dr. wolf's chm 201 & 202 20-1 chapter 20 enols and enolates
TRANSCRIPT
Dr. Wolf's CHM 201 & 202 20-1
Chapter 20Chapter 20Enols and EnolatesEnols and Enolates
Dr. Wolf's CHM 201 & 202 20-2
Aldehyde, Ketone, and Aldehyde, Ketone, and
Ester EnolatesEster Enolates
Dr. Wolf's CHM 201 & 202 20-3
The reference atom is the carbonyl carbon.The reference atom is the carbonyl carbon.
Other carbons are designated Other carbons are designated , , , , , etc. on the , etc. on the
basis of their position with respect to the carbonyl basis of their position with respect to the carbonyl
carbon.carbon.
Hydrogens take the same Greek letter as the Hydrogens take the same Greek letter as the
carbon to which they are attached.carbon to which they are attached.
TerminologyTerminology
CHCH33CHCH22CHCH22CHCH
OO
Dr. Wolf's CHM 201 & 202 20-4
Acidity of Acidity of -Hydrogen-Hydrogen
+ + HH++
RR22CC CR'CR'
OO••••
•••• ••••––
••••
RR22CC CR'CR'
OO ••••
––
••••
OO••••
RR22CC CR'CR'
••••
HH
ppKKaa = 16-20 = 16-20
enolate ionenolate ion
Dr. Wolf's CHM 201 & 202 20-5
Acidity of Acidity of -Hydrogen-Hydrogen
(CH(CH33))22CCHHCHCH
OO CCCCHH33
OO
ppKKaa = 15.5 = 15.5 ppKKaa = 18.3 = 18.3
Dr. Wolf's CHM 201 & 202 20-6
HH33CCCC
CHCH33
OO
CCCC
OO
HH HH
HH33CCCC
CHCH33
OO
CCCC
OO
HH
HH++++••••––
-Diketones are much more acidic-Diketones are much more acidic
ppKKaa = 9 = 9
Dr. Wolf's CHM 201 & 202 20-7
-Diketones are much more acidic-Diketones are much more acidic
HH33CCCC
CHCH33
OO
CCCC
OO
HH
••••––
•••• ••••••••••••
HH33CCCC
CHCH33
OO
CCCC
OO
HH
–– •••• •••••••••••• •••• enolate of enolate of -diketone -diketone
is stabilized; negative is stabilized; negative charge is shared by charge is shared by both oxygensboth oxygens
Dr. Wolf's CHM 201 & 202 20-8
-Diketones are much more acidic-Diketones are much more acidic
HH33CCCC
CHCH33
OO
CCCC
OO
HH
••••––
•••• ••••••••••••
––
HH33CC
HH
CCCHCH33
OO
CCCC
OO•••• ••••
•••••••• ••••
HH33CCCC
CHCH33
OO
CCCC
OO
HH
–– •••• •••••••••••• ••••
Dr. Wolf's CHM 201 & 202 20-9
Esters
Hydrogens Hydrogens to an ester carbonyl group are less to an ester carbonyl group are less acidic, pKacidic, pKaa 24, than 24, than of aldehydes and of aldehydes and
ketones, pKketones, pKaa 16-20. 16-20.
The decreased acidity is due the decreased The decreased acidity is due the decreased electron withdrawing ability of an ester carbonyl.electron withdrawing ability of an ester carbonyl.
Electron delocalization decreases the positive Electron delocalization decreases the positive character of the ester carbonyl group.character of the ester carbonyl group.
OR
H
O
OR
H
O
OR
H
O
Dr. Wolf's CHM 201 & 202 20-10
Esters
A proton on the carbon flanked by the two A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions.quantitatively removed by alkoxide ions.
CCCCRR
CCOR'OR'
HH HH
OO OO
Dr. Wolf's CHM 201 & 202 20-11
CCCCRR
CCOR'OR'
HH HH
OO OO
CCCCRR
CCOR'OR'
HH
OO OO
••••––
ppKKaa ~ 11 ~ 11
CHCH33CHCH22OO––
Dr. Wolf's CHM 201 & 202 20-12
The resulting carbanion is stabilized by The resulting carbanion is stabilized by enolate resonance involving both carbonyl enolate resonance involving both carbonyl groups.groups.
CCCCRR
CCOR'OR'
HH
OO OO
••••––
•••• ••••••••••••
CCCCRR
CCOR'OR'
HH
OO OO–– •••• ••••••••
••••••••
Dr. Wolf's CHM 201 & 202 20-13
The resulting carbanion is stabilized by The resulting carbanion is stabilized by enolate resonance involving both carbonyl enolate resonance involving both carbonyl groups.groups.
CCCCRR
CCOR'OR'
HH
OO OO
••••––
•••• •••••••••••• •••• ••••
CCCCRR
CCOR'OR'
HH
OO OO––•••• ••••••••
Dr. Wolf's CHM 201 & 202 20-14
The Aldol CondensationThe Aldol Condensation
Dr. Wolf's CHM 201 & 202 20-15
A basic solution contains comparable amounts A basic solution contains comparable amounts of the aldehyde and its enolate.of the aldehyde and its enolate.
Aldehydes undergo nucleophilic addition.Aldehydes undergo nucleophilic addition.
Enolate ions are nucleophiles.Enolate ions are nucleophiles.
What about nucleophilic addition of enolate to What about nucleophilic addition of enolate to aldehyde?aldehyde?
RCHRCH22CHCH
OO
++ ••••OHOH••••
••••––
RCHCHRCHCH
OO
++ ••••HOHHOH
••••––••••ppKKaa = 16-20 = 16-20 ppKKaa = 16 = 16
Some thoughts...Some thoughts...
