19.1 (a) Write a mechanism for all steps of the Claisen condensation that take place when ethyl
propanoate reacts with ethoxide ion. (b) What products form when the reaction mixture is
acidified?
Answer:
(a)
O
O
COC2H5 + OC2H5
H3CHC
O
COC2H5 + C2H5OH
H3CHC
H3CHC
COC2H5
H
H3CH2C
O
O
O
COC2H5 + H3CHC
COC2H5
O
H
C
H3 CH2CC
C2H5O
COC2H5
CH3
O
O
H
C
H3CH2CC
COC2H5 + OC2H5
CH3
O
H
O
H3CH2CC
C
COC2H5 + OC2H5
O
H3 CH2CC
CH3
O
C
O
COC2H5
H3 CH2CC
CH3
O
C
COC2H5 + C2H5OH
O
COC2H5
O
C
COC2H5
CH3
O
H3CH2CC
C
CH3
O
H3CH2CC
O
H3O+
(rapid)
O
H
C
H3 CH2CC
CH3
OH
COC2H5
CH3
H3 CH2CC
O
H
C
CH3
OH
COC2H5
H3CH2CC
and
C
CH3
(b)
O
H3CH2CC
O
O
C
CH3
COC2H5
COC2H5
19.2 What product would you expect from a Dieckmann condensation of diethyl heptanedioate
(diethyl pimelate)? (b) Can you account for the fact that diethyl pentanedioate (diethyl glutarate)
does not undergo a Dieckmann condensation?
Answer:
(a) Ethyl-2-oxocyclohexanecarboxylate
O
O
COC2H5
(b) Because the four members ring is not stable.
19.3 Write mechanisms that account for the products that are formed in the two crossed Claisen
condensations just illustrated.
(1)
O
O
O
+
C
OC2H5
C
(1)NaOC2H5
OC2H5
(2)H3O
H3C
O
H2
C
C
+
C
OC2H5
Mechanism:
O
O
O
Ph
C
C
OC2H5
OC2H5
C
O
H2C
OC2H5
H2C
C
O
H2
C
C
OC2H5
OC2H5
OC2H5
H
O
H2C
C
OC2 H5
O
O
O
C
O
O
H
C
C
C
H
C
C
H3O+
C
OC2H5
H
OC2 H5
(2)
O
O
O
C
+
C
OC2H5 C2H5O
(1)NaOC2H5
(2)H3O+
C
OC2H5
C
OC2H5
CH
OC2H5
O
Mechanism:
C
OC2 H5
OC2H5
H2
C
O
H2
C
O
OC2H5
C
H
C2H5O
Ph
OC2H5
CH
OC2H5
O
H
O
OC2H5
OC2H5
OC2H5
C
OC2H5
C
O
C
Ph
C
Ph
C
Ph
H
C
C
C
OC2H5
O
CH
O
O
OC2H5
OC2H5
H
O
H
O
O
H
C
C
OC2H5
C
OC2H5
OC2H5
CH
Ph
C
C
OC2H5
O
O
19.4 What products would you expect to obtain from each of the following crossed Claisen
condensations?
(a)
Ethyl propanoate + diethyl oxalate
(1)NaOCH2 CH3
(2)H3 O+
(b)
Ethyl acetate
ethyl formate
+
(1)NaOCH2CH3
(2)H3O+
Answer: (a)
H3C
O
O
C
C
OC2H5
CH
C
OC2H5
O
(b)
O
H
C
O
H2
C
C
OC2H5
19.5 Show how you might synthesize each of the following compounds using, as your starting
materials, esters, ketones, acyl halides, and so on.
O
O
H
(a)
O
O
O
O
NaOEt
HCCH2CH2CH2CH2CH2 COC2 H5
H
H 3O
O
(b)
O
O
O
O
NaOEt
NaOEt
CH3 CCH2 CH2CH2COEt
T.M
CH3 Br
H 3O
O
O
CO2C2 H5
(c)
O
CO2C2 H5
EtO
OEt
CH3
+
O
NaOEt
EtOOCCH2CCH2COOEt
CH3
O
H3O
T.M
19.6 Keto esters are capable of undergoing cyclization reactions similar to the Dieckmann
condensation. Write a mechanism that accounts for the product formed in the following reaction:
O
O
O
CH3 C(CH2 )4COC2 H5
(1)NaOEt
O
(2)H3O
2-Acetyleyclopentanone
Mechanism:
O
O
O
(1)NaOEt
CH3 C(CH2 )4COC2 H5
(2)H3O
O
CH3CCHCH2 CH2CH2COC2H5
H
OEt
OC2 H5
O
O
O
O
CH3CCHCH2CH2 CH2 COC2H5
T.M
19.7 Occasional side products of alkylations of sodioacetoacetic esters are compounds with the
following general structure:
OR
O
H3CC
CHCOC2H5
Explain how these are formed.
