Taller Parcial 2

908 Chapter 23 Substitution Reactions of Carbonyl Compounds at the Carbon

PROBLEMS

Enols, Enolates, and Acidic Protons

23.30 Draw enol tautomer(s) for each compound.

a. CH3CH2CH2CHO c. CH3CH2CH2CH2CO2CH2CH3 e. CH3CH2CHCOOHCH3

b. O

d.

O O(mono enol form) f.

O

OEt

O

23.31 Both 2,4-pentanedione and ethyl acetoacetate have two carbonyl groups separated by a single carbon atom. Although an

equilibrium mixture of 2,4-pentanedione tautomers contains 76% of the enol forms, an equilibrium mixture of ethyl acetoacetate

tautomers contains only 8% of the enol forms. Suggest a reason for this difference.

OCH2CH32,4-pentanedione ethyl acetoacetate

OO OO

23.32 What hydrogen atoms in each compound have a pKa 25?

a. CH3CH2CH2CO2CH(CH3)2 c. OOH

e. CO

NCCH2CH3

b.

O

O

d. CH2CNCH3O f. OHOOC

23.33 Rank the labeled protons in each compound in order of increasing acidity.

a. CO

OHCH3CH2

HcHbHa

c.

H H

OO

Ha HbHc

CH3 e.

HHO

H

O

Hb HcHa

b. CO

H

HcHbHa

CH2CH3 d.

H

COOHO

Ha

H Hb

Hc

23.34 What is the major enolate (or carbanion) formed when each compound is treated with LDA?

a.

O

c.

O

e.

O

b.

O

OCH3 d. CN

f.

OO

23.35 How could IR spectroscopy be used to detect the presence of enol tautomers?

Problems 909

23.36 Why is the pKa of the Ha protons in 1-acetylcyclohexene higher than the pKa of the Hb protons?

O

Hb

HbHa

Ha

1-acetylcyclohexene

23.37 Explain why 5,5-dimethyl-1,3-cyclohexanedione exists predominantly in its enol form, but 2,2-dimethyl-1,3-cyclohexanedione

does not.O

5,5-dimethyl-1,3-cyclohexanedione

OO

2,2-dimethyl-1,3-cyclohexanedione

O

23.38 Explain why an optically active solution of (R)--methylbutyrophenone loses its optical activity when either dilute acid or base is added to the solution.

H

O

(R)--methylbutyrophenone

23.39 Although ibuprofen is sold as a racemic mixture, only the S enantiomer acts as an analgesic. In the body, however, some of

the R enantiomer is converted to the S isomer by tautomerization to an enol and then protonation to regenerate the carbonyl

compound. Write a stepwise mechanism for this isomerization.

R isomerinactive enantiomer

HHA

CO2H

S isomeractive enantiomer

H

CO2H

23.40 Explain why the protons of an ester are less acidic than the protons of a ketone by ~5 pKa units.

23.41 Explain why reactions that use LDA as base must be carried out under anhydrous conditions; that is, all traces of H2O must be

rigorously excluded.

23.42 Explain why 2,4-pentanedione forms two different alkylation products (A or B) when the number of equivalents of base is

increased from one to two.

O

A

O O

B

OO

2,4-pentanedione

O[1] base (1 equiv)

[2] CH3I[3] H2O

[1] base (2 equiv)[2] CH3I[3] H2O

23.43 The cis ketone A is isomerized to the trans ketone B with aqueous NaOH. A similar isomerization reaction does not occur with

the cis ketone C. Explain this difference in reactivity.

NaOHH2O

(CH3)3C(CH3)3CO

A

(CH3)3C

OC

O

B

23.44 Treatment of ,-unsaturated carbonyl compound X with base forms the diastereomer Y. Write a stepwise mechanism for this reaction. Explain why one stereogenic center changes con! guration but the other does not.

O

OHH2O O

X Y


Halogenation

23.45 Acid-catalyzed bromination of 2-pentanone (CH3COCH2CH2CH3) forms two products: BrCH2COCH2CH2CH3 (A) and

CH3COCH(Br)CH2CH3 (B). Explain why the major product is B, with the Br atom on the more substituted side of the

carbonyl group.

23.46 Draw a stepwise mechanism for each reaction.

a.

O OBr

Br2CH3CO2H

+ HBr b.

O O

OI2 (excess)OH + CHI3

Malonic Ester Synthesis

23.47 What alkyl halides are needed to prepare each carboxylic acid using the malonic ester synthesis?

a. CH3OCH2CH2COOH b. COOHC6H5 c.

COOH

23.48 Use the malonic ester synthesis to prepare each carboxylic acid.

a. CH3CH2CH2CH2CH2CH2COOH b. COOH c. COOH

23.49 Devise a synthesis of valproic acid [(CH3CH2CH2)2CHCO2H], a medicine used to treat epileptic seizures, using the malonic

ester synthesis.

23.50 Synthesize each compound from diethyl malonate. You may use any other organic or inorganic reagents.

a. COOH b. CH2OH c. C OHCH3

CH3

d.

