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1818
18-1
OrganicOrganic
ChemistryChemistryWilliam H. Brown &William H. Brown &
Christopher S. FooteChristopher S. Foote
1818
18-2
CarboxylCarboxyl
DerivativesDerivatives
1818
18-3
Carboxyl DerivativesCarboxyl 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
An acidchloride An ester
An acidanhydride
OO
RCCl RCOR'RCOCR'
O
RC-OH H-Cl
O
RC-OH H-OCR'
O
RC-OH H-OR'
O
O O
1818
18-4
Carboxyl DerivativesCarboxyl 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
An amide A nitrile
O
RC NRCNH2
O
RC-OH H-NH2 RC=N
HO H
The enol ofan amide
1818
18-5
Structure: Acid ChloridesStructure: Acid Chlorides The functional group of an acid halide is an acyl
group bonded to a halogen• to name, change the suffix -ic acid-ic acid to -yl halide-yl halide
RC-
O
RCCl
O
CH3CCl
O
CCl
O
ClC(CH2)4CCl
OO
Benzoyl chloride
Ethanoyl chloride(Acetyl chloride)
An acyl chloride(An acid chloride)
An acyl group
Hexanedioyl chloride (Adipoyl chloride)
1818
18-6
Acid ChloridesAcid Chlorides• replacement of -OH in a sulfonic acid by -Cl gives a
sulfonyl chloride
SOHH3C
O
O
CH3SOH
O
O
SClH3C
O
O
CH3SCl
O
O
Methanesulfonicacid
p-Toluenesulfonic acid
Methanesulfonyl chloride(Mesyl chloride, MsCl)
p-Toluenesulfonyl chloride (Tosyl chloride, TsCl)
1818
18-7
Acid AnhydridesAcid 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 acidacid of the parent acid by anhydrideanhydride
Acetic benzoic anhydride
Benzoic anhydrideAcetic anhydride
COCCH3COCCH3CH3COC
OOOO OO
1818
18-8
Acid AnhydridesAcid Anhydrides Cyclic anhydrides are named from the
dicarboxylic acids from which they are derived
Maleic anhydride
O
O
O
Phthalic anhydride
Succinicanhydride
O
O
O
O
O
O
1818
18-9
Acid AnhydridesAcid Anhydrides A phosphoric acid anhydride contains two
phosphoryl groups bonded to an oxygen atom
Triphosphoric acid
Diphosphate ion(Pyrophosphate ion)
Diphosphoric acid(Pyrophosphoric acid)
HO-P-O-P-OH-O-P-O-P-O
-
HO-P-O-P-O-P-OH-O-P-O-P-O-P-O
-
Triphosphate ion
OH
O
OH
O
O-
O
O-
O
O-
O
O-
O
O-
O
O-
O
O- O-
OO
1818
18-10
Esters 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-ic acid to -ate-ate
Ethyl ethanoate(Ethyl acetate)
Diethyl butanedioate(Diethyl succinate)
O
OO
OO
O
O
O
Isopropyl benzoate
1818
18-11
Esters Esters Cyclic esters are called lactones
• name the parent carboxylic acid, drop the suffix -ic -ic acidacid, and add -olactone-olactone
5-Hexanolactone(δ-Caprolactone)
4-Butanolactone(γ-Butyrolactone)
3-Butanolactone(β-Butyrolactone)
δβ
α
γβ
αβ
α
γO O
OO O
O
H3C CH3
23 1
22 1
3
1
3 4 45
1818
18-12
AmidesAmides The functional group of an amide is an acyl
group bonded to a nitrogen atom• IUPAC: drop -oic acidoic acid from the name of the parent
acid and add -amide-amide• if the amide nitrogen is bonded to an alkyl or aryl
group, name the group and show its location on nitrogen by N-N-
N-Methylacetamide(a 2° amide)
Acetamide(a 1° amide)
CH3CNH2 CH3CNHCH3 HCN(CH3)2
N,N-Dimethyl-formamide (DMF)
(a 3° amide)
O O O
1818
18-13
AmidesAmides Cyclic amides are called lactams Name the parent carboxylic acid, drop the suffix
-ic acid-ic acid and add -lactam-lactamα
β
γ
δ ε6-Hexanolactam(ε-Caprolactam)
