18
William H. Brown &
Christopher S. Foote
18-1

18
18-2

18
 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 group
O
RCCl
An acid chloride
O O
RCOCR'
An acid anhydride
O
RCOR'
An ester
O
RC- OH H- Cl
O O
RC- OH H- OCR'
O
RC- OH H- OR'
18-3

18
• an amide is formally related to a carboxyl group by loss of -OH from the carboxyl and -H from ammonia
• loss of -OH and -H from an amide gives a nitrile
O
RCN H
2
An amide
RC N
A nitrile
O
RC- OH H- NH
2
HO H
RC= N
The enol of an amide
18-4

18
 The functional group of an acid halide is an acyl group bonded to a halogen
• to name, change the suffix -ic acid to -yl halide
O O
RC-
An acyl
group
RCCl
An acyl chloride
(An acid chloride)
O
CH
3
CCl
Ethanoyl chloride
(Acetyl chloride)
O
CCl
Benzoyl chloride
O O
ClC(CH
2
)
4
CCl
Hexanedioyl chloride
(Adipoyl chloride)
18-5

18
• replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride
O O
CH
3
SOH
O
Methanesulfonic acid
CH
3
SCl
O
Methanesulfonyl chloride
(Mesyl chloride, MsCl)
O
H
3
C SOH
O
p-Toluenesulfonic
acid
O
H
3
C SCl
O
p-Toluenesulfonyl chloride
(Tosyl chloride, TsCl)
18-6

18
 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
CH
3
COCCH
3
O O
COC
O O
CH
3
COC
Acetic anhydride Benzoic anhydride
Acetic benzoic anhydride
18-7

18
 Cyclic anhydrides are named from the dicarboxylic acids from which they are derived
O
O
O
Succinic anhydride
O
O
O
Maleic anhydride
O
Phthalic anhydride
O
O
18-8

18
 A phosphoric acid anhydride contains two phosphoryl groups bonded to an oxygen atom
O O
HO- P-O- P-OH
-
O O
O- P-O-P- O
-
O
-
O
-
OH OH
Diphosphoric acid
(Pyrophosphoric acid)
Diphosphate ion
(Pyrophosphate ion)
O O O
HO- P-O- P-O-P- OH
O
-
O
-
O
-
Triphosphoric acid
-
O O O
O- P-O-P- O-P- O
-
O
-
O
-
O
-
Triphosphate ion
18-9

18
 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
Ethyl ethanoate
(Ethyl acetate)
O
Isopropyl benzoate
O
O
O
O
Diethyl butanedioate
(Diethyl succinate)
18-10

18
 Cyclic esters are called lactones
• name the parent carboxylic acid, drop the suffix -ic acid , and add -olactone
O
H
3
C


2
3
O
1
O
 3-Butanolactone
 -Butyrolactone)
O

2
1
O

3 4

 4-Butanolactone
 -Butyrolactone)


1
2
3

4
5
O

CH
3
5-Hexanolactone
 -Caprolactone)
18-11

18
 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
CH
3
CN H
2
Acetamide
(a 1° amide)
O
CH
3
CN HCH
3
N-Methylacetamide
(a 2° amide)
O
HCN ( CH
3
)
2
N,N-Dimethylformamide (DMF)
(a 3° amide)
18-12

18
 Cyclic amides are called lactams
 Name the parent carboxylic acid, drop the suffix
-ic acid and add -lactam
H
3
C


O
2 1
3
N H
3-Butanolactam
 -Butyrolactam)



2
O
3 1
4
5 6
 
N H
6-Hexanolactam
 -Caprolactam)
18-13

18

The penicillins are a family of

-lactam antibiotics the penicillins differ in the group bonded to the acyl carbon
CH
2
C
O
Penicillin G
H
N
O
H H
N
S CH
3
CH
3
COOH
18-14

18
 Amoxicillin
HO
O
N H
2
HN
O
H H
N
S
COOH
18-15

18
 The cephalosporins are also

-lactam antibiotics the cephalosporins differ in the group bonded to the acyl carbon and the side chain bonded to the thiazine ring
S
H
2
N
N C
Cefetamet
CH
3
O
N
H
N
O
H H
S
N
CH
3
COOH
18-16

