TOPIC 6: ALDOL REACTIONS AND THE SYNTHESIS AND REACTIONS...

Notes: D.M. Collard, 2009CHEM2312: Spring 2009

TOPIC 6: ALDOL REACTIONS

L

TOPIC 6: ALDOL REACTIONSAND THE SYNTHESIS AND

REACTIONS OF β-DICARBONYL COMPOUNDS (Chapters 17 and 19)

OBJECTIVES1. Provide a rationale for the acidity of α-hydrogens

2. Illustrate the behavior of enols and enolates as nucleophiles inreactions with a variety of electrophiles

3. Develop stategies for the formation of complex molecules form simple t ti t i l b ki b b b dstarting materials by making carbon-carbon bonds

4. Describe the reactions of ester enolates (nucleophiles) with esters (electrophiles) to give β-keto esters via Claisen and crossed Claisen condensatiions.

5. Describe the synthesis of ketones using the above products.

6. Describe the reactions of other active methyene compounds and the synthesis of acid derivativessynthesis of acid derivatives.

7. Describe the preparation and alkylation of enamines.

8. Use this knowledge to predict the products of reactions of this type and to be able to synthesize compounds using these procedures.


REVIEW OF THE ELECTROPHILICITY OF CARBONYLS

Aldehydes and ketones undergo addition-elimination pathways

CO

COH

C

Nucleophile: H-Nu

RNH2

Acid Derivatives undergo substitution via addition-elimination pathways

C CH-Nu .

CNu

NuPh3P-CR2

O O ORCOCl(RCO)2O RCOOH

RCOR'

CL

CNu

Nu

CNu

O (RCO)2ORCOOR'RCONR'2

RCOOH

PREVIEW OF ENOLATE CHEMISTRY

Hydrogens α- to a carbonyl are acidic

OC

CH

OC

C

NaOEt

C CLDA

OC

CC

NaOEtO

H

OC

CCO

Enolates are nucleophilicOC

C

OC

CCO


Enolates react with….

Alkyl halides

OC

C

R Br

OC

CR

Aldehydes andketones C

OCOH

C

OCC

OC

CH

OC

C

Esters COR

OC ORO

CO

OCC

O

CC

OC

C

O

THE ACIDITY OF THE α-HYDROGENS OF CARBONYL COMPOUNDS:

ENOLATE ANIONSProtons α- to Carbonyl Groups are More Acidic ThanOther Protons on Carbon

S:17.1Prob: 17.34

pKa pKa

H3C CH3

H2C CH2

HC CH

OH

O O

H

p a

19.2

9.0

a

50

44

25

O

HR

Note: Protons attached to the carbonyl carbon of aldehydes are not particularly acidic, the conjugate base is not resonance stabilized.


KETO AND ENOL TAUTOMERS S17.2

Base Catalyzed Tautomerization

O O

H

B-HB

Keto and enol forms are in equilibrium

Rapidly interconverting are called tautomers

Acid Catalyzed Tautomerization

O

H

O

H

H A H OH

e.g., H3O+A H A

The keto form is usually more stable

O

H

OHKeq


H

OH

OH

H

OH

OH

K = 3 x 10-7

K = 6 x 10-9

Equilibrium Constants for Tautomerization

H

OH

O O

OH

K = 1 x 10-2

K = 4

OH

H

K > 10+13

OO OHO

a b

OH

O

b

C

C D C

a

bD


REACTIONS VIA ENOLS ANDENOLATE ANIONS

Preview: Both Enols and enolates are nucleophilic

S:17.3Prob:17.37,39

O O OH

E E E

compare to:

R OH CR2 CR2

NO

Diethylpropion is a stimulant, is marketed as Tenuate™ for appetite suppression. Propose a synthesis of diethylpropion from benzene and any other starting materials. ??


α-Halogenation of Aldehydes and Ketones

Under Acidic conditionsEnolizable protons are subject to substitution with bromine upon treatment with Br2.

