Download 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
2003, Prentice Hall
Acid Derivatives
• All can be converted to the carboxylic
acid by acidic or basic hydrolysis.
• Esters and amides common in nature.
O
R C X
RCOX
O
O
R C O C R'
(RCO)2O
O
R C O R
RCOOR
O
R C NH2
R C N
RCONH2
RCN
=>
Chapter 21
2
Naming Esters
• Esters are named as alkyl carboxylates.
• Alkyl from the alcohol, carboxylate from
the carboxylic acid precursor.
CH3
O
O
CH3CHCH2OCCH3
isobutyl acetate
2-methylpropyl ethanoate
HCOCH2
benzyl formate
benzyl methanoate
=>
Chapter 21
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
-methyl--valerolactone
CH3
=>
Chapter 21
4
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
5
=>
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
6
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
N-ethyl-N,2-dimethylpropanamide
CH2CH3 N-ethyl-N-methylisobutyramide
CH3
Chapter 21
7
=>
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
-valerolactam
=>
Chapter 21
8
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
9
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
10
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
-bromobutyryl bromide
=>
benzoyl chloride
Chapter 21
11
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
R C O H
O
O
H O C
R
O
R C O C
R
=>
Chapter 21
12
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
O
C O C CH3
O
ethanoic anhydride
acetic anhydride
O
CH3
1,2-benzenedicarboxylic anhydride
phthalic anhydride
=>
Chapter 21
13
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
14
Boiling Points
Even 3 amides have
strong attractions.
Chapter 21
=> 15
Melting Points
• Amides have very high melting points.
• Melting points increase with increasing
number of N-H bonds.
O
H C N
CH3
CH3
m.p. -61C
O
CH3
C N
O
H
CH3
m.p. 28C
CH3CH2
C N
H
H
m.p. 79C
=>
Chapter 21
16
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
=>17
IR Spectroscopy
=> =>
Chapter 21
18
1H
NMR Spectroscopy
=>
Chapter 21
19
13C
NMR Spectroscopy
=>
Chapter 21
20
Interconversion of
Acid Derivatives
• Nucleophile adds to the carbonyl to form a
tetrahedral intermediate.
• Leaving group leaves and C=O regenerates.
_
O
_
Nuc
R
C
O
Y
O
R C Y
Nuc
R
C
Nuc
_
+ Y
=>
Chapter 21
21
Reactivity
Reactivity decreases as leaving group
becomes more basic.
=>
Chapter 21
22
Interconversion of Derivatives
More reactive
derivatives can be
converted to less
reactive
derivatives.
=>
Chapter 21
23
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
C
O
- H+
Cl
R
H
C
+O
Cl
R
C
O
O
C
R'
+
HCl
C R'
O
Chapter 21
24
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
R
C
O
Cl
R C Cl
+O
H
R'
Chapter 21
O
- H+
R
C
O
R' + HCl
25
Acid Chloride to Amide
• Ammonia yields a 1 amide
• A 1 amine yields a 2 amide
• A 2 amine yields a 3 amide
_
O
R'2
N H
R
C
Cl
R'2
O
O
R C Cl
+N
H
R'2
C
R
N
R'2
+
+
N H
=>
Chapter 21
-
R'2NH2 Cl
26
Anhydride to Ester
• Alcohol attacks one C=O of anhydride.
• Tetrahedral intermediate forms.
• Carboxylate ion leaves, C=O is
restored, H+ is abstracted.
=>
R'
O H
R
O
O
C
C
O
_
O
R
O
R C O C R
+O
H
R'
Chapter 21
O
_
O C R
O
+
R
C
27
OR'
Anhydride to Amide
• Ammonia yields a 1 amide
• A 1 amine yields a 2 amide
• A 2 amine yields a 3 amide
O
R'2
N H
R
C
_
O
O
C
O
R
O
R C O C R
+N
H
R'2
O
_
O C R
O
+
R
C
NR'2
=>
Chapter 21
28
Ester to Amide
• Nucleophile must be NH3 or 1 amine.
• Prolonged heating required.
_
O
R'
NH2
R
C
O
OCH3
R C OCH3
+N
H
R'
H
O
_
OCH3
+
R
C
NH
R'
Surprise!
=>
Chapter 21
29
Leaving Groups
A strong base is not usually a leaving
group unless it’s in an exothermic step.
