3. Carboxyl Derivatives
x In this chapter, we study five classes of
organic compounds
• under the structural formula of each is a drawing
to help you see its relationship to the carboxyl
O
group O O O O
RCCl RCOCR' RCOR' RCNH2 RC N
An acid An acid An ester An amide A nitrile
chloride anhydride
-H2 O
-H2 O -H2 O -H2 O -H2 O
O O O O O HO H
RC-OH H-Cl RC-OH H-OCR' RC-OH H-OR' RC-OH H-NH2 RC=N
The enol of
an amide
18-3
4. Structure: Acid Chlorides
x The functional group of an acid halide is an
acyl group bonded to a halogen
• the most common are the acid chlorides
• to name, change the suffix -ic acid to -yl halide
O O
O O Cl Cl
Cl
RC- CH3 CCl
O
An acyl Ethanoyl chloride Benzoyl chloride Hexanedioyl chloride
group (Acetyl chloride) (Adipoyl chloride)
18-4
5. Sulfonyl Chlorides
• replacement of -OH in a sulfonic acid by -Cl gives
a sulfonyl chloride
O O
CH3 SOH CH3 SCl
O O
Methanesulfonic Methanesulfonyl chloride
acid (Mesyl chloride, MsCl)
O O
H3 C SOH H3 C SCl
O O
p-Toluenesulfonic p-Toluenesulfonyl chloride
acid (Tosyl chloride, TsCl)
18-5
6. Acid Anhydrides
x The functional group of an acid anhydride is
two acyl groups bonded to an oxygen atom
• the anhydride may be symmetrical (two identical
acyl groups) or mixed (two different acyl groups)
• to name, replace acid of the parent acid by
anhydride O O O O
CH3 COCCH3 COC
Acetic anhydride Benzoic anhydride
18-6
7. Acid Anhydrides
x Cyclic anhydrides are named from the
dicarboxylic acids from which they are
derived O O O
O O O
O O O
S u c c in ic M le ic
a P h t h a lic
a n h y d r i d ea n h y d r i d e n h y d r i d e
a
18-7
8. Phosphoric Anhydrides
x A phosphoric anhydride contains two
phosphoryl groups bonded to an oxygen
atom O O O O
- -
HO-P-O-P-OH O- P-O-P-O
OH OH O- O-
D ip h o s p h o r ic a c D ip h o s p h a t e io n
id
( P y r o p h o s p h o r i c (a cyir o p h o s p h a t e i o n )
P d)
O O O O O O
- -
HO-P-O-P-O-P-OH O- P-O-P-O-P-O
O- O- O- O- O- O-
T r i p h o s p h o r i c a c iT r i p h o s p h a t e i o n
d
18-8
9. Esters
x The functional group of an ester is an acyl
group bonded to -OR or -OAr
• name the alkyl or aryl group bonded to oxygen
followed by the name of the acid
• change the suffix -ic acid to -ate
O O
O
O OEt
EtO
O
O
Ethyl ethanoate Isopropyl Diethyl butanedioate
(Ethyl acetate) benzoate (Diethyl succinate)
18-9
10. Esters
x Cyclic esters are called lactones
• name the parent carboxylic acid, drop the suffix
-ic acid and add -olactone
O a O
a O b 2
2 1 1 3 1
a 2 O
b3 O g 4 O
H3 C 3 4 5 6
b g d e
3-Butanolactone 4-Butanolactone 6-H exanolactone
(b-Butyrolactone) (g-Butyrolactone) (e-Caprolactone)
18-10
11. Esters of Phosphoric Acid
• phosphoric acid forms mono-, di-, and triesters
• name by giving the name of the alkyl or aryl
group(s) bonded to oxygen followed by the word
phosphate
• in more complex phosphoric esters, it is common
to name the organic molecule and then indicate
the presence of the phosphoric ester by the word
phosphate CHOthe prefix phospho- O
or CHO O
O
HO C-H O HO CH2 O-P-O- CO- O
CH3 OPOH -
CH2 -O-P-O- O- C O P O
OCH3 O- H3 C N CH2 O-
Dimethyl Glyceraldehyde Pyridoxal phosphate Phosphoenol-
phosphate 3-phosphate pyruvate
18-11
12. Amides
x The functional group of an amide is an acyl
group bonded to a nitrogen atom
• IUPAC: drop - oic acid from the name of the
parent acid and add -amide
