Carboxylic Acid Derivatives
• Adapted from:
Organic Chemistry, 6th Edition;
Chapter 21, Carboxylic Acid Derivatives
L. G. Wade, Jr.
Chapter 21
2
1
Acid Derivatives
• All can be converted to the carboxylic
acid by acidic or basic hydrolysis.
• Esters and amides common in nature.
=>
Chapter 21
3
Chapter 21
4
2
Naming Esters
• Esters are named as alkyl carboxylates.
• Alkyl from the alcohol, carboxylate from
the carboxylic acid precursor.
O
CH3CH2
OH
O
+
H
CH3CH2
+ HO C CH3
O C CH3 +
ethanol
ethanoic acid
ethyl ethanoate
ethyl alcohol
acetic acid
ethyl acetate
H2O
=>
Chapter 21
5
Name These
CH3
O
O
HCOCH2
CH3CHCH2OCCH3
isobutyl acetate
2-methylpropyl ethanoate
benzyl formate
benzyl methanoate
=>
Chapter 21
6
3
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
H3C
O
4-hydroxy-2-methylpentanoic acid lactone
α-methyl-γ-valerolactone
CH3
=>
Chapter 21
7
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.
O
C
H
O
N
H
H
C + H
N
H
H
Bond angles around N
are close to 120°.
Chapter 21
8
=>
4
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
9
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 Nto indicate their position.
O CH3
CH3CHC N CH2CH3
CH3
N-ethyl-N,2-dimethylpropanamide
N-ethyl-N-methylisobutyramide
Chapter 21
10
=>
5
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.
O
N H
CH3
4-aminopentanoic acid lactam
γ-valerolactam
=>
Chapter 21
11
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).
=>
Chapter 21
12
6
Naming Nitriles
• For IUPAC names, add -nitrile to the alkane
name.
• Common names come from the carboxylic
acid. Replace -ic acid with -onitrile.
Br
C N
CH3CHCH2CH2CH2CN
5-bromohexanenitrile
∂-bromocapronitrile
Cyclohexanecarbonitrile
=>
Chapter 21
13
Acid Halides
• More reactive than acids; the halogen
withdraws e- density from carbonyl.
• Named by replacing -ic acid with -yl halide.
O
C
Br
Cl
O
CH3CHCH2C Br
3-bromobutanoyl bromide
β-bromobutyryl bromide
=>
benzoyl chloride
Chapter 21
14
7
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.
O
O
O
R C O H
H O C
R
O
R C O C
R
=>
Chapter 21
15
Naming Anhydrides
• The word acid is replaced with anhydride.
• For a mixed anhydride, name both acids.
• Diacids may form anhydrides if a 5- or 6membered ring is the product. O
O
CH3
O
C O C
O
CH3
ethanoic anhydride
acetic anhydride
O
1,2-benzenedicarboxylic anhydride
phthalic anhydride
=>
Chapter 21
16
8
Multifunctional Compounds
• The functional group with the highest
priority determines the parent name.
• Acid > ester > amide > nitrile >
aldehyde > ketone > alcohol > amine >
alkene > alkyne.
O
C
OCH2CH3
ethyl o-cyanobenzoate
=>
CN
Chapter 21
17
Boiling Points
Even 3° amides have
strong attractions.
Chapter 21
=>
18
9
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
=>
Chapter 21
19
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
=>20
10
IR Spectroscopy
=>
Chapter 21
1H
21
NMR Spectroscopy
=>
Chapter 21
22
11
13C
NMR Spectroscopy
=>
Chapter 21
23
Interconversion of
Acid Derivatives
• Nucleophile adds to the carbonyl to form a
tetrahedral intermediate.
• Leaving group leaves and C=O regenerates.
=>
Chapter 21
24
12
Reactivity
Reactivity decreases as leaving group
becomes more basic.