Ph CH

O

Ph CH

OBrBr2, H+

Mechanistic Rationale: The nucleophilic enol undergoes reaction with bromine

Ph CH3 Ph CH2

Ph CH3

O

Ph CH2

OH Br BrH+

Under basic conditions:

All of the enolizable protons are substituted with bromine and the resulting trihalomethyl group itself is cleaved.

Ph CH3

O

Ph O

OBr2, HO-

CHBr3

Mechanistic Rationale:

1. The nucleophilic enolate undergoes reaction with bromine

Ph CH2

O

Ph CH2

O Br BrH HO

All enolizable H’s substituted with Br


Ph CBr3

OHO

Cl2 HCCl3 - chloroform

Br2 HCBr3 - bromoform

I2 HCI3 - iodoform pale yellow solidgood test for presenceof a methyl ketone

Chemical Tests for Functional GroupsMethyl ketones give positive iodoform test

I2, NaOHin EtOH, H2O


α-Halo Carboxylic AcidsHell-Volhard-Zelinski reaction

OH

OH

1. P, Br22. H2O

Reactions of α-halo acids http://cc.oulu.fi/~genetwww/

OH

OBr

1. NaOH2. H3O+

http

://w

ww

.lef.o

rg/p

rod_

desc

/item

0012

8.ht

ml

OH

OBr

NH3

OH

OBr

KCN

Racemization of Aldehydes and Ketones

Experimental Observation: Compounds with a stereogenic center bearing a hydrogen atom adjacent to a carbonyl group undergo rapid racemization in mildly acidic or basic conditions.

O OHO or H

PhPh

MeHPh

Ph

HMe


Mechanistic Rationale:

Ph

OH

MePh

HO

OHO

CH3

H

Ibuprofen• Ibuprofen marketed as racemate• Only the S isomer is active• Body converts R to S by

inversion of stereogenic centeradjacent to carbonyl

H/D Exchange ReactionsExperimental Observation: Treatment of ketones with NaOD/D2O results in replacement of α-hydrogen atoms with deuerium.

NaODD2O

O O via

H

H

H

D

D

H

NaODD2O

via

OH OH

D

D

OD


O ODD

NaODD2O

O

DD

via allylic anion

NaODD2O

O

H-D exchangeH

O


?? Problems 17.37,39 ??

THE ALDOL REACTION: ADDITION OF ENOLATES TO ALDEHYDES & KETONES –

SYNTHESIS OF 3-HYDROXY CARBONYL COMPOUNDS AND α,β-UNSATURATED

CARBONYL COMPOUNDS

Th Ald l R ti Th R ti f Ald h d ith

S:17.4,5Prob:17.31,

33,35

L

The Aldol Reaction: The Reaction of an Aldehyde with an Aldehyde Enolate

H3C H

O NaOH, H2O5 oC


H3C H

O NaOH, H2OΔ

Aldol CondensationHeating causes dehydration to form α,β-unsaturated aldehyde

Mechanism:

O

H

H3CH

OH

H

OPh

NaOH, H2OΔ

e.g.

Recognizing Products and Starting Materials of Aldol ReactionsAldol condensations give α,β-unsaturated carbonyl compounds

H

O

H


Crossed-Aldol (or “Mixed Aldol”) ReactionsProblem: Propose starting materials to prepare 2-methyl-2-pentenal by an aldol reaction

H

O

H

Mixed aldols between two aldehydes with enolizable protons can givefour different products

H

OOO

H

O

H

O NaOH, H2OΔ

H

HHH

H

O

H

O

H

OH

O

O

H

H

H

O

H

H

O H

H

O H

O


Crossed aldol condensations are only useful when one of the components is non-enolizable and a good electrophile (e.g., an aldehyde)

e.g.,

H

O

H H

O O

HCH3C

CH3H3C

H

O

H3C H

O NaOH, H2OΔ

Examples of Aldol Reactions with Ketones

H

O

H3C CH3

O NaOH, H2OΔ

H3C CH3

O NaOH, H2OΔ

Remember: Avoid proposing crossed-aldol reactions if both components are enolizable


Problem [Solomons 17.31b] - How would you achieve the following transformation? ??

