enols and enolates
TRANSCRIPT
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Enols and Enolates
A major type of reaction with carbonyl compounds is an -substitution
O O
E
In the preceding chapters we were concerned
with the carbonyl reacting as an electrophile
O
OH
NUC
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Enols
As observed previously an enol and a ketone are tautomers
O OH
Usually the ketone is far more stable than the enol and it predominates
Under either slightly basic or acidic conditions the concentration of enol can be increasedThe keto form still predominates
With aldehydes there is relatively more enol form than with ketones
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Reactions of Enols
The enol form can react with electrophiles
A common reaction is halogenation
O OHNaOH/H2O Br BrOH
Br
under basic conditions it is hard to stop at one addition because
hydrogen abstraction of product is more favored than starting material
O
Br
OH
Br
O
Br
Br
Br2
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Haloform Reaction
This polyhalogenation is exploited with a haloform reaction
A methyl ketone will react until three halogens have been substituted on -carbon
O O
CI3
I2
NaOH
with three halogens attached to the carbon it becomes a good leaving group
O
CI3
O
O
NaOH
HCI3
iodoform
the three halogens stabilize the negative charge of the leaving group
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Acid Catalyzed Enol Formation
Under acidic conditions the enol can react with halogen and stop after one addition
O OH O
Br
H+ Br2
with acidic conditions we do not form anion adjacent to halogen as in basic mechanism
therefore the reaction can be stopped after one addition
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Enolizable Positions
A consequence of the ability to form enols is that chiral carbons can racemize
O
Et
OH
Et
O
Et
H+ or NaOH
chiral achiral racemic
since the -position can form an enol, and the enol is achiral, chiral atoms that are to
carbonyls will lose chiralty whenever enol formation is favored
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Bromination of Acids
Carboxylic acids can also be brominated
First need to convert carboxylic acid into acid halide (labile H would interfere)
O
OH
PBr3/Br2
O
Br
this acid bromide can form enol under these conditions, which will react with Br2
O
Br
OH
Br
O
Br
Br Br
O
OH
Br2 H2O
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Enolates
Enolates are similar to enols but they are far more nucleophilic
In order to generate an enolate need a base to abstract an -hydrogen
H3C
O
CH3
pKa of-hydrogens ~ 20
the -hydrogens are more acidic than normal alkane hydrogens due to electron
withdrawing carbonyl group that can delocalize the resultant negative charge
O O
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Base Abstraction
Since the pKa of an -hydrogen of a ketone is ~20 the choice of base will determine
extent of enolate formation
H3C
O
CH3
NaOH
H3C
O
CH2
both water (pKa of ~15.7) or alcohols (pKa ~>16) are less acidic
therefore with these bases the majority of the compounds will be in the keto form
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Basicity vs. Nucleophilicity
Most strong bases are also strong nucleophiles - remember SN2 vs. E2
With carbonyls need to balance two different type of reactions:
A strong nucleophile reacting with the carbonyl and a strong base abstracting -hydrogen
H3C
O
CH3
H3C
O
CH3
NUC
H3C
O
NUC
CH3
B
H3C
O
CH2
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Enolate
To generate enolate need to use a base that will not act as a nucleophile
Common choice is to use lithium diisopropylamine (LDA)
HN N
Li
BuLi
LDA
LDA is a strong base (pKa of conjugate is close to 40)
At the same time it is very bulky so it will not react as a nucleophile
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LDA will quantitatively form enolate
H3C
O
CH3
LDA
H3C
O
CH2
using LDA the enolate will be formed quantitatively
with weaker bases will only form the enolate in a small fraction
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Enolate as a Nucleophile
We have already seen many reactions with a nucleophile reacting
-see any SN2 reaction
an enolate is simply another type of nucleophile
it can react in exactly the same manner we have observed other nucleophiles react
H3C
O
CH2 H3C
O
E
E+
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Alkylation of Enolates
One common reaction is to alkylate the enolate
H3C
O
CH2 H3C
O
CH3
CH3Br
This reaction will place an alkyl substituent at the -position of a carbonyl
Any electrophile that will react in an SN2 reaction can be used in this reaction
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Unsymmetrical Carbonyls
With an unsymmetrical carbonyl can obtain two different enolates
O O O
O O
LDA
CH3Br CH3Br
how to obtain one product preferentially?