Answer:
O
O
O
O
R
Br
OR
H3CC
O
CHCOC2H5
OEt
OEt
Na
19.8 Show how you would use the acetoacetic ester synthesis to prepare each of the following:
(a) 2-pentanone , (b) 3-propyl-2-hexanone, and (c) 4-phenyl-2-butanone.
Answer:
(a)
O
O
O
+
OEt
Br
(1)NaOEt/EtOH
(2)H
2-pentanone
(b)
O
O
Br
O
+
(1)NaOEt/EtOH
OEt
OEt
(2)H
O
O
Br
(1)NaOEt/EtOH
+
(2)H
3-propyl-2-hexanone
(c)
O
O
O
(1)NaOEt/EtOH
Br
+
(2)H
OEt
4-phenyl-2-butanone
19.9 The acetoacetic ester synthesis generally gives best yields when primary halides are used in
the alkylation step. Secondary halides give low yields, and tertiary halides give practically no
alkylation product at all. (a) Explain. (b) What products would you expect from the reaction of
sodioacetoacetic ester and tert-butyl bromides? (c) Bromobenzene cannot be used as an arylating
agent in an acetoacetic ester synthesis in the manner we have just described. Why not?
a) The alkylation reaction is typical SN2 reaction. Therefore, primary alkyl halide reacts fastest,
and the tertiary alkyl halide doesn’t undergo SN2 at all.
b)
O
O
H
Na
O
+
H
Br
H
sodioacetoacetic ester
O
tert-butyl bromide
O
O
+
c) In my thought, because Bromobenzene have a conjugation effect between benzene and bromide,
it is so stable and can’t be substituted so easily.
19.10 Since the products obtained from Claisen condensations are β-keto esters, subsequent
hydrolysis and decarboxylation of these products give a general method for the synthesis of
ketones. Show how you would employ this technique in a synthesis of 4-heptanone.
Answer:
19.11 In the synthesis of the keto acid just given, the dicarboxylic acid decarboxylates in a specific
way, it gives
O
O
OH
O
rather than
OH
O
Explain.
The answer:
O
O
O
OH
O
OH
O
OH
O
O
O
O
O
OH
O
OH
O
Resonance-stablized anion
Forβ－keto acid can form Enol form which is more stabilized, the acid decarboxylation occur in
theβposition.
19.12 How would you use the acetoacetic ester synthesis to prepare the following?
O
O
The answer:
O
O
OC2H5
(1) C2H5ONa
O
O
OC2H5
CH2Br
(2)
O
O
O
OH
O
O
(1) dilute NaOH
heat
T.M
-CO2
H3O
O
O
O
O
H 3O +
NaOEt
O
O
EtOH
19.13 How would you use the acetoacetic ester synthesis to prepare the following?
O
O
CCH2CCH3
Answer:
O
O
O
O
O
O
Cl
1)dilute NaOH
NaH
O
O
O
2) H3O+
aprotic solvent
3)△
O
19.14 Outline a step-by-step mechanism for the phenylation of acetoacetic ester by bromobenzene
and two molar equivalents of sodium amide. (Why are two molar equivalents of NaNH2
necessary?)
Answer:
O
O
O
O
O
O
H
H
O
O
NaNH2
O
Br
H
NH3
NaNH2
O
O
O
C6H5
(a) What product would be obtained by hydrolysis and decarboxylation of the acetoacetic ester?
Answer:
O
(b) How would you prepare phenylacetic acid from malonic ester?
Answer:
O
Cl
O
O
C2H5
O
C2 H5
O
C2 H5
1) 2NaNH2
+
O
C2H5
2) liq. NH3
O
O
COOH
△
1) dilute NaOH
2) H3+O
COOH
COOH
19.15 Show how you could
C6H5CH2CH2COCH2COOCH2H5.
use
ethyl
acetoacetate
in
a
synthesis
of
Answer:
O
O
O
O
+
O
Br 1) 2 NaNH /NH
2
3
O
2)NH 4Cl
19.16 Outline all steps in a malonic ester synthesis of each of the following: (a) pentanoic acid, (b)
2-methylpentanoic acid, and (c) 4-methylpentanoic acid.