Ph H

O

O

PhCH

Aldol Reactions are also Catalyzed by Acid….Problem: Write the mechanistic steps of the following reaction (show curved arrows and intermediates)

H3C CH3

O H3O+

Δ CH3

O

CHH C3 3 CH3H3C

O protonation

C deprotonation C=O deprotonation

OH protonation

elimination acidcatalyzed

dehydration(Org-I)

CH3

O

OHH3CH3C

H2C CH3

OH

H

H2C CH3

OH

CH3

OH

OHH3CH3C

C deprotonation

nucleophilicaddition

C=O deprotonation

H3C CH3

O


… and ReversibleThe aldol reaction is reversible. The reverse reaction proceeds through exactly the same intermediates as the forward reaction.Problem: Write the mechanistic steps of the following reaction (show curved arrows and intermediates).

H3C CH3

OCH3

O

CHH C

H3O+

Δ

CH3H3C

CH3

O

OHH3CH3C

H2C CH3

OH

H

O deprotonation

C protonation C=O protonation

deprotonation

addition

H2C CH3

OH

CH3

OH

OHH3CH3CH3C CH3

O

C protonation

elimination

C O protonation

Problem: Pulegone, which has a pleasant peppermint-camphor smell, is isolated from the oil of pennyroyal (pennyroyal tea is commonly used as an herbal remedy; pulegone is extremely toxic). Treatment of pulegone with steam yields 3-methylcyclohexanone. Propose a pathway for this reaction. What is the byproduct of this reaction.

O

http://wicca.com/celtic/herbal/images/pennyroyal.gif


Cyclizations via Aldol CondensationsS:17.6

O O NaOH, H2OΔ

OnotO

O O

O O+

S:17.6O NaOH, H2OΔ

O

H

OO

O

CH3

H

major product

H3CO

H

H3C

OH

+

H

CH3

O

CH3

H

CH3

O

CH3

O

H3CO H

H2C

O

O

H

+

CH

O

H

H

CH2

O

O

O

H


??Problem [Solomons 17.33] – Identify the structures of compounds A-C.

HC CH A (C5H8O) C (C12H14O2)B (C5H10O2)

1. NaNH22. acetone3. NH4Cl, H2O

Hg2+, H3O+

H2OPhCHO NaOH

?? Problems 17.31,33,35 ??


ALKYLATION OF ALDEHYDES AND KETONES

Problem:With OH¯ or EtO¯, enolates are generated in equilibrium. They are not isolated, but react in situ with a second molecule of carbonyl compound (aldehyde or ketone) in an aldol reaction.

S.19.11Prob.19.50

L

CH3 CH3

O

CH3 CH2

ONa OH H2ONa

pKa = 20 pKa = 16

Keq=10-4

O O

R BrNaOEt R

O O

R Br R1. LDA2.

Solutions:

1. Use a much stronger base – lithium diisopropylamide (LDA)

ONN

HR Br1.

2. H2O

OR

2. Convert ketone to enamine, alkylate and hydrolyze

enamine2° amine


Lithium EnolatesUse of a stronger base (e.g., lithium diisopropylamide, LDA) allows for generation of the lithium enolate, and then, in a separate step, the addition of an electrophile.

LiNO O N HKeq=1018

S:17.7Prob:17.34

Lithium Enolates in Alkylation Reactions

CH3 CH3 CH3 CH2Li

N H

pKa = 20 pKa = 38

Keq 10

O1. LDA in THF, -78 oC2. R-Br (1o R)

3. H3O

O OR

The Effect of Temperature on the Alkylation of Lithium Enolates: Kinetic and Thermodynamic ProductsThe regiochemistry of lithiation is controlled by temperature

Oo O

Major Product via:

O

O

1. LDA -78 oC2. kinetic

product

R Br

1. LDA room temp2. R Br

O

R

Rthermodynamic

product

R


Lithium Enolates in Directed Crossed-aldol Reactions

OO

1. LDA in THF, -78 oC2.

3. H3O

H

O

OHH

H

O

OH

H

O

OH

O

OH

not:

H OH OHHOH

Synthesis of EnaminesRecall that aldehydes and ketones react with primary amines to form imines. Analogous reactions with secondary amines form enamines.