CH3CO2Et

23.51 The enolate derived from diethyl malonate reacts with a variety of electrophiles (not just alkyl halides) to form new carbon

carbon bonds. With this in mind, draw the products formed when Na+ CH(COOEt)2 reacts with each electrophile, followed by

treatment with H2O.

a. O

CH3 b. OCH2 c.

OC

CICH3 d.

OC

OCH3

OC

CH3

Acetoacetic Ester Synthesis

23.52 What alkyl halides are needed to prepare each ketone using the acetoacetic ester synthesis?

a.

O

b.

O

c.

O

d.

O

23.53 Synthesize each compound from ethyl acetoacetate. You may use any other organic or inorganic reagents.

a.

OC

CH2CH2CH3CH3 b.

OC

CH(CH3)2CH3 c.

OC

CH(CH3)2CH3CH2 d.

OC

C(CH3)3CH3

Problems 911

Reactions

23.54 Draw the organic products formed in each reaction.

a.

O

Br

Li2CO3, LiBrDMF

f.

O

[1] Br2, CH3CO2H[2] Li2CO3, LiBr, DMF

b.

COOH

COOH

O

g.

O

I2 (excess)OH

c. [1] LDA[2] CH3CH2I

CH3CH2CH2CO2Et h. CI CNNaH C6H9N

d. (CH3)2CHNH2

OBr

i.

OBr2 (excess)

OH

e. [1] LDA[2] CH3CH2I

O

j.

O

Cl

NaI

23.55 Draw the products formed (including stereoisomers) in each reaction.

a. [1] LDA[2]

O

CI b. [1] LDA

D

C

H

O

[2]CH3 I

c. [1] LDA

H

O

[2] CH3I

23.56 a. Identify intermediates AC in the following stepwise conversion of p-isobutylbenzaldehyde to the analgesic ibuprofen.

NaBH4CH3OH

H3O+

[1] PBr3[2] NaCN

[1] LDA[2] CH3I

COOH

p-isobutylbenzaldehyde

CHO

ibuprofen

A B C

b. Direct alkylation of D by treatment with one equivalent of LDA and CH3I does not form ibuprofen. Identify the product of this

reaction and explain how it is formed.

COOH

D


23.57 a. Clopidogrel is the generic name for Plavix, a drug used to prevent the formation of blood clots in patients that have a history

of heart attacks or strokes. The racemic drug can be prepared from the racemic -halo ester by the following reaction. What is the structure of clopidogrel?

Cl

Cl

CO2CH3

K2CO3clopidogrel(racemic)

NH

S+

b. A single enantiomer of clopidogrel can be prepared in three steps from the chiral -hydroxy acid A. Identify B and C in the following reaction sequence, and designate the con! guration of the enantiomer formed by this route as R or S.

Cl

HO

NH

Sclopidogrel

(single enantiomer)H2SO4CH3OH

pyridineTsCl

A

B C

H COOH

23.58 What reaction conditionsbase, solvent, and temperatureare needed to convert ketone A to either B or C by an

intramolecular alkylation reaction?

O O O

Bror

A B C

23.59 Explain why each of the following reactions will not proceed as written.

a. CO2COOH

O O

+ c.

O O

[1] LDA[2] CH3CH2I

b. [1] NaOEt[2] (CH3CH2)3CBr

CH2(CO2Et)2 (CH3CH2)3CCH(CO2Et)2

Mechanism

23.60 Draw a stepwise mechanism showing how two alkylation products are formed in the following reaction.

O

+ +

OO

[1] LDA[2] CH3I

I

23.61 Draw a stepwise mechanism for the following reaction.

CH2(CO2Et)2 O[1] NaOEt[2][3] H3O+

CO2Et

OO

23.62 Draw stepwise mechanisms illustrating how each product is formed.

O

BrC6H5

C6H5LDA

KOC(CH3)3(CH3)3COH

O

major product

C6H5

O

major product

O

C6H5 C6H5

O+

+

+

O

C6H5

23.63 A key step in the synthesis of -vetivone, a major constituent of vetiver, a perennial grass found in tropical and subtropical regions of the world, involved the reaction of compound A and dihalide B with two equivalents of LDA to form C. Draw a stepwise

mechanism for this reaction. -Vetivone contains a spiro ring systemthat is, two rings that share a single carbon atom.OCH2CH3 CI

CI

LDA(2 equiv)

O+

A

OCH2CH3O

CB

O

two steps

-vetivone

Synthesis

23.64 Convert acetophenone (C6H5COCH3) into each of the following compounds. You may use any other organic compounds or

required inorganic reagents. More than one step may be required.

a.

ONHC(CH3)3

b.

COOH c.

OH

d.

O

23.65 Synthesize each compound from cyclohexanone and organic halides having 4 Cs. You may use any other inorganic reagents.

a.

OBr

c.

OH

e.

O

g.

O

b.

OOCH3

d.

O

f.

O

h.

O

23.66 Bupropion, sold under the trade name of Zyban, is an antidepressant that was approved to aid smoking cessation in 1997.

Devise a synthesis of bupropion from benzene, organic compounds that have fewer than ! ve carbons, and any required inorganic

reagents.

