Transcript Document

18
Organic
Chemistry
William H. Brown &
Christopher S. Foote
18-1
18
Carboxyl
Derivatives
18-2
18 Carboxyl Derivatives
 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
RC- OH H- Cl
O O
RCOCR'
An acid
anhydride
O
O
RC- OH H- OCR'
O
RCOR'
An ester
O
RC- OH H- OR'
18-3
18 Carboxyl Derivatives
• 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
O
RC- OH H- NH 2
RC N
A nitrile
HO H
RC= N
The enol of
an amide
18-4
18 Structure: Acid Chlorides
 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-
RCCl
An acyl
group
O
CH3 CCl
Ethanoyl chloride
(Acetyl chloride)
An acyl chloride
(An acid chloride)
O
CCl
Benzoyl
chloride
O
O
ClC(CH2 ) 4 CCl
Hexanedioyl chloride
(Adipoyl chloride)
18-5
18 Acid Chlorides
• replacement of -OH in a sulfonic acid by -Cl gives a
sulfonyl chloride
O
O
CH3 SOH
CH3 SCl
O
Methanesulfonic
acid
O
Methanesulfonyl chloride
(Mesyl chloride, MsCl)
O
H3 C
SOH
O
p-Toluenesulfonic
acid
O
H3 C
SCl
O
p-Toluenesulfonyl chloride
(Tosyl chloride, TsCl)
18-6
18 Acid Anhydrides
 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
CH3 COCCH3
O O
O O
COC
CH3 COC
Acetic anhydride
Benzoic anhydride
Acetic benzoic
anhydride
18-7
18 Acid Anhydrides
 Cyclic
anhydrides are named from the
dicarboxylic acids from which they are derived
O
O
O
Succinic
anhydride
O
O
O
Maleic
anhydride
O
O
O
Phthalic
anhydride
18-8
18 Acid Anhydrides
A
phosphoric acid anhydride contains two
phosphoryl groups bonded to an oxygen atom
O
O
O
-
HO- P-O- P-OH
OH OH
Diphosphoric acid
(Pyrophosphoric acid)
O
O
O- O- OTriphosphoric acid
O- P-O-P- O
O-
-
O-
Diphosphate ion
(Pyrophosphate ion)
O
O
HO- P-O- P-O-P- OH
O
-
O
O
O- P-O-P- O-P- O
-
O- O- OTriphosphate ion
18-9
18 Esters
 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
O
Ethyl ethanoate
(Ethyl acetate)
Isopropyl
benzoate
O
O
O
Diethyl butanedioate
(Diethyl succinate)
18-10
18 Esters
 Cyclic
esters are called lactones
• name the parent carboxylic acid, drop the suffix -ic
acid, and add -olactone

2
3
H3 C
O
O
1
O
3-Butanolactone
-Butyrolactone)

1
2
O
3 4
 
4-Butanolactone
-Butyrolactone)
O


2
3
1
4
O
5
CH3

5-Hexanolactone
-Caprolactone)
18-11
18 Amides
 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 NO
CH3 CN H2
O
CH3 CN HCH3
O
HCN ( CH3 ) 2
Acetamide
(a 1° amide)
N-Methylacetamide
(a 2° amide)
N,N-Dimethylformamide (DMF)
(a 3° amide)
18-12
18 Amides
 Cyclic
amides are called lactams
 Name the parent carboxylic acid, drop the suffix
-ic acid and add -lactam


H3 C
O
2
3
1
NH
3-Butanolactam
-Butyrolactam)



O
2 1
3
4
NH
6
5


6-Hexanolactam
-Caprolactam)
18-13
18 Penicillins
penicillins are a family of -lactam
antibiotics
 The
the penicillins differ
in the group bonded
to the acyl carbon
H
CH2 C
O
Penicillin G
N
O
H H
S CH3
N
CH3
COOH
18-14
18 Penicillins
 Amoxicillin
HO
O
H
H
S
HN
N H2
N
O
COOH
18-15
18 Cephalosporins

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
H
S
H 2N
Cefetamet
N
C
N
CH3 O
H H
N
N
O
S
CH3
COOH
18-16
18 Cefetamet
H
S
H 2N
N
C
N
N
H H
O
OCH 3
N
S
CH 3
COOH
18-17
18 Nitriles
 The
functional group of a nitrile is a cyano group
 IUPAC: name as an alkanenitrile
 Common: drop the -ic acid and add -onitrile
CH3 C N
Ethanenitrile
(Acetonitrile)
C N
Benzonitrile
CH2 C N
Phenylethanenitrile
(Phenylacetonitrile)
18-18
18 Acidity of N-H bonds
 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
CH3 CNH2
O
O