• if the amide nitrogen is bonded to an alkyl or aryl
group, name the group and show its location on
nitrogen by N -
O O H O CH3
CH3 CNH2 CH3 C-N H-C-N
CH3 CH3
Acetamide N-Methylacetamide N,N-Dimethyl-
(a 1¡ amide) (a 2¡ amide) formamide (DMF)
(a 3¡ amide)
18-12
13. Amides
x Cyclic amides are called lactams
• name the parent carboxylic acid, drop the suffix
-ic acid and add -lactam
α O
a O β 2
3 1
2 1
b3 γ 4 NH
NH 5 6
H3 C δ ε
3-Butanolactam 6-Hexanolactam
(b-Butyrolactam) (e-Caprolactam)
18-13
14. Penicillins
• the penicillins are a family of β-lactam antibiotics
HO
Ο
Τηε πενιχιλ ιν σ
λ H H
διφφερ ιν τηε NH S
γρουπ βονδ εδ H2 N
το τηε αχψλ χαρ ον
β N
β− αχταµ
λ O
COOH
Amoxicillin
(a β− αχταµ αν τιβ ιοτιχ)
λ
18-14
15. Cephalosporins
• the cephalosporins are also β-lactam antibiotics
The cephalosporins differ in the
group bonded to the acyl carbon and
the side chain of the thiazine ring
O
H H
S
N
NH2 H
N
O Me
β− αχταµ
λ COOH
Cephalexin
(Keflex)
18-15
16. Imides
x The functional group of an imide is two acyl
groups bonded to nitrogen
• both succinimide and phthalimide are cyclic
imides O O
NH NH
O O
Succinimide Phthalimide
18-16
17. Nitriles
x The functional group of a nitrile is a cyano
group
• IUPAC names: name as an alkanenitrile
• common names: drop the -ic acid and add
CH3 C N C N CH2 C N
-onitrile
Ethanenitrile Benzonitrile Phenylethanenitrile
(Acetonitrile) (Phenylacetonitrile)
18-17
18. Acidity of N-H bonds
x Amides are comparable in acidity to alcohols
• water-insoluble amides do not react with NaOH or
other alkali metal hydroxides to form water-
soluble salts
x Sulfonamides and imides are more acidic
than amides O O
O
O
SNH2 NH NH
CH3 CNH2
O
O O
Acetamide Benzenesulfonamide Succinimide Phthalimide
pKa 15-17 pKa 10 pKa 9.7 pKa 8.3
18-18
19. Acidity of N-H bonds
x Imides are more acidic than amides because
1. the electron-withdrawing inductive of the two
adjacent C=O groups weakens the N-H bond,
and
2. the imide anion is stabilized by resonance
delocalization of the negative charge
O O O
N N N
O O O
A resonance-stabilized anion
18-19
20. Acidity of N-H
• imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts
O O
- +
NH + NaOH N Na + H 2 O
O O
p Ka8 . 3 p Ka15 . 7
( s t r o n g e r( s t r o n g e r (w eaker (w eaker
a c id ) bas e) bas e) a c id )
18-20
21. Characteristic Reactions
x Nucleophilic acyl substitution: an addition-
elimination sequence resulting in
substitution of one nucleophile for another
-
O :O O
- -
C + :Nu C C + :Y
R Y R Nu R Nu
Y
Tetrahedral carbonyl Substitution
addition intermediate product
18-21
22. Characteristic Reactions
• in the general reaction, we showed the leaving
group as an anion to illustrate an important point
about them: the weaker the base, the better the
leaving group
O
- - - -
R2 N RO RCO X
Increasing leaving ability
Increasing basicity
18-22
23. Characteristic Reactions
• halide ion is the weakest base and the best
leaving group; acid halides are the most reactive
toward nucleophilic acyl substitution
• amide ion is the strongest base and the poorest
leaving group; amides are the least reactive
toward nucleophilic acyl substitution
18-23
24. Reaction with H 2 O - Acid Chlorides
• low-molecular-weight acid chlorides react rapidly
with water
• higher molecular-weight acid chlorides are less
soluble in water and react less readily
O O
CH3 CCl + H2 O CH3 COH + HCl
Acetyl chloride