O

Cl

NHC(CH3)3+

bupropion

organic compounds with < 5 Cs

Problems 913


23.67 Synthesize each product from ethyl acetoacetate (CH3COCH2CO2Et) and the given starting material. You may also use any

other organic compounds or required inorganic reagents.

a. OHO

O

c.

CH3

OH

b.

O

HC CCH2Br

23.68 Synthesize each compound from 3-pentanone [(CH3CH2)2CO]. You may also use benzene, organic alcohols having 3 Cs, and any required inorganic reagents.

a.

HNCH2CH3

O

b.

OH

c.

O

C6H5 d. OH

C6H5

23.69 Treatment of ketone A with LDA followed by CH3CH2I did not form the desired alkylation product B. What product was formed instead? Devise a multistep method to convert A to B, a synthetic intermediate used to prepare the anticancer drug tamoxifen

(Section 23.8C and the chapter-opening molecule).

HO

O

A

HO

B

O

23.70 Capsaicin, the spicy component of hot peppers, can be prepared from amine X and acid chloride Y. Devise a synthesis of Y

from (4E)-6-methyl-4-hepten-1-ol [(CH3)2CHCHCH(CH2)3OH], CH2(CO2Et)2, and any required inorganic reagents.

HO

CH3O

X Y

NH2

HO

capsaicin

CH3O NH+ CI

OO

Spectroscopy

23.71 Treatment of W with CH3Li, followed by CH3I, affords compound Y (C7H14O) as the major product. Y shows a strong absorption in its IR spectrum at 1713 cm1, and its 1H NMR spectrum is given below. (a) Propose a structure for Y. (b) Draw a stepwise

mechanism for the conversion of W to Y.

W

Y

O

O [1] CH3Li[2] CH3I

1 H

ppm

1H NMR of Y

8 7 6 5 4 3 2 1 0

2 H

2 H

6 H

3 H

Challenge Problems

23.72 Explain why Ha is much less acidic than Hb. Then draw a mechanism for the following reaction.

HHb CO2CH3

O OH

[1] NaOCH3

[3] H2O

[2]

Ha

CO2CH3

Br

23.73 The last step in the synthesis of -vetivone (Problem 23.63) involves treatment of C with CH3Li to form an intermediate X, which forms -vetivone with aqueous acid. Identify the structure of X and draw a mechanism for converting X to -vetivone.

OCH2CH3O

C

CH3Li H3O+O

-vetivone

[X]

23.74 Keeping in mind the mechanism for the dissolving metal reduction of alkynes to trans alkenes in Chapter 12, write a stepwise

mechanism for the following reaction, which involves the conversion of an ,-unsaturated carbonyl compound to a carbonyl compound with a new alkyl group on the carbon.

[1] Li, NH3[2] RX

OR

O

X+

Problems 915

[3] Dieckmann reaction (24.7)

a. With 1,6-diesters: [2] H3O+[1] NaOEt

OEt

OEt

OO C OEt

OO

b. With 1,7-diesters: [2] H3O+[1] NaOEt

OEt

COEt

OOOEt

OO

PROBLEMS

The Aldol Reaction

24.27 Draw the product formed from an aldol reaction with the given starting material(s) using OH, H2O.

a. (CH3)2CHCHO only

b. (CH3)2CHCHO + CH2 O

c. C6H5CHO + CH3CH2CH2CHO f. + C6H5CHO

O

d. (CH3CH2)2C O only

e. (CH3CH2)2C O + CH2 O

24.28 What four -hydroxy aldehydes are formed by a crossed aldol reaction of CH3CH2CH2CHO and C6H5CH2CHO? 24.29 Draw the product formed in each directed aldol reaction.

a. [2] CH3CH2CH2CHO[3] H2O

[1] LDAC

CH3 CH3

O b. [2]

[3] H2O

[1] LDAC

CH3CH2 OEt

O

O OCHO

24.30 Draw the product formed when each dicarbonyl compound undergoes an intramolecular aldol reaction followed by dehydration.

a.

O

CHO b. CHOOHC c.

O O

24.31 What starting materials are needed to synthesize each compound using an aldol or similar reaction?

a.

O OH b. C6H5

O

c.

O

d. C6H5

O

C6H5

e.

CH3

CH CHCN

24.32 A published synthesis of the analgesic nabumetone uses a crossed aldol reaction to form X. What is the structure of X? X

is converted to nabumetone in one step by hydrogenation with H2 and Pd-C. (See Problem 23.29 for another way to make

nabumetone.)

CHOXNaOEt

EtOHCH3O nabumetone

O

CH3O

(CH3)2C OPd-C

H2

Problems 941

24.33 What dicarbonyl compound is needed to prepare each compound by an intramolecular aldol reaction?

a.

O

b.

O

c.

O

d.