SNH2
NH
O
NH
O
Acetamide
pKa 15-17
Benzenesulfonamide
pKa 10
O
Succinimide
pK a 9.7
O
Phthalimide
pKa 8.3
18-19
18 Acidity of N-H bonds
 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
N -H + H2 O
O
Phthalimide
O
N-
O+
N + H3 O
O
O
A resonance-stabilized anion
18-20
18 Acidity of N-H
• imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts
O
O
N H + N aOH
O
pK a 8.3
(stronger
acid)
-
N Na
+
+
H2 O
O
(stronger
base)
(weaker
base)
pK a 15.7
(weaker
acid)
18-21
18 IR Spectroscopy
C=O Stretch
Cmpd (cm-1 )
O O 1740-1760
and
RCOCR 1800-1850
O
RCOR
1735-1800
O
1700-1725
RCOH
O
RCN H2
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 NMR Spectroscopy
 1H-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)
O
 3.68(s)
CH3 -CH2 -C-O-CH 3
 13C-NMR
Methyl propanoate
• the carbonyl carbons of esters show characteristic
resonance at  160-180
18-23
18 Characteristic Reactions
 Nucleophilic
acyl substitution: an additionelimination sequence resulting in substitution of
one nucleophile for another
O
+ : N u-
C
R
Y
R
: O-
O
C
C
Nu
Y
Tetrahedral carbonyl
addition intermediate
R
+ :Y-
Nu
Substitution
product
18-24
18 Characteristic Reactions
• 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
R2 N -
RO -
O
RCO -
X-
Increasing leaving ability
Increasing basicity
18-25
18 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
O
RCN H2
Amide
O
RCOR'
Ester
RCOCR'
O
RCX
Anhydride
Acid halide
O O
Increasing reactivity toward nucleophilic acyl substitution
18-26
18 Rexn with H O - RCOCl
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
CH3 CCl +
O
H2 O
CH3 COH +
HCl
18-27
18 Rexn with H O - RCO OR
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
CH3 COCCH3 + H2 O
O
O
CH3 COH + HOCCH3
18-28
18 Rexn with H O - Esters
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 Rexn with H O - Esters
2
 Acid-catalyzed
R
O
C
ester hydrolysis
OH
C
+
+
OCH3
H2 O
H
R
H
+
OH
R
O
C
+
OH
CH3 OH
OCH3
Tetrahedral carbonyl
addition intermediate
18-30
18 Rexn with H O - Esters
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
RCOCH3 + NaOH
H2 O
O
-
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
18-31
18 Rexn with H O - Amides
2
 Hydrolysis
of an amide in aqueous acid requires
1 mole of acid per mole of amide
O
O
N H2
+
Ph
2-Phenylbutanamide
H2 O + HCl
H2 O
heat
OH + N H4
+
Cl
-
Ph
2-Phenylbutanoic acid
18-32
18 Rexn with H O - Amides
2
 Hydrolysis
of an amide in aqueous base requires
1 mole of base per mole of amide
O
CH3 CNH
+ NaOH
N-Phenylethanamide
(N-Phenylacetamide,
Acetanilide)
H2 O
heat
O
CH3 CO-Na+
Sodium acetate
+ H2 N
Aniline
18-33
18 Rexn with H O - Nitriles
2
 The
cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion
CH2 C
N + 2 H2 O + H2 SO 4
H2 O
heat
Phenylacetonitrile
O
CH2 COH
Phenylacetic acid
+
+
N H4 H SO 4
-
Ammonium
hydrogen sulfate
18-34
18 Rexn with H O - Nitriles
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
+
R-C N + H2 O
H
OH
R-C
O
NH
An imidic acid
(enol of an amide)
R-C-NH2
An amide
18-35
18 Rexn with H O - Nitriles
2
• hydrolysis of a cyano group in aqueous base gives a
carboxylic anion and ammonia; acidification converts
the carboxylic anion to the carboxylic acid
CH3 ( CH2 ) 9 C N + H2 O + N aOH
Undecanenitrile
H2 O
heat
O
+
CH3 ( CH2 ) 9 CO Na
Sodium undecanoate
HCl
H2 O
O
CH3 ( CH2 ) 9 COH
Undecanoic acid
18-36
18 Rexn with H O - Nitriles
2
 Hydrolysis