18-24
25. Reaction with H 2 O - Anhydrides
• low-molecular-weight acid anhydrides react
readily with water to give two molecules of
carboxylic acid
• higher-molecular-weight acid anhydrides also
react with water, but less readily
O O O O
CH 3 COCCH3 + H2 O CH3 COH + HOCCH3
Acetic anhydride
18-25
26. Reaction with H 2 O - Anhydrides
• Step 1: addition of H 2 O to give a TCAI
H + H
O O H
O O O +
CH3 -C-O-C-CH3 CH3 -C-O-C-CH3 CH3 -C-O-C-CH3 + H-O-H
+ O H
O H
O-H H H
O-H Tetrahedral carbonyl
H H addition intermediate
• Step 2: protonation followed collapse of the TCAI
H H H H H H
+O O +O
H H H H
H + H
O O O O O O
CH3 -C-O-C-CH3 CH3 C O C CH3 CH3 C + O C CH3
O O O
H H H
18-26
27. Reaction with H 2 O - Esters
x Esters are hydrolyzed only slowly, even in
boiling water
• hydrolysis becomes more rapid if they are heated
with either aqueous acid or base
x Hydrolysis in aqueous acid is the reverse of
Fischer esterification
• the role of the acid catalyst is to protonate the
carbonyl oxygen and increase its electrophilic
character toward attack by water (a weak
nucleophile) to form a tetrahedral carbonyl
addition intermediate
• collapse of this intermediate gives the carboxylic
acid and alcohol
18-27
28. Reaction with H 2 O - Esters
x Acid-catalyzed ester hydrolysis
O +
OH + O
C H C H C
+ H2 O + CH3 OH
R OCH3 R OH R OH
OCH3
Tetrahedral carbonyl
addition intermediate
18-28
29. Reaction with H 2 O - Esters
x Hydrolysis of an esters in aqueous base is
often called saponification
• each mole of ester hydrolyzed requires 1 mole of
base
• for this reason, ester hydrolysis in aqueous base
is O
said to be base promoted
O
H2 O - +
RCOCH 3 + NaOH RCO Na + CH3 OH
• hydrolysis of an ester in aqueous base involves
formation of a tetrahedral carbonyl addition
intermediate followed by its collapse and proton
transfer
18-29
30. Reaction with H 2 O - Esters
• Step 1: attack of hydroxide ion (a nucleophile) on
the carbonyl carbon (an electrophile)
• Step 2: collapse of the TCAI
• Step 3: proton transfer to the alkoxide ion; this
step is irreversible and drives saponification to
completion
O O O O
(1) (2 )
R-C-OCH3 + OH R-C OCH3 R-C + OCH3 (3 ) R-C + HOCH3
OH O O
H
18-30
31. Reaction with H 2 O - Amides
x Hydrolysis of an amide in aqueous acid
requires 1 mole of acid per mole of amide
• reaction is driven to completion by the acid-base
reaction between the amine or ammonia and the
acid O O
H2 O + -
N H 2 + H 2 O + HCl heat
OH + N H4 Cl
Ph Ph
2-Phenylbutanamide 2-Phenylbutanoic acid
18-31
32. Reaction with H 2 O - Amides
x Hydrolysis of an amide in aqueous base
requires 1 mole of base per mole of amide
• reaction is driven to completion by the
irreversible formation of the carboxylate sale
O O
H2 O - +
CH3 CNH + NaOH CH 3 CO Na + H2 N
hea t
N-Phenylethanamide Sodium Aniline
(N-Phenylacetamide, acetate
Acetanilide)
18-32
33. Reaction with H 2 O - Amides
• Step1: protonation of the carbonyl oxygen gives a
resonance-stabilized cation intermediate
O +
R C NH2 + H O H
H
+H H H
O O O
+
R C NH2 R C NH2 R C NH2 + H2 O
+
Resonance-stabilized cation intermediate
18-33
34. Reaction with H 2 O - Amides
• Step 2: addition of water (a nucleophile) to the
carbonyl carbon (an electrophile) followed by
proton transfer gives a TCAI
proton
OH transfer from OH
OH
+ O to N
R C NH2 + O H R C NH2 R C NH3 +
H O+ O
H H H
• Step 3: collapse of the TCAI and proton transfer