Dr. Wolf's CHM 201 & 202 20-16
••••RCHCHRCHCH
OO•••• ••••
––
RCHRCH22CHCH
OO••••
••••
––
RCHRCH22CHCH
OO••••
••••
•••• ••••
RCHCHRCHCH
OO
••••••••
RCHRCH22CHCH
OO
•••• ••••
RCHCHRCHCH
OO
•••• HH
2RCH2RCH22CHCH
OONaOHNaOH
RCHRCH22CHCH
OHOH
CHCHCHCH
OO
RR
Dr. Wolf's CHM 201 & 202 20-17
product is called an "aldol" because it is product is called an "aldol" because it is both an aldehyde and an alcoholboth an aldehyde and an alcohol
Aldol AdditionAldol Addition
RCHRCH22CHCH
OHOH
CHCHCHCH
OO
RR
Dr. Wolf's CHM 201 & 202 20-18
Aldol Addition of AcetaldehydeAldol Addition of Acetaldehyde
AcetaldolAcetaldol(50%)(50%)
NaOH, HNaOH, H22OO
5°C5°C2CH2CH33CHCH
OO
CHCH33CHCH
OHOH
CHCH22CHCH
OO
Dr. Wolf's CHM 201 & 202 20-19
Aldol Addition of ButanalAldol Addition of Butanal
KOH, HKOH, H22OO 6°C6°C
2CH2CH33CHCH22CHCH22CHCH
OO
(75%)(75%)
CHCH33CHCH22CHCH22CHCH
OHOH
CHCHCHCH
OO
CHCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-20
2RCH2RCH22CHCH
OONaOHNaOH
RCHRCH22CHCH
OHOH
CHCHCHCH
OO
RR
Aldol CondensationAldol Condensation
Dr. Wolf's CHM 201 & 202 20-21
2RCH2RCH22CHCH
OONaOHNaOH
RCHRCH22CHCH
OHOH
CCHHCHCH
OO
RR
Aldol CondensationAldol Condensation
RR
heatheat
RCHRCH22CHCH CCHCCH
OO
NaOHNaOHheatheat
Dr. Wolf's CHM 201 & 202 20-22
Aldol Condensation of ButanalAldol Condensation of Butanal
NaOH, HNaOH, H22OO 80-100°C80-100°C
2CH2CH33CHCH22CHCH22CHCH
OO
(86%)(86%)
CHCH33CHCH22CHCH22CHCH CCHCCH
OO
CHCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-23
dehydration of dehydration of -hydroxy aldehyde can be-hydroxy aldehyde can becatalyzed by either acids or basescatalyzed by either acids or bases
Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product
CC OO
CC
CCOHOH
HHCC OO
CC
CC
Dr. Wolf's CHM 201 & 202 20-24
in base, the enolate is formed in base, the enolate is formed
Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product
OHOH
HHCC OO
CC
CC
NaOHNaOH
OHOH
CC OO
CC
CC
••••––
Dr. Wolf's CHM 201 & 202 20-25
the enolate loses hydroxide to form the the enolate loses hydroxide to form the ,,-unsaturated aldehyde-unsaturated aldehyde
Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product
OHOH
HHCC OO
CC
CC
NaOHNaOH
OHOH
CC OO
CC
CC
••••––
Dr. Wolf's CHM 201 & 202 20-26
Aldol reactions of ketonesAldol reactions of ketones
the equilibrium constant for aldol addition the equilibrium constant for aldol addition reactions of ketones is usually unfavorablereactions of ketones is usually unfavorable
2%2%
98%98%2CH2CH33CCHCCH33
OO OO
CHCH33CCHCCH22CCHCCH33
OHOH
CHCH33
Dr. Wolf's CHM 201 & 202 20-27
Intramolecular Aldol CondensationIntramolecular Aldol Condensation
NaNa22COCO33, H, H22O O
heatheat
OO
OO
OO
(96%)(96%) OO
OHOH
via:via:
Dr. Wolf's CHM 201 & 202 20-28
Intramolecular Aldol CondensationIntramolecular Aldol Condensation
NaNa22COCO33, H, H22O O
heatheat
OO
OO
OO
(96%)(96%)
even ketones give good yields of aldol even ketones give good yields of aldol condensation products when the reaction is condensation products when the reaction is intramolecular intramolecular
Dr. Wolf's CHM 201 & 202 20-29
Mixed Aldol CondensationsMixed Aldol Condensations
Dr. Wolf's CHM 201 & 202 20-30
What is the product?What is the product?
There are 4 possibilities because the There are 4 possibilities because the reaction mixture contains the two reaction mixture contains the two aldehydes plus the enolate of each aldehydes plus the enolate of each aldehyde.aldehyde.
NaOHNaOHCHCH33CHCH
OO
CHCH33CHCH22CHCH
OO
++
Dr. Wolf's CHM 201 & 202 20-31
What is the product?What is the product?
CHCH33CHCH
OO
CHCH33CHCH22CHCH
OO
++
CHCH22CHCH
OO
CHCH33CHCHCHCH
OO
••••––
••••
––
CHCH33CHCH
OHOH
CHCH22CHCH
OO
Dr. Wolf's CHM 201 & 202 20-32
What is the product?What is the product?
CHCH33CHCH
OO
CHCH33CHCH22CHCH
OO
++
CHCH22CHCH
OO
CHCH33CHCHCHCH
OO
••••––
••••
––
CHCH33CHCH22CHCH
OHOH
CHCHCHCH
OO
CHCH33
Dr. Wolf's CHM 201 & 202 20-33
What is the product?What is the product?
CHCH33CHCH
OO
CHCH33CHCH22CHCH
OO
++
CHCH22CHCH
OO
CHCH33CHCHCHCH
OO
••••––
••••
––
CHCH33CHCH
OHOH
CHCHCHCH
OO
CHCH33
Dr. Wolf's CHM 201 & 202 20-34
What is the product?What is the product?
CHCH33CHCH
OO
CHCH33CHCH22CHCH
OO
++
CHCH22CHCH
OO
CHCH33CHCHCHCH
OO
••••––
••••
––
CHCH33CHCH22CHCH
OHOH
CHCH22CHCH
OO
Dr. Wolf's CHM 201 & 202 20-35
In order to effectively carry outIn order to effectively carry outa mixed aldol condensation:a mixed aldol condensation:
need to minimize reaction possibilitiesneed to minimize reaction possibilities
usually by choosing one component that cannot usually by choosing one component that cannot form an enolateform an enolate
Dr. Wolf's CHM 201 & 202 20-36
FormaldehydeFormaldehyde
formaldehyde cannot form an enolateformaldehyde cannot form an enolate
formaldehyde is extremely reactive toward formaldehyde is extremely reactive toward nucleophilic additionnucleophilic addition
OO
HCHHCH
Dr. Wolf's CHM 201 & 202 20-37
FormaldehydeFormaldehyde
OO
HCHHCH ++ (CH(CH33))22CHCHCHCH22CHCH
OO
(CH(CH33))22CHCHCHCHCHCH
OO
CHCH22OHOH
(52%)(52%)
KK22COCO33
water-water-
etherether
Dr. Wolf's CHM 201 & 202 20-38
Aromatic AldehydesAromatic Aldehydes
CHCH33OO CHCH
OO
aromatic aldehydes cannot form an enolatearomatic aldehydes cannot form an enolate
Dr. Wolf's CHM 201 & 202 20-39
Aromatic AldehydesAromatic Aldehydes
CHCH33OO CHCH
OO
++ CHCH33CCHCCH33
OO
NaOH, HNaOH, H22OO 30°C30°C
CHCH33OO CHCH
CHCCHCHCCH33
OO
(83%)(83%)
Dr. Wolf's CHM 201 & 202 20-40
Deprotonation of Aldehydes, Ketones, and Esters
Simple aldehydes, ketones, and esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original carbonyl, and Aldol or Claisen condensation occurs.Are there bases strong enough to completely deprotonate simple carbonyls, giving enolates quantitatively?
