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Chapter 21Carboxylic Acid Derivatives
Jo BlackburnRichland College, Dallas, TX
Dallas County Community College District2003,Prentice Hall
Organic Chemistry, 5th EditionL. G. Wade, Jr.
Chapter 21 2
Acid Derivatives
• All can be converted to the carboxylic acid by acidic or basic hydrolysis.
• Esters and amides common in nature.
=>
R C
O
X R C
O
O C
O
R' R C
O
O R R C
O
NH2 R C N
RCOX (RCO)2O RCOOR RCONH2 RCN
Chapter 21 3
Naming Esters
• Esters are named as alkyl carboxylates.
• Alkyl from the alcohol, carboxylate from the carboxylic acid precursor.
isobutyl acetate2-methylpropyl ethanoate
CH3CHCH2OCCH3
CH3 O
HCOCH2
O
benzyl formatebenzyl methanoate
=>
Chapter 21 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.
O
O
H3C
CH3
4-hydroxy-2-methylpentanoic acid lactone-methyl--valerolactone
=>
Chapter 21 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.
HC
O
N
H
HH
C
O
N
H
H
_
+
Bond angles around Nare close to 120. =>
Chapter 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).
=>
Chapter 21 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.
CH3CHC N
O
CH2CH3
CH3
CH3
N-ethyl-N,2-dimethylpropanamideN-ethyl-N-methylisobutyramide
=>
Chapter 21 8
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
O
CH3
H4-aminopentanoic acid lactam
-valerolactam
=>
Chapter 21 9
Nitriles• -CN 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).
=>
Chapter 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 =>
Chapter 21 11
Acid Halides
• More reactive than acids; the halogen withdraws e- density from carbonyl.
• Named by replacing -ic acid with -yl halide.
C
O
Cl CH3CHCH2C
Br O
Br
benzoyl chloride
3-bromobutanoyl bromide-bromobutyryl bromide
=>
Chapter 21 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.
R C
O
O H RC
O
OH R C
O
O C
O
R
=>
Chapter 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
O1,2-benzenedicarboxylic anhydride
phthalic anhydride =>
Chapter 21 14
Multifunctional Compounds
• The functional group with the highest priority determines the parent name.
• Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne.
C
CN
O
OCH2CH3 ethyl o-cyanobenzoate=>
Chapter 21 15
Boiling Points
Even 3 amides havestrong attractions.
=>
Chapter 21 16
Melting Points
• Amides have very high melting points.
• Melting points increase with increasing number of N-H bonds.
H C
O
NCH3
CH3CH3 C
O
NH
CH3
CH3CH2 C
O
N
H
H
m.p. -61C m.p. 28C m.p. 79C
=>
Chapter 21 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 acetateDimethylformamide (DMF)Acetonitrile
=>
Chapter 21 18
IR Spectroscopy
=> =>
Chapter 21 19
1H NMR Spectroscopy
=>
Chapter 21 20
13C NMR Spectroscopy
=>
Chapter 21 21
Interconversion ofAcid Derivatives
• Nucleophile adds to the carbonyl to form a tetrahedral intermediate.
• Leaving group leaves and C=O regenerates.
C
O
R YNuc_
C
O
R Y
Nuc
_
C
O
R Nuc+ Y
_
=>
Chapter 21 22
ReactivityReactivity decreases as leaving group
becomes more basic.
=>
Chapter 21 23
Interconversion of Derivatives
More reactive derivatives can be converted to less reactive derivatives.
=>
Chapter 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+
Chapter 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 26
Acid Chloride to Amide• Ammonia yields a 1 amide
• A 1 amine yields a 2 amide
• A 2 amine yields a 3 amide
C
O
R NR'2
_
C
O
R Cl
NH R'2
C
O
R Cl+
R'2 N H
R'2 N HR'2NH2
+ Cl
-
+
=>
Chapter 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. =>
_
C
O
R OR'C
O
R OC
O
RR' O H+
C
O
R O
OH R'
C
O
R
_
O C
O
R +
Chapter 21 28
Anhydride to Amide
• Ammonia yields a 1 amide
• A 1 amine yields a 2 amide
• A 2 amine yields a 3 amide
_
C
O
R NR'2
C
O
R OC
O
RR'2 N H+
C
O
R O
NH R'2
C
O
R
_
O C
O
R +
=>
Chapter 21 29
Ester to Amide• Nucleophile must be NH3 or 1 amine.