Answer:
(a)
COOCH2CH3
COOCH2CH3
COOCH2CH3
CH3CH2CH2Br
NaOCH2CH3
COOCH2CH3
H3CH2CH2C
COOCH2CH3
COOCH2CH3
COO
OH-,heat
H+,heat
H3CH2CH2C
COOH
COO
(b)
COOCH 2CH 3
COOCH 2CH 3
COOCH2CH3
CH3CH2CH2 Br
NaOCH2CH3
COOCH 2CH 3
H 3CH 2CH 2C
COOCH2CH3
COOCH 2CH 3
COO
NaOC(CH3 )3
COO
H 3CH 2CH 2C
OH-,heat
H3CH2CH 2C
H+,heat
CH3 I
COO
COO
COOH
(c)
COOCH2CH3
COOCH2CH3
COOCH2CH3
NaOCH2CH3
COOCH2CH3
(CH3)2CHCH2Br
(H3C)2HCH2C
COOCH2CH3
COOCH2CH3
COO
OH-,heat
H+,heat
(H3C)2HCH2C
COOH
COO
19.17 The antiepileptic drug valproic acid is 2-propylpentanoic acid (administered as the sodium
salt). One commercial synthesis of valproic acid begins with ethyl cyanoacetate. The penultimate
step of this synthesis involves a decarboxylation, and the last step involves hydrolysis of a nitrile.
Outline this synthesis.
Answer:
O
O
N
O
N
CH3CH2CH2ONa
CH3CH2CH2Cl
CH3CH2CH2ONa
O
CH3CH2CH2Cl
N
O
N
O
2
O
O
1 NaOH
H 3O
N
heat
+
-
HO
CO2
OH
H 3O +
19.18 (a) Which aldehyde would you use to prepare 1,3-dithiane itself?
(b) How would you synthesize C6H5CH2CHO using a 1,3-dithiane as an intermediate?
(c) How would you convert benzaldehyde to acetophenone?
Answer: (a) HCHO
(b)
S
S
(1) C4H9Li (-C4H10) (2) -LiCl
S
H
S
(-HSCH2CH2 CH2 SH)
Cl
H
H
HgCl2, CH3OH,H2 O
O
H
(c)
O
H3O+
+
S
H
H
S
S
HSCH2CH2CH2SH
(1) C4H9Li (-C4H10)
(2)CH3I (-LiI)
O
S
HgCl2, CH3 OH,H2O
(- HSCH2CH2CH2SH)
19.19 The Corey-Seebach method can also be used to synthesize molecules with the structure
RCH2CH2R’. How might this be done?
Answer:
(1)
S
(1) C4H 9Li(-C4H10)
(2) RCH2X(-LiX)
S
R'
S
H
Raney Ni
S
R'
R'CH2CH2R
(H2)
CH2R
19.20 (a) The Corey –Seebach method has been used to prepare the following highly strained
molecule called a metaparacyclophane. What are the structures of the intermediates A-D?
2 HSCH2CH2CH2 SH
HC
acid
CH
(1) 2 C4H9Li
A (C14H18S4)
(2)
BrH2C
CH2Br
O
O
B (C22H24S4)
Hydrolysis
C (C16 H12 O2 )
NaBH4
D (C16H16O2)
(1) 2 TsCl
(2) 2 KOC(CH 3)3
(b) What compound would be obtained by treating B with excess Raney Ni?
Answer:
(a)
A
S
B
S
S
S
(b)
S
S
S
C
D
O
S
O
HO
OH
19.21 How would you prepare HOCOCH2C(CH3)2CH2COOH from the product of the Michael
addition given above?
CH3
H3CC
H3O
CH2COOC2H5
CH3
HOOC
+
heat
H2
C
C
CH
CH(CO2C2H5)2
O
HOOC
CH3
O
CH3
HO
C
C
OH
CH2CCH2COOH
CH3
19.22: Outline reasonable mechanisms that account for the products of the following Mannich
reactions:
(a)
O
O
CH2N(CH3)2
+
CH2O +
(CH3)2 NH
Answer:
H+
H3C
H
H3C
NH
+
C
H3 C
N
N
O
H3C
H3C
H
O
OH
O
H3C
OH
CH2N(CH3)2
CH3
HA
N
CH3
O
CCH3
+
CH2 O +
N
H
O
CCH2CH2
(b)
Answer:
N
H+
H
OH
C
NH
N
O
N
H
O
OH
CCH3
C
N
CH2
O
CCH2CH2
N
(c)
OH
OH
(H3C)2 NCH2
2CH2O +
+
CH2N(CH3)2
2(CH3)2NH
CH3
CH3
Answer:
H3C
NH
H3C
OH
H+
OH
H
C
N
O
N
H
O
(H3C)2NCH2
OH
(H3C)2NCH2
OH
(H3C)2NCH2
CH3
CH2 N(CH3)2
N
CH3
CH3
CH3
19.23 Show how you could employ enamines in systhneses of the following compounds:
O
O
O
C(CH2)4CH3
CH2COCH3
(c)
(a)
CH2COOC2H5
O
CH2CHCHCH3
(b)
O
(d)
Answer:
Cl(a)
O
N
+
N
C(CH)4CH3
Cl
heat
O
C(CH2)4CH3
H 2O
O
O
C(CH2)4CH3
(b)
N
N
+
CH2COCH 3
Br
O
H2 O
heat
CH2COCH3
CH2COCH3
(c)
O
N
CH2CH
N
+
Br
CH2CH
CHCH3
heat
CH2CH=CHCH3
O
O
CH2COC2H5
CH2COC2H5
O
N
(d)