18
H
2
N
S
N
H
N
C
N
O
OCH
3
H H
S
N
CH
3
COOH
18-17

18
 The functional group of a nitrile is a cyano group
 IUPAC: name as an alkanenitrile
 Common: drop the -ic acid and add -onitrile
CH
3
C N
Ethanenitrile
(Acetonitrile)
C N CH
2
C N
Benzonitrile Phenylethanenitrile
(Phenylacetonitrile)
18-18

18
 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
 Sulfonamides and imides are more acidic than amides
O O
O
O
CH
3
CNH
2
SNH
2
NH NH
O
Acetamide pKa 15-17
Benzenesulfonamide pKa 10
O
Succinimide pKa 9.7
O
Phthalimide pKa 8.3
18-19

18
 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 -H + H
2
O N
-
N + H
3
O
+
O
Phthalimide
O
A resonance-stabilized anion
O
18-20

18
• imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts
O O
N H + N aOH N
-
Na
+
+ H
2
O
O pKa 8.3
(stronger acid)
(stronger base)
O
(weaker base) pKa 15.7
(weaker acid)
18-21

18
Cmpd
O O
RCOCR
C=O Stretch
(cm
-1
)
1740-1760 and
1800-1850
O
RCOR 1735-1800
O
RCOH
1700-1725
O
RCN H
2
1630-1680
Additional
Stretchings (cm -1 )
C-O at 900-1300
C-O at 1000-1100 and 1200-1250
O-H at 2400-3400
C-O at 1210-1320
N-H at 3200 and 3400
(1° have two N-H peaks)
(2° have one N-H peak)
18-22

18
 1 H-NMR
• H on the

-carbon to a C=O group are slightly deshielded and come into resonance at

2.1-2.6
• H on the carbon of the ester oxygen are more strongly deshielded and come into resonance at

3.7-4.7
 2.33(q)  3.68(s)
O
CH
3
-CH
2
-C-O-CH
3
Methyl propanoate
 13 C-NMR
• the carbonyl carbons of esters show characteristic resonance at

160-180
18-23

18
 Nucleophilic acyl substitution: an additionelimination sequence resulting in substitution of one nucleophile for another
:
O
-
O O
R
C
Y
+ : N u
-
C
R
N u
Y
Tetrahedral carbonyl addition intermediate
R
C
N u
Substitution
product
+ : Y
-
18-24

18
• in this general reaction, we have shown the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group
R
2
N
-
RO
-
O
RCO
-
X
-
Increasing leaving ability
Increasing basicity
18-25

18
• 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
O
RCN H
2
Amide
O
RCOR'
Ester
O O O
RCOCR' RCX
Anhydride Acid halide
Increasing reactivity toward nucleophilic acyl substitution
18-26

18
2
• 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
CH
3
CCl + H
2
O CH
3
COH + HCl
18-27

18
2
2
• 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
CH
3
COCCH
3
+ H
2
O
O
CH
3
COH + HOCCH
3
18-28

18

2
Esters are hydrolyzed only slowly, even in boiling water
 Hydrolysis becomes more rapid if they are heated with either aqueous acid or base
 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 to form a tetrahedral carbonyl addition intermediate
• collapse of this intermediate gives the carboxylic acid and alcohol
18-29

18

2
Acid-catalyzed ester hydrolysis
O
C
R OCH
3
+ H
2
O
H
+
OH
H
+
C
R
OCH
OH
3
Tetrahedral carbonyl addition intermediate
O
C
R OH
+ CH
3
OH
18-30

18

2
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 said to be base promoted
O
RCOCH
3
+ NaOH
H
2
O
O
RCO
-
Na
+
+ CH
3
OH
• hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer
18-31