1° amines

O NCH3HO N CH3

H

2° amines

+ H3C NH2 + H2O

imine

ON

NH3C

HN CH3

CH3

HO

3

+ + H2O

enamine

NH3C

H


Examples of Enamines Reacting as Nucleophiles

N 1. CH3COCl

2. H3O+

H

N(CH3)2

1. PhCH2Cl

2. H3O+

1 CNN

1.

2. H3O+

CN

α,β-UNSATURATED CARBONYL COMPOUNDS

Synthesis of α,β-unsaturated Carbonyl Compounds

Aldol reactions (see above)

S17.8,9Prob:17.32

α-Selenation

Ph

O

Ph

O

1. LDA in THF, -78 oC2. PhSeCl3. H2O2

Ph Ph


Selective Reduction of α,β-Unsaturated Carbonyl Compounds

O

H

H3C H

H2 (high pressure) Ni

H2 (2-3 atm)

Pd

LiAlH4

O OO

Electron Distribution in α,β-unsaturated Ketones

O

In the absence of the electron-withdrawing C=O, akenes are weakly nucleophilic.


Nucleophilic Additions to α,β-unsaturated Ketones

O

Nu

1,2-addition

conjugaadjugate

additionNucleophile (Nu )

RMgBrRLi

CNRNH2R2CuLienolate anions

Use of Nucleophilicity of Enolates and Electrophilicityof Enones in the Design of Syntheses.

OR

OR Br

O

R

O

R MR R M


β-DICARBONYL COMPOUNDS:INTRODUCTION

S.19.1

O

R

O

β di b l

Oαβ

OR'

O

R

O

R'

O

β diketoneβ keto ester

RO

O

OR'

O

β diester

L

β−dicarbonyl β−diketoneβ−keto ester

O O

H

+ B

O O

+ B H

β−diester

Question: Why is the β-dicarbonyl system more acidic than an alcohol (pKa~18)?

HpKa~10

O O O O O O

Answer: The anion is stabilized by resonance

O O

H

Consequently, there is a lot of enol in equilibrium


SYNTHESIS OF 1,3-DICARBONYL COMPOUNDS: THE CLAISEN CONDENSATION

Overall Reaction: The Reaction of Ester Enolates with Esters

S:19.2Prob:19.25,41

O O O1. NaOEt

OEt OEtHH

EtOH2. H3O+2

+ EtOHH

HH

OEt

OOEt

OH

HH

OEt

O 1. NaOEt EtOH2. H3O+2

H

PhH

HH

MechanismFirst step – formation of enolate

OEt

OH

HR

Question: How much enolate forms? What are the pKa values?

O Et


Second step - attack of enolate (nucleophile) on the carbonyl carbon (electrophile) of another molecule of ester

OEt

OH

HRO

OEtH

R

Question: Is this reaction favorable?

Third step - deprotonation of β-dicarbonyl compound(product) to form enolate

O

OEt

O

HR

R

Question: Is this reaction favorable? What are the pKa values?

O Et


Fourth step - protonation of enolate to form the β-dicarbonyl product by addition of acid

O

OEt

O

RO

H

R

H

Question: It this reaction favorable? What are the pKa values?

OH

free

ener

gy

DeprotonationK 1

Gib

bs

RCH2COEt

NaO O O

O

O Na

DeprotonationK<1

(ester is weaker acid than ethanol)

Nucleophilic addition

K<1(C=O → C-O)

Elimination

K>1(1,3-dicarbonyl is

stronger acid than ethanol)

RCH2COEt

Na OEt

2

RCHCOEt

Na

HOEt

Na OEt

HOEt 2 HOEtHOEt

CRCH2

RCHCOEt

O

CRCH2

RCHCOEt

O

OEt CRCHRCCOEt

O

O

O


So, why does the reaction fail when the ester has two substituents on the αcarbon?