=>
Chapter 21
30
Transesterification
• One alkoxy group can be replaced by
another with acid or base catalyst.
• Use large excess of preferred alcohol.
O
O
C OCH CH
2
3
+
+ CH3OH
-
H or OCH3
C OCH
3
+ CH3CH2OH
=>
Chapter 21
31
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.
O
O
CH3
CH3
C Cl + HOH
C OH
+ HCl
=>
Chapter 21
32
Acid Hydrolysis of Esters
• Reverse of Fischer esterification.
• Reaches equilibrium.
• Use a large excess of water.
O
CH3
C OCH3 + HOH
O
+
H
CH3
C OH
+ CH3OH
=>
Chapter 21
33
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
34
Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40%
aqueous NaOH is required.
O
CH3
-
C NHCH3 + OH
O
CH3
C NHCH3 + HCl
H2O
H2O
O
CH3
C O
-
+ CH3NH2
O
CH3
+
-
C OH + CH3NH3 Cl
=>
Chapter 21
35
Hydrolysis of Nitriles
• Under mild conditions, nitriles hydrolyze
to an amide.
• Heating with aqueous acid or base will
hydrolyze a nitrile to an acid.
C N
+ H2O
-
OH
O
O
C NH
2
C O-
-
OH
heat
+ NH3
=>
Chapter 21
36
Reduction to Alcohols
Lithium aluminum hydride reduces acids,
acid chlorides, and esters to primary
alcohols.
O
C OCH CH
2
3
CH2OH
1) LiAlH4
2) H2O
+ CH3CH2OH
=>
Chapter 21
37
Reduction to Aldehydes
Acid chlorides will react with a weaker
reducing agent to yield an aldehyde.
CH3
O
CH3CHCH2C
Cl
LiAl(t-BuO)3H
CH3
O
CH3CHCH2C
H
=>
Chapter 21
38
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.
O
CH3
C NHCH3
1) LiAlH4
2) H2O
CH3 CH2 NHCH3
=>
Chapter 21
39
Organometallic Reagents
Grignard reagents and organolithium
reagents add twice to acid chlorides and
esters to give alcohols after protonation.
OH
O
C OCH CH
2
3
2 CH3MgBr
ether
H3O
+
C CH
3
CH3
=>
Chapter 21
40
Grignard Reagents
and Nitriles
A Grignard reagent or organolithium reagent
attacks the cyano group to yield an imine
which is hydrolyzed to a ketone.
H3C
C N
CH3MgBr
ether
C N
H3C
MgBr
H3O
+
C O
=>
Chapter 21
41
Acid Chloride Synthesis
• Use thionyl chloride, SOCl2, or oxalyl
chloride, (COCl)2.
• Other products are gases.
O
O
C OH
C Cl
SOCl2
+ SO2 + HCl
=>
Chapter 21
42
Acid Chloride Reactions (1)
O
H2O
R C OH + HCl
acid
O
O
R'OH
+ HCl
ester
R C NHR' + HCl
amide
R C OR'
O
R C Cl
R'NH2
O
R'COOH
O
R C O C R' + HCl
acid anhydride
Chapter 21
=>
43
Acid Chloride Reactions (2)
OH
(1) 2 R'MgX
(2) H2O
R'2CuLi
O
R C
R C R'
3° alcohol
R'
O
R C
ketone
R'
Cl
(1) LiAlH4
(2) H2O
Li(t-BuO)3AlH
R CH2OH
1° alcohol
O
aldehyde
R C H
O
Z
AlCl3
C R
Z
acylbenzene
=>
Chapter 21
44
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
H
C C O
H
O
O
C C O + CH3 C OH
O
CH3 C O C CH3
=>
Chapter 21
45
Lab Synthesis
of Anhydrides
• React acid chloride with carboxylic acid
or carboxylate ion.
O
C Cl
O
O
O
C O C CH
3
_
+ CH3 C O
• Heat dicarboxylic acids to form cyclic
O
O
anhydrides.
C OH
O
C OH
O
Chapter 21
O
=>
46
Anhydride Reactions
O
H2O
R
C
R
O
O
C
O C
+
RCOOH
acid
OR'
+
RCOOH
ester
NHR' +
RCOOH
amide
O
+
R'OH, H
OH
R
C
O
R
R'NH2
R
C
O
Z
AlCl3
C
R
Z
acylbenzene
=>
Chapter 21
47
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.