CHCH3
H2O
O
N
Cl
CH2COC2H5
H2O
heat
19.24 Outlined here is a synthesis of phenobarvital.
(a ) What are compounds A-F? (b) Propose an alternative synthesis of E from diethyl malonate.
C6H5CH3
EtOH
NBS
CCl4
A (C7H7Br)
(1) Mg,Et2O
(2) CO2, then H3O+
D (C10H12O2) EtOCOOEt
NaOEt
Answer:
B (C8H8O2 ) SOCl2
E (C13 H16O4) KOC(CH3)
CH3CH2Br
C (C8H7ClO)
F (C15H20O4)
NH2CONH2
phenobarbital
NaOEt
(a)
A
OH
B
Br
O
Cl
OEt
C
D
O
O
COOEt
Et
OEt
E
COOEt
COOEt
F
O
Phenobarbital:
O
NH
Et
O
NH
O
(b)
Et
Et
COOEt
NH2CONH2
1. t-BuOK
1. NaOEt
EtOOC
Et
COOEt
EtOOC
2. EtBr
2. EtBr
T. M.
COOEt
EtOOC
19.25 Starting with diethyl malonate, urea, and any other required reagents, outline a synthesis of
veronal and seconal.
O
EtO
O
OEt
H
+
O
H2 N
O
O
N
NaOEt
NH2
urea
C2H5
H
C2H5
CH3CH2Br
O
N
O
veronal
H
N
NaOEt
O
N
H
O
O
EtO
OEt
O
NaOEt
EtO
OEt
H2C CHCH2Br
O
O
NaNH2
CH3 CH(CH2)2CH3
O
CH(CH2)2CH3
CH2CH CH2
EtO
Br
CH3
EtO
O
diethyl malonate
O
O
H
H2N
NH2
CH(CH2)2CH3
CH2CH CH2
N
O
CH3
N
O
H
Seconal
19.26 Show all steps in the following synthesis. You may use any other needed reagents but you
should begin with the compound given. You need not repeat steps carried out in earlier parts of
this exercise.
(a)
O
O
O
CH3CH2CH2CCHCOC2 H5
CH3CH2 CH2 COC2H5
CH2
CH3
Answer:
O
O
2 CH3 CH2CH2COC2H5
NaOEt
O
CH3CH2 CH2 CCHCOC2H5
CH2
CH3
(b)
O
O
CH3CH2CH2CCH2CH2 CH3
CH3CH2CH2 COC2 H5
Answer:
O
O
CH3CH2CH2 COC2 H5
CH3 CH2CH2)2 CuLi
CH3CH2CH2 CCH2 CH2CH3
Et2O
(c)
O
C6 H5CH2COC2H5
CH3
C6H5CHCO2H
Answer:
O
CH3
NaOEt
C6 H5CH2COC2H5
C6H5CHCO2H
CH3I
(d)
O
O
CH3 CH2CHCOC2H5
CH3CH2CH2COC2H5
C
COC2H5
O
O
O
O
NaOEt
CH3CH2CH2COC2H5
C2H5OC
COC2H5
CH3CH2CHCOC2 H5
C
COC2H5
O
O
O
O
(e)
O
O O
CH3CH2CH2 COC2 H5
CH3CH2CH2C
Answer:
product of (d)
H 3O
O O
CH3CH2CH2C
COC2H5
(f)
O
O
C6H5CHCOC2 H5
CH
C6H5CH2COC2 H5
O
Answer:
O
O
C6H5CH2COC2 H5
NaOEt
HCOC2H5
O
(g)
C6H5CHCOC2 H5
CH
O
COC2H5
O
O
O
CCH3
Answer:
O
O
O
N
CH3CCl
H3O
O
CCH3
(h)
O
O
CH3
CCH3
O
Answer:
O
CH3
CCH3
NaOEt
product of (h)
CH3 I
O
(i)
O
O
O
COC2H5
CH2CH3
Answer:
O
O
O
COC2H5
O
CH2CH3
NaOEt
CH3CH2I
H 3O
COOEt
19.27 Outline syntheses of each of the following from acetoacetic ester and any other required
reagents.