H
O + H
O O
+
R C NH3
+
R C + NH3 R C OH + NH4
OH OH
18-34
35. Reaction with H 2 O - Nitriles
x The cyano group is hydrolyzed in aqueous
acid to a carboxyl group and ammonium ion
O
H2 O + -
Ph CH 2 C N + 2 H2 O + H2 SO4 Ph CH2 COH + NH4 HSO4
he at
Phenylacetonitrile Phenylacetic Ammonium
acid hydrogen sulfate
• protonation of the cyano nitrogen gives a cation
that reacts with water to give an imidic acid
• keto-enol tautomerism gives the amide
+
OH O
H
R-C N + H2 O R-C NH R-C-NH2
An imidic acid An amide
(enol of an amide)
18-35
36. Reaction with H 2 O - Nitriles
• hydrolysis of a cyano group in aqueous base
gives a carboxylic anion and ammonia;
acidification converts the carboxylic anion to the
carboxylic acid O
NaOH, H O 2 - +
CH3 ( CH2 ) 9 C N CH3 ( CH 2 ) 9 CO Na + NH3
heat
Undecanenitrile Sodium undecanoate
HCl H 2 O
O
CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl
Undecanoic acid
18-36
37. Reaction with H 2 O - Nitriles
• hydrolysis of nitriles is a valuable route to
carboxylic acids
O
KCN H2 SO4 , H2 O
CH3 ( CH2 ) 8 CH2 Cl CH3 (CH2 ) 9 C N CH3 ( CH2 ) 9 COH
ethanol, heat
1-Chlorodecane Undecanenitrile Undecanoic acid
water
OH OH
CHO HCN, KCN
CN H2 SO4 , H2 O COOH
ethanol, heat
water
Benzaldehyde Benzaldehyde cyanohydrin 2-Hydroxyphenylacetic acid
(Mandelonitrile) (Mandelic acid)
(racemic) (racemic)
18-37
38. Reaction with Alcohols
x Acid halides react with alcohols to give
esters
• acid halides are so reactive toward even weak
nucleophiles such as alcohols that no catalyst is
necessary
• where the alcohol or resulting ester is sensitive
to HCl, reaction is carried out in the presence of
a 3° amine to neutralize the acid O
O
Cl + HO O + HCl
Butanoyl Cyclohexanol Cyclohexyl butanoate
chloride
18-38
39. Reaction with Alcohols
• sulfonic acid esters are prepared by the reaction
of an alkane- or arenesulfonyl chloride (Section
18.1A) with an alcohol or phenol
• the key point here is that OH - (a poor leaving
group) is transformed into a sulfonic ester (a
good leaving group) with retention of
configuration at the chiral center
OH OTs
+ TsCl pyridine
(R)-2-Octanol p-Toluenesulfonyl (R)-2-Octyl p-toluenesulfonate
chloride [(R)-2-Octyl tosylate]
(Tosyl chloride)
18-39
40. Reaction with Alcohols
x Acid anhydrides react with alcohols to give
one mole of ester and one mole of carboxylic
acid O O O
CH3 COCCH3 + HOCH2 CH3 CH3 COCH2 CH 3 + CH3 COH
Acetic anhydride Ethanol Ethyl acetate Acetic acid
• cyclic anhydrides react with alcohols to give one
O
O and one carboxyl group
ester group
O
O +
HO OH
O O
Phthalic 2-Butanol
anhydride (sec-Butyl alcohol) (sec-Butyl hydrogen
phthalate
18-40
41. Reaction with Alcohols
• aspirin is synthesized by treating salicylic acid
with acetic anhydride
COOH
OH O O
+ CH COCCH
3 3
A e t ic
c
2 - H y d r o x y b e n z o acn h y d r i d e
i
a c id
( S a lic y lic a c id ) COOH
O CH 3 O
+ CH 3 COH
O
A c e t y l s a l i c y l i c a A i de t i c a c i d
c c
( A s p ir in )
18-41
42. Reaction with Alcohols
x Esters react with alcohols in the presence of
an acid catalyst in an equilibrium reaction
called transesterification
O
+ HCl
OCH 3 HO
M e t h y l p r o p e n o a t1- B u t a n o l
e
( M e t h y l a c r y l a t e () b p 117 ° C )
( b p 8 1° C )
O
O + CH 3 OH
B u t y l p r o p e n o a tM e t h a n o l
e
( B u t y l a c r y la t e ) b p 6 5 °C )
(
( b p 14 7 ° C )