Dr. Wolf's CHM 201 & 202 20-41
Lithium diisopropylamide
Lithium dialkylamides are strong bases (just as NaNH2 is a very strong base).
Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups.
LiLi++
CC NN CC HHHH
CHCH33
CHCH33
CHCH33
CHCH33
••••
••••
––
Dr. Wolf's CHM 201 & 202 20-42
Lithium diisopropylamide (LDA)
Lithium diisopropylamide converts simple esters to the corresponding enolate.
CHCH33CHCH22CHCH22COCHCOCH33
OO
++
ppKKaa ~ 22 ~ 22
LiN[CH(CHLiN[CH(CH33))22]]22
CHCH33CHCH22CHCOCHCHCOCH33
OO
++ HN[CH(CHHN[CH(CH33))22]]22••••
––++ LiLi+
+
ppKKaa ~ 36 ~ 36
Dr. Wolf's CHM 201 & 202 20-43
Lithium diisopropylamide (LDA)
Enolates generated from esters and LDA can be alkylated.
CHCH33CHCH22CHCOCHCHCOCH33
OO
CHCH33CHCH22CHCOCHCHCOCH33
OO
••••
––
CHCH33CHCH22II
CHCH22CHCH33
(92%)(92%)
Dr. Wolf's CHM 201 & 202 20-44
Aldol addition of ester enolates
Ester enolates undergo aldol addition to aldehydes and ketones.
CHCH33COCHCOCH22CHCH33
OO1. LiNR1. LiNR22, THF, THF
2. 2. (CH(CH33))22CC OO
3. H3. H33OO++
CCHH33CC
CHCH33
HOHO
CHCH22COCHCOCH22CHCH33
OO
(90%)(90%)
Dr. Wolf's CHM 201 & 202 20-45
Ketone Enolates
Lithium diisopropylamide converts ketones quantitatively to their enolates.
CHCH33CHCH22CC(CHCC(CH33))33
OO1. LDA, THF1. LDA, THF
2. 2. CHCH33CHCH22CHCH OO
3. H3. H33OO++
CHCH33CHCC(CHCHCC(CH33))33
OO
HOCHCHHOCHCH22CHCH33(81%)(81%)
Dr. Wolf's CHM 201 & 202 20-46
The Claisen Condensation(gives -keto esters)
Dr. Wolf's CHM 201 & 202 20-47
The Claisen Condensation
-Keto esters are made by the reaction shown, which is called the Claisen condensation.
Ethyl esters are typically used, with sodium ethoxide as the base.
2RCH2RCH22COR'COR'
OO1. NaOR'1. NaOR'
2. H2. H33OO++++ R'OHR'OH
OO OO
RCHRCH22CCHCOR'CCHCOR'
RR
Dr. Wolf's CHM 201 & 202 20-48
Example
Product from ethyl acetate is called ethyl acetoacetate or acetoacetic ester.
2CH2CH33COCHCOCH22CHCH33
OO1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
(75%)(75%)
Dr. Wolf's CHM 201 & 202 20-49
Mechanism
Step 1:Step 1:
CHCH33CHCH22 OO––•••• ••••
••••
••••
COCHCOCH22CHCH33
OO
CHCH22HH
••••
Dr. Wolf's CHM 201 & 202 20-50
Mechanism
Step 1:Step 1:
CHCH33CHCH22 OO––•••• ••••
••••
••••
COCHCOCH22CHCH33
OO
CHCH22HH
••••
––••••
••••
COCHCOCH22CHCH33
OO
CHCH22CHCH33CHCH22 OO••••
••••HH
••••
Dr. Wolf's CHM 201 & 202 20-51
Mechanism
Step 1:Step 1:
––••••
••••
COCHCOCH22CHCH33
OO
CHCH22
•••• ––••••
COCHCOCH22CHCH33
OO
CHCH22
•••• ••••
Anion produced is stabilized by electron delocalization; it is the enolate of an ester.
Dr. Wolf's CHM 201 & 202 20-52
Mechanism
Step 2:Step 2:
––••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
CHCH33COCHCOCH22CHCH33
OO ••••••••
Dr. Wolf's CHM 201 & 202 20-53
Mechanism
Step 2:Step 2:
––••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
CHCH33COCHCOCH22CHCH33
OO •••••••• CHCH33CC
––OO•••• ••••••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
OCHOCH22CHCH33••••••••
Dr. Wolf's CHM 201 & 202 20-54
Mechanism
Step 2:Step 2:
CHCH33CC
––OO•••• ••••••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
OCHOCH22CHCH33••••••••
Dr. Wolf's CHM 201 & 202 20-55
Mechanism
Step 3:Step 3:
CHCH33CC
––OO•••• ••••••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
OCHOCH22CHCH33••••••••
––
OCHOCH22CHCH33••••••••
••••CHCH33CC
OO•••• ••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
++
Dr. Wolf's CHM 201 & 202 20-56
Mechanism
––OCHOCH22CHCH33••••
••••••••
CHCH33CC
OO•••• ••••
••••
COCHCOCH22CHCH33
OO
CHCH22
••••
++
Step 3:Step 3:
The product at this point is ethyl acetoacetate.
However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small.
Something else does happen. Ethoxide abstracts a proton from the CH2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable.
Dr. Wolf's CHM 201 & 202 20-57
Mechanism
––OCHOCH22CHCH33••••
••••••••
CHCH33CC
OO•••• ••••
••••
COCHCOCH22CHCH33
OO
CCHH22
••••
++
Step 4:Step 4:
++ OCHOCH22CHCH33••••
••••HH
––
••••
COCHCOCH22CHCH33
OO ••••
CHCH33CC
OO•••• ••••
CCHH••••
Dr. Wolf's CHM 201 & 202 20-58
MechanismStep 5:Step 5:
––
••••
COCHCOCH22CHCH33
OO
CHCH33CC
OO•••• ••••
CCHH••••
In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate.
Dr. Wolf's CHM 201 & 202 20-59
Mechanism
++
Step 5:Step 5:
––
••••
COCHCOCH22CHCH33
OO
CHCH33CC
OO•••• ••••
CCHH••••
++OOHH
••••
HH
HH
OO
HH
••••
HH
••••CHCH33CC
OO•••• ••••
••••
COCHCOCH22CHCH33
OO
CCHH
••••
HH
Dr. Wolf's CHM 201 & 202 20-60
Another example
Reaction involves bond formation between the -carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other.