O

HO

24.34 Identify the structures of C and D in the following reaction sequence.

C10H14O[2] (CH3)2S

C DNaOHH2O

[1] O3

The Claisen and Dieckmann Reactions

24.35 Draw the Claisen product formed from each ester.

a. C6H5CH2CH2CH2CO2Et c. CH2COOEtCH3O b. (CH3)2CHCH2CH2CH2CO2Et

24.36 What four compounds are formed from the crossed Claisen reaction of CH3CH2CH2CH2CO2Et and CH3CH2CO2Et?

24.37 Draw the product formed from a Claisen reaction with the given starting materials using OEt, EtOH.

a. CH3CH2CH2CO2Et only

b. CH3CH2CH2CO2Et + C6H5CO2Et

c. CH3CH2CH2CO2Et + (CH3)2C O g. + HCO2Et

O

O h. +

O

CCl OEt

O

d. EtO2CC(CH3)2CH2CH2CH2CO2Et

e. C6H5COCH2CH3 + C6H5CO2Et

f. CH3CH2CO2Et + (EtO)2C O

24.38 What starting materials are needed to synthesize each compound by a crossed Claisen reaction?

a. CH3O

O

CO2Et b.

O

C6H5

O

c.

OCHO d. C6H5CH(COOEt)2

24.39 The 1,3-diketone shown below can be prepared by two different Claisen reactionsnamely, one that forms bond (a) and one

that forms bond (b). What starting materials are needed for each of these reactions?

O

bond (a) bond (b)

O

24.40 Even though B contains three ester groups, a single Dieckmann product results when B is treated with NaOCH3 in CH3OH,

followed by H3O+. Draw the structure and explain why it is the only product formed.

O

OCH3CH3O

O

OCH3O

B

942 Chapter 24 Carbonyl Condensation Reactions

Michael Reaction

24.41 Draw the product formed from a Michael reaction with the given starting materials using OEt, EtOH.

a.

O OC6H5C6H5+ c.

O

CH2(CN)2+

b.

O

CO2Et+

O

d. +

OO

CO2Et

24.42 What starting materials are needed to prepare each compound using a Michael reaction?

a.

O

O

O

b.

CO2Et

OO

c.

CO2Et

O

C6H5

d.

O

CN

CO2Et

24.43 -Vetivone is isolated from vetiver, a perennial grass that yields a variety of compounds used in traditional eastern medicine, pest control, and fragrance. In one synthesis, ketone A is converted to -vetivone by a two-step process: Michael reaction, followed by intramolecular aldol reaction. (a) What Michael acceptor is needed for the conjugate addition? (See Problem 23.63

for another method to form the bicyclic ring system of -vetivone.) (b) Draw a stepwise mechanism for the aldol reaction, which forms the six-membered ring.

O

OA -vetivone

aldolreaction

O O

Michaelreaction

Robinson Annulation

24.44 Draw the product of each Robinson annulation from the given starting materials using OH in H2O solution.

a.

O

O

O+ c.

OO

+

b. +

O O

C6H5 d.

OO

+

24.45 What starting materials are needed to synthesize each compound using a Robinson annulation?

a.

O

O b.

O c.

O d.

O

Problems 943

Reactions

24.46 Draw the organic products formed when butanal (CH3CH2CH2CHO) is treated with each reagent.

a. OH, H2O f. NaBH4, CH3OH k. CrO3, H2SO4 b. OH, CH2 O, H2O g. H2, Pd-C l. Br2, CH3COOH

c. [1] LDA; [2] CH3CHO; [3] H2O h. HOCH2CH2OH, TsOH m. Ph3P CH2 d. CH2(CO2Et)2, NaOEt, EtOH i. CH3NH2, mild acid n. NaCN, HCl

e. [1] CH3Li; [2] H2O j. (CH3)2NH, mild acid o. [1] LDA; [2] CH3I

24.47 Draw the organic products formed in each reaction.

a.

O

H2OOH

e. [2] CH3CH2CHO[3] H2O

[1] LDAC

CH3 CH3

O

b.

O

(CH3)2C=ONaOEt, EtOH

O f. + CH3OH

NaOCH3O

O

C6H5

c.

O

NaOEt, EtOHNCCH2CO2Et g. + H2O

OH

C6H5

CHO O

d. + CCH3 CH3

O

H2OOH

O CHO h.

CH2CO2Et

CH2CO2Et[2] H3O+[1] NaOEt, EtOH

24.48 Fill in the lettered reagents needed for each reaction.

O

A

G

O

O

CO2Et

H

B

O

CO2EtC

O HO

D

E F K

OI J

OO

H

O

O

O

O

24.49 Explain why vinyl halides such as CH2 CHCl undergo elimination by an E1cB mechanism more readily than alkyl halides such

as CH3CH2Cl.

24.50 Identify lettered intermediates AD in the following reaction sequence.

[2] (CH3)2SA

CrO3H2SO4H2O

B

EtOHH2SO4

D

C13H20O2

C

[1] NaOEt, EtOH[2] H3O+

[1] O3


24.51 Identify compounds A and B, two synthetic intermediates in the 1979 synthesis of the plant growth hormone gibberellic acid by

Corey and Smith. Gibberellic acid induces cell division and elongation, thus making plants tall and leaves large.

H

OHHHO

O

CO

CO2H

O

O

[1] O3[2] (CH3)2S

C15H22O4

NaOHEtOH

Aseveral steps

gibberellic acid

B

Mechanisms

24.52 When acetaldehyde (CH3CHO) is treated with three equivalents of formaldehyde (CH2 O) in the presence of aqueous Na2CO3,

(HOCH2)3CCHO is formed as product. Draw a stepwise mechanism for this process.