α
βH3C
O
NH
O
NH1
2 1
234
5 63
3-Butanolactam(β-Butyrolactam)
1818
18-14
PenicillinsPenicillins The penicillins are a family of β-lactam
antibiotics
N
S CH3
CH3
COOHO
NC
H
O
CH2
Penicillin G
H H
the penicillins differin the group bondedto the acyl carbon
1818
18-15
PenicillinsPenicillins Amoxicillin
N
S
COOHO
HN
O
NH2
HH
HO
1818
18-16
CephalosporinsCephalosporins The cephalosporins are also β-lactam
antibiotics
NO
NC
H
N
S
COOHCH3
S
NH2N
Cefetamet
H
CH3O
H
the cephalosporins differin the group bonded to theacyl carbon and the side chainbonded to the thiazine ring
1818
18-17
CefetametCefetamet
NO
NC
H
N
S
COOHCH3
S
NH2N
H
OCH3
H
1818
18-18
NitrilesNitriles The functional group of a nitrile is a cyano group IUPAC: name as an alkanenitrilealkanenitrile Common: drop the -ic acid-ic acid and add -onitrile-onitrile
CH3C N C N CH2C N
Ethanenitrile(Acetonitrile)
Benzonitrile Phenylethanenitrile(Phenylacetonitrile)
1818
18-19
Acidity of N-H bondsAcidity 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
CH3CNH2
ONH
O
O
NH
O
OO
SNH2
O
pKa 8.3pKa 9.7pKa 10PhthalimideSuccinimideBenzenesulfonamideAcetamide
pKa 15-17
1818
18-20
Acidity of N-H bondsAcidity 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
Phthalimide A resonance-stabilized anion
+N-H
O
O O
O
N- N
O-
O
H3O++ H2O
1818
18-21
Acidity of N-HAcidity of N-H• imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts
(stronger acid)
(weakeracid)
(weakerbase)
(strongerbase)
pKa 15.7pKa 8.3
++
O
O
NH N- Na
+
O
O
NaOH H2 O
1818
18-22
IR SpectroscopyIR SpectroscopyAdditional Stretchings (cm-1)
O-H at 2400-3400C-O at 1210-1320
(2° have one N-H peak)(1° have two N-H peaks)N-H at 3200 and 3400
C-O at 900-1300
C-O at 1000-1100and 1200-1250
(cm-1)C=O Stretch
1740-1760 and
1800-1850
1630-1680
1735-1800
1700-1725
O
O
O
O
RCOH
RCOCR
RCOR
RCNH2
Cmpd
O
1818
18-23
NMR SpectroscopyNMR Spectroscopy 1H-NMR
• H on the α-carbon to a C=O group are slightly deshielded and come into resonance at δ 2.1-2.6
• H on the carbon of the ester oxygen are more strongly deshielded and come into resonance at δ 3.7-4.7
13C-NMR • the carbonyl carbons of esters show characteristic
resonance at δ 160-180
Methyl propanoate
δ 3.68(s)δ 2.33(q)O
CH3-CH2-C-O-CH3
1818
18-24
Characteristic ReactionsCharacteristic Reactions Nucleophilic acyl substitution:Nucleophilic acyl substitution: an addition-
elimination sequence resulting in substitution of one nucleophile for another
Tetrahedral carbonyladdition intermediate
-- ++ CNuR
CY R
Y
O O-
Nu Y
Substitution product
:
:
:R
CNu
O
1818
18-25
Characteristic ReactionsCharacteristic 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
Increasing basicity
Increasing leaving ability
X-RO-R2N- RCO-O
1818
18-26
Characteristic ReactionsCharacteristic 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
ORCXRCOCR'RCOR'RCNH2
Increasing reactivity toward nucleophilic acyl substitution
Amide Ester Anhydride Acid halide
OO OO
1818
18-27
Rexn with HRexn with H22O - RCOClO - RCOCl• 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
CH3CCl H2O CH3COH HCl
1818
18-28
Rexn with HRexn with H22O - RCOO - RCO22OROR• 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