2 CH2 CH33CHCH22COCHCOCH22CHCH33
OO
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
(81%)(81%)
OO OO
CHCH33CHCH22CCCCHCOCHHCOCH22CHCH33
CHCH33
Dr. Wolf's CHM 201 & 202 20-61
Intramolecular Claisen Condensation:The Dieckmann Reaction
Dr. Wolf's CHM 201 & 202 20-62
CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CHCH22COCHCOCH22CHCH33
OO OO
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
Example
COCHCOCH22CHCH33
OO OO
(74-81%)(74-81%)
Dr. Wolf's CHM 201 & 202 20-63
CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHH22COCHCOCH22CHCH33
OO OO
NaOCHNaOCH22CHCH33
via
CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHHCOCHCOCH22CHCH33
OO OO
••••
––
•••• ••••
•••• ••••
•••• ••••
Dr. Wolf's CHM 201 & 202 20-64
via
CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHHCOCHCOCH22CHCH33
OO OO
••••
––
•••• •••••••• ••••
Dr. Wolf's CHM 201 & 202 20-65
via
CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHHCOCHCOCH22CHCH33
OO OO
••••
––
•••• •••••••• ••••
CCHHCOCHCOCH22CHCH33
OO
––•••• ••••
CHCH22HH22CC
HH22CC
CC
OO•••• ••••••••CHCH33CHCH22OO
••••
••••
Dr. Wolf's CHM 201 & 202 20-66
via
CCHHCOCHCOCH22CHCH33
OO
––•••• ••••
CHCH22HH22CC
HH22CC
CC
OO•••• ••••••••CHCH33CHCH22OO
••••
••••
Dr. Wolf's CHM 201 & 202 20-67
via
CCHHCOCHCOCH22CHCH33
OO
––•••• ••••
CHCH22HH22CC
HH22CC
CC
OO•••• ••••••••CHCH33CHCH22OO
••••
••••
CHCH33CHCH22OO
••••
••••••••––
•••• ••••
CCHHCOCHCOCH22CHCH33
OO
CHCH22HH22CC
HH22CC
CC
OO••••••••
++
Dr. Wolf's CHM 201 & 202 20-68
Mixed Claisen Condensations
Dr. Wolf's CHM 201 & 202 20-69
Mixed Claisen Condensations
As with mixed aldol condensations, mixedClaisen condensations are best carried outwhen the reaction mixture contains one compound that can form an enolate and another that cannot.
Dr. Wolf's CHM 201 & 202 20-70
Mixed Claisen Condensations
These types of esters cannot form an enolate.
HCORHCOR
OO
ROCORROCOR
OO
ROCROC
OO
CORCOR
OO CORCOR
OO
Dr. Wolf's CHM 201 & 202 20-71
Example
1. NaOCH1. NaOCH33
2. H2. H33OO++
(60%)(60%)
CCOCHOCH33
OO
++ CHCH33CCHH22COCHCOCH33
OO
OO OO
CCCCHCOCHHCOCH33
CHCH33
Dr. Wolf's CHM 201 & 202 20-72
Acylation of Ketones with Esters
Dr. Wolf's CHM 201 & 202 20-73
Acylation of Ketones with Esters
Esters that cannot form an enolate can be used to acylate ketone enolates.
Dr. Wolf's CHM 201 & 202 20-74
Example
1. NaH1. NaH
2. H2. H33OO++
(60%)(60%)
++CHCH33CHCH22OOCCOCHOCH22CHCH33
OO
OO
OO
CCOCHOCH22CHCH33
OO
Dr. Wolf's CHM 201 & 202 20-75
Example
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
(62-71%)(62-71%)
CCOCHOCH22CHCH33
OO
++
OO
CCHH33CC
OO OO
CCCCHH22CC
Dr. Wolf's CHM 201 & 202 20-76
Example
1. NaOCH1. NaOCH33
2. H2. H33OO++
(70-71%)(70-71%)
CHCH33CCHH22CCHCCH22CHCH22COCHCOCH22CHCH33
OO OO
OO
OO
CHCH33
Dr. Wolf's CHM 201 & 202 20-77
Alkylation of Enolate AnionsAlkylation of Enolate Anions
Dr. Wolf's CHM 201 & 202 20-78
Enolate ions are nucleophiles and react with
alkyl halides.
However, alkylation of simple enolates does
not work well.
Enolates derived from -diketones can be
alkylated efficiently.
Enolate Ions in SEnolate Ions in SNN2 Reactions2 Reactions
Dr. Wolf's CHM 201 & 202 20-79
ExampleExample
CHCH33CCHCCH22CCHCCH33
OO OO
++ CHCH33IIKK22COCO33
CHCH33CCHCCHCCHCCH33
OO OO
CHCH33
(75-77%)(75-77%)
Dr. Wolf's CHM 201 & 202 20-80
The Acetoacetic Ester Synthesis
Dr. Wolf's CHM 201 & 202 20-81
Acetoacetic Ester
Acetoacetic ester is another name for ethyl acetoacetate.
The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones.
CCCC
CCOCHOCH22CHCH33
HH HH
OO OO
HH33CC
Dr. Wolf's CHM 201 & 202 20-82
Deprotonation of Ethyl Acetoacetate
CHCH33CHCH22OOCCCC
CCOCHOCH22CHCH33
HH HH
OO OO
HH33CC++
––
ppKKaa ~ 11 ~ 11Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
Dr. Wolf's CHM 201 & 202 20-83
Deprotonation of Ethyl Acetoacetate
ppKKaa ~ 16 ~ 16
CHCH33CHCH22OOCCCC
CCOCHOCH22CHCH33
HH HH
OO OO
HH33CC
++
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC ++ CHCH33CHCH22OHOH
––
ppKKaa ~ 11 ~ 11
Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
KK ~ 10 ~ 1055
Dr. Wolf's CHM 201 & 202 20-84
Alkylation of Ethyl Acetoacetate
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC
The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2:
primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).
RR XX
Dr. Wolf's CHM 201 & 202 20-85
Alkylation of Ethyl Acetoacetate
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC
The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2:
primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).
RR XX
CCCC
CCOCHOCH22CHCH33
HH
OO OO
HH33CC
RR
Dr. Wolf's CHM 201 & 202 20-86
Conversion to Ketone
Saponification and acidification convert the alkylated derivative to the corresponding -keto acid.
The -keto acid then undergoes decarboxylation to form a ketone.
CCCC
CCOCHOCH22CHCH33
HH
OO OO
HH33CC
RR
CCCC
CCOHOH
HH
OO OO
HH33CC
RR
1. HO1. HO––, H, H22OO2. H2. H++
Dr. Wolf's CHM 201 & 202 20-87
Conversion to Ketone
Saponification and acidification convert the alkylated derivative to the corresponding -keto acid.
The -keto acid then undergoes decarboxylation to form a ketone.
CCCC
CCOHOH
HH
OO OO
HH33CC
RR
CCCHCH22RR
COCO22
OO
HH33CC++
Dr. Wolf's CHM 201 & 202 20-88
Example
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCCCHH22COCHCOCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-89
Example
(70%)(70%)
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCCCHH22COCHCOCH22CHCH33
OO OO
CHCH33CCCCHCOCHHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-90
Example
(60%)(60%)
OO
CHCH33CCCCHH22CHCH22CHCH22CHCH22CHCH33
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
OO OO
CHCH33CCCCHCOCHHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-91
Example: Dialkylation
OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
Dr. Wolf's CHM 201 & 202 20-92
Example: Dialkylation
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22II
OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
(75%)(75%)
Dr. Wolf's CHM 201 & 202 20-93
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
Example: Dialkylation CHCH33CCHCCH CHCH22CHCH CHCH22
OO
CHCH33CHCH22
Dr. Wolf's CHM 201 & 202 20-94
Another Example
OO OOHH
COCHCOCH22CHCH33
-Keto esters other than ethyl acetoacetate may be used.