24.53 In theory, the intramolecular aldol reaction of 6-oxoheptanal could yield the three compounds shown. It turns out, though, that

1-acetylcyclopentene is by far the major product. Why are the other two compounds formed in only minor amounts? Draw a

stepwise mechanism to show how all three products are formed.

OO

CHO6-oxoheptanal 1-acetylcyclopentene

major product

+ +OHH2O

OCHO

24.54 Draw a stepwise mechanism for each cyclization reaction.

a. [2] H3O+[1] NaOEt, EtOH

O OO

CO2Et

b. [2] H2O[1] NaOCH3 O

OOCOOCH3

OCH3OOC

24.55 Draw a stepwise mechanism for the following variation of the aldol reaction, often called a nitro aldol reaction.

CC6H5 H

OOHH2O

CH3NO2 C6H5CH+ CHNO2

24.56 Draw a stepwise mechanism for the following Robinson annulation. This reaction was a key step in a synthesis of the steroid

cortisone by R. B. Woodward and co-workers at Harvard University in 1951.

O+

O O

O

O

ONaOH

cortisone

H2O severalsteps

OH

OH

Problems 945

24.57 Green polymer synthesisthe preparation of polymers by environmentally friendly methods using starting materials that are not

derived from petroleumis an active area of research. One example is the polymerization of tulipalin A, a natural product

derived from tulips, to afford polytulipalin. Polytulipalin has properties similar to some petroleum-derived polymers, but its

availability from a natural source has made it a possible attractive alternative to these polymers. Polymerization occurs in the

presence of a strong base (B:), and each new C C bond in polytulipalin is formed by a Michael reaction. Draw a stepwise

mechanism for the formation of one C C bond in polytulipalin. (See Section 30.8 for other aspects of green polymer chemistry.)

tulipalin A(-methylene--butyrolactone)

polytulipalin

O B

OO

O

BO

OO

O

new C C bonds

24.58 Coumarin, a naturally occurring compound isolated from lavender, sweet clover, and tonka bean, is made in the laboratory from

o-hydroxybenzaldehyde by the reaction depicted below. Draw a stepwise mechanism for this reaction. Coumarin derivatives are

useful synthetic anticoagulants.

o -hydroxybenzaldehyde

CHO

OH

OC

OCH3COO Na+ CH3COOH++ H2O+

coumarin

O O

OC

CH3CH3

24.59 (a) Draw a stepwise mechanism for the reaction of ethyl 2,4-hexadienoate with diethyl oxalate in the presence of base. (b) How

does your mechanism explain why a new carboncarbon bond forms on C6? (c) Why is this reaction an example of a crossed

Claisen reaction?

+ +

OCO2Et

ethyl 2,4-hexadienoate

(CO2Et)2diethyl oxalate

EtOHCO2EtEtO2CEtOHNaOEt

Synthesis

24.60 Convert acetophenone (C6H5COCH3) into each compound. In some cases, more than one step is required. You may use any

other organic compounds or required inorganic reagents.

a.

O

C6H5C6H5 c.

O

C6H5

O e.

OH

C6H5 C6H5

b.

OCHO

C6H5 d.

OH

C6H5

24.61 How would you convert alkene A into ,-unsaturated aldehyde B?CHO

A B

24.62 Synthesize each compound from cyclohexanone and any other organic compounds or required inorganic reagents. More than

one step may be needed.

a.

O

b.

O O

c.

O

O d.

CN

CN e.

O


24.63 Devise a synthesis of each compound from cyclopentanone, benzene, and organic alcohols having 3 C's. You may also use any required organic or inorganic reagents.

a.

O OH

b.

O O

c.

O

C6H5 d.

HO

C6H5 e.

O

24.64 Devise a synthesis of each compound from CH3CH2CH2CO2Et, benzene, and alcohols having 2 C's. You may also use any required organic or inorganic reagents.

a.

OCO2Et b.

OCO2Et c.

OH

OH

C6H5

d.

O

C6H5

O

24.65 Devise a synthesis of each compound from cyclohexene. You may also use any required reagents.

a. CHO b. OH

c.

O

CO2Et d.

O

24.66 Octinoxate is an unsaturated ester used as an active ingredient in sunscreens. (a) What carbonyl compounds are needed to

synthesize this compound using a condensation reaction? (b) Devise a synthesis of octinoxate from the given organic starting

materials and any other needed reagents.

HOoctinoxate

alcohols with < 5 Cs

O

CH3O

O+

General Problems

24.67 Four steps in the synthesis of helminthosporal, a toxin produced by a wheat plant fungus, are shown below.

O O

+

O OCHO

CHO

helminthosporal

OHC

O CHO

NaOEt, EtOH

HCO2EtH3O+

O

O

[1] [2]

[4]

[3]

a. What compounds are needed to carry out Step [1]?

b. What compounds are needed to carry out Step [2]?

c. Write a detailed mechanism for Step [3].

d. Write a detailed mechanism for Step [4]. What is unusual about the product of this reaction?

e. Step [1] adds a formyl group (HCO ) and Step [3] removes it. Why was this apparently unnecessary process done?

