topic 6: aldol reactions and the synthesis and reactions...
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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.
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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.
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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. ??
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
O ODD
NaODD2O
O
DD
via allylic anion
NaODD2O
O
H-D exchangeH
O
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
?? 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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
… 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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
??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 ??
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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.
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
?? 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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
O O
Problem [Solomons 19.26e,27] - How would you achieve the following transformations? ??OHOEt
OO OH
EtO OEt
OOOH
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
?? 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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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.
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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 ??
Notes: D.M. Collard, 2009CHEM2312: Spring 2009
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.
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