18

2
Hydrolysis of an amide in aqueous acid requires
1 mole of acid per mole of amide
O O
H
2
O
N H
2
+
Ph
2-Phenylbutanamide
H
2
O + HCl heat
Ph
OH + N H
4
+
Cl
-
2-Phenylbutanoic acid
18-32

18

2
Hydrolysis of an amide in aqueous base requires
1 mole of base per mole of amide
O
CH
3
CNH + NaOH
H
2
O heat
N-Phenylethanamide
(N-Phenylacetamide,
Acetanilide) O
CH
3
CO
-
Na
+ + H
2
N
Sodium acetate Aniline
18-33

18

2
The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion
CH
2
C N + 2 H
2
O + H
2
SO
4
Phenylacetonitrile
O
CH
2
COH
H
2
O heat
+ N H
4
+
H SO
4
-
Phenylacetic acid Ammonium hydrogen sulfate
18-34

18
2
• protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid
• keto-enol tautomerism of the imidic acid gives the amide
H
+
OH O
R-C N + H
2
O R-C NH
An imidic acid
(enol of an amide)
R-C-NH
2
An amide
18-35

18
2
• hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid
CH
3
( CH
2
)
9
C N
Undecanenitrile
+ H
2
O + N aOH
H
2
O heat
CH
3
( CH
2
)
9
O
CO
-
Na
+
HCl
Sodium undecanoate
H
2
O
O
CH
3
( CH
2
)
9
COH
Undecanoic acid
18-36

18

2
Hydrolysis of nitriles is a valuable route to carboxylic acids
O
HCN , KCN
CH ethanol,
Benzaldehyde
water
HO
CC N
H
2
SO
4
, H
2
O heat
H
Benzaldehyde cyanohydrin
(Mandelonitrile)
HO O
CHCOH
2-Hydroxyphenylacetic acid
(Mandelic acid)
18-37

18
 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
Cl + HO
Butanoyl chloride
Cyclohexanol
O
+ HCl O
Cyclohexyl butanoate
18-38

18
• sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol
O H
3
C pyridine
H
3
C S- Cl
O
+ C OH
H
C
6
H
1 3
p-Toluenesulfonyl chloride
(Tosyl chloride; TsCl)
(R)-2-Octanol
H
3
C
O
C O-S CH
3 H
O
C
6
H
1 3
(R)-2-Octyl p-toluenesulfonate
[(R)-2-Octyl tosylate]
18-39

18
 Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid
O O
CH
3
COCCH
3
Acetic anhydride
+ HOCH
2
CH
Ethanol
3
O
CH
3
COCH
2
CH
Ethyl acetate
3
O
+ CH
3
COH
Acetic acid
18-40

18
• cyclic anhydrides react with alcohols to give one ester group and one carboxyl group
O
O
O
Phthalic anhydride
+
HO
2-Butanol
(sec-Butyl alcohol)
O
O
OH
O
1-Methylpropyl hydrogen phthalate
(sec-Butyl hydrogen phthalate)
18-41

18
• aspirin is synthesized by treatment of salicylic acid with acetic anhydride
COOH
OH O O
+
2-Hydroxybenzoic acid
(Salicylic acid)
CH
3
COCCH
Acetic anhydride
3
COOH
O CH
3
+
O
CH
3
COH
O
Acetic acid
Acetylsalicylic acid
(Aspirin)
18-42

18
 Esters react with alcohols in the presence of an acid catalyst in a reaction called transesterification, an equilibrium reaction
O
HCl
OCH
3
Methyl propenoate
(Methyl acrylate)
(bp 81°C)
+
HO
1-Butanol
(bp 117°C)
O
O
Butyl propenoate
(Butyl acrylate)
(bp 147°C)
+ CH
3
OH
Methanol
(bp 65°C)
18-43

18
 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
Hexanoyl chloride
Cl + 2 N H
3
Ammonia
N H
2
Hexanamide
+
+
Cl
-
N H
4
Ammonium chloride
18-44