• Prolonged heating required.
C
O
R NHR'
_
C
O
R OCH3
NH R'
H
C
O
R OCH3+
R' NH2 +OCH3
_
Surprise!
=>
Chapter 21 30
Leaving Groups
A strong base is not usually a leaving group unless it’s in an exothermic step.
=>
Chapter 21 31
Transesterification
• One alkoxy group can be replaced by another with acid or base catalyst.
• Use large excess of preferred alcohol.
C
O
OCH2CH3
+ CH3OHH
+ or
-OCH3
C
O
OCH3
CH3CH2OH+
=>
Chapter 21 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.
+CH3 C
O
Cl HOH CH3 C
O
OH + HCl
=>
Chapter 21 33
Acid Hydrolysis of Esters
• Reverse of Fischer esterification.
• Reaches equilibrium.
• Use a large excess of water.
+CH3 C
O
OCH3 HOH CH3 C
O
OH + CH3OHH+
=>
Chapter 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 - a soap.
• One example of a soap is sodium stearate, Na+ -OOC(CH2)16CH3. =>
Chapter 21 35
Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40% aqueous NaOH is required.
+CH3 C
O
NHCH3-OH CH3 C
O
O-
+ CH3NH2H2O
+CH3 C
O
NHCH3 HCl CH3 C
O
OH + CH3NH3+Cl-
H2O
=>
Chapter 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.
+ H2O
C N -OH
C
O
NH2 -OHheat
C
O
O-
+ NH3
=>
Chapter 21 37
Reduction to Alcohols
Lithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols.
=>
CH3CH2OH+
CH2OH
H2O2)
1) LiAlH4
C
O
OCH2CH3
Chapter 21 38
Reduction to Aldehydes
Acid chlorides will react with a weaker reducing agent to yield an aldehyde.
=>
CH3CHCH2C
CH3 O
HLiAl(t-BuO)3HCH3CHCH2C
CH3 O
Cl
Chapter 21 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.
CH3 C
O
NHCH3 CH3 CH2 NHCH3LiAlH41)
2) H2O
=>
Chapter 21 40
Organometallic Reagents
Grignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.
C
O
OCH2CH3 CH3MgBr
ether
C
OH
CH3CH3
2 H3O+
=>
Chapter 21 41
Grignard Reagentsand Nitriles
A Grignard reagent or organolithium reagent attacks the cyano group to yield an imine which is hydrolyzed to a ketone.
C NCH3MgBr
etherH3O
+C N
H3C MgBrC O
H3C
=>
Chapter 21 42
Acid Chloride Synthesis
• Use thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2.
• Other products are gases.
C
O
OH SOCl2C
O
Cl+ +SO2 HCl
=>
Chapter 21 43
Acid Chloride Reactions (1)
H2O
R'OH
R'NH2
R'COOH
R C
O
Cl
R C
O
OH + HCl
R C
O
OR'
R C
O
NHR'
R C
O
O C
O
R' + HCl
+ HCl
+ HCl
acid
ester
amide
acid anhydride =>
Chapter 21 44
Acid Chloride Reactions (2)
R C
O
H
R CH2OH
R C
O
R'
R C
OH
R'
R'
R C
O
Cl
H2O(2)
(1) 2 R'MgX
R'2CuLi
(1)
(2) H2O
LiAlH4
Li( BuO)3AlHt-
Z
AlCl3
C
O
RZ
3° alcohol
ketone
1° alcohol
aldehyde
acylbenzene =>
Chapter 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 46
Lab Synthesisof 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
OHO
O
O=>
Chapter 21 47
Anhydride Reactions
R C
O
O C
O
R
R C
O
OH + RCOOH
R C
O
OR'
R C
O
NHR' + RCOOH
+ RCOOH
AlCl3
H2O
R'OH, H+
R'NH2
ZC
O
RZ
acid
ester
amide
=>acylbenzene
Chapter 21 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.