18-42
43. Reaction with Ammonia, etc.
x Acid halides react with ammonia, 1° amines,
and 2° amines to form amides
• 2 moles of the amine are required per mole of
acid chloride
O O
+ -
Cl + 2 NH3 NH2 + NH4 Cl
Hexanoyl Ammonia Hexanamide Ammonium
chloride chloride
18-43
44. Reaction with Ammonia, etc.
x Acid anhydrides react with ammonia, and 1°
and 2° amines to form amides
• 2 moles of ammonia or amine are required
O O O O
CH3 COCCH3 + 2 NH3 CH3 CNH2 + CH3 CO- NH 4 +
Acetic Ammonia Acetamide Ammonium
anhydride acetate
18-44
45. Reaction with Ammonia, etc.
x Esters react with ammonia, and 1° and 2°
amines to form amides
• esters are less reactive than either acid halides
or acid anhydrides
O O
Ph Ph
OEt + NH3 NH2 + Et OH
Ethyl phenylacetate Phenylacetamide Ethanol
x Amides do not react with ammonia, or 1° or
2° amines
18-45
46. Acid Chlorides with Salts
x Acid chlorides react with salts of carboxylic
acids to give anhydrides
• most commonly used are sodium or potassium
salts
O O O O
+ -
CH3 CCl + Na OC CH3 COC + Na + Cl -
Acetyl Sodium benzoate Acetic benzoic
chloride anhydride
18-46
48. Reaction with Grignard Reagents
• treating a formic ester with 2 moles of Grignard
reagent followed by hydrolysis in aqueous acid
gives a 2° alcohol
O magnesium H O, HCl OH
HCOCH3 + 2 RMgX alkoxide 2 HC-R + CH 3 OH
salt R
An ester of A 2¡ alcohol
formic acid
18-48
49. Reaction with Grignard Reagents
• treating an ester other than formic with a
Grignard reagent followed by hydrolysis in
aqueous acid gives a 3° alcohol
O magnesium H O, HCl OH
CH3 COCH3 + 2 RMgX alkoxide 2 CH3 C-R + CH3 OH
salt R
An ester of any acid A 3¡ alcohol
other than formic acid
18-49
50. Reaction with Grignard Reagents
1. addition of 1 mole of RMgX to the carbonyl
carbon gives a TCAI
2. collapse of the TCAI gives a ketone (an
aldehyde from a formic ester)
- +
1 O 2 O [MgX] O
- +
CH3 -C-OCH3 + R MgX CH3 -C OCH3 CH3 -C + CH3 O [ MgX]
R 2 R
1
A magnesium salt A ketone
(a tetrahedral carbonyl
addition intermediate)
18-50
51. Reaction with Grignard Reagents
3. reaction of the ketone with a 2nd mole of RMgX
gives a second TCAI
4. treatment with aqueous acid gives the alcohol
- +
O 3 O [MgX] OH
3
CH3 -C + R MgX CH 3 -C-R H2 O, HCl
CH 3 -C-R
R R (4)
R
A ketone Magnesium salt A 3¡ alcohol
18-51
52. Reactions with RLi
x Organolithium compounds are even more
powerful nucleophiles than Grignard
reagents
• they react with esters to give the same types of
2° and 3° alcohols as do Grignard reagents
• and often in higher yields OH
O
1 . 2 R' Li
RCOCH 3 R- C-R' + CH3 OH
2 . H2 O, HCl
R'
18-52
53. Gilman Reagents
x Acid chlorides at -78° C react with Gilman
reagents to give ketones
• under these conditions, the TCAI is stable, and it
is not until acid hydrolysis that the ketone is
liberated O
O
1 . (CH 3 ) 2 CuLi, ether, -78 °C
Cl 2 . H O
2
P e n t a n o y l c h lo r id e 2 -H e x a n o n e
18-53