18
 Acid anhydrides react with ammonia, and 1 ° and
2 ° amines to form amides.
• 2 moles of ammonia or amine are required
O O
CH
3
COCCH
3
Acetic anhydride
+ 2 N H
3
Ammonia
O
CH
3
CN H
2
Ethanamide
(Acetamide)
+
O
CH
3
CO
-
N H
4
Ammonium acetate
+
18-45

18
 Esters react with ammonia, and 1 ° and 2° amines to form amides
• esters are less reactive than either acid halides or acid anhydrides
O
Ph
O
Ethyl phenylacetate
+ N H
3
O
Ph
N H
2
Phenylacetamide
+ HO
Ethanol
 Amides do not react with ammonia, or 1 ° or 2° amines
18-46

18
QuickTime™ and a
Photo - JPEG decompressor are needed to see this picture.
18-47

18
 Acid chlorides react with salts of carboxylic acids to give anhydrides
• most commonly used are sodium or potassium salts
O
CH
3
CCl + N a
+
O
-
OC
Acetyl chloride
Sodium benzoate
O O
CH
3
COC
Acetic benzoic anhydride
+ N a
+
Cl
-
18-48

18
• treatment of a formic ester with 2 moles of Grignard reagent followed by hydrolysis with aqueous acid gives a 2 ° alcohol
O
HCOCH
3
An ester of formic acid
+ 2 RMgX magnesium
alkoxide
salt
OH
H
2
O, HCl
HC- R + CH
3
OH
R
A secondary alcohol
18-49

18
• treatment of an ester other than formic with a
Grignard reagent followed by hydrolysis in aqueous acid gives a 3 ° alcohol
O
CH
3
COCH
3
An ester other than a formate
+ 2 RMgX magnesium alkoxide salt
H
2
O, HCl
OH
CH
3
C- R + CH
3
OH
R
A tertiary alcohol
18-50

18
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)
O
CH
3
-C- OCH
3
+ R Mg Br
O
–
[ MgBr ]
+
CH
3
-C OCH
3
R
A magnesium salt
(a TCAI)
O
CH
3
-C + CH
3
O
-
[ MgBr]
+
R
A ketone
18-51

18
• 3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI
• 4. treatment with aqueous acid gives the alcohol
O
CH
3
-C
R
A ketone
+ R Mg Br
O
-
[ MgBr]
+
CH
3
-C- R
R
Magnesium salt
OH
H
2
O, HCl
CH
3
-C- R
R
A tertiary alcohol
18-52

18
 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
O
RCOCH
3
1 . 2 R' Li
2 . H
2
O, HCl
OH
R- C-R'
R'
+ CH
3
OH
18-53

18
 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
Pentanoyl chloride
2 . H
2
O
2-Hexanone
18-54

18
• Gilman reagents react only with acid chlorides
• they do not react with acid anhydrides, esters, amides, or nitriles under the conditions described
H
3
CO
O
O
Cl
1 . ( CH
3
)
2
CuLi, ether, -78°C
2 . H
2
O
O
H
3
CO
O
18-55

18

4
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
1 . LiA lH
4
, e t he r OH + CH
3
OH
Ph
OCH
3
2 . H
2
O, HCl
Methyl 2-phenylpropanoate
2-Phenyl-1propanol
Methanol
18-56

18

4
Reduction occurs in three steps plus workup
O
R- C-OR'
An ester
+ :H
-
: O
–
(1)
(2)
R- C-OR'
H
A tetrahedral carbonyl addition intermediate
O
R- C +
H
An aldehyde
-
:OR'
O
R- C + :H
-
H
(3)
: O
-
R- C-H
H
H
2
O
(4)
OH
R- C-H
H
A primary alcohol
18-57

18

4
NaBH
4 does not normally reduce esters, but it does reduce aldehydes and ketones
 Selective reduction is often possible by the proper choice of reducing agents and experimental conditions
OH O O O
N aBH
4
Et OH O O
18-58

18
 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
OCH
3
Methyl hexanoate
1 . DIBALH , toluene, -78°C
2 . H
2
O, HCl
O
H
+ CH
3
OH
Hexanal
18-59