OEt

OH

RR

1. NaOEt EtOH2. H3O+2 No Reaction

ROEt

OR

H

O Et O

OEt

OR

R

ROEt

O

R

ROEt

OR

H

R H

R

O Et

Cyclizations via Claisen Condensation

EtO

O O

OEt

1. NaOEt EtOH

2. H3O+

O O

OEt

O O

OEt

not

+

EtO

O O

OEt

O O

O O

OEt

O O

OEt

O O

OEtEtO OEt

OEt


Crossed Claisen and other CondensationsRemember the rule for crossed aldol condensation reactions (i.e., one component cannot form an enolate)

1. NaOEt EtOH

2. H3O++

Ph OEt

O

H3C OEt

O

1. NaOEt EtOH

2. H3O+

O

+H OEt

O

1. NaOEtO O

EtOH

2. H3O++ OEt

EtO

Oethyl oxalate

Problem – How would you achieve the following transformations?

??O

OEt OEt

OO

PhO

OEtPh

OEt

O

OH


?? Problems 19.25,41 ??

THE ACETOACETIC ESTER SYNTHESIS: SYNTHESIS OF METHYL KETONES

Overall reaction

S:19.3Prob: 19.26

L

1. NaOEt, EtOH2. R-X

3. H2OOEt

OO

OEt

OO

R

1. NaOH H2O

2. H3O+ heat

RO

R=CH3, 1°

Reminder: Simple esters cannot be alkylated in this fashion

1. NaOEt, EtOH2. R-X

3. H2OOEt

O

OEt

OR


PathwayDeprotonation: Enolate formation

OEt

OO

OEt

O

H

+ EtOHO NaOEt

Alkylation

O

OEt

O

H

R X

SaponificationS:18.10

OEt

OO1. NaOH2. H3O+

ROH

OO

R

Decarboxylation of β-Keto Carboxylic Acids

OH

OO heat to100-150 °C

R

O

OOH

R


Examples

O

OEt

O1. NaOEt, CH3I2. NaOEt, CH3CH2Br

3. H2O. NaOH4. H3O+, heat

O

OEt

O1. NaOEt BrCH2CO2Et

2. H2O. NaOH3. H3O+, heat

Synthetic Design

OH


O

O

THE MALONIC ESTER SYNTHESIS: SYNTHESIS OF SUBSTITUTED ACETIC ACIDS

S:19.4Prob: 19.27

Overall reaction

OO

OEt

O

EtO

O 1. NaOHH2O

OH

O1. NaOEt, EtOH2. R-X

OEtEtO OEtEtOR

2

2. H3O+

heat

OH

R=CH3, 1° (2°)

R3. H2O


MechanismDeprotonation: Enolate formation

OEt

OEtO

O

OEt

O

H

+ EtOHEtO

O NaOEt

Alkylation

EtO

O

OEt

O

H

R X

EtO

O

OEt

O

R H

Ester hydrolysis (see 18.7B) and decarboxylation (see 18.10)

EtO

O

OEt

O

H RHO

O

OH

O

R HHO

OH

R H

Examples

EtO

O

OEt

O 1. NaOEt, CH3I

2. H2O, NaOH3. H3O+, heat

1. NaOEt

EtO

O

OEt

O

O O1. 2NaOEt Br(CH2)3Br

2. H2O, NaOH3. H3O+, heat

BrCH2COPh

EtO OEt 2. H2O, NaOH3. H3O+, heat


PRSPRS

What is the major organic product of the following sequence of reactions?

OO1. NaOEt, EtOH2. PhCH2Br

1. NaOH, H2O2. H3O+

3 heat1. LiAlH42 H2O

11 22 33

OEtEtO

O

OHPh

O

HPh

O

2. PhCH2Br 3. heat 2. H2O

Ph

OH

44 55 66

OHPh OHPh

Ph

Synthetic Design Using Malonate Ester Synthesis

HO OH

Ph


O O

Problem [Solomons 19.26e,27] - How would you achieve the following transformations? ??OHOEt

OO OH

EtO OEt

OOOH


?? Problems 19.36 ??

