs Slide 21-11
Acid Halides
• More reactive than acids; the halogen withdraws e- density fromcarbonyl.
• Named by replacing -ic acid with -yl halide.
C
O
Cl CH3CHCH2C
Br O
Br
benzoyl chloride3-bromobutanoyl bromideβ-bromobutyryl bromide =>
Chapter 21 Carboxylic Acids Derivs Slide 21-12
Acid Anhydrides
• Two molecules of acid combine with the loss of water to formthe anhydride.
• Anhydrides are more reactive than acids, but less reactivethan acid chlorides.
• A carboxylate ion is the leaving group in nucleophilic acylsubstitution reactions.
• Symmetric vs. Asymmetric anhydrides
R C
O
O H RC
O
OH R C
O
O C
O
R
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-13
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.
CH3 C
O
O C
O
CH3
ethanoic anhydrideacetic anhydride
O
O
O
1,2-benzenedicarboxylic anhydridephthalic anhydride =>
Chapter 21 Carboxylic Acids Derivs Slide 21-14
Multifunctional Compounds
• The functional group with the highest priority determines theparent name.
• Acid > ester > amide > nitrile > aldehyde > ketone > alcohol >amine > alkene > alkyne.
C
CN
O
OCH2CH3ethyl o-cyanobenzoate
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-15
Boiling Points
Even 3° amides have strongattractions.
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-16
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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Chapter 21 Carboxylic Acids Derivs Slide 21-17
Solubility
• Acid chlorides and anhydrides are too reactive to be used withwater or alcohol.
• Esters, 3° amides, and nitriles are good polar aprotic solvents.• Solvents commonly used in organic reactions:
Ethyl acetateDimethylformamide (DMF)Acetonitrile
Chapter 21 Carboxylic Acids Derivs Slide 21-18
IR Spectroscopy
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Chapter 21 Carboxylic Acids Derivs Slide 21-19
1H NMR Spectroscopy
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-20
13C NMR Spectroscopy
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-21
Interconversion of Acid Derivatives
• Nucleophile adds to the carbonyl to form a tetrahedralintermediate. (Nothing new!)
• Leaving group leaves and C=O regenerates. (Nucleophilicaddition-elimination reaction)
Chapter 21 Carboxylic Acids Derivs Slide 21-22
Reactivity
Reactivity decreases as leaving group becomes more basic.
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-23
Interconversion of Derivatives
More reactive derivatives canbe converted to lessreactive derivatives.
Chapter 21 Carboxylic Acids Derivs Slide 21-24
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.
+ HClC
O
R OC
O
R'
_
C
O
R Cl
OH C
OR'
C
O
R ClR' C
O
O H
+
- H+
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Chapter 21 Carboxylic Acids Derivs Slide 21-25
Acid Chloride to Ester
• Alcohol attacks the C=O.• Tetrahedral intermediate forms.• Chloride ion leaves, C=O is restored, H+ is abstracted.
+ HClC
O
R OR'
_
C
O
R Cl
OH R'
C
O
R Cl+
- H+
R' O H
Chapter 21 Carboxylic Acids Derivs Slide 21-26
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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Chapter 21 Carboxylic Acids Derivs Slide 21-27
Anhydride to Ester
• Alcohol attacks one C=O of anhydride.• Tetrahedral intermediate forms.• Carboxylate ion leaves, C=O is restored, H+ is abstracted.• See a theme here????
Chapter 21 Carboxylic Acids Derivs Slide 21-28
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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Chapter 21 Carboxylic Acids Derivs Slide 21-29
Ester to Amide
• Nucleophile must be NH3 or 1° amine.• Prolonged heating required.• More reactive esters will do this better!
Chapter 21 Carboxylic Acids Derivs Slide 21-30
Leaving Groups
A strong base is not usually a leaving group unless it’s in anexothermic step (reason RO- leaves)
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-31
Transesterification
• One alkoxy group can be replaced by another with acid or basecatalyst.