CH3COCCH3
O OH2O CH3COH
O O
HOCCH3++
1818
18-29
Rexn with HRexn with H22O - EstersO - Esters 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
1818
18-30
Rexn with HRexn with H22O - EstersO - Esters Acid-catalyzed ester hydrolysis
R OCH3
CO
H2OH+
OHC
ROCH3
OHH+
R OHCO
CH3OH+ +
Tetrahedral carbonyladdition intermediate
1818
18-31
Rexn with HRexn with H22O - EstersO - Esters 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
• hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer
O
RCOCH3 NaOHH2O
O
RCO- Na
+ CH3OH++
1818
18-32
Rexn with HRexn with H22O - AmidesO - Amides Hydrolysis of an amide in aqueous acid requires
1 mole of acid per mole of amide
2-Phenylbutanoic acid2-Phenylbutanamide
++ +heat
H2 O HClH2 O
NH4+ Cl
-
PhNH2
O
PhOH
O
1818
18-33
Rexn with HRexn with H22O - AmidesO - Amides Hydrolysis of an amide in aqueous base requires
1 mole of base per mole of amide
CH3CNH
O
NaOH H2O
CH3CO-Na+O
H2N
AnilineSodium acetate
N-Phenylethanamide(N-Phenylacetamide, Acetanilide)
+
+heat
1818
18-34
Rexn with HRexn with H22O - NitrilesO - Nitriles The cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion
Ammoniumhydrogen sulfate
Phenylacetic acid
Phenylacetonitrile
+
heat++CH2C
CH2COH
N 2H2 O H2 SO4H2 O
NH4+HSO4
-O
1818
18-35
Rexn with HRexn with H22O - NitrilesO - Nitriles• 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 H2OH
+
R-C
OH
NH
O
R-C-NH2
An imidic acid(enol of an amide)
+
An amide
1818
18-36
Rexn with HRexn with H22O - NitrilesO - Nitriles• hydrolysis of a cyano group in aqueous base gives a
carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid
Undecanenitrileheat
++CH3(CH2)9 C H2 O NaOHH2 O
Undecanoic acidSodium undecanoate
CH3(CH2)9 CO-Na
+ HCl
H2 OCH3(CH2)9 COH
OO
N
1818
18-37
Rexn with HRexn with H22O - NitrilesO - Nitriles Hydrolysis of nitriles is a valuable route to
carboxylic acids
heat
Benzaldehyde
Benzaldehyde cyanohydrin
(Mandelonitrile)
2-Hydroxyphenyl-acetic acid
(Mandelic acid)
CH
HO
CC
H
N CHCOHH2 SO4, H2O
ethanol, water
HCN, KCN
HO
O
O
1818
18-38
Rexn with AlcoholsRexn 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
Butanoyl chloride
Cyclohexyl butanoate
+
Cyclohexanol
HO
HCl
Cl
O
+
O
O
1818
18-39
Rexn with AlcoholsRexn with Alcohols• sulfonic acid esters are prepared by the reaction of an
alkane- or arenesulfonyl chloride with an alcohol or phenol
S-ClH3C
O
O
C OH
C6H13
H
H3C
O
O
CH3O-SC
C6H13
H
H3C
+
(R)-2-Octanolp-Toluenesulfonylchloride
(Tosyl chloride; TsCl)
pyridine
(R)-2-Octyl p-toluenesulfonate[(R)-2-Octyl tosylate]
1818
18-40
Rexn with AlcoholsRexn with Alcohols Acid anhydrides react with alcohols to give one
mole of ester and one mole of carboxylic acid
Acetic acidEthyl acetate
EthanolAcetic anhydride
+
+
O
OO
CH3COCCH3 HOCH2CH3
CH3COCH2CH3 CH3COH
O
1818
18-41
Rexn with AlcoholsRexn with Alcohols• cyclic anhydrides react with alcohols to give one ester
group and one carboxyl group
1-Methylpropyl hydrogen phthalate(sec-Butyl hydrogen phthalate)
2-Butanol(sec-Butyl alcohol)
+
Phthalicanhydride
O
O
O
O
O
O
OH
HO
1818
18-42
Rexn with AlcoholsRexn with Alcohols• aspirin is synthesized by treatment of salicylic acid