EtO

O

OEt

O+

H2NO

H2N

NaOEt

NH

NHO

O-2EtOH

S:19.12Prob: 19.27

O

barbituric acid (pKa~4)

O O+

H2N NaOEt NHO

OPh

EtO OEt+ O

H2N NHO

O

phenobarbital - a highlyaddictive sleep inducerand tranquilizer

Ph

How would yousynthesize this malonicester? (see prob. 19.24)

-2EtOH


Michael additionConjugate addition of a stabilized enolate to an α,β-unsaturated carbonyl compound

O

OTHER C-C BOND FORMING REACTIONS

OO

OEtEtO

O

EtONa

Robinson annulationMichael addition and subsequent aldol cyclization

O

NaOH, H2O

OO

OOO

O

O

Michael Aldol

O


The Knoevenagel Condensation

Aldol condensation of a stabilized enolate

S:19.8Prob:19.31

O

-H2O1. base

2.

O OO O

OH

O O

e.g.,

H

O

NaOH

O O

OH

OTHER COMPOUNDS WITH ACIDIC HYDROGEN ATOMS ON CARBON

Esters, nitriles and nitroalkanes can also be deprotonated with a strong base (LDA)….

S:19.5

CH3 CO

CH2 CO

L

CH3 C N

O

CH2 C N

O

CH3 COCH3

CH2 COCH3

….and the conjugate bases react as nucleophiles with alkyl halides (alkylation via SN2), carbonyls (addition, or addition-elimination, e.g., aldol reaction), and esters (addition-elimination, e.g., Claisen condensation).

CH3 NO

OCH2 N

O

O


Compounds with two electron withdrawing groups attached to the same carbon are deprotonated with weaker bases (NaOEt, NaOH).

NCNC NC

cyanoacetone

O

OEt

O

H

O

cyanoacetaldehyde ethyl cyanoacetate

NC CN

malonitrile

PhO

phenylacetone

Ph CN

benzylcyanide

Direct Alkylation of Esters, Nitriles, NitroalkanesS:19.6

OEt

O

1. LDA

2. PhCH2Br

Ph C1. NaOEt

2. CH3BrN

NO21. LDA

PhCH CH B2. PhCH2CH2Br


Methadone, a synthetic opioid, is used to treat addiction to heroin. Methadone occupies the opioid receptor in the brain hereby blocking the binding of other drugs from attaching to the receptor.

Br2C

Br

NC

N AlCl3 H

NaOH

CN

N

NCl

N Cl

N

brominationvia enol

Friedel-Crafts alkylation

SN

CN

O

1. EtMgBr

2. HCl(aq)

OH

O O O pKa19.2 enolate

TOPIC 5 REVIEW

Enolate AnionsProtons α- to carbonyl groups are more acidic than other protons on carbon; enotates are nucleophilic

L

H

O O

H

H

E

9.0

R-H(50)

OHE

enol

Enols are nucleophilic


The aldol reaction: The reaction of an aldehyde with an aldehyde enolate

H3C H

O NaOH, H2O5 oC

OH

H3CHHO

-H+

H+

ONaOH, H2O

Δ

H2C H

O

CH3

HO

OH

H3CH

O

H

H3C

heat

-H2O

H3C H

H

OPh

NaOH, H2OΔ

OH

H

Crossed aldol condensations are only useful when one of the components is non-enolizable and a good electrophile (e.g., an aldehyde).e.g.,

H

O

H H

O O

HCH3C

CHH3C

H

O

H3C H

O

CH33

O O

NaOH, H2OΔ

NaOH, H2OΔ

H H3C CH3

Δ


Lithium enolates are useful in directed crossed-aldol reactions and in alkylation reactions

OO

1. LDA in THF, -78 oC2.

3. H3O

H

O

OHH

1. LDA in THF, -78 oC2. R-Br (1o R)

3. H3O

O OR

Additions to α,β-unsaturated ketones

3

ORMgBrRLi

CNRNH2R2CuLienolate anions

Michael addition and subsequent aldol cyclization(Robinson annulation)