of nitriles is a valuable route to
carboxylic acids
O
CH
HCN , KCN
ethanol,
water
Benzaldehyde
HO
CC N
H2 SO 4 , H2 O
H
Benzaldehyde
cyanohydrin
(Mandelonitrile)
heat
HO O
CHCOH
2-Hydroxyphenylacetic acid
(Mandelic acid)
18-37
18 Rexn with Alcohols
 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
O
+
HCl
Cyclohexyl butanoate
18-38
18 Rexn with Alcohols
• sulfonic acid esters are prepared by the reaction of an
alkane- or arenesulfonyl chloride with an alcohol or
phenol
O
H3 C
S- Cl
O
p-Toluenesulfonyl
chloride
(Tosyl chloride; TsCl)
H3 C
+
C OH
pyridine
H
C6 H1 3
(R)-2-Octanol
H3 C
H
O
C O-S
C6 H1 3
CH3
O
(R)-2-Octyl p-t oluenesulfonate
[(R)-2-Octyl tosylate]
18-39
18 Rexn with Alcohols
 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 3
Ethanol
O
O
CH 3 COCH2 CH3 + CH3 COH
Ethyl acetate
Acetic acid
18-40
18 Rexn with Alcohols
• 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 Rexn with Alcohols
• aspirin is synthesized by treatment of salicylic acid
with acetic anhydride
COOH
OH
O O
+ CH COCCH
3
3
2-Hydroxybenzoic
acid
(Salicylic acid)
Acetic
anhydride
COOH
O
CH 3
O
Acetylsalicylic acid
(Aspirin)
+
O
CH 3 COH
Acetic acid
18-42
18 Rexn with Alcohols
 Esters
react with alcohols in the presence of an
acid catalyst in a reaction called
transesterification, an equilibrium reaction
O
+
OCH3
Methyl propenoate
(Methyl acrylate)
(bp 81°C)
HCl
HO
1-Butanol
(bp 117°C)
O
O
Butyl propenoate
(Butyl acrylate)
(bp 147°C)
+
CH3 OH
Methanol
(bp 65°C)
18-43
18 Rexn with Ammonia, etc.
 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
Hexanoyl
chloride
O
Cl + 2 N H3
Ammonia
+
-
NH2 + NH4 Cl
Hexanamide
Ammonium
chloride
18-44
18 Rexn with Ammonia, etc.
 Acid
anhydrides react with ammonia, and 1° and
2° amines to form amides.
• 2 moles of ammonia or amine are required
O O
CH3 COCCH3 + 2 N H3
Ammonia
Acetic
anhydride
O
O
-
CH3 CN H2 + CH3 CO N H4
Ethanamide
Ammonium
(Acetamide)
acetate
+
18-45
18 Rexn with Ammonia, etc.
 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
O
+
Ethyl phenylacetate
 Amides
N H3
Ph
N H2 + HO
Phenylacetamide
Ethanol
do not react with ammonia, or 1° or 2°
amines
18-46
18 Interconversions
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18-47
18 Acid Chlorides with Salts
 Acid
chlorides react with salts of carboxylic
acids to give anhydrides
• most commonly used are sodium or potassium salts
O
O
+
CH3 CCl + N a - OC
Acetyl
chloride
Sodium benzoate
O O
CH3 COC
+
N a+ Cl
-
Acetic benzoic
anhydride
18-48
18 Rexns with Grignards
• treatment of a formic ester with 2 moles of Grignard
reagent followed by hydrolysis with aqueous acid
gives a 2° alcohol
O
HCOCH3 + 2 RMgX
An ester of
formic acid
OH
magnesium H O, HCl
2
alkoxide
HC- R + CH3 OH
salt
R
A secondary
alcohol
18-49
18 Rexn with Grignards
• treatment of an ester other than formic with a
Grignard reagent followed by hydrolysis in aqueous
acid gives a 3° alcohol
O
CH3 COCH3 + 2 RMgX
An ester other
than a formate
magnesium H2 O, HCl
alkoxide salt
OH
CH3 C- R + CH3 OH
R
A tertiary
alcohol
18-50
18 Rexns with Grignards
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
CH3 -C- OCH 3 + R Mg Br
O – [ MgBr ] +
CH3 -C OCH3
R
A magnesium salt
(a TCAI)
O
CH3 -C + CH3 O - [ MgBr] +
R
A ketone
18-51
18 Reaction with Grignards
• 3. reaction of the ketone with a 2nd mole of RMgX
gives a second TCAI
• 4. treatment with aqueous acid gives the alcohol