(a) tert-Butyl methyl ketone
(b) 2-Hexanone
(c) 2,5-Hexanedione
(d) 4-Hydroxypentanoic acid
(e) 2-Ethyl –1,3-butaneiol
(f) 1-Phenyl-1,3-butanediol
Answer:
(a)
O
O
O
+ 3
I
O
LDA
O
O
O
H3O
heat
（b）
O
O
O
O
O
Br NaOEt
+
O
O
heat
(c)
O
O
O
NaOEt
O
O
H3 O
CH3 COCH2Br
O
O
heat
O
O
(d)
O
O
O
NaOEt
O
O
H3 O
BrCH2COOEt
O
O
OH
heat
OEt
O
NaBH4
OH
O
OH
O
(e)
O
O
NaOEt
+
O
(f)
O
OH
O
LiAlH4
I
O
OH
O
O
O
NaOEt
O
O
O
H 3O +
PhCOCl
O
O
Ph
Ph
LiAlH4
O
OH
OH
Ph
19.28 Outline syntheses of each of the following from diethyl malonate and any other
required reagents.
(a) 2-Methylbutanoic acid
(b) 4-Methyl-1-pentanol
(c) CH3CH2CH(CH2OH)2
(d) HOCH2CH2CH2CH2OH
(a)
O
O
O
O
1
2
O
O
O
O
1. t-BuOK
NaOEt
O
O
O
O
2. CH3I
CH3CH2Br
O
H3O
heat
OH
(b)
O
O
O
O
NaOEt
+
O
O
O
O
Br
O
H3O
heat
LiAlH4
OH
OH
(c)
O
O
O
O
NaOEt
+
O
O
O
O
Br
O
H3O
O
HO
LiAlH4
OH
HO
OH
(d)
COOEt
NaOEt
BrCH2COOEt
EtOOC
COOEt
LiAlH4
COOEt
H 3O +
HOOC
COOEt
COOH
HO
OH
19.29 The synthesis of cyclobutanecarboxylic acid given in Section 19.4 was first carried out by
William Perkin. Jr. in 1883, and it represented one of the first syntheses of an organic compound
with a ring smaller than six carbon atoms. (There was a general feeling at the time that such
compounds would be too unstable to exist.) Earlier in 1883, Perkin reported what he mistakenly
believed to be a cyclobutane derivative obtained from the reaction of acetoacetic ester and
1,3-dibromopropane. The reaction that Perkin had expected to take place was the following:
O
O
BrCH2CH2CH2Br
+
O
CH3CCCH2COC2H5
C2 H5ONa
CH2
CCH3
C
CH2
CH2
COC2H5
O
The molecular formula for his product agreed with the formulation given in the preceding reaction,
and alkaline hydrolysis and acidification gave a nicely crystalline acid (also having the expected
molecular formula). The acid, however, was quite stable to heat and resisted decarboxylation.
Perkin later found that both the ester and the acid contained six-membered rings (five carbon
atoms and one oxygen atom). Recall the charge distribution in the enolate ion obtained from
acetoacetic ester and propose structures for Perkin’s ester and acid.
Solution:
CH3
O
CH3
O
COC2H5
COH
O
O
ester
acid
19.30 (a) In 1884 Perkin achieved a successful synthesis of cyclopropanecarboxylic acid from
sodiomalonic ester and 1,2-dibromoethane. Outline the reactions involved in this synthesis. (b) In
1885 Perkin synthesized five-membered carbocyclic compounds D and E in the following way:
C H O Na Br2
A (C17H28O8) 2 2 5
2 Na CH(CO2C2H5)2 + BrCH2CH2CH2Br
B (C17H26O8)
(1) OH /H2 O
(2) H3O
C (C9 H10 O8 )
heat
D (C7 H10 O4 ) + E (C7H10O4)
D and E are diastereomers; D can be resolved into enantiomeric forms while E cannot. What are
the structures of A – E? (c) Ten years later Perkin was able to synthesize 1,4-dibromobutane; he
later used this compound and diethyl malonate to prepare cyclopentanecarboxylic acid. Show the
reactions involved.
Solution: (a)
H5C2O2C
Na CH(CO2 C2H5)2
H5C2O2C
CO2C2 H5
+ BrCH2 CH2Br
CO2C2H5
H3O /H2 O
HOOC
COOH
(b)
O
O
C2H5OC
COC2H5
CHCH2CH2CH2 CH
C2H5OC
COC2 H5
O
O
A
O
O
COC2H5
C2H5OC
COC2H5
C2H5OC
O
O
B
OH
OH
O
O
O
O
COH
HOC
O
O
COH
HOC
O
O
HO
HO
C
D
E
(c)
H2C
CH
C
H
CH2
Br2
Br
H2/Pt
Br
O
O
O
O
Br
+ Br
EtONa
EtOH
O
O
O
O
O
O
H3O /H2O
O
O
HO
OH
O
O
T.M.