Problems 947


Challenge Problems

24.68 Propose a stepwise mechanism for the following reaction of a -keto ester. Suggest a reason why this rearrangement reaction occurs.O

CO2CH2CH3

OCO2CH2CH3

[1] NaOCH2CH3,CH3CH2OH

[2] H3O+

24.69 Isophorone is formed from three molecules of acetone [(CH3)2C O] in the presence of base. Draw a mechanism for this process.

O

isophorone

24.70 Draw a stepwise mechanism for the following reaction. [Hint: Two Michael reactions are needed.]

O

[1] strong base[2] H2O

CO2CH3CO2CH3

O

24.71 4-Methylpyridine reacts with benzaldehyde (C6H5CHO) in the presence of base to form A. (a) Draw a stepwise mechanism for

this reaction. (b) Would you expect 2-methylpyridine or 3-methylpyridine to undergo a similar type of condensation reaction?

Explain why or why not.

4-methylpyridine

CHO NOHH2O

CH3+ H2O+CH NCH

A

Problems 833

glycolysis (p. 826)haloform reaction (p. 796)HellVolhardZelinski (HVZ) reaction

(p. 796)Hunsdiecker reaction (p. 820)

(p. 788)ketoenol interconversion (p. 792)a-hydrogen

ketoenol tautomerization (p. 792)ester (p. 791)

KolbeSchmitt carboxylation reaction(p. 801)

malonic ester synthesis (p. 821)Michael reaction (p. 804)mixed aldol addition (p. 809)

b-ketomixed Claisen condensation (p. 812)Robinson annulation (p. 817)

reaction (p. 793)Stork enamine reaction (p. 805)tautomers (p. 791)

a-substitution

Problems

44. Write a structure for each of the following:a. ethyl acetoacetateb. acidc. a esterd. the enol tautomer of cyclopentanonee. the carboxylic acid obtained from the malonic ester synthesis when the alkyl halide is propyl bromide

45. Give the products of the following reactions:a. diethyl heptanedioate: (1) sodium ethoxide; (2) HClb. pentanoic acid , followed by hydrolysisc. acetate: (1) sodium ethoxide; (2) HCld. diethyl 2-ethylhexanedioate: (1) sodium ethoxide; (2) HCle. diethyl malonate: (1) sodium ethoxide; (2) isobutyl bromide; (3) HCl,f. carbonate: (1) sodium ethoxide; (2) HClg.h.i. cyclopentanone: (1) (2) ethyl bromide; (3) HCl,j. in THF followed by methyl iodidek.l. in m. diethyl (1) excess sodium ethoxide; (2) HCl

46. The chemical shifts of nitromethane, dinitromethane, and trinitromethane are at and Match each chemicalshift with the compound. Explain how chemical shift correlates with

47. a. Explain why a racemic mixture of 2-methyl-1-phenyl-1-butanone is formed when (R)-2-methyl-1-phenyl-1-butanone isdissolved in an acidic or basic aqueous solution.

b. Give an example of another ketone that would undergo acid- or base-catalyzed racemization.

48. Identify AL. (Hint: A shows three singlets in its spectrum with integral ratios and gives a positive iodoform test;see Section 19.4)

1. CH3O

2. CH3Br

HCl, H2O HO

H3O+

AC5H8O3B C D

HCl, H2O

HO

excess

I2excess

SOCl2E H

1. CH3O

2. CH3Br

HCl, H2O

F G

2. HCl

1. CH3O

LI JCH3OH

K

3 : 2 : 31H NMR

pKa .d 7.52.d 4.33,d 6.10,

1,2-benzenedicarboxylate + ethyl acetate:D2Ocyclohexanone + NaOD

2,7-octanedione + sodium hydroxideg-butyrolactone + LDA

H2Opyrrolidine + catalytic H+;vinyl ketone + excess sodium hydroxidedibenzyl ketone + methyl

bromide + sodium hydroxide1,3-cyclohexanedione + allylacetophenone + diethyl

H2O +

acetone + ethyl+ PBr3 + Br2

b-ketoa-methylmalonic

834 C H A P T E R 1 9 Carbonyl Compounds III

49. Show how the following compounds could be prepared from cyclohexanone:

50. A carbonyl compound rearranges to a more stable conjugated compound in the presence of eitheracid or base.a. Propose a mechanism for the base-catalyzed rearrangement.b. Propose a mechanism for the acid-catalyzed rearrangement.

51. There are other condensation reactions similar to the aldol and Claisen condensations:a. The Perkin condensation is the condensation of an aromatic aldehyde and acetic anhydride. Give the product obtained from the

following Perkin condensation:

b. What compound would result if water were added to the product of the Perkin condensation?c. The Knoevenagel condensation is the condensation of an aldehyde or a ketone that has no and a compound such

as diethyl malonate that has an flanked by two electron-withdrawing groups. Give the product obtained from thefollowing Knoevenagel condensation:

d. What product would be obtained if the product of the Knoevenagel condensation were heated in an aqueous acidic solution?