with acetic anhydride
Acetylsalicylic acid (Aspirin)
2-Hydroxybenzoic acid
(Salicylic acid)
+
+
Acetic acid
Acetic anhydride
CH3COH
CH3COCCH3
OOCOOH
CH3
O
OHCOOH
O O
1818
18-43
Rexn with AlcoholsRexn with Alcohols Esters react with alcohols in the presence of an
acid catalyst in a reaction called transesterification, an equilibrium reaction
Butyl propenoate(Butyl acrylate)
(bp 147°C)
1-Butanol(bp 117°C)
Methyl propenoate(Methyl acrylate)
(bp 81°C)
+
+ HCl
CH3OHMethanol(bp 65°C)
OCH3
O
HO
O
O
1818
18-44
Rexn with Ammonia, etc.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
+ +
Hexanoylchloride
Ammonia Hexanamide Ammoniumchloride
2NH3 NH4+Cl-Cl
O
NH2
O
1818
18-45
Rexn with Ammonia, etc.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
Ammonia+
Ammoniumacetate
Ethanamide(Acetamide)
+
Aceticanhydride
O O OCH3COCCH3 2NH3 CH3CNH2 CH3CO
-NH4
+O
1818
18-46
Rexn with Ammonia, etc.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
Amides do not react with ammonia, or 1° or 2° amines
PhenylacetamideEthyl phenylacetate
+ +NH3Ph
O
O
PhNH2
O
HO
Ethanol
1818
18-47
InterconversionsInterconversions
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
1818
18-48
Acid Chlorides with SaltsAcid Chlorides with Salts Acid chlorides react with salts of carboxylic
acids to give anhydrides • most commonly used are sodium or potassium salts
+
Acetyl chloride
Sodium benzoate Acetic benzoicanhydride
+CH3 CCl -OC CH3 COC Na+Cl -Na+O O O O
1818
18-49
Rexns with GrignardsRexns with Grignards• treatment of a formic ester with 2 moles of Grignard
reagent followed by hydrolysis with aqueous acid gives a 2° alcohol
+
magnesium alkoxide salt
A secondaryalcohol
An ester offormic acid
OH
R
HCOCH3 2RMgX
H2 O, HClHC-R + CH3OH
O
1818
18-50
Rexn with GrignardsRexn with Grignards• treatment of an ester other than formic with a
Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol
magnesium alkoxide salt
+
A tertiaryalcohol
An ester other than a formate
O
R
OH
CH3COCH3 2RMgX
H2 O, HClCH3C-R + CH3OH
1818
18-51
Rexns with GrignardsRexns with Grignards1. 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)
CH3-C-OCH3 R MgBr
O– [MgBr]+
CH3-C OCH3
R
O
R
CH3-C CH3O- [MgBr]+
+
+
A magnesium salt(a TCAI)
A ketone
O
1818
18-52
Reaction with GrignardsReaction 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
R
O
CH3-C R MgBr
R
O- [MgBr]+
CH3-C-RH2O, HCl
OH
R
CH3-C-R
Magnesium salt
A ketone
+
A tertiary alcohol
1818
18-53
Rexns with RLiRexns 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
RCOCH3
1. 2R'Li
2. H2O, HClR-C-R'
O
R'
OH
+ CH3OH
1818
18-54
Gilman ReagentsGilman 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
1. (CH3)2CuLi, ether, -78°C
2. H2OPentanoyl chloride 2-Hexanone
Cl
O O
1818
18-55
Gilman ReagentsGilman Reagents• Gilman reagents react only with acid chlorides• they do not react with acid anhydrides, esters,
amides, or nitriles under the conditions described
1. (CH3)2CuLi, ether, -78°C
2. H2OO
H3COCl
O
O
H3COO
1818
18-56
Redn - Esters by LiAlHRedn - Esters by LiAlH44 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
Methanol2-Phenyl-1-propanolMethyl 2-phenyl-
propanoate
+1. LiAlH4 , ether