• Use large excess of preferred alcohol.• Later: reason that reactions done on esters using alkoxide
bases are done as they are.
Chapter 21 Carboxylic Acids Derivs Slide 21-32
Hydrolysis of Acid Chlorides and Anhydrides
• Hydrolysis occurs quickly, even in moist air with no acid or basecatalyst.
• Reagents must be protected from moisture.• Best: make, then use immediately
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Chapter 21 Carboxylic Acids Derivs Slide 21-33
Acid Hydrolysis of Esters
• Reverse of Fischer esterification (previously discussed).• Reaches equilibrium (remember: esterification is an
equilibrium process!)• Use a large excess of water to drive reaction (LeChat!).
+CH3 C
O
OCH3 HOH CH3 C
O
OH + CH3OH
H+
Chapter 21 Carboxylic Acids Derivs Slide 21-34
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 - asoap.
• Products (before neutralization) are alcohol andcarboxylate salt
• One example of a soap is sodium stearate,Na+ -OOC(CH2)16CH3.
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Chapter 21 Carboxylic Acids Derivs Slide 21-35
Hydrolysis of Amides
Due to their increased stability, prolonged heating in 6 M HCl or40% aqueous NaOH is required.
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Chapter 21 Carboxylic Acids Derivs Slide 21-36
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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Chapter 21 Carboxylic Acids Derivs Slide 21-37
Reduction to Alcohols
Lithium aluminum hydride reduces acids, acid chlorides, andesters to primary alcohols.
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-38
Reduction to Aldehydes
Acid chlorides will react with a weaker reducing agent to yield analdehyde.
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-39
Reduction to Amines
• Lithium aluminum hydride reduces amides and nitriles toamines.
• Nitriles and 1° amides reduce to 1° amines.• A 2° amide reduces to a 2° amine.• A 3° amide reduces to a 3° amine.
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-40
Organometallic Reagents
Grignard reagents and organolithium reagents add twice to acidchlorides and esters to give alcohols after protonation(previously discussed).
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-41
Grignard Reagents and Nitriles
A Grignard reagent or organolithium reagent attacks the cyanogroup to yield an imine which is hydrolyzed to a ketone.
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Chapter 21 Carboxylic Acids Derivs Slide 21-42
Acid Chloride Synthesis
• Previously discussed.• Use thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2.• Other products are gases.• Make in situ and use immediately
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-43
Acid Chloride Reactions (1)
acid
ester
amide
acid anhydride =>
Chapter 21 Carboxylic Acids Derivs Slide 21-44
Acid Chloride Reactions (2)
3° alcohol
ketone
1° alcohol
aldehyde
acylbenzene =>
AlCl3
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Chapter 21 Carboxylic Acids Derivs Slide 21-45
Industrial Synthesis of Acetic Anhydride
• Four billion pounds/year produced.• Use high heat (750°C) and triethyl phosphate catalyst to
produce ketene.
CH3 C
O
OH(EtO)3P O
heat
CH
HC O
CH
HC O + CH3 C
O
OH CH3 C
O
O C
O
CH3
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-46
Lab Synthesis of Anhydrides
• React acid chloride with carboxylic acid or carboxylate ion.
C
O
Cl+ CH3 C
O
O_ C
O
O C
O
CH3
• Heat dicarboxylic acids to form cyclic anhydrides.
C
O
OH
C
O
OH
O
O
O =>
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Chapter 21 Carboxylic Acids Derivs Slide 21-47
Anhydride Reactions
acid
ester
amide
=>acylbenzene
AlCl3
Chapter 21 Carboxylic Acids Derivs Slide 21-48
Anhydride vs. Acid Chloride
• Acetic anhydride is cheaper, gives a better yield than acetylchloride (reactivity and conditions issues).
• Use acetic formic anhydride to produce formate esters andformamides.
• Use cyclic anhydrides to produce a difunctional molecule.