19.31 Write mechanisms that account for the products of the following reactions:
(a)
O
O
C6H5HC
CH2(COC2H5)2
+
CHCOC2H5
C6H5 CH
NaOCH2CH3
O
CH2COC2H5
CH
C2H5O
C
C
O
O
OC2 H5
(b)
O
COCH3
O
CH3NH2
H2C
CHCOCH3
O
CH3 N(CH2CH2COCH3 )2
Base
O
N
CH3
(c)
CH3
O
C
H3C
CH2 COC2H5
CH3
C2 H 5 O -
O
+
CH3C
(-C2H5OH)
CH(CO2C2H5)2
CHCOC2H5
CH(CO2C2 H5)2
Answer:
(a)
CH2(COC2H5)2
NaOCH2 CH3
CH(CH2 OC2H5)2
O
O
O
C6 H5HC
HO
H
C6H5CH
CHCOC2H5
O
O
CHCOC2H5
C6H5CH
CH
C2H5O
CH2COC2H5
CH
C
C
O
O
OC2H5
C2H5O
C
C
O
O
OC2H5
(b)
H
CH3NH
H
CH3NHCH2CHCOCH3
O
H2C
O
CHCOCH3
O
CH3NHCH2CH2COCH3
O
O
CH2CH2COCH3
CH3N
CH2CH2COCH3
H2C
CHCOCH3
O
-OH
O
O
O
COCH3
CH2CHCOCH3
CH3N
CH2CH2 COCH3
N
O
CH3
(c)
C2 H5 OCH3
C
H3C
CH3
O
C
H3C
CH2COC2H5
CHCOC2H5
CH(CO2C2H5)2
CH(CO2C2H5)2
CH3
O
O
+
CH3C
CH(CO2C2H5)2
CHCOC2H5
19.32 Knoevenagel condensations in which the active hydrogen compound is aβ-keto ester or a
β-diketone often yield products that result from one molecule of aldehyde or ketone and two
molecules of the active methylene component. For example,
R
CH(COCH )
C
O
+
3 2
base
CH2(COCH3 )2
R
C
CH(COCH3 )2
R'
R'
Suggest a reasonable mechanism that account for the formation of these prouducts.
Answer:
R
R
C
R'
O
+ CH2(COCH3)2
COCH3
CH(COCH3)2
R
C
C
R'
CH(COCH3)2
COCH3
R'
CH(COCH3)2
19.33 Thymine is one of the heterocyclic bases found in DNA (see the chapter opening vignette).
Starting with ethyl propanoate and using any other needed reagents, show how you might
synthesize thymine.
NH
O
N
H
O
thymine
Answer:
O
HCO2Et/NaOEt
CH3CHCO2 CH2 CH3
CH3CH2COCH2CH3
H3 O
CHO
H2N
NH
O
C
H2N
NaOEt
O
N
O
H
19.34 The mandibular glands of queen bees secrete a fluid that contains a remarkable compound
known as “queen substance.” When even an exceedingly small amount of the queen substance is
transferred to worker bees, it inhibits the development of their ovaries and prevents the workers
from bearing new queens. Queen substance, a monocarboxylic acid with the molecular formula
C10H16O3, has been synthesized by the following route:
Cycloheptanone
(1) CH3MgI
HA,heat
A(C8 H16O)
B (C8H14)
(2) H3O
(1) O3
(2) Zn,HOAc
CH2 (CO2H)2
C (C8H14O2)
pyridine
queen substance (C10H16O3)
On catalytic hydrogenation queen substance yields compound D, which, on treatment with iodine
in sodium hydroxide and subsequent acidification, yields a dicarboxylic acid E; that is,
Queen substance
H2
D (C10H18O3)
Pd
(1) I2 in aq.NaOH
(2)
H3O
E (C9H16O4)
Provide structures for the queen substance and compounds A－E.
Answer:
HO
CH3
C: OHC(CH2)5COCH3
A:
B:
D: HOOC(CH2)7COCH3
E: HOOC(CH2)7COOH
queen substance:
HOOC
(CH2)5COCH3
19.35 Linalool, a fragrant compound that can be isolated from a variety
of plants, is 3,7-dimethyl-1,6-octadien-3-ol.Linaool is used in making
perfumes, and it can be synthesized in the following way:
C
C
CH2
sodioacetoacetic
H2C
H
F (C5H9Br)
+ HBr
ester
CH3
(1) dilute NaOH
G C11H18O3
(1) LiC
C8H14O
H
CH
I
(2) H3O
(2) H3O (3) heat
H2
linalool
linldar's catalyst
Outline in the reaction involved.