18

LiAlH
4
4 reduction of an amide gives a 1 °, 2°, or 3° amine, depending on the degree of substitution of the amide
O
N H
2
Octanamide
1 . LiA lH
4
2 . H
2
O
1-Octanamine
N H
2
O
N
1 . LiA lH
2 . H
2
O
N,N-Dimethylbenzamide
4
N
N,N-Dimethylbenzylamine
18-60

18

4
The mechanism is divided into 4 steps
• Step 1: transfer of a hydride ion to the carbonyl carbon
• Step 2: formation of an oxygen-aluminum bond
A lH
3
-
O H
C
R N H
2
(1)
: O
-
R C H
A lH
3
(2)
N H
2
O
A lH
3
-
R C H
N H
2
18-61

18
4
• Step 3: redistribution of electrons gives an iminium ion
• Step 4: transfer of a second hydride ion completes the reduction to the amine
R
O
A lH
3
-
(3)
C H
H:
-
R C H
(4)
R
H
C H
N
H
N
H
N
H H
An iminium ion
H H
18-62

18

4
The cyano group of a nitrile is reduced by LiAlH
4 to a 1 ° amine
CH
3
CH= CH( CH
2
)
4
6-Octenenitrile
C N
1 . LiA lH
4
2 . H
2
O
CH
3
CH= CH ( CH
2
)
4
6-Octen-1-amine
CH
2
N H
2
18-63

18
Problem: show reagents and experimental conditions to bring about each reaction
PhCH
2
PhCH
2
O
COH
(c)
CH
2
(a)
OH
(b)
(j)
O
PhCH
2
CCl
(e)
(d)
O
PhCH
2
COCH
3
(k)
(f)
O
PhCH
2
CNH
2
(g)
(h)
O
PhCH
2
CH
(i)
PhCH
2
CH
2
NH
2
18-64

18
 When a 1 ° amide is treated with bromine or chlorine in aqueous NaOH or KOH,
• the carbonyl carbon is lost as carbonate ion, and
• the amide is converted to an amine of one fewer carbon atoms
O
Ph
N H
2
Br
2
, N aOH Ph N H
2
+ N a
2
CO
3
H
2
O
H
3
C H
(S)-2-Phenylpropanamide
H
3
C H
(S)-1-Phenylethanamine
18-65

18
Stage 1: acid-base reaction gives an amide anion, which reacts as a nucleophile with Br
2
O
R C N H
HO
-
R
O
C N :
Br Br
R
O
C N Br + :Br
-
H H
An amide anion
H
An N-bromoamide
Stage 2: a 2nd acid-base reaction followed by elimination of Br gives a nitrene, an electron-deficient species, that rearranges to an isocyanate
O
R- C-N -Br
H
HO
-
- H
2
O
O
R- C-N -Br
- :Br
-
O
R- C-N
An acyl nitrene
R- N= C= O
An isocyanate
18-66

18
• Stage 3: reaction of the isocyanate with water gives a carbamic acid
O
R- N= C= O
+
H
2
O R- N- C-OH
An isocyanate H
A carbamic acid
• Stage 4: decarboxylation of the carbamic acid gives the primary amine
O
R- N- C-OH
H
R- NH
2
+
H
2
O
18-67

18
Propose a structural formula for each compound.
(a) C
5
H
1 0
O
2
1 H-NMR
0.96 (d, 6H)
1.96 (m, 1H)
13 C-NMR
161.11
70.01
3.95 (d, 2H)
8.08 (s, 1H)
27.71
19.00
(b) C
7
H
1 4
O
2
1 H-NMR 13 C-NMR
0.92 (d, 6H)
1.52 (m, 2H)
171.15
63.12
1.70 (m, 1H) 37.31
2.09 (s, 3H)
4.10 (t, 2H)
25.05
22.45
21.06
18-68