O
CH3 -C
R
A ketone
+ R Mg Br
O - [ MgBr] +
CH3 -C- R
R
Magnesium salt
H2 O, HCl
OH
CH3 -C- R
R
A tertiary alcohol
18-52
18 Rexns with RLi
 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
RCOCH3
1 . 2 R' Li
2 . H2 O, HCl
OH
R- C-R' + CH3 OH
R'
18-53
18 Gilman Reagents
 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
1 . ( CH3 ) 2 CuLi, ether, -78°C
Cl 2 . H O
2
Pentanoyl chloride
O
2-Hexanone
18-54
18 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
H 3 CO
O
1 . ( CH3 ) 2 CuLi, ether, -78°C
Cl 2 . H O
2
O
H 3 CO
O
18-55
18 Redn - Esters by LiAlH
4
 Most
reductions of carbonyl compounds now
use hydride reducing agents
• esters are reduced by LiAlH4 to two alcohols
• the alcohol derived from the carbonyl group is
primary
O
Ph
OCH3
Methyl 2-phenylpropanoate
1 . LiA lH4 , e t he r
2 . H2 O, HCl
Ph
OH + CH3 OH
2-Phenyl-1propanol
Methanol
18-56
18 Redn - Esters by LiAlH
4
 Reduction
occurs in three steps plus workup
: O–
O
R- C-OR'
+
:H-
(1)
(2)
R- C-OR'
O
R- C +
H
An ester
H
:OR'
H
A tetrahedral carbonyl
An
addition intermediate aldehyde
: O-
O
R- C + :H -
-
(3)
R- C-H
H
H 2O
(4)
OH
R- C-H
H
A primary
alcohol
18-57
18 Redn - Esters by LiAlH
4
 NaBH4
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
O
O
N aBH4
O
Et OH
OH O
O
18-58
18 Redn - Esters by DIBAlH
 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
OCH3
2 . H2 O, HCl
Methyl hexanoate
O
H + CH 3 OH
Hexanal
18-59
18 Redn - Amides by LiAlH
4
 LiAlH4
reduction of an amide gives a 1°, 2°, or 3°
amine, depending on the degree of substitution
of the amide
O
N H2
Octanamide
1 . LiA lH4
2 . H2 O
N H2
1-Octanamine
O
N
1 . LiA lH4
2 . H2 O
N,N-Dimethylbenzamide
N
N,N-Dimethylbenzylamine
18-60
18 Redn - Amides by LiAlH
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 lH3 O H
C
N H2
R
(1)
A lH3
:O R C H
N H2
(2)
A lH3 O
R C H
N H2
18-61
18 Redn - Amides by LiAlH
4
• Step 3: redistribution of electrons gives an iminium
ion
• Step 4: transfer of a second hydride ion completes the
reduction to the amine
A lH3 O
R C H
(3)
R C H
(4)
N
H
H
H
An iminium ion
H
R C H
N
:
H
:
N
H: -
H
H
18-62
18 Redn - Nitriles by LiAlH
4
 The
cyano group of a nitrile is reduced by LiAlH4
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
18-63
18 Interconversions
Problem: show reagents and experimental conditions to
bring about each reaction
O
PhCH2 CCl
O
PhCH2 COH
(a)
(d)
(b)
(c)
(f)
O
PhCH2 COCH3
(j)
PhCH2 CH2 OH
(e)
(h)
(k)
(i)
O
PhCH2 CNH2
(g)
PhCH2 CH2 NH2
O
PhCH2 CH
18-64
18 Hofmann Rearrangement
 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 H2
H3 C H
(S)-2-Phenylpropanamide
Br2 , N aOH
H2 O
Ph
N H2
+ N a2 CO 3
H3 C H
(S)-1-Phenylethanamine
18-65
18 Hofmann Rearrangement
Stage 1: acid-base reaction gives an amide anion, which
reacts as a nucleophile with Br2
H
O
R C N:
Br
Br
O
:
N H
-
:
HO
:
O
R C
R
C N
Br + :Br -
H
H
An amide anion
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
- :Br
-
An acyl
nitrene
:
O
R- C-N
:
:
- H2 O
O
R- C-N -Br
:
HO
-
:
:
O
R- C-N -Br
H
R- N= C= O
An isocyanate
18-66
18 Hofmann Rearrangement
• Stage 3: reaction of the isocyanate with water gives a
carbamic acid
R- N= C= O + H2 O
An isocyanate
O
R- N- C-OH
H
A carbamic acid
• Stage 4: decarboxylation of the carbamic acid gives
the primary amine
O
R- N- C-OH
H
R- NH 2
+ H2 O
18-67
18 Prob 18.19
Propose a structural formula for each compound.