Answer:
(1)
C10H16O
C
H 2C
C
H
CH2
+
H 3C
HBr
C
CH3
H2
C
C
H
Br
CH3
O
H3C
(2)
C
C
H
H2
C
Br sodioacetoacetic
H3C
C
H2
C
C
H
ester
O
CH3
CH3
H
C
CCH3
O
H3C
C
C
H
CH3
H2
C
O
H
C
O
(1) dilute NaOH
CCH3
H3C
(2) H3O (3) heat
C
COCH2 CH3
H2
C
C
H
H2
C
CCH3
(4)
CH3
O
H3C
C
C
H
H2
C
H2
C
(3)
COCH2CH3
CCH3
OH
(1) LiC
(2) H3 O
CH
H3 C
C
CH3
C
H
H2
C
CH3
H2
C
HC
CCH3
C
(5)
OH
OH
H3C
C
CH3
C
H
H2
C
H2
C
HC
H2
CCH3
C
H3C
linldar's catalyst
C
CH3
C
H
H2
C
H2
C
H2 C
CCH3
CH
19.36 Compound J, a compound with two four-membered rings, has been synthesized by the
following route. Outline the steps that are involved.
(C10H17BrO4)
NaCH(CO2C2H5)2 + BrCH2 CH2CH2Br
C10H16O4
(1) LiAlH4
HBr
(2) H2O C6 H12 O2
C13H20 O4
(1) OH-,H2O
(2) H3O+
C9H12O4
C6 H10Br2
heat
NaOC2 H5
CH2(CO2C2H5)2
2 NaOC2H5
J (C8H12O2) + CO2
Solution:
O
NaCH(CO2C2H5)2 + BrCH2CH2CH2Br
O
C2H5
C
O
C2H5
Br
O
O
C
C
O
H2
C
C2H5
OH
(1) LiAlH4
(2) H2O
NaOC2H5
C
O
HBr
C
H2
C2H5
OH
O
O
H2
C
C
H2
Br
Br
C
O
C2H5
CH2(CO2C2H5)2
2 NaOC2H5
C
O
OH
heat
C
C2H5
O
O
C
O
(1) OH-,H2 O
(2) H3O+
C
OH
+ CO2
OH
O
19.37 When an aldehyde or a ketone is condensed with ethyl α-chloroacetate in the presence of
sodium ethoxide, the product is an α,β-epoxy ester called a glycidic ester. The synthesis is called
the Darzens condensation.
R'
R'
C
O + ClCH2CO2C2 H5
C2 H5 ONa
R
C
CHCO2C2 H5 + NaCl + C2H5OH
R
O
(a) Outline a reasonable mechanism for the Darzens condensation. (b) Hydrolysis of the epoxy
ester leads to an epoxy acid that, on heating with pyridine, furnishes an aldehyde. What is
happening here?
R'
R
C
CHCOOH
C5H5N
heat
R
R'
O
C
H
CH + CO2
O
(c) Starting with β-ionone (Problem 17.15), show how you might synthesize the following
aldehyde. (This aldehyde is an intermediate in an industrial synthesis of vitamin A.)
CH
O
Answer:
(a):
OC2H5
H
Cl
O
ClCH
CO2C2H5
Cl
R'
HCC
R
R
OC2H5
CO2C2H5
C
R'
C
R'
R
C
CHCO2C2H5
O
O
O
(b):
R'
R
O
C
R'
CHCO
O
R
O
H
C
C
R'
H
C
R
O
O
H
N
R
O
H
N
(c):
R'
O
C
H
CH
O
C2H5ONa
ClCH2CO2C2 H5
CO2H
O
CO2 C2H5
O
CHO
C 5H 5N
heat
CHOH
19.38 The Perkin condensation is an aldol-type condensation in which an aromatic aldehyde
(ArCHO) reacts with a carboxylic acid anhydride(RCH2CO)2O, to give an α,β-unsaturated acid
(ArCH=CRCO2H). The catalyst that is usually employed is the potassium salt of the carboxylic
acid (RCH2CO2K).
(a) Outline the Perkin condensation that takes place when benzaldehyde reacts with propanoic
anhydride in the presence of potassium propanoate.
O
OH
O
O
H
O
+
OH
(CH3CH2CO)2O
O
O
O
H 3O +
OH
+ CH3CH2COOH
Δ
O
(b) How would you use a Perkin condensation to prepare p-chlorocinnamic acid,
p-ClC6H4CH=CHCO2H?
Cl2
+
FeCl3
Cl
(1)
;
O
O
Cl
AlCl3
+
H
(2)
H
Cl
Cl
;
O
H
H
+ (CH3CO)2O
Cl
(3)
H2 O
Δ Cl
H
+ CH3 COOH
O
.
19.39 (+)-Fenchone is a terpenoid that can be isolated from fennel oil.