2. H2O, HCl
CH3OHPhOCH3
O PhOH
1818
18-57
Redn - Esters by LiAlHRedn - Esters by LiAlH44 Reduction occurs in three steps plus workup
:H- R-C-H
H
(3):
H2OR- C-H
H
OH
A primary alcohol
R-C
H
O +
(4)
O-
O
R-C-OR' :H- R-C-OR'
H
O–
R-C
H
O -:OR'+
An ester A tetrahedral carbonyladdition intermediate
+(1) (2)
An aldehyde
:
1818
18-58
Redn - Esters by LiAlHRedn - Esters by LiAlH44 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
NaBH4
EtOHO
O O
O
OH O
1818
18-59
Redn - Esters by DIBAlHRedn - 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
Hexanal
Methyl hexanoate
+
1. DIBALH, toluene, -78°C
2. H2O, HCl
CH3OH
OCH3
O
H
O
1818
18-60
Redn - Amides by LiAlHRedn - Amides by LiAlH44 LiAlH4 reduction of an amide gives a 1°, 2°, or 3°
amine, depending on the degree of substitution of the amide
Octanamide 1-Octanamine
1. LiAlH42. H2ONH2
O
NH2
N,N-Dimethylbenzamide N,N-Dimethylbenzylamine
1. LiAlH4
2. H2ON
O
N
1818
18-61
Redn - Amides by LiAlHRedn - Amides by LiAlH44 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
CR NH2
O
CR
NH2
O
H
AlH3-
CR
NH2
O-
AlH3
H
HAlH3
-
:(1) (2)
1818
18-62
Redn - Amides by LiAlHRedn - Amides by LiAlH44• Step 3: redistribution of electrons gives an iminium
ion• Step 4: transfer of a second hydride ion completes the
reduction to the amine
:
CR
N
O
H
AlH3-
H H
CR
N
H
H H
H:-
CR
N
HH
H H
An iminium ion
(3) (4)
:
1818
18-63
Redn - Nitriles by LiAlHRedn - Nitriles by LiAlH44 The cyano group of a nitrile is reduced by LiAlH4
to a 1° amine
6-Octenenitrile
6-Octen-1-amine
CH3CH=CH(CH2)4C1. LiAlH4
2. H2O
CH3CH=CH(CH2)4CH2NH2
N
1818
18-64
InterconversionsInterconversionsProblem:Problem: show reagents and experimental conditions to bring about each reaction
PhCH2COHO
PhCH2CClO
PhCH2COCH3
O
PhCH2CH2OH
PhCH2CNH2
O
PhCH2CHO
PhCH2CH2NH2
(a)
(c)
(b)
(d)
(f)
(e)
(g)
(j) (h) (i)
(k)
1818
18-65
Hofmann RearrangementHofmann 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
PhNH2
H3C H
O
Br2 , NaOH
H2O
Ph NH2
H3C HNa2CO3
(S)-2-Phenyl-propanamide
+
(S)-1-Phenyl-ethanamine
1818
18-66
Hofmann RearrangementHofmann RearrangementStage 1: acid-base reaction gives an amide anion, which
reacts as a nucleophile with Br2
Stage 2: a 2nd acid-base reaction followed by elimination of Br- gives a nitrene, an electron-deficient species, that rearranges to an isocyanate
:: +-
An N-bromoamideAn amide anion
R C N H
H
O
N
H
CRBr Br
O
N
H
BrCRHO-
:Br-: :O
HO-
-H2OAn acyl nitrene
-:Br -R-C-N-Br
H
O :R-C-N-Br
O :: R-C-N
O ::
An isocyanate
R-N=C=O:
1818
18-67
Hofmann RearrangementHofmann Rearrangement• Stage 3: reaction of the isocyanate with water gives a
carbamic acid
• Stage 4: decarboxylation of the carbamic acid gives the primary amine
An isocyanateA carbamic acid
+ H2O R-N-C-OHH
OR-N=C=O
+ H2OR-N-C-OHH
OR-NH2
1818
18-68
Prob 18.19Prob 18.19Propose a structural formula for each compound.
1H-NMR 13C-NMR13C-NMR1H-NMR
22.4521.06
4.10 (t, 2H)2.09 (s, 3H)
0.92 (d, 6H)1.52 (m, 2H)1.70 (m, 1H)
25.05
37.31 63.12171.15161.11
70.01
27.71 19.008.08 (s, 1H)
3.95 (d, 2H)1.96 (m, 1H)0.96 (d, 6H)
(b)(a) C7H1 4O2C5H1 0O2
1818
18-69
Prob 18.19 (cont’d)Prob 18.19 (cont’d)Propose a structural formula for each compound.