52. The Reformatsky reaction is an addition reaction in which an organozinc reagent is used instead of a Grignard reagent to attack thecarbonyl group of an aldehyde or a ketone. Because the organozinc reagent is less reactive than a Grignard reagent, a nucleophilicaddition to the ester group does not occur. The organozinc reagent is prepared by treating an a-bromo ester with zinc.

CH3CH2O

C2H5OCCH2COC2H5+

O

CH O O

a-carbona-hydrogens

CH3CO

O

CH3COCCH3+

O

CH OO

H3O+ or HO

O O

an , -unsaturatedcarbonyl compound

a , -unsaturatedcarbonyl compound

a,b-unsaturatedb,g-unsaturated

O

COH CHO O

OHO

CH2CH2CH3

CH2CH3

CH2COH

CH2CCH3

CH3

O

O

CCH2CH2CH3O O

O

O

O

O

O

Problems 835

Describe how each of the following compounds could be prepared, using a Reformatsky reaction:

a. c.

b. d.

53. The ketone whose spectrum is shown here was obtained as the product of an acetoacetic ester synthesis. What alkylhalide was used in the synthesis?

54. Indicate how the following compounds could be synthesized from cyclohexanone and any other necessary reagents:

a. c. e.

b. d. f.

55. Compound A with molecular formula has two peaks in its spectrum, both of which are singlets (with ratio ).Compound A reacts with an acidic aqueous solution containing mercuric sulfate to form compound B that gives a positiveiodoform test (Section 19.4) and that has an spectrum that shows two singlets (with ratio ). Identify A and B.3 : 11H NMR

9 : 11H NMRC6H10

OO

COCH2CH3

OOCCH2CH2CH3

(two ways)

O

OCH

OOCH2CH2CCH3

OOCH2CH2CH2CH3

48 7 6910 3 2 1 05(ppm)

frequency

1H NMR

CH3CH2CCH2COCH3

OH

CH2CH3

O

CH3CH2CHCHCOH

OH

CH2CH3

O

CCOHCH3CH2CH

CH3

O

CH3CH2CH2CHCH2COCH3

OH O

CH3CH2CH +

O

CH3CHCOCH3ZnBr

an organozincreagent

a -hydroxy ester

O

CH3CH2CHCHCOCH3CH3

H2O

OO+ZnBr

CH3CH2CHCHCOCH3CH3

OOH


56. Indicate how each of the following compounds could be synthesized from the given starting material and any other necessaryreagents:

a. d.

b. e.

c. f.

57. Bupropion hydrochloride is an antidepressant marketed under the trade name Wellbutrin. Propose a synthesis of bupropionhydrochloride, starting with benzene.

58. What reagents would be required to carry out the following transformations?

59. Give the products of the following reactions:

a.

b.

60. a. Show how the amino acid alanine can be synthesized from propanoic acid.b. Show how the amino acid glycine can be synthesized from phthalimide and diethyl 2-bromomalonate.

CH3CHCOO

+NH3alanine

CH2COO

+NH3glycine

CH

CH+

O O

OO

HO

2 CH3CH2OCCH2CH2COCH2CH3

OO1. CH3CH2O

2. H3O+

O O

CH CH CHCCH3

O

CH CHCOO

CH CHCOCH2CH3

CCHCH3+NH2C(CH3)3Cl

O

Cl

bupropion hydrochloride

OOO

(CH2)2CH3CH3CH2OC(CH2)4COCH2CH3CCH2CH3

O

CCH2CH2CH2COH

O O

O O

OO

CH3CCH2COCH2CH3

OO

CH3CCH2

CH3C(CH2)3COCH3OO CH3

CH3

O

O

O

CH3CCH3

O O

CH3CCH2CH

Problems 837

61. Cindy Synthon tried to prepare the following compounds using aldol condensations. Which of these compounds was she successfulin synthesizing? Explain why the other syntheses were not successful.

a. d. g.

b. e. h.

c. f. i.

62. Explain why the following bromoketone forms different bicyclic compounds under different reaction conditions:

63. Explain why the product obtained in the following reactions depends on the number of equivalents of base used in the reaction:

64. A Mannich reaction puts an group on the of a carbon acid. Propose a mechanism for the reaction.

OCH2N

HCH

OO

CH3

CH3HNCH3

CH3++

catalyticH+

a-carbonNCH2

CH3CCH2COCH2CH3

OO

CH3CCHCOCH2CH3

O

CH3

O1. CH3CH2O one equivalent

2. CH3Br

CH3CCH2COCH2CH3

OO

CH3CH2CCH2COCH2CH3

OO1. CH3CH2O two equivalents

2. CH3Br3. H3O

+

25 C

LDATHF

78 C

CH3O

CH3OHC

CH3

CH3

Br

O

CO

O

O

CH3CCH2CH

CH3

CCH

CH3

CH3CH

OO

CH2CH3

CCCH2CH2CH3

O

CH3CCH

CH3

CCH

CH3

CH3CH2CH3O

O

CH3CH

CH3

CCH

CH

CH3

OO

CH3C

CH3

CHCH

O

CH2 CHCCH3


65. What carbonyl compounds are required to prepare a compound with molecular formula whose spectrum isshown?

66. Ninhydrin reacts with an amino acid to form a purple-colored compound. Propose a mechanism to account for the formation of thecolored compound.