=>
Chapter 21
25
Chapter 21
26
13
Interconversion of Derivatives
More reactive
derivatives can be
converted to less
reactive
derivatives.
=>
Chapter 21
27
Chapter 21
28
14
Chapter 21
29
Chapter 21
30
15
Chapter 21
31
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.
_
=>
O
O
O
R' C
O
H
R
O
- H+
C
Cl
R
C
Cl
R
+O
H
O
C
C
O
R'
+ HCl
C R'
O
Chapter 21
32
16
Acid Chloride to Ester
• Alcohol attacks the C=O.
• Tetrahedral intermediate forms.
• Chloride ion leaves, C=O is restored, H+
is abstracted.
=>
_
O
R'
O H
O
C
R
Cl
O
- H+
R C Cl
+O
H
R'
C
R
O
Chapter 21
R' +
HCl
33
Acid Chloride to Amide
• Ammonia yields a 1° amide
• A 1° amine yields a 2° amide
• A 2° amine yields a 3° amide
=>
Chapter 21
34
17
Anhydride to Ester
• Alcohol attacks one C=O of anhydride.
• Tetrahedral intermediate forms.
• Carboxylate ion leaves, C=O is
restored, H+ is abstracted.
=>
Chapter 21
35
Anhydride to Amide
• Ammonia yields a 1° amide
• A 1° amine yields a 2° amide
• A 2° amine yields a 3° amide
=>
Chapter 21
36
18
Ester to Amide
• Nucleophile must be NH3 or 1° amine.
• Prolonged heating required.
Surprise!
=>
Chapter 21
37
Leaving Groups
A strong base is not usually a leaving
group unless it’s in an exothermic step.
=>
Chapter 21
38
19
Transesterification
• One alkoxy group can be replaced by
another with acid or base catalyst.
• Use large excess of preferred alcohol.
Chapter 21
39
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.
=>
Chapter 21
40
20
Acid Hydrolysis of Esters
• Reverse of Fischer esterification.
• Reaches equilibrium.
• Use a large excess of water.
O
CH3
O
+
C OCH3 + HOH
H
CH3
C OH
+ CH3OH
=>
Chapter 21
41
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
42
21
Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40%
aqueous NaOH is required.
=>
Chapter 21
43
Hydrolysis of Nitriles
• Under mild conditions, nitriles hydrolyze
to an amide.
• Heating with aqueous acid or base will
hydrolyze a nitrile to an acid.
Chapter 21
=>
44
22
Reduction to Alcohols
Lithium aluminum hydride reduces acids,
acid chlorides, and esters to primary
alcohols.
=>
Chapter 21
45
Reduction to Aldehydes
Acid chlorides will react with a weaker
reducing agent to yield an aldehyde.
=>
Chapter 21
46
23
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.
=>
Chapter 21
47
Organometallic Reagents
Grignard reagents and organolithium
reagents add twice to acid chlorides and
esters to give alcohols after protonation.
=>
Chapter 21
48
24
Grignard Reagents
and Nitriles
A Grignard reagent or organolithium reagent
attacks the cyano group to yield an imine
which is hydrolyzed to a ketone.
=>
Chapter 21
49
Acid Chloride Synthesis
• Use thionyl chloride, SOCl2, or oxalyl
chloride, (COCl)2.
• Other products are gases.
=>
Chapter 21
50
25
Acid Chloride Reactions (1)
acid
ester
amide
acid anhydride
=>
Chapter 21
51
Acid Chloride Reactions (2)
3°alcohol
ketone
1°alcohol
aldehyde
acylbenzene
=>
Chapter 21
52
AlCl3
26
Industrial Synthesis
of Acetic Anhydride
• Four billion pounds/year produced.
• Use high heat (750°C) and triethyl
phosphate catalyst to produce ketene.