13C-NMR1H-NMR
14.25
1.18 (d, 6H)1.26 (t, 3H)2.51 (m, 1H)
4.13 (q, 2H) 19.01
34.04 60.17177.16
(c) C6H1 2O2
1H-NMR 13C-NMR
1H-NMR 13C-NMR
13C-NMR1H-NMR2.29 (m, 2H)2.50 (t, 2H)4.36 (t, 2H)
22.17
27.79 68.58177.81
(f)
(d)
(e)
1.28 (t, 6H)3.36 (s, 2H)4.21 (q, 4H)
14.0741.69
61.43166.52
170.51 52.92 52.32
21.52
4.42 (q, 1H)3.80 (s, 3H)1.68 (d, 3H)
C4H7 ClO2
C7H1 2O4
C4H6 O2
1818
18-70
Prob 18.20Prob 18.20Draw a structural formula for the product formed on treatment of benzoyl chloride with each reagent.
(a) (b)OH OH, pyridine
(d)(c) (two equivalents)SH, pyridine NH2
(e) (f) (CH3)2CuLi, then H3O+O- Na+
O
(h)
(g) NH2, pyridineCH3O
(two equivalents), then H3O+C6H5 MgBr
1818
18-71
Prob 18.26Prob 18.26Draw a structural formula for the product of treating this αβ-unsaturated ketone with each reagent.
(a) (b)
(c)1. LiAlH4 , THF
2. H2O
H2 (1 mol)
Pd, EtOH
NaBH4
CH3OH
OEt
O O
(d)1. DIBALH, -78°
2. H2O
1818
18-72
Prob 18.28Prob 18.28Draw a structural formula for the product of treating this anhydride with each reagent.
heatheat(a) (b) (c)
H2 O, HCl H2 O, NaOH 1. LiAlH4
2. H2O
O
H
H
O
O
(e)(d) CH3OH NH3 (2 moles)
1818
18-73
Prob 18.31Prob 18.31Show how to bring about each step in this conversion of nicotinic acid to nicotinamide.
O
COH
NNicotinic acid (Niacin)
O
COCH2CH3
N
O
CNH2
NEthyl nicotinate Nicotinamide
? ?
1818
18-74
Prob 18.32Prob 18.32Complete these reactions.
CH3CCl
O
CH3COCH3
O
NH2
CH3O NH2
HN
HN
CH3(CH2)5CHO
CH3COCCH3
O O+(a)
+(b) 2
(d)
(c) +
+
1818
18-75
Prob 18.35Prob 18.35Draw structural formulas for the products of complete hydrolysis of each compound in hot aqueous acid.
Meprobamate
Pentobarbital
Phenobarbital
(a) (b)H2N O O NH2
O O
NH
HNO O
O
NH
HNO O
O
(c)
1818
18-76
Prob 18.36Prob 18.36Show reagents to bring about each step in this synthesis of anthranilic acid.
(3)
Phthalic anhydride
Anthranilic acid
(1) (2)
COH
CNH2
O
OCNH2
CO-NH4+O
O
COH
NH2
O
O
O
O
1818
18-77
Prob 18.37Prob 18.37Propose a mechanism for each step in this sequence.
A carbamateAn isocyanateA primaryamide
+
O O
RCNH2 Br2 RN=C=OCH3O
-Na
+
CH3OH
CH3OHRNHCOCH3
1818
18-78
Prob 18.38Prob 18.38Propose a mechanism for each step in this sequence.
CH3O-Na+O
COCH3
O
CH3OH
(R)-(+)-Pulegone
Br2
OBr
Br
1818
18-79
Prob 18.39Prob 18.39Show how to prepare the insect repellent DEET from 3-methyltoluic acid.
N,N-Diethyl-m-toluamideDEET)
3-Methylbenzoic acid(m-Toluic acid)
N
O
OH
O
1818
18-80
Prob 18.40Prob 18.40Show how to prepare isoniazid from 4-pyridinecarboxylic acid.
4-Pyridine-carboxylic acid
N COH?
N CNHNH2
4-Pyridine-carboxylic acid hydrazide
(Isoniazid)
OO
1818
18-81
Prob 18.41Prob 18.41Show how to bring about this conversion.