+ CH3 C
O
OHCH3 C
O
O C
O
H R NH2 H C
O
NHR +
• Use cyclic anhydrides to produce a difunctional molecule.
C
O
OCH2CH3
C
O
OHO
O
O
CH3CH2OH=>
Chapter 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'OHH+
+ RCOOH
acid anhydride
R C
O
OH CH2N2+ R C
O
OCH3 N2+methyl ester =>
Chapter 21 50
Reactions of Esters
R C
O
OR'
R C
O
OH + R'OH
R C
O
OR''
R C
O
NHR'' + R'OH
+ R'OH
R CH2OH
R C
OH
R''
R''H2O(2)
(1) 2 R''MgX
(1)
(2) H2O
LiAlH4
H2O
R''OH,
R''NH2
H+ or -OR''
acid
ester
amide
1° alcohol
3° alcohol
=>
Chapter 21 51
Lactones• Formation favored for five- and six-
membered rings.O
OCOOH
OH H+
H2O+
• For larger rings, remove water to shift equilibrium toward products
H+
H2O+O
O
OH
COOH
=>
Chapter 21 52
Synthesis of AmidesR C
O
OH + HOH+ R'NH2heat
R 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 + H2OH+ or OH-
nitrile =>
acid chlorideR'2NH2
+Cl-+R C
O
NR'2R'2NH+ 2R C
O
Cl
Chapter 21 53
Reactions of Amides
R C
O
OH + R'NH2
R C
O
NHR'
R CH2NHR'(1)
(2) H2O
LiAlH4
H2OH+ or -OH
Br-, OH-
R NH2 + CO2
POCl3
(or P2O5)R C N
acid and amine
amine
1° amine
=>
nitrile
Chapter 21 54
Lactam Formation
• Five- and six-membered rings can be formed by heating - and -amino acids.
NH
OCOOH
NH2 heat+ H2O
• Smaller or larger rings do not form readily. =>
Chapter 21 55
-Lactams
• Highly reactive, 4-membered ring.
• Found in antibiotics isolated from fungi.
Amide ester !!
=>
Chapter 21 56
Synthesis of Nitriles
R C
O
NH2 R C NPOCl3
1° amide
R C N +R X NaCN Na+X-
alkyl halide
+Ar N N+ CuCN Ar CN N2
diazonium salt
R C
O
R'HCNKCN
R C R'
HO CN
aldehyde or ketone
cyanohydrin =>
Chapter 21 57
Reactions of Nitriles
R C
O
NH2
R CH2NH2(1)
(2)LiAlH4
H2OH+ or -OH
R C N
H+ or -OH
H2O R C
O
OH
H2O
R'MgXR C
N
R'
MgXH3O
+
R C
O
R'ketone
=>
amide acid
1° amine
Chapter 21 58
ThioestersMore reactive than esters because:
-S-R is a better leaving group than -O-RResonance overlap is not as effective.
=>
Chapter 21 59
Carbonic Acid Esters
• CO2 in water contains some H2CO3.
• Diesters are stable.
• Synthesized from phosgene.
+C
O
ClCl CH3CH2OCOCH2CH3
O
2 CH3CH2OH
diethyl carbonate
=>
Chapter 21 60
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
H2ONH C OH
O
a carbamic acid
ROHNH C OR
O
a urethane =>
Chapter 21 61
Polymers
• Polycarbonates are long-chain esters of carbonic acid.
• Polyurethanes are formed when a diol reacts with a diisocyanate.
N C ONCO
CH3
HOCH2CH2OH
NH CHN
CH3
C
O
OCH2CH2O
O
n
=>
Chapter 21 62
End of Chapter 21