Dr. Wolf's CHM 201 & 202 20-95
Another Example
OO OOHH
COCHCOCH22CHCH33
1. NaOCH1. NaOCH22CHCH33
2. 2. HH22CC CHCHCHCH22BrBr
OO OOCHCH22CHCH
COCHCOCH22CHCH33
CHCH22(89%)(89%)
Dr. Wolf's CHM 201 & 202 20-96
Another Example
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
Dr. Wolf's CHM 201 & 202 20-97
Another Example OO
HH
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH CHCH22 (66%)(66%)
Dr. Wolf's CHM 201 & 202 20-98
The Malonic Ester Synthesis
Dr. Wolf's CHM 201 & 202 20-99
Malonic Ester
Malonic ester is another name for diethyl malonate.
The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids.
CCCC
CCOCHOCH22CHCH33
HH HH
OO OO
CHCH33CHCH22OO
Dr. Wolf's CHM 201 & 202 20-100
An Analogy
OO OO
CHCH33CCCCHH22COCHCOCH22CHCH33
OO OO
CHCH33CHCH22OCOCCCHH22COCHCOCH22CHCH33
OO
CHCH33CCCCHH22RR
OO
HOCHOCCCHH22RR
The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.
Dr. Wolf's CHM 201 & 202 20-101
Example
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
HH22CC CHCHCHCH22CHCH22CHCH22BrBr2.2.
CHCH22CHCH22CHCH22CHCH22CHCH
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
(85%)(85%)
Dr. Wolf's CHM 201 & 202 20-102
Example
(75%)(75%)
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH22CHCH22CHCH CHCH22
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
HOCCHHOCCH22CHCH22CHCH22CHCH22CHCH CHCH22
Dr. Wolf's CHM 201 & 202 20-103
Dialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. 2. CHCH33BrBr
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33 (79-83%)(79-83%)
Dr. Wolf's CHM 201 & 202 20-104
Dialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
2. 2. CHCH33(CH(CH22))88CHCH22BrBr
CHCH33CHCH33(CH(CH22))88CHCH22
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-105
Dialkylation OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH33
OO
CHCH33(CH(CH22))88CHCH22CHCOHCHCOH
CHCH33CHCH33(CH(CH22))88CHCH22
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
(61-74%)(61-74%)
Dr. Wolf's CHM 201 & 202 20-106
Another Example
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. Br2. BrCHCH22CHCH22CHCH22BrBr
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-107
Another Example
This product is not isolated, but cyclizes in the presence of sodium ethoxide.
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
Dr. Wolf's CHM 201 & 202 20-108
Another Example
NaOCHNaOCH22CHCH33
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22
(60-65%)(60-65%)
Dr. Wolf's CHM 201 & 202 20-109
Another Example
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
HH22CC CHCH22
CCHH22
CC
HH COCO22HH
(80%)(80%)
Dr. Wolf's CHM 201 & 202 21-110
Barbiturates
Dr. Wolf's CHM 201 & 202 21-111
Barbituric acid is made from diethyl malonate
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
Dr. Wolf's CHM 201 & 202 21-112
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
1. NaOCH1. NaOCH22CHCH33
2. H2. H++
HH22CC
OO
CC
CC
OO
CC
NN
OO
NN
HH
HH
(72-78%)(72-78%)
Barbituric acid is made from diethyl malonate and urea
Dr. Wolf's CHM 201 & 202 21-113
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
1. NaOCH1. NaOCH22CHCH33
2. H2. H++
OO
OO
NN
OO
NN
HH
HH
(72-78%)(72-78%)
Barbituric acid is made from diethyl malonate and urea
Dr. Wolf's CHM 201 & 202 21-114
Substituted derivatives of barbituric acid are made
from alkylated derivatives of diethyl malonate
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
1. 1. RRX,X,NaOCHNaOCH22CHCH33
2. 2. R'R'X,X,NaOCHNaOCH22CHCH33
CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
RR
R'R'
Dr. Wolf's CHM 201 & 202 21-115
Substituted derivatives of barbituric acid are made
from alkylated derivatives of diethyl malonate OO
OO
NNOO
NN
HH
HH
RR
R'R'CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
RR
R'R'
(H(H22N)N)22CC OO
Dr. Wolf's CHM 201 & 202 21-116
Examples OO
OO
NNOO
NN
HH
HH
CHCH33CHCH22
CHCH33CHCH22
5,5-Diethylbarbituric acid5,5-Diethylbarbituric acid(barbital; Veronal)(barbital; Veronal)
Dr. Wolf's CHM 201 & 202 21-117
Examples OO
OO
NNOO
NN
HH
HH
CHCH33CHCH22
5-Ethyl-5-(1-methylbutyl)barbituric acid5-Ethyl-5-(1-methylbutyl)barbituric acid(pentobarbital; Nembutal)(pentobarbital; Nembutal)
CHCH33CHCH22CHCH22CHCH
HH33CC
Dr. Wolf's CHM 201 & 202 21-118
Examples OO
OO
NNOO
NN
HH
HH
5-Allyl-5-(1-methylbutyl)barbituric acid5-Allyl-5-(1-methylbutyl)barbituric acid(secobarbital; Seconal)(secobarbital; Seconal)
CHCH33CHCH22CHCH22CHCH
HH33CC
CHCHCHCH22HH22CC
Dr. Wolf's CHM 201 & 202 20-119
Enolization and Enol ContentEnolization and Enol Content
Dr. Wolf's CHM 201 & 202 20-120
Mechanism of EnolizationMechanism of Enolization(In general)(In general)
OO••••
CR'CR'
••••
RR22CC
HHOOHH
HH
••••••••
OO
HH
HH ••••••••
RR22CC CR'CR'
OO••••
•••• HH
Dr. Wolf's CHM 201 & 202 20-121
Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)
OO••••
RR22CC CR'CR'
HH
OO
HH
•••••••••••• ––
••••
Dr. Wolf's CHM 201 & 202 20-122
Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)
HHOO
HH
••••••••
OO••••
RR22CC CR'CR'
––•••••••• OO
HH
HH ••••••••
Dr. Wolf's CHM 201 & 202 20-123
Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)
OO
HH
HH ••••
OO••••
RR22CC CR'CR'
––••••••••••••
Dr. Wolf's CHM 201 & 202 20-124
Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)
HHOO••••
RR22CC CR'CR'
•••• OO