18
Propose a structural formula for each compound.
(c) C
6
H
1 2
O
2
(d) C
7
H
1 2
O
4
1 H-NMR
1.18 (d, 6H)
1.26 (t, 3H)
13 C-NMR
2.51 (m, 1H)
177.16
60.17
34.04
4.13 (q, 2H) 19.01
14.25
1 H-NMR 13 C-NMR
1.28 (t, 6H) 166.52
3.36 (s, 2H) 61.43
4.21 (q, 4H) 41.69
14.07
(e) C
4
H
7
ClO
2
1 H-NMR
1.68 (d, 3H)
3.80 (s, 3H)
13 C-NMR
170.51
52.92
4.42 (q, 1H) 52.32
21.52
(f) C
4
H
6
O
2
1 H-NMR 13 C-NMR
2.29 (m, 2H)
2.50 (t, 2H)
177.81
68.58
4.36 (t, 2H) 27.79
22.17
18-69

18
Draw a structural formula for the product formed on treatment of benzoyl chloride with each reagent.
(a) (b)
OH OH, py ridine
(c)
(e)
SH , py r idine
O
O
-
N a
+
(d)
N H
2
(two equivalents)
(f) ( CH
3
)
2
CuLi, then H
3
O
+
(g)
CH
3
O N H
2
, pyridine
(h)
C
6
H
5
MgBr (two equivalents), then H
3
O +
18-70

18
Draw a structural formula for the product of treating this
,
-unsaturated ketone with each reagent.
O O
OEt
(a)
H
2
( 1 mol )
Pd, EtOH
(b)
N aBH
4
CH
3
OH
(c)
1 . LiA lH
4
, THF
2 . H
2
O
(d)
1 . DIBALH , - 7 8 °
2 . H
2
O
18-71

18
Draw a structural formula for the product of treating this anhydride with each reagent.
O H
O
(a) H
2
O, HCl heat
H O
(b)
H
2
O, N aOH heat
(c)
1 . LiA lH
4
2 . H
2
O
(d) CH
3
OH (e)
N H
3
( 2 m ole s)
18-72

18
Show how to bring about each step in this conversion of nicotinic acid to nicotinamide.
O O O
COH
?
COCH
2
CH
3 ?
CNH
2
N
Nicotinic acid
(Niacin)
N
Ethyl nicotinate
N
Nicotinamide
18-73

18
Complete these reactions.
(a)
CH
3
O NH
2
+
O O
CH
3
COCCH
3
O
(b)
CH
3
CCl + 2 HN
O
(c)
CH
3
COCH
3
+ HN
(d)
NH
2
+
O
CH
3
(CH
2
)
5
CH
18-74

18
Draw structural formulas for the products of complete hydrolysis of each compound in hot aqueous acid.
O O O
H
N O
N H
(a)
H
2
N O O N H
2
(b)
O
Meprobamate Phenobarbital
(c)
O
H
N O
N H
O
Pentobarbital
18-75

18
Show reagents to bring about each step in this synthesis of anthranilic acid.
O
(1)
O
CO
-
NH
4
+
(2)
O
O
Phthalic anhydride
CNH
2
O
O
O
COH
(3)
COH
N H
2 CNH
2
O
Anthranilic acid
18-76

18
Propose a mechanism for each step in this sequence.
O O
RCN H
2
A primary amide
+ Br
2
CH
3
O
-
N a
+
CH
3
OH
RN = C= O
An isocyanate
CH
3
OH
RN HCOCH
3
A carbamate
18-77

18
Propose a mechanism for each step in this sequence .
Br O O
Br
2
Br
CH
3
O
-
N a
+
CH
3
OH
O
COCH
3
(R)-(+)-Pulegone
18-78

18
Show how to prepare the insect repellent DEET from 3methyltoluic acid.
O O
OH N
3-Methylbenzoic acid
(m-Toluic acid)
N,N-Diethyl- m-toluamide
DEET)
18-79

18
Show how to prepare isoniazid from 4-pyridinecarboxylic acid.
O
?
N COH N
O
CNH NH
2
4-Pyridinecarboxylic acid
4-Pyridinecarboxylic acid hydrazide
(Isoniazid)
18-80