(±)-Fenchone has been synthesized through the following route. Supply
the missing intermediates and reagents.
CO2CH3
(1) (b)
CH2=CH－CH=CH2＋(a)
(2) (c)
CO2CH3
(g)
(d)
mixture of (e) and (f)
(h)
CO2CH3
CO2CH3
CO2H
CO2CH3
(i)
(j)
O
O
CO2CH3
H3 O+
CH2 CO2CH3
(l)
(k)
heat
OH
COOCH3
O
(m)
CH2 CO2CH3
O
Answer:
(a) CH2=C(CH3)CO2CH3
(n)
+
(b) KMnO4 OH H3O
+
(c) EtOH, H
+
(d) CH3ONa H3O
(e) and (f)
CO2CH3
CO2CH3
CO2CH3
H3CO2C
O
(g)
(h)
(i)
(j)
(k)
△
O
OHH3O+, △
CH3 OH
Zn, BrCH2COOMe
CO2CH3
CHCO2CH3
(l) H2 Pt
+
(m) CH3ONa H3O
(n) NaNH2 CH3I
19.40 Outline a synthesis of the analgesic Darvon (below) starting with ethyl phenyl ketone.
CH3
H2
C
C
O
C
H
C
O
Answer:
H2
C
H2
C
N(CH3)2
CH3
O
O
C
O
+
H
H2
C
C
CH3
C2H5
H
+
CH
HN
1. PhCH2MgBr
N
CH3
H3C
CH3
CH2Ph
HO
CH3
CH3
C
N
2. H3O+
CH3
CH3
CH3CH2COO
CH2Ph
CH3
C
(CH3CH2CO)2O
N
CH3
CH3
19.41 Explain the variation in enol content that is observed for solutions of acetylacetone
(2,4-pentanedione) in the several solvents indicated.
Solvent
% Enol
H2O
15
CH3CN
58
C6H14
92
Gas phase
92
Answer:
H3C
O
O
C
C
C
H2
H3C
CH3
OH
O
C
C
O
OH
O
O
C
C
C
C
C
H
CH3
H3C
C
CH3
H
H3C
C
CH3
H
In a polar solvent, such as water, the keto form is stabilized by solvation. When the interaction
with the solvent becomes minimal, the enol form achieves stability by the internal hydrogen
bonding.
19.42 When a Dieckmann condensation is attempted with diethyl succinate, the product obtained
has the molecular formula C12H16O6. What is the structure of this compound?
Answer:
O
OC2H5
C2 H5O
O
19.43 Ethyl crotonate, CH3CH=CHCOOC2H5, reacts with diethyl oxalate, C2H5OOCCOOC2H5, to
form a Claisen-type condensation product.
O
C2H5OC
O
O
CCH2CH
CHCOC2H5
Write a detailed mechanism for the formation of this compound.
O
H2C
C
H
C
H
O
COC2H5
H2C
C
H
C
H
C
OC2H5
H
O
EtOH2C
EtO
O
O
C
C
C2H5 OC
C
H
C
O
OEt
H2 C
O
C
H
O
C
H
O
C
H
CHCOC2H5
O
CCH2CH
OC2H5
CHCOC2H5
OEt
O
CCHCH
O
C2H5OC
C
OC2H5
O
O
C2H5OC
C
O
H
C
C
H
C
H
COC2H5
H
EtO-
O
C2H5 OC
O
C2H5OC
O
O
CCH
CHCH
COC2H5
O
C
O
O
C2H5OC
C
O
H
C
C
H
C
H
O
C
H
C
H
O
COC2H5
C
H
O
COC2H5
O
H3O+
C2H5OC
CCH2CH
CHCOC2 H5
19.44 Show how this diketone could be prepared by a condensation reaction:
O
O
Answer:
O
O
COOEt
CH3COOEt
CH2 COOEt
NaH
COOEt
NaH
COOEt
COOEt
O
H 3O
T.M.
19.45 (a) Deduce the structure of product A, which is highly symmetrical.
O
N
A
+
ethanol
The following are selected spectral date for A:
MS (m/z): 220(M.+)
IR (cm-1): 2930, 2860, 1715
H NMR (δ): 1.25(m), 1.29(m), 1.76(m), 1.77(m), 2.14(s), 2.22(t); (area rations 2:1:2:1:2:2,
respectively)
1
C NMR (δ): 23 (CH2), 26 (CH2), 27 (CH2), 29 (C), 39 (CH), 41 (CH2), 46 (CH2), 208 (C)
(b) Write the mechanism that explain formation of A.
answer:
(a)
13
O
O
(b)
N
N
O
O
+
O
O
ethanol
O
O
O
O
O
NaoEt
ethanol
HO
O
O
ethanol
O