HH
••••––••••
••••
Dr. Wolf's CHM 201 & 202 20-125
Mechanism of EnolizationMechanism of Enolization(Acid-catalyzed)(Acid-catalyzed)
OO
HH
HH ••••
HHRR22CC
HH
OO••••
CR'CR'
••••++
Dr. Wolf's CHM 201 & 202 20-126
Mechanism of EnolizationMechanism of Enolization(Acid-catalyzed)(Acid-catalyzed)
OO••••
RR22CC CR'CR'
••••
HH
OO
HH
HH ••••
HH
++
Dr. Wolf's CHM 201 & 202 20-127
Mechanism of EnolizationMechanism of Enolization(Acid-catalyzed)(Acid-catalyzed)
OO••••
RR22CC CR'CR'
HH
HH++
OOHH
HH
••••••••
Dr. Wolf's CHM 201 & 202 20-128
Mechanism of EnolizationMechanism of Enolization(Acid-catalyzed)(Acid-catalyzed)
HHOOHH
HH
••••++
OO••••
RR22CC CR'CR'
HH••••
Dr. Wolf's CHM 201 & 202 20-129
percent enol is usually very smallpercent enol is usually very small
keto form usually 45-60 kJ/mol more stableketo form usually 45-60 kJ/mol more stablethan enolthan enol
Enol ContentEnol Content
RR22CHCR'CHCR'
OO
RR22CC CR'CR'
OHOH
enolenolketoketo
Dr. Wolf's CHM 201 & 202 20-130
Enol ContentEnol Content
CHCH33CHCH
OO
HH22CC CHCH
OHOH
KK = 3 x 10 = 3 x 10-7-7
AcetaldehydeAcetaldehyde
CHCH33CCHCCH33
OO
HH22CC CCHCCH33
OHOH
KK = 6 x 10 = 6 x 10-9-9
AcetoneAcetone
Dr. Wolf's CHM 201 & 202 20-131
Halogenation ofHalogenation of
Aldehydes and KetonesAldehydes and Ketones
Dr. Wolf's CHM 201 & 202 20-132
XX22 is Cl is Cl22, Br, Br22, or I, or I22..
Substitution is specific for replacement of Substitution is specific for replacement of
hydrogen.hydrogen.
Catalyzed by acids. One of the products is an acid Catalyzed by acids. One of the products is an acid
(HX); the reaction is (HX); the reaction is autocatalyticautocatalytic..
NotNot a free-radical reaction.a free-radical reaction.
General ReactionGeneral Reaction
OO
RR22CCR'CCR'
HH
++ XX22
OO
RR22CCR'CCR'
XX
++ HHXXHH++
Dr. Wolf's CHM 201 & 202 20-133
ExampleExample
HH22OO
(61-66%)(61-66%)
ClCl22++
OOHHClCl
OOClCl
++
Dr. Wolf's CHM 201 & 202 20-134
ExampleExample
CHClCHCl33
(80%)(80%)
BrBr22++ HHBrBr++
HH
CHCH
OO BrBr
CHCH
OO
Notice that it is the proton on the Notice that it is the proton on the carbon carbon that is replaced, not the one on the carbonyl that is replaced, not the one on the carbonyl carbon.carbon.
Dr. Wolf's CHM 201 & 202 20-135
specific for replacement of H at the specific for replacement of H at the carbon carbon
equal rates for chlorination, bromination, and equal rates for chlorination, bromination, and
iodinationiodination
first order in ketone; zero order in halogenfirst order in ketone; zero order in halogen
Mechanism of Mechanism of Halogenation Halogenation
Experimental FactsExperimental Facts
InterpretationInterpretation
no involvement of halogen until after theno involvement of halogen until after therate-determining steprate-determining step
Dr. Wolf's CHM 201 & 202 20-136
first stage is conversion of aldehyde or first stage is conversion of aldehyde or
ketone to the corresponding enol; is rate-ketone to the corresponding enol; is rate-
determiningdetermining
second stage is reaction of enol with halogen; second stage is reaction of enol with halogen;
is faster than the first stageis faster than the first stage
Mechanism of Mechanism of Halogenation Halogenation
Two stages:Two stages:
Dr. Wolf's CHM 201 & 202 20-137
Mechanism of Mechanism of Halogenation Halogenation
RCHRCH22CR'CR'
OOXX22
fastfastRCHCR'RCHCR'
OO
XX
RCHRCH CR'CR'
OHOHslowslow
enolenol
Enol is key intermediate
Dr. Wolf's CHM 201 & 202 20-138
first stage is conversion of aldehyde or first stage is conversion of aldehyde or ketone to the corresponding enol; is rate-ketone to the corresponding enol; is rate-determiningdetermining
second stage is reaction of enol with halogen; second stage is reaction of enol with halogen; is faster than the first stageis faster than the first stage
Mechanism of Mechanism of Halogenation Halogenation
Two stages:Two stages:
examine second stage nowexamine second stage nowexamine second stage nowexamine second stage now
Dr. Wolf's CHM 201 & 202 20-139
Reaction of enol with BrReaction of enol with Br22
carbocation is carbocation is stabilized by stabilized by electron release electron release from oxygenfrom oxygen
BrBr BrBr•••• ••••
••••••••••••••••
RR22CC CR'CR'
OHOH••••••••
BrBr••••
••••••••
RR22CC CR'CR'
OHOH••••••••
++BrBr••••
•••••••• ••••
––++
••••
BrBr••••
••••••••
RR22CC CR'CR'
OHOH++
Dr. Wolf's CHM 201 & 202 20-140
Loss of proton from oxygen completes the processLoss of proton from oxygen completes the process
••••BrBr•••••••• ••••
–– OO••••
CR'CR'
BrBr••••
••••••••
RR22CC
••••
HH BrBr•••• ••••••••
HH••••
BrBr••••
••••••••
RR22CC CR'CR'
OO++
Dr. Wolf's CHM 201 & 202 20-141
-Halogenation of Carboxylic Acids:
The Hell-Volhard-Zelinsky Reaction
Dr. Wolf's CHM 201 & 202 20-142
analogous to -halogenation of aldehydes and ketones
key question: Is enol content of carboxylic acids high enough to permit reaction to occur at reasonable rate? (Answer is NO)
-Halogenation of Carboxylic Acids
-Halogenation of Carboxylic Acids
++ XX22++ HHXXRR22CCOHCCOH
OO
HH
RR22CCOHCCOH
OO
XX
Dr. Wolf's CHM 201 & 202 20-143
reaction works well if a small amount ofphosphorus or a phosphorus trihalide is added tothe reaction mixture
this combination is called the Hell-Volhard-Zelinsky reaction
But...But...