O
O
CH3 C O C H
O
+ R NH2
O
H C NHR + CH3 C OH
• Use cyclic anhydrides to produce
a difunctional molecule.
O
O
C OCH CH
2
3
O
O
CH3CH2OH
Chapter 21
C OH
O
=>
48
Synthesis of Esters
O
O
+
R C OH
+ R'OH
H
R C OR'
+ HOH
acid
O
O
R C Cl
R C OR' + HCl
+ R'OH
acid chloride
O
O
R C O C R + R'OH
O
+
H
R C OR' + RCOOH
acid anhydride
O
R C OH + CH2N2
O
R C OCH3 + N2
methyl ester
Chapter 21
=>
49
Reactions of Esters
O
H2O
R
C OH +
R'OH
acid
R'OH
ester
O
R''OH,
+
-
H or OR''
O
R
C OR'
R
C OR'' +
O
R''NH2
(1) LiAlH4
(2) H2O
(1) 2 R''MgX
(2) H2O
R
C NHR'' +
R
CH2OH
R'OH
amide
1° alcohol
OH
R
C
R''
3° alcohol
R''
Chapter 21
=>
50
Lactones
• Formation favored for five- and sixmembered rings.
OH
H+
O
+ H2O
COOH
O
• For larger rings, remove water to
shift equilibrium toward products
OH
+
O
H
COOH
+
H2O
O
=>
Chapter 21
51
Synthesis of Amides
O
O
heat
R C OH + R'NH2
R C NHR' + HOH
acid
O
O
R C NR'2 + R'2NH2+Cl-
R C Cl + 2 R'2NH
acid chloride
O
O
O
R C NR'2 + RCOOH
R C O C R + R'2NH
acid anhydride
O
O
R C OR'' + R'NH2
R C NHR' + R''OH
ester
+
R C N + H2O
-
H or OH
nitrile
O
R C NH2
=>
Chapter 21
52
Reactions of Amides
O
H2O
H+ or -OH
O
R C NHR'
(1) LiAlH4
(2) H2O
Br-, OHPOCl3
(or P2O5)
R C OH + R'NH2
acid and amine
R CH2NHR'
amine
R NH2 + CO2
R C N
1° amine
nitrile
=>
Chapter 21
53
Lactam Formation
• Five- and six-membered rings can be
formed by heating - and -amino acids.
NH2
NH
heat
+ H2O
COOH
O
• Smaller or larger rings do not form readily.
=>
Chapter 21
54
-Lactams
• Highly reactive, 4-membered ring.
• Found in antibiotics isolated from fungi.
Amide  ester !!
=>
Chapter 21
55
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
=>
56
Reactions of Nitriles
O
O
H2O
+
H or OH
R C N
(1) LiAlH4
(2) H2O
R'MgX
R C NH2
amide
R CH2NH2
N MgX
R C R'
H2O
+
H or OH
R C OH
acid
1° amine
+
H3O
O
R C R'
ketone
=>
Chapter 21
57
Thioesters
More reactive than esters because:
-S-R is a better leaving group than -O-R
Resonance overlap is not as effective.
=>
Chapter 21
58
Carbonic Acid Esters
• CO2 in water contains some H2CO3.
• Diesters are stable.
• Synthesized from phosgene.
O
Cl
C Cl
O
+
2 CH3CH2OH
CH3CH2OCOCH2CH3
diethyl carbonate
=>
Chapter 21
59
Urea and Urethanes
• Urea is the diamide of carbonic acid.
• Urethanes are esters of a monoamide
of carbonic acid.
O
O
Cl
C Cl
+
N C O
H2O
H2N C NH2
urea
2 NH3
O
O
NH C OH
NH C OR
a carbamic acid
Chapter 21
ROH
=>
a urethane
60
Polymers
• Polycarbonates are long-chain esters of
carbonic acid.
• Polyurethanes are formed when a diol
reacts with a diisocyanate.
O
O C N
N C O
O CH2CH2
O C HN
O
NH C
HOCH2CH2OH
CH3
CH3
n
=>
Chapter 21
61
End of Chapter 21
Chapter 21
62