67. A carboxylic acid is formed when an reacts with hydroxide ion. This reaction is called a Favorskii reaction. Proposea mechanism for the following Favorskii reaction. (Hint: In the first step, removes a proton from the that is notbonded to Br; a three-membered ring is formed in the second step; and is a nucleophile in the third step.)

68. Give the products of the following reactions. (Hint: See Problem 67.)

69. An carbonyl compound can be prepared by a reaction known as a selenenylationoxidation reaction. A selenoxideis formed as an intermediate. Propose a mechanism for the reaction.

1. LDA/THF2. C6H5SeBr

a selenoxide

3. H2O2

SeC6H5O

O O O+

a,b-unsaturated

OCCH3O

O OBr

b.a. HOH2O

HO

H2O

CH3CH2CHCOO

CH3

HO

H2OCH3CHCCH2CH3

Br

O

HO-a-carbonHO-

a-haloketone

+

R

H2NCHCO N2

O

+ CO2

+ 3 H2O

+ RCH

OO

O

OH

OH

O

O

O

Oan amino acidninhydrin purple-colored

compound

catalyticH+

8 7 6 5 3 2 1 04 (ppm)

frequency

1H NMRC10H10O

CH3

orsellinic acid

COOH

OHHO

Problems 839

70. a. What carboxylic acid would be formed if the malonic ester synthesis were carried out with one equivalent of malonic ester, oneequivalent of 1,5-dibromopentane, and two equivalents of base?

b. What carboxylic acid would be formed if the malonic ester synthesis were carried out with two equivalents of malonic ester,one equivalent of 1,5-dibromopentane, and two equivalents of base?

71. A Cannizzaro reaction is the reaction of an aldehyde that has no with concentrated aqueous sodium hydroxide. In thisreaction, half the aldehyde is converted to a carboxylic acid and the other half is converted to an alcohol. Propose a reasonablemechanism for the following Cannizzaro reaction:

72. Propose a reasonable mechanism for each of the following reactions:

a. b.

73. The following reaction is known as the benzoin condensation. The reaction will not take place if sodium hydroxide is used insteadof sodium cyanide. Propose a mechanism for the reaction.

74. Orsellinic acid, a common constituent of lichens, is synthesized from the condensation of acetyl thioester and malonyl thioester. Ifa lichen were grown on a medium containing acetate that was radioactively labeled with at the carbonyl carbon, which carbonswould be labeled in orsellinic acid?

14C

C H

O

C CH

OH

ONaC

benzoin

CH3OH

N

O

O

H3O+

HO

OH

OO O

H3O+

O

CH concentrated NaOHO

CO + CH2OH

a-hydrogens

O

HN

O

O

NH

CH2CH2CHCH3

CH3

CH2CH3

Amytal

Hagemanns ester

COCH2CH3

CH3

O

O

75. A compound known as Hagemanns ester can be prepared by treating a mixture of formaldehyde and ethyl acetoacetate first withbase and then with acid and heat. Write the structure for the product of each of the steps.a. The first step is an aldol-like condensation.b. The second step is a Michael addition.c. The third step is an intramolecular aldol condensation.d. The fourth step is a hydrolysis followed by a decarboxylation.

76. Amobarbital is a sedative marketed under the trade name Amytal. Propose a synthesis of amobarbital, using diethyl malonate andurea as two of the starting materials.


77. Propose a reasonable mechanism for each of the following reactions:

a.

b.

78. Tyramine is an alkaloid found in mistletoe, ripe cheese, and putrefied animal tissue. Dopamine is a neurotransmitter involved in theregulation of the central nervous system.

a. Give two ways to prepare from chloride.b. How can be prepared from benzyl chloride?c. How can be prepared from benzaldehyde?d. How can tyramine be prepared from e. How can dopamine be prepared from tyramine?

79. Show how estrone, a steroid hormone, can be prepared from the given starting materials. (Hint: Start with a Robinson annulation.)

80. a. Ketoprofen, like ibuprofen, is an anti-inflammatory analgesic. How could ketoprofen be synthesized from the given startingmaterial?

b. Ketoprofen and ibuprofen both have a propanoic acid substituent (see Problem 70 in Chapter 17). Explain why the identicalsubunits are synthesized in different ways.

O O

CHCOH

CH3

CH3

ketoprofen

O

CH3O CH2CH2CH2CCH CH2+

HOestrone

OH3C

CH3 O

O

HOO

b-phenylethylamine?b-phenylethylamineb-phenylethylamine

b-phenylethylb-phenylethylamine

CH2CH2NH2HO HO

HO

CH2CH2NH2

tyramine dopamine

CH2Br

O O ONO2

OH+

NO2

O

O

CCH3

OCH3CH2CH3CCH2COCH2CH3

OO1. CH3CH2O

2. O

CH2CH3

Taller Parcial 2

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