++ XX22++ HHXXRR22CCOHCCOH
OO
HH
RR22CCOHCCOH
OO
XX
P or PXP or PX33
Dr. Wolf's CHM 201 & 202 20-144
ExampleExample CHCH22COHCOH
OO
PClPCl33 benzenebenzene80°C80°C
CHCOHCHCOH
OO
BrBr
(60-62%)(60-62%)
++ BrBr22
Dr. Wolf's CHM 201 & 202 20-145
ValueValue
CHCH33CHCH22CHCH22COHCOH
OOBrBr22
PPCHCH33CHCH22CHCOHCHCOH
OO
BrBr
(77%)(77%)
-Halogen can be replaced by nucleophilic -Halogen can be replaced by nucleophilic substitutionsubstitution
Dr. Wolf's CHM 201 & 202 20-146
ValueValue
CHCH33CHCH22CHCH22COHCOH
OOBrBr22
PPCHCH33CHCH22CHCOHCHCOH
OO
BrBr
CHCH33CHCH22CHCOHCHCOH
OO
OHOH
(77%)(77%)
(69%)(69%)
KK22COCO33
HH22OO
heatheat
Dr. Wolf's CHM 201 & 202 20-147
Synthesis of -Amino AcidsSynthesis of -Amino Acids
(CH(CH33))22CHCHCHCH22COHCOH
OOBrBr22
PClPCl33(CH(CH33))22CHCHCOHCHCHCOH
OO
BrBr
(CH(CH33))22CHCHCOHCHCHCOH
OO
NHNH22
(88%)(88%)
(48%)(48%)
NHNH33
HH22OO
Dr. Wolf's CHM 201 & 202 20-148
Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage.
Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products.
The Haloform ReactionThe Haloform Reaction
Dr. Wolf's CHM 201 & 202 20-149
ExampleExample
(CH(CH33))33CCCCCCHH33
OO
BrBr22, NaOH, H, NaOH, H22OO
CCHHBrBr33++(CH(CH33))33CCONaCCONa
OO
(CH(CH33))33CCOHCCOH
OO
HH++
(71-74%)(71-74%)
Dr. Wolf's CHM 201 & 202 20-150
The haloform reaction is sometimes used as a The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well method for preparing carboxylic acids, but works well only when a single enolate can form.only when a single enolate can form.
The Haloform ReactionThe Haloform Reaction
ArCArCCHCH33
OO
(CH(CH33))33CCCCCHCH33
OO
RRCHCH22CCCHCH33
OO
yesyes yesyes nono
Dr. Wolf's CHM 201 & 202 20-151
RCCHRCCH33
OO
XX22, HO, HO––
RCCHRCCH22XX
OOXX22, HO, HO––
RCCHRCCHXX22
OO
XX22, HO, HO––
RCCRCCXX33
OO
MechanismMechanism
First stage is substitution of all available First stage is substitution of all available hydrogens hydrogens by halogen by halogen
Dr. Wolf's CHM 201 & 202 20-152
MechanismMechanism
Formation of the trihalomethyl ketone is followed by Formation of the trihalomethyl ketone is followed by its hydroxide-induced cleavageits hydroxide-induced cleavage
HOHO •••• ––••••
••••
RCRC
OO ••••••••
CCXX33
•••• ––
RCRC
OO ••••
HOHO ••••••••
••••
CCXX33
++
••••––
HCHCXX33
••••
RCRC
OO ••••
OO••••
••••++
––•••• CCXX33
••••
RCRC
OO ••••
OHOH••••
••••++
Dr. Wolf's CHM 201 & 202 20-153
Some Chemical and StereochemicalSome Chemical and Stereochemical
Consequences of EnolizationConsequences of Enolization
Dr. Wolf's CHM 201 & 202 20-154
Hydrogen-Deuterium ExchangeHydrogen-Deuterium Exchange OO
HH
HH HH
HH++ 44DD22OO OO
DD
DD DD
DD++ 44DDOHOH
KOKODD, heat, heat
Dr. Wolf's CHM 201 & 202 20-155
MechanismMechanism
OODD••••––
••••
••••++
HOHODD
••••
••••++HH
OO
HH
HH
••••––•••• ••••
OO
HH
HH
HH
••••••••
HH
Dr. Wolf's CHM 201 & 202 20-156
MechanismMechanism
HH
OO
HH
HH
••••––•••• ••••
OODD••••––
••••
••••++
OO
HH
HH
DD
••••••••
HH
OODD••••
••••DD
Dr. Wolf's CHM 201 & 202 20-157
Stereochemical Consequences of EnolizationStereochemical Consequences of Enolization CC CCCC66HH55
OOHH
CHCH33CHCH22
HH33CC
100% R100% R
HH33OO++
HH22O, HOO, HO––
50% R50% S
50% R50% S
50% R50% S
50% R50% S
Dr. Wolf's CHM 201 & 202 20-158
Enol is achiralEnol is achiral CC CCCC66HH55
OOHH
CHCH33CHCH22
HH33CC
RR
CCCC66HH55
OHOH
CC
HH33CC
CHCH33CHCH22
Dr. Wolf's CHM 201 & 202 20-159
Enol is achiralEnol is achiral CC CCCC66HH55
OOHH
CHCH33CHCH22
HH33CC
RR
CCCC66HH55
OHOH
CC
HH33CC
CHCH33CHCH22
CC CCCC66HH55
OOHH
CHCH33CHCH22
HH33CC
SS50%50%
50%50%
Dr. Wolf's CHM 201 & 202 20-160
Results of Rate StudiesResults of Rate Studies CC CCCC66HH55
OOHH
CHCH33CHCH22
HH33CC
Equal rates for:Equal rates for:racemizationracemizationH-D exchangeH-D exchangebrominationbrominationiodinationiodination
Enol is intermediate and Enol is intermediate and its formation is rate-its formation is rate-determiningdetermining
Dr. Wolf's CHM 201 & 202 20-161
Effects of Conjugation in Effects of Conjugation in
-Unsaturated Aldehydes and -Unsaturated Aldehydes and
KetonesKetones
Dr. Wolf's CHM 201 & 202 20-162
Relative StabilityRelative Stability
aldehydes and ketones that contain a carbon-aldehydes and ketones that contain a carbon-carbon double bond are more stable when the carbon double bond are more stable when the double bond is conjugated with the carbonyl double bond is conjugated with the carbonyl group than when it is notgroup than when it is not
compounds of this type are referred to as compounds of this type are referred to as ,, unsaturated aldehydes and ketonesunsaturated aldehydes and ketones
Dr. Wolf's CHM 201 & 202 20-163
Relative StabilityRelative Stability
CHCH33CHCH
OO
CHCHCHCH22CCHCCH33 (17%)(17%)
KK = 4.8 = 4.8
(83%)(83%)
OO
CHCH33CHCH22CHCH CHCCHCHCCH33
Dr. Wolf's CHM 201 & 202 20-164
AcroleinAcrolein
HH22CC CHCHCHCH
OO
Dr. Wolf's CHM 201 & 202 20-165
AcroleinAcrolein
HH22CC CHCHCHCH
OO
Dr. Wolf's CHM 201 & 202 20-166
AcroleinAcrolein
HH22CC CHCHCHCH
OO
Dr. Wolf's CHM 201 & 202 20-167
AcroleinAcrolein
HH22CC CHCHCHCH
OO
Dr. Wolf's CHM 201 & 202 20-168
Resonance DescriptionResonance Description
CCOO•••• ••••
CCCC
++
––
CCOO•••• ••••
CCCC ••••
++
––
CCOO•••• ••••
CCCC ••••
Dr. Wolf's CHM 201 & 202 20-169
-Unsaturated aldehydes and ketones are -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones. more polar than simple aldehydes and ketones.