C CH2COCH2CH=CH2
Phenylacetylene Allyl phenylacetate
CH
O
1818
18-82
Prob 18.42Prob 18.42Propose a mechanism for the formation of this bromolactone, and account for the observed stereochemistry of each substituent on the cyclohexane ring.
CH3
COOH
COOH Br2
O
Br
CH3
O
COOH
O
HO
COOH
OH
A bromolactone
PGE1 (alprostadil)
manysteps
1818
18-83
Prob 18.43Prob 18.43Propose a mechanism for this reaction.
5,5-Diethylbarbituric acid (Barbital)
Diethyldiethylmalonate
Urea
+
12
3456
+
OH2N
H2N
NH
NH
O
O
O
1. EtO-Na
+
2. H2O
2EtOH
OEt
OEt
O
O
1818
18-84
Prob 18.44Prob 18.44Propose a synthesis of this β-chloroamine from anthranilic acid.
several steps
2-Aminobenzoic acid (Anthranilic acid)
+ 2NH2
COOH
O
O
N
O
Cl
1818
18-85
Prob 18.45Prob 18.45Show reagents for the synthesis of 5-nonanone from 1-bromobutane as the only organic starting material.
O
5-NonanoneOH
O
BrC N1-Bromobutane
1818
18-86
Prob 18.46Prob 18.46Describe a synthesis of procaine from the three named starting materials.
Procaine
+
+
4-Aminobenzoic acid
Ethylene oxideDiethylamine
ON
H2N
O
OH
H2N
O
HON
NH
O
1818
18-87
Prob 18.47Prob 18.47The following sequence converts (R)-2-octanol to (S)-2-octanol. Propose structural formulas for A and B, and specify the configuration of each.
(S)-2-Octanol
(R)-2-Octanol
pyridineC
H3C
OHH
C6H1 3
C
CH3
HOH
C6H1 3
CH3COO-Na
+
DMSO
1. LiAlH4
2. H2O
p-TsCl
B
A
1818
18-88
Prob 18.48Prob 18.48Propose a mechanism for this reaction.
+
+
Diethyl carbonateButylamine
Ethyl N-butylcarbamate
EtOH
EtO OEt
O
EtO NH
O
H2N
1818
18-89
Prob 18.49Prob 18.49Propose a mechanism for this reaction.
+
Tolbutamide(Oramide, Orinase)
Sodium salt of p-toluenesulfonamide
A carbamic ester
NH
SNH
H3C
O O O
EtO NH
ONH- Na+S
O O
1818
18-90
Prob 18.50Prob 18.50Show 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.
Tolazamide(Tolamide, Tolinase)
Gliclazide(Diamicron)
(a) (b)NH
SNH
NO O O
NH
SNH
O O ON
1818
18-91
Prob 18.51Prob 18.51Propose a mechanism for Step 1, and reagents for Step 2 in the synthesis of the antiviral agent amantadine.
Brin H2SO4
CH3C N
NHCCH3
O
NH2(2)
(1)
1-Bromoadamantane
Amantadine
1818
18-92
Prob 18.52Prob 18.52• Propose structural formulas for intermediates A-F and
for the configuration of the bromoepoxide.
HOOCCOOH
H OH
1. CH3CH2OH, H+
O, H+
C (C9H18O4) D
5. NaBr, DMSO
4. TsCl, pyridine
3. LiAlH4, then H2O
A (C8H14O5)
F (C4H8OBr2)
7. KOH
B
6. H2O, CH3COOH
BrO
2.
1 2 3
4 5 E 6
7
(S)-Malic acid
A bromoepoxide
1818
18-93
Prob 18.53Prob 18.53Show reagents for the synthesis of (S)-Metolachlor from the named starting materials
NO
(S)-Metolachlor
ClO
HNO
NH2
+
2-Ethyl-6-methyl- aniline
Chloroacetic acid
Acetone
1 2
3
5
+
4CH3OH
Methanol+ OCH3
OCl
OO
NO
OHCl
O
1818
18-94
Derivatives of Derivatives of
Carboxylic Carboxylic AcidsAcids
End Chapter 18End Chapter 18