(a) C5 H1 0 O 2
(b) C7 H1 4 O 2
1
1
13
H-NMR
C-NMR
0.96 (d, 6H)
161.11
1.96 (m, 1H)
70.01
3.95 (d, 2H)
27.71
8.08 (s, 1H)
19.00
H-NMR 13 C-NMR
0.92 (d, 6H) 171.15
1.52 (m, 2H)
63.12
1.70 (m, 1H)
37.31
2.09 (s, 3H)
25.05
4.10 (t, 2H)
22.45
21.06
18-68
18 Prob 18.19 (cont’d)
Propose a structural formula for each compound.
(c) C6 H 1 2 O 2
(d) C 7 H 1 2 O 4
1
H-NMR 13 C-NMR
1.18 (d, 6H)
177.16
1.26 (t, 3H)
60.17
2.51 (m, 1H)
34.04
4.13 (q, 2H)
19.01
14.25
(e) C 4 H 7 ClO 2
1
H-NMR 13 C-NMR
1.68 (d, 3H) 170.51
3.80 (s, 3H)
52.92
4.42 (q, 1H)
52.32
21.52
1
13
H-NMR
C-NMR
1.28 (t, 6H)
166.52
3.36 (s, 2H)
61.43
4.21 (q, 4H)
41.69
14.07
(f) C4 H 6 O2
1
H-NMR 13 C-NMR
2.29 (m, 2H) 177.81
2.50 (t, 2H)
68.58
4.36 (t, 2H)
27.79
22.17
18-69
18 Prob 18.20
Draw a structural formula for the product formed on
treatment of benzoyl chloride with each reagent.
(a)
(b)
OH, py ridine
SH , py r idine
(d)
N H 2 (two equivalents)
-
(f) ( CH3 ) 2 CuLi, then H 3 O+
OH
(c)
O
(e)
(g) CH3 O
O Na
+
N H 2 , pyridine
(h) C 6 H5 MgBr (two equivalents), then H 3 O+
18-70
18 Prob 18.26
Draw a structural formula for the product of treating this
,-unsaturated ketone with each reagent.
O
O
OEt
(a)
(c)
H2 ( 1 mol)
Pd, EtOH
1 . LiA lH4 , THF
2 . H2 O
(b)
(d)
N aBH4
CH3 OH
1 . DIBALH , - 7 8 °
2 . H2 O
18-71
18 Prob 18.28
Draw a structural formula for the product of treating this
anhydride with each reagent.
H
O
O
H
(a)
(d)
H2 O, HCl
heat
CH3 OH
(b)
(e)
O
H2 O, N aOH
heat
(c)
1 . LiA lH4
2 . H2 O
N H3 ( 2 m ole s)
18-72
18 Prob 18.31
Show how to bring about each step in this conversion of
nicotinic acid to nicotinamide.
O
O
COH
COCH 2 CH 3
N
Nicotinic acid
(Niacin)
?
N
Ethyl nicotinate
O
?
CNH 2
N
Nicotinamide
18-73
18 Prob 18.32
Complete these reactions.
(a) CH3 O
O O
NH2 + CH3 COCCH3
O
(b) CH3 CCl + 2HN
O
(c) CH3 COCH3 + HN
(d)
O
NH2 + CH3 (CH2 ) 5 CH
18-74
18 Prob 18.35
Draw structural formulas for the products of complete
hydrolysis of each compound in hot aqueous acid.
O
(a) H 2 N
O
O
O
O
N H2
H
N
O
NH
(b)
O
Meprobamate
O
H
N
Phenobarbital
O
NH
(c)
O
Pentobarbital
18-75
18 Prob 18.36
Show reagents to bring about each step in this synthesis
of anthranilic acid.
O
O
(1)
O
Phthalic anhydride
O
+
CO NH 4
(2)
CNH 2
O
O
COH
CNH 2
O
O
COH
(3)
N H2
Anthranilic acid
18-76
18 Prob 18.37
Propose a mechanism for each step in this sequence.
O
+
CH3 O N a
RCN H2 + Br2
RN = C= O
CH3 OH
A primary
An isocyanate
amide
CH3 OH
O
RN HCOCH 3
A carbamate
18-77
18 Prob 18.38
Propose a mechanism for each step in this sequence.