O

NaOH, H2O

O O

OOO


The ß-dicarbonyl system more acidic than an alcohol (pKa~18). The anion is stabilized by resonance

The Claisen condensation: the synthesis of ß-keto esters

O O O O O O

OEt

O O

OEt

O1. NaOEt

2. H3O+2

1 NaOEt

+ EtOHH

H R H R

R

O1. NaOEt

2. H3O+2 NROEtH

R R

Crossed Claisen and other CondensationsRemember the rule for crossed aldol condensation reactions (i.e., one component cannot form an enolate)

1. NaOEt EtOH

2. H3O++

Ph OEt

O

H3C OEt

O

1. NaOEt EtOH

2. H3O+

O

+H OEt

O

1. NaOEtEtOH

O OEtO EtOH

2. H3O++ OEt

EtO

O


The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones

OEt

OO

OEt

OO

RR

O1. NaOEt, EtOH2. R-X R=CH3, 1°

3. H2O

1. NaOH H2O

2. H3O+

heat

The Malonic Ester Synthesis: Synthesis of Substituted Acetic Acids

OO OO O1. NaOHH O

1. NaOEt, EtOH2 R X

OEtEtO OEtEtOR

OHR

H2O

2. H3O+

heat

2. R-X R=CH3, 1°

3. H2O

Synthesis Of Enamines

Stork Enamine ReactionsReaction of ketones and aldehydes with secondary amines form enamines

O

+

NNH

nitrogen nucleophilic

carbon nucleophilic- H2O

++ H2O

enamine2° amine

NH3C I

N N


PROBLEM SOLVING AND SYNTHETIC STATEGIES

Problem - Propose a synthetic pathway to achieve the following transformation. O ??

Problem [Solomons 19.39] - How could you prepare Darvon, a powerful analgesic, from ethyl phenyl ketone?

NO

O

O

February 20, 2009yFDA Panel Recommends Davron Be Removed From MarketAn FDA panel, citing safety risks, voted Jan. 30 to remove a pair of painkillers from pharmacy shelves. The panel of outside experts voted to end sales of Davronbecause of concerns that their safety risks outweigh their benefits. Davron (propoxyphene) is a opioidpainkiller used for mild to moderate pain. Like all opioids, it carries a high potential for addiction and abuse and are not safefor addiction and abuse and are not safe when combined with alcohol.


Problem [Solomons 19.38] - Fenchone is a terpenoidisolated from fennel oil. Provide the structure of intermediates and reagents (a)-(n) in the following scheme (cont. next slide). ??

+ (a)

CO2CH3(b)

(c)

(d) mixture of (e) and (f)CO2CH3

CO2CH3

Δ

O

Fenchone

CO2H CO2CH3

(c) and (f)

1. (g)2. (h) (i) (j)

CO2CH32 3

CO2CH3

OOH

CO2CH3

( ) ( ) (j)

O

CO2CH3 CO2CH3

CO CH(k) (l)H3O+

OHCO2CH3 CO2CH3

(m) (n) OO(m) (n) OO


Problem [Solomons 17.32] – Describe the key mechanistic steps in the following reaction (i.e., write a mechanism). ??O

Ph

OO

Ph+

NaOH

?? Problems 19.30,31,50 ??


TOPIC 6 (CHAPTER 17,19) ON EXAM 5

Types of Questions- Predict the products obtained from given starting materials- Rationalize the outcome of a reaction (i.e., propose a mechanism, draw key

intermediates)- Develop multistep synthetic strategies.

Do the problems in the book; they are great examples of the types of problems on the exam!

Preparing for Exam 5- Get up-to-date NOW!- Work as many problems as possible. Do the problems first, then consult the

solutions manual.- Work in groups, discuss chemistry, teach and test each other. - Do the “Learning Group Problem” at the end of the chapter.

TOPIC 6: ALDOL REACTIONS AND THE SYNTHESIS AND REACTIONS...

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