-Unsaturated aldehydes and ketones contain -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack two possible sites for nucleophiles to attack
carbonyl carboncarbonyl carbon
-carbon-carbon
PropertiesProperties
CCOO•••• ••••
CCCC
Dr. Wolf's CHM 201 & 202 20-170
Dipole MomentsDipole Moments
ButanalButanal transtrans-2-Butenal-2-Butenal
= 2.7 D= 2.7 D = 3.7 D= 3.7 D
OO OO–– ––
++
++
++
greater separation greater separation of positive and of positive and negative chargenegative charge
Dr. Wolf's CHM 201 & 202 20-171
Conjugate Addition to Conjugate Addition to
-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds
Dr. Wolf's CHM 201 & 202 20-172
1,2-addition (direct addition)1,2-addition (direct addition)
nucleophile attacks carbon of C=Onucleophile attacks carbon of C=O
1,4-addition (conjugate addition)1,4-addition (conjugate addition)
nucleophile attacks nucleophile attacks -carbon-carbon
Nucleophilic Addition to Nucleophilic Addition to -Unsaturated Aldehydes and Ketones -Unsaturated Aldehydes and Ketones
Dr. Wolf's CHM 201 & 202 20-173
attack is faster at C=Oattack is faster at C=O
attack at attack at -carbon gives the more stable -carbon gives the more stable productproduct
Kinetic versus Thermodynamic ControlKinetic versus Thermodynamic Control
Dr. Wolf's CHM 201 & 202 20-174
HH YY++CC CC
CC
OO
1,2-addition1,2-addition
CC CC
CC
OOHH
YY
formed fasterformed faster
major product under major product under conditions of kinetic conditions of kinetic control control (i.e. when (i.e. when addition is not readily addition is not readily reversible)reversible)
Dr. Wolf's CHM 201 & 202 20-175
HH YY++CC CC
CC
OO
1,4-addition1,4-addition
CC CC
CC
OOHH
YY
enolenol
goes to keto form goes to keto form under reaction under reaction conditionsconditions
Dr. Wolf's CHM 201 & 202 20-176
HH YY++CC CC
CC
OO
1,4-addition1,4-addition
keto form is isolated keto form is isolated product of 1,4-additionproduct of 1,4-addition
is more stable than is more stable than 1,2-addition product1,2-addition product CC CC
CC
OO
HHYY
Dr. Wolf's CHM 201 & 202 20-177
HH YY++CC CC
CC
OO
1,2-addition1,2-addition
CC CC
CC
OOHH
YY
1,4-addition1,4-addition
CC CC
CC
OO
HHYY
C=O is stronger
than C=C
C=O is stronger
than C=C
Dr. Wolf's CHM 201 & 202 20-178
Addition of Carbanions toAddition of Carbanions to
-Unsaturated Carbonyl Compounds:-Unsaturated Carbonyl Compounds:
The Michael ReactionThe Michael Reaction
Dr. Wolf's CHM 201 & 202 20-179
Stabilized carbanions, such as those Stabilized carbanions, such as those derived from derived from -diketones undergo conjugate-diketones undergo conjugateaddition to addition to ,,-unsaturated ketones.-unsaturated ketones.
Michael AdditionMichael Addition
Dr. Wolf's CHM 201 & 202 20-180
ExampleExample
(85%)(85%)
OO
HH22CC CHCCHCHCCH33
CHCH33
OO
OO
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
KOH, methanolKOH, methanol
++
Dr. Wolf's CHM 201 & 202 20-181
The Michael reaction is a useful method forThe Michael reaction is a useful method forforming carbon-carbon bonds.forming carbon-carbon bonds.
It is also useful in that the product of the It is also useful in that the product of the reaction can undergo an intramolecularreaction can undergo an intramolecularaldol condensation to form a six-membered aldol condensation to form a six-membered ring. One such application is called the Robinsonring. One such application is called the Robinsonannulation.annulation.
Michael AdditionMichael Addition
Dr. Wolf's CHM 201 & 202 20-182
ExampleExample
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
NaOHNaOH
heatheat
(85%)(85%)
OOOO
CHCH33
OHOH
OO CHCH33
OO
not isolated;not isolated;
dehydrates under dehydrates under
reaction conditionsreaction conditions
Dr. Wolf's CHM 201 & 202 20-183
Stabilized Anions The anions derived by deprotonation of -keto esters and diethyl malonate are weak bases.
Weak bases react with ,-unsaturated carbonyl compounds by conjugate addition.
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC
CCCC
CCOCHOCH22CHCH33
HH
OO OO
CHCH33CHCH22OO••••
––
Dr. Wolf's CHM 201 & 202 20-184
ExampleOO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33++ HH22CC CHCCHCHCCH33
OO
Dr. Wolf's CHM 201 & 202 20-185
Example
KOH, ethanolKOH, ethanol
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
(85%)(85%)
++ HH22CC CHCCHCHCCH33
OO
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
Dr. Wolf's CHM 201 & 202 20-186
Example
1. KOH, ethanol-water1. KOH, ethanol-water
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
2. H2. H++
3. heat3. heat
CHCH33CCHCCH22CHCH22CHCH22COHCOH
OOOO
(42%)(42%)
Dr. Wolf's CHM 201 & 202 20-187
Conjugate Addition of Organocopper ReagentsConjugate Addition of Organocopper Reagents
to to
-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds
Dr. Wolf's CHM 201 & 202 20-188
The main use of organocopper reagents is toThe main use of organocopper reagents is toform carbon-carbon bonds by conjugate form carbon-carbon bonds by conjugate addition to addition to ,,-unsaturated ketones.-unsaturated ketones.
Addition of Organocopper Reagents toAddition of Organocopper Reagents to-Unsaturated Aldehydes and Ketones-Unsaturated Aldehydes and Ketones
Dr. Wolf's CHM 201 & 202 20-189
ExampleExampleOO CHCH33
(98%)(98%)
++ LiCu(LiCu(CHCH33))22
OO CHCH33
CHCH33
1. diethyl ether1. diethyl ether
2. H2. H22OO
Dr. Wolf's CHM 201 & 202 20-190
End of Chapter 20