Br O
O
O
CH3 O - N a+
Br2
Br
COCH 3
CH3 OH
(R)-(+)-Pulegone
18-78
18 Prob 18.39
Show how to prepare the insect repellent DEET from 3methyltoluic acid.
O
O
OH
3-Methylbenzoic acid
(m-Toluic acid)
N
N,N-Diethyl- m-toluamide
DEET)
18-79
18 Prob 18.40
Show how to prepare isoniazid from 4-pyridinecarboxylic
acid.
O
O
?
N
COH
4-Pyridinecarboxylic acid
N
CNH NH2
4-Pyridinecarboxylic acid hydrazide
(Isoniazid)
18-80
18 Prob 18.41
Show how to bring about this conversion.
C CH
Phenylacetylene
O
CH2 COCH 2 CH = CH 2
Allyl phenylacetate
18-81
18 Prob 18.42
Propose a mechanism for the formation of this
bromolactone, and account for the observed
stereochemistry of each substituent on the cyclohexane
Br
ring.
COOH
COOH
Br2
COOH
CH3
O
CH 3
A bromolactone
O
many
steps
O
HO
COOH
OH
PGE 1 (alprostadil)
18-82
18 Prob 18.43
Propose a mechanism for this reaction.
O
H2 N
OEt
O
+
OEt
O
Diethyl
diethylmalonate
-
H2 N
Urea
1 . Et O Na
+
2 . H2 O
O
6
5
NH
1
4 3
2
O + 2 Et OH
NH
O
5,5-Diethylbarbituric acid
(Barbital)
18-83
18 Prob 18.44
Propose a synthesis of this -chloroamine from
anthranilic acid.
Cl
N H2
+ 2
COOH
2-Aminobenzoic acid
(Anthranilic acid)
O
several
steps
N
O
O
18-84
18 Prob 18.45
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 Prob 18.46
Describe a synthesis of procaine from the three named
starting materials.
O
O
H 2N
Procaine
N
O
OH
H 2N
4-Aminobenzoic acid
N
+ HO
O
+
Ethylene oxide
N
H
Diethylamine
18-86
18 Prob 18.47
The following sequence converts (R)-2-octanol to (S)-2octanol. Propose structural formulas for A and B, and
specify the configuration of each.
H3 C
C OH
H
C6 H1 3
p- Ts Cl
pyridine
-
A
CH3 COO Na
+
DMSO
(R)-2-Octanol
B
1 . LiA lH4
2 . H2 O
CH3
HO C
H
C6 H1 3
(S)-2-Octanol
18-87
18 Prob 18.48
Propose a mechanism for this reaction.
O
Et O
OEt + H 2 N
Diethyl carbonate
Butylamine
O
Et O
N
+ Et OH
H
Ethyl N-butylcarbamate
18-88
18 Prob 18.49
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
N
H
H
H3 C
Tolbutamide
(Oramide, Orinase)
18-89
18 Prob 18.50
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
N
S
N
N
H
H
Tolazamide
(Tolamide, Tolinase)
(b)
O O O
N
S
N
N
H
H
Gliclazide
(Diamicron)
18-90
18 Prob 18.51
Propose a mechanism for Step 1, and reagents for Step 2
in the synthesis of the antiviral agent amantadine.
Br
CH3 C N
in H2 SO4
( 1)
1-Bromoadamantane
O
NHCCH3
( 2)
NH2
Amantadine
18-91
18 Prob 18.52
• Propose structural formulas for intermediates A-F and
for the configuration of the bromoepoxide.
H OH
1
COOH
HOOC
(S)-Malic acid
C (C9 H1 8 O4 )
4
A ( C8 H1 4 O5 )
D
5
E
2
B
3
6
F (C4 H8 OBr 2 )
7
O
Br
A bromoepoxide
1 . CH3 CH2 OH, H+
+
2.
,H
O
3 . LiAlH4 , then H2 O
4 . TsCl, pyridine
6 . H2 O, CH3 COOH
7 . KOH
5 . NaBr, DMSO
18-92
18 Prob 18.53
Show reagents for the synthesis of (S)-Metolachlor from
the named starting materials
O
Cl
N
O
O
1
Cl
O
HN
2
OH +
O
N
Chloroacetic acid
(S)-Metolachlor
O
Acetone
3
5
O
Cl +
CH3 OH
Methanol
4
N H2
O
OCH3 +
2-Ethyl-6-methylaniline
18-93
18
Derivatives of
Carboxylic
Acids
End Chapter 18
18-94