18
Show how to bring about this conversion.
C CH
Phenylacetylene
O
CH
2
COCH
2
CH = CH
2
Allyl phenylacetate
18-81

18
Propose a mechanism for the formation of this bromolactone, and account for the observed stereochemistry of each substituent on the cyclohexane ring.
Br
COOH
COOH
Br
2
COOH
O
CH
3
A bromolactone
CH
3
O
O many steps
COOH
HO
OH
PGE
1
(alprostadil)
18-82

18
Propose a mechanism for this reaction.
O
H
2
N OEt
+ O
1 . Et O
-
Na
+
2 . H
2
O OEt
O
Diethyl diethylmalonate
H
2
N
Urea
O
5
6
4
1
N H
2
3
N H
O +
O
5,5-Diethylbarbituric acid
(Barbital)
2 Et OH
18-83

18
Propose a synthesis of this

-chloroamine from anthranilic acid.
Cl
N H
2
+ 2
O several
steps N
O COOH
2-Aminobenzoic acid
(Anthranilic acid)
O
18-84

18
Show reagents for the synthesis of 5-nonanone from 1bromobutane as the only organic starting material.
O O
OH
5-Nonanone
C N Br
1-Bromobutane
18-85

18
Describe a synthesis of procaine from the three named starting materials.
H
2
N
O
N
O
O
Procaine
OH
H
2
N
4-Aminobenzoic acid
+
HO
N
O
+ H
N
Ethylene oxide Diethylamine
18-86

18
The following sequence converts (R)-2-octanol to (S)-2octanol. Propose structural formulas for A and B, and specify the configuration of each.
H
3
C
C
H
C
6
H
1 3
OH
(R)-2-Octanol p- Ts Cl pyridine
A
CH
3
COO
-
Na
+
DMSO
B
1 . LiA lH
4
2 . H
2
O
CH
3
HO C
C
6
H
H
1 3
(S)-2-Octanol
18-87

18
Propose a mechanism for this reaction.
O
Et O OEt + H
2
N
Diethyl carbonate Butylamine
O
Et O N
H
+
Ethyl N-butylcarbamate
Et OH
18-88

18
Propose a mechanism for this reaction.
O O
S
N H
-
N a
+
Sodium salt of p-toluenesulfonamide
O
+
Et O N
H
A carbamic ester
O O O
S
N
H
N
H
H
3
C
Tolbutamide
(Oramide, Orinase)
18-89

18
Show how each hypoglycemic drug can be synthesized by converting an appropriate amine to a carbamate ester, and then treating its sodium salt with a substituted benzenesufonamide.
(a)
O O O
S
N
H
N
H
N
Tolazamide
(Tolamide, Tolinase)
(b)
O O O
S
N
H
N
H
N
Gliclazide
(Diamicron)
18-90

18
Propose a mechanism for Step 1, and reagents for Step 2 in the synthesis of the antiviral agent amantadine.
Br
1-Bromoadamantane
CH
3 in H
2
C N
SO
4
( 1)
O
NHCCH
3
( 2)
NH
2
Amantadine
18-91

18
• Propose structural formulas for intermediates A-F and for the configuration of the bromoepoxide.
H OH
COOH
HOOC
(S)-Malic acid
1
A ( C
8
H
1 4
O
5
)
2
B
3
4 5
C ( C
9
H
1 8
O
4
) D E
6
F ( C
4
H
8
OBr
2
)
7
O
Br
A bromoepoxide
2.
1 . CH
3
CH
2
OH, H
+
, H
+
O
3 . LiAlH
4
, then H
2
O
4 . TsCl, pyridine
5 . NaBr, DMSO
6 . H
2
O, CH
3
COOH
7 . KOH
18-92

18
Cl
Show reagents for the synthesis of (S)-Metolachlor from the named starting materials
O
N
O
1
O
Cl
OH
Chloroacetic acid
+
HN
O
2
N
O
(S)-Metolachlor
3
O
Acetone
5
O
Cl
+
CH
3
OH
Methanol
4 O
N H
2
OCH
3
+
2-Ethyl-6-methyl-
aniline
18-93

18
End Chapter 18
18-94