C
O
OCH2CH3
C
O
OH
O
O
O
CH3CH2OH =>
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Chapter 21 Carboxylic Acids Derivs Slide 21-49
Synthesis of Esters
R C
O
OR'R C
O
OH + R'OHH
+
+ HOH
acid
R C
O
OR'R C
O
Cl + R'OH + HCl
acid chloride
R C
O
OR'R C
O
O C
O
R + R'OH
H+
+ RCOOH
acid anhydride
R C
O
OH CH2N2+ R C
O
OCH3 N2+
methyl ester =>
Chapter 21 Carboxylic Acids Derivs Slide 21-50
Reactions of Esters
acid
ester
amide
1° alcohol
3° alcohol=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-51
Lactones
• Formation favored for five- and six-membered rings.
O
OCOOH
OH H+
H2O+
• For larger rings, remove water to shift equilibrium towardproducts
H+
H2O+
O
O
OH
COOH
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-52
Polyesters
• Dacron® thread• Mylar® tape
• Glyptal resin• PET bottles
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-53
Synthesis of Amides
R C
O
OH + HOH+ R'NH2
heatR C
O
NHR'
acid
R C
O
O C
O
R + RCOOHR'2NH R C
O
NR'2+
acid anhydride
R C
O
OR'' + R''OHR'NH2 R C
O
NHR'+
ester
R C
O
NH2R C N + H2O
H+ or OH
-
nitrile =>
acid chlorideR'2NH2
+Cl
-+R C
O
NR'2R'2NH+ 2R C
O
Cl
Chapter 21 Carboxylic Acids Derivs Slide 21-54
Reactions of Amides
acid and amine
amine
1° amine
=>
nitrile
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Chapter 21 Carboxylic Acids Derivs Slide 21-55
Lactam Formation
• Five- and six-membered rings can be formed by heating γ-and δ-amino acids.
• Smaller or larger rings do not form readily.
Chapter 21 Carboxylic Acids Derivs Slide 21-56
β-Lactams
• Highly reactive, 4-membered ring.• Found in antibiotics isolated from fungi.
Amide → ester !!
=>
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Chapter 21 Carboxylic Acids Derivs Slide 21-57
Synthesis of Nitriles
R C
O
NH2 R C NPOCl3
1° amide
R C N +R XNaCN
Na+X-
alkyl halide
+Ar N N+ CuCN
Ar CN N2diazonium salt
R C
O
R'HCN
KCNR C R'
HO CN
aldehyde or ketone
cyanohydrin =>
Chapter 21 Carboxylic Acids Derivs Slide 21-58
Reactions of Nitriles
ketone
=>
amide acid
1° amine
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Chapter 21 Carboxylic Acids Derivs Slide 21-59
Thioesters
More reactive than esters because: -S-R is a better leaving group than -O-RResonance overlap is not as effective.
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-60
Carbonic Acid Esters
• CO2 in water contains some H2CO3.• Diesters are stable.• Synthesized from phosgene.
+C
O
ClCl CH3CH2OCOCH2CH3
O
2 CH3CH2OH
diethyl carbonate
=>
phosgene
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Chapter 21 Carboxylic Acids Derivs Slide 21-61
Urea and Urethanes
• Urea is the diamide of carbonic acid.• Urethanes are esters of a monoamide of carbonic acid.
+C
O
ClCl C
O
NH2H2N2 NH3urea
N C O
H2O
NH C OH
O
a carbamic acid
ROHNH C OR
O
a urethane =>
Chapter 21 Carboxylic Acids Derivs Slide 21-62
Polycarbonates
Long-chain esters of carbonic acid
=>
32
Chapter 21 Carboxylic Acids Derivs Slide 21-63
Polyurethanes
A diol reacts with a diisocyanate.
=>
Chapter 21 Carboxylic Acids Derivs Slide 21-64
End of Chapter 21
Homework: 48-50, 54, 57, 59, 60, 64, 65