O
CH3 C OH
H
H
heat
(EtO)3P O
C C O
H
O
C
H
O
C O + CH3 C OH
O
CH3 C O C
CH3
=>
Chapter 21
53
Lab Synthesis
of Anhydrides
• React acid chloride with carboxylic acid
or carboxylate ion.
O
C Cl
O
O
_
+ CH3 C O
O
C O C CH
3
• Heat dicarboxylic acids to form cyclic
O
O
anhydrides.
C OH
O
C OH
O
Chapter 21
O
=>
54
27
Anhydride Reactions
acid
ester
amide
acylbenzene
AlCl3
=>
Chapter 21
55
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.
O
O
C OCH CH
2
3
O
O
CH3CH2OH
Chapter 21
C OH
=>
56
O
28
Synthesis of Esters
O
O
+
+ R'OH
R C OH
H
R C OR'
+ HOH
acid
O
R
C
O
Cl
R
+ R'OH
C OR' + HCl
acid chloride
O
O
R C O C
H+
R + R'OH
O
R C OR' + RCOOH
acid anhydride
O
R
O
C OH + CH2N2
R C OCH3 + N2
=>
methyl ester
Chapter 21
57
Reactions of Esters
acid
ester
amide
1°alcohol
Chapter 21
3°alcohol
=>
58
29
Lactones
• Formation favored for five- and sixmembered rings.
H+
OH
O
COOH
+ H2O
O
• For larger rings, remove water to
shift equilibrium toward products
+
OH
O
H
COOH
+
H2O
O
=>
Chapter 21
59
Polyesters
• Dacron® thread
• Mylar® tape
• Glyptal resin
• PET bottles
Chapter 21
=>
60
30
Synthesis of Amides
O
C OH + R'NH2
R
O
heat
R C NHR' + HOH
acid
O
O
R
C
Cl + 2 R'2NH
C NR'2 + R'2NH2+Cl-
R
acid chloride
O
O
O
R C NR'2 + RCOOH
R C O C R + R'2NH
acid anhydride
O
R
O
C OR'' + R'NH2
R
ester
R C N + H2O
H+ or OH-
nitrile
C NHR' + R''OH
O
R C NH2
=>
Chapter 21
61
Reactions of Amides
acid and amine
amine
1°amine
nitrile
=>
Chapter 21
62
31
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
63
β-Lactams
• Highly reactive, 4-membered ring.
• Found in antibiotics isolated from fungi.
Amide → ester !!
=>
Chapter 21
64
32
Polyamides
Nylon 6.6
=>
Chapter 21
65
Synthesis of Nitriles
O
R
C NH2
POCl3
R
C N
1°amide
R X
NaCN
+ R C N + Na X
alkyl halide
Ar
+
N N
diazonium salt
O
R C R'
aldehyde
or ketone
CuCN
Ar
CN + N2
HO CN
HCN
R C R'
KCN cyanohydrin
Chapter 21
=>
66
33
Reactions of Nitriles
amide
acid
1°amine
ketone
Chapter 21
=>
67
Thioesters
More reactive than esters because:
-S-R is a better leaving group than -O-R
Resonance overlap is not as effective.
=>
Chapter 21
68
34
Carbonic Acid Esters
• CO2 in water contains some H2CO3.
• Diesters are stable.
• Synthesized from phosgene.
O
O
+
Cl C Cl
phosgene
2 CH3CH2OH
CH3CH2OCOCH2CH3
diethyl carbonate
=>
Chapter 21
69
Urea and Urethanes
• Urea is the diamide of carbonic acid.
• Urethanes are esters of a monoamide
of carbonic acid.
O
O
Cl
C
Cl
+
H2N C NH2
urea
2 NH3
O
N C O
H2O
NH C OH
a carbamic acid
Chapter 21
O
ROH
NH C OR
=>
a urethane
70
35
Polycarbonates
Long-chain esters of carbonic acid
=>
Chapter 21
71
Polyurethanes
A diol reacts with a diisocyanate.
=>
Chapter 21
72
36