54. Gilman Reagents
• Gilman reagents react only with acid chlorides
• they do not react with acid anhydrides, esters,
amides, or nitriles under the conditions described
O
1 . ( CH3 ) 2 CuLi, ether, -78¡ C
H3 CO
Cl 2 . H2 O
O O
H3 CO
O
18-54
55. Reduction - Esters by LiAlH 4
x Most reductions of carbonyl compounds now
use hydride reducing agents
• esters are reduced by LiAlH 4 to two alcohols
• the alcohol derived from the carbonyl group is
primary
O Ph
Ph 1 . LiAlH 4 , e t her OH + CH 3 OH
OCH 3
2 . H 2 O, HCl
2 - P h e n y l - 1- M t h a n o l
e
M e t h y l 2 -p h e n y l- propa nol
p ro p a no a te
18-55
56. Reduction - Esters by LiAlH 4
x Reduction occurs in three steps plus workup
• Steps 1 and 2 reduce the ester to an aldehyde
O O O
(1) (2)
R C OR' + H R C OR' R C + OR'
H H
A tetrahedral carbonyl
addition intermediate
• Step 3 reduction of the aldehyde followed by
work up gives a 1° alcohol
O O OH
(3) (4)
R C + H R C H R C H
H H H
A 1¡ alcohol
18-56
57. Reduction - Esters by NaBH 4
x NaBH 4 does not normally reduce esters, but
it does reduce aldehydes and ketones
x Selective reduction is often possible by the
proper choice of reducing agents and
experimental conditions
O O OH O
NaBH4
OEt EtOH OEt
(racemic)
18-57
58. Reduction - Esters by DIBAlH
x Diisobutylaluminum hydride (DIBAlH) at
-78° C selectively reduces an ester to an
aldehyde
• at -78° C, the TCAI does not collapse and it is not
until hydrolysis in aqueous acid that the carbonyl
group of the aldehyde is liberated
O
1 . DIBALH , toluene, -78¡C
OCH 3
2 . H2 O, HCl
Methyl hexanoate
O
H + CH3 OH
Hexanal
18-58
59. Reduction - Amides by LiAlH 4
x LiAlH 4 reduction of an amide gives a 1° , 2° ,
or 3° amine, depending on the degree of
substitution of the amide
O
1 . LiAlH4
NH2 NH2
2 . H2 O
Octanamide 1-Octanamine
O
NMe2
NMe 2 1 . LiAlH4
2 . H2 O
N,N-Dimethylbenzamide N,N-Dimethylbenzylamine
18-59
60. Reduction - Amides by LiAlH 4
x The mechanism is divided into 4 steps
• Step 1: transfer of a hydride ion to the carbonyl
carbon
• Step 2: a Lewis acid-base reaction and formation
of an oxygen-aluminum bond
O O AlH3
O
(1) (2)
R C NH2 + H AlH3 R C NH2 + AlH3 R C NH2
H H
18-60
61. Reduction - Amides by LiAlH 4
• Step 3: redistribution of electrons and ejection of
H 3 AlO - gives an iminium ion
• Step 4: transfer of a second hydride ion to the
iminium ion completes the reduction to the amine
AlH3 H
O
(3) (4)
R C N H R C N H R-CH2 -NH2
H H H H
An iminium ion A 1¡ amine
18-61
62. Reduction - Nitriles by LiAlH 4
x The cyano group of a nitrile is reduced by
LiAlH 4 to a 1° amine
1 . LiA lH4
CH3 CH= CH( CH 2 ) 4 C N
2 . H2 O
6-Octenenitrile
CH3 CH= CH ( CH2 ) 4 CH2 N H2
6-Octen-1-amine
18-62
63. Interconversions
Problem: show reagents and experimental
conditions to bring about each reaction
O
Ph
Cl
(a) (b) (c)
O O
O
Ph (d) (e) Ph
OH Ph NH2
OMe
Phenylacetic
acid (g) (h)
(f) Ph
Ph NH2
OH
18-63