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Thermodynamic vs. Kinetic Control
The key is which enolate is generated
The enolate can be preferentially generated at either site depending upon conditions
O O OLDA
kinetic enolate thermodynamic enolate
more stable double bondeasier hydrogen to abstract
lower temperatures favor kinetic product
higher temperatures (in this case usually room temp. and above) favor thermodynamic
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Product Formation
By controlling which enolate is generated,
where the -substitution occurs can be controlled
O 1) LDA, -78C
2) CH3BrO
O1) LDA. RT2) CH3Br
O
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Cannot follow this procedure with Aldehydes
Will not obtain -substitution with aldehydes through enolate chemistry
The aldehyde carbonyl is too reactive and it will interfere
with the formation of the enolate
O
H
O
H
self condenses
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-Alkylation of Aldehydes
to alkylate an aldehyde we first need to convert the aldehyde to a less reactive system
an imine or imine derivative is used most frequently
O
H
NH2
N
H
N
H
N
H
O
H
1) CH3Br
2) H+/H2OLDA
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Enamines
Another option instead of enolate formation is to form an enamine
React carbonyl with 2 amine
O
HN
N N OCH3Br H+/H2O
the enamine is not as reactive as an enolate but it is more reactive than an enol
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Aldol Condensation
Instead of reacting the enolate with an alkyl halide
We can also react the enolate with a carbonyl compound
The carbonyl can react as an electrophile
O
OO OH
upon work-up obtain a -hydroxy ketone
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Dehydration of Aldol Product
The -hydroxy ketone that is formed can also loss water
to form an ,-unsaturated ketone
O OH O
-H2O
the loss of water can sometimes occur during work-up,
it can be driven to this product through heat and either acidic or basic conditions
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Procedure for Aldol Reaction
When reacting in a self-condensation can use an alkoxide base
OO O OHCH3
ONa
O
the alkoxide base will only deprotonate a small proportion of ketone,
but those enolates will react quickly with keto forms in an aldol reaction
can drive the reaction to completion
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Using Different Carbonyl Compounds
If there are different carbonyl compounds (a mixed aldol or crossed aldol)
then conditions need to be considered
CH3ONaO O O OH
O OH
if using unsymmetrical ketones than will obtain four regioproducts for this reaction
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A couple of options to reduce number of products
Use one carbonyl that does not have -hydrogens
Therefore there are no hydrogens to abstract and can only react as electrophile
O
O
H CH3ONa
O OH
want to add compound with -hydrogens (acetone in above example)
slowly to basic benzaldehyde solution
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Another option: quantitatively form enolate first
If need to use two carbonyls that both contain -hydrogens need to first generate the
enolate quantitatively (strong base) and then add the second carbonyl compound
O LDA OLi
OO OH
can generally obtain high yield of the desired aldol product with this method
remember that with weak base will obtain a mixture of products with these reactants
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Claisen Condensation
There are many "Name" reactions that are modifications of the aldol condensation
A Claisen condensation is an aldol where one carbonyl is an ester
By using an ester this changes the chemistry due to the presence of a leaving group
CH3ONaO O
O
O O
O
O O
can run this reaction with both carbonyls present and a weak base
due to differences in pKa (ketones are ~20 and esters are ~24)
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Reactions are Driven to Completion
Unlike other aldol reactions, which are under equilibrium control, Claisen condensations
give very high yield without adjusting equilibrium conditions
The last step generates an alkoxide with a -diketone
O OCH3ONa
O ONa
diketones have a pKa ~10, therefore methoxide will quantitatively abstract the hydrogen
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Dieckmann
A Dieckmann condensation is an intramolecular Claisen condensation
O
O
O
O
O
O
O
O
CH3ONaOO
O
convenient method to form 5- or 6-membered rings
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-Dicarbonyls
both Claisen and Dieckmann condensations form -dicarbonyl compounds
-keto esters are another type of dicarbonyl systems that are very useful synthetically
O O
OCH3
CH3ONaONa O
OCH3
O O
OCH3
R
RBr
due to the acidity of the methylene position alkylation reactions are easy to perform,
with only one carbonyl often need to use LDA to quantitatively form enolate
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Decarboxylation
After alkylation, the ester group can be hydrolyzed and then decarboxylated
O O
OCH3
R
O O
O
R
H
1) NaOH2) W-U
O
H
R
-CO2
O
R
allows alkylation of ketone in much milder method than starting with ketone
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Michael Addition
If we add enolate to ,-unsaturated system the reaction often reacts with 1,4-addition
Called Michael addition
O
NUC
O
NUC
O1
2
3
4
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Calicheamicin 11: An Example of Michael Addition in Drug Action
In chapter 4 we first saw a drug that uses a Michael addition
O
I
OCH3
OCH3
O
SO
OHO
H3CO OH
OH
ON
O
O
O
O
NHCO2CH3
H3CSSS
HO
O
H3CO
HN
HO
binding group
reactive functionality
H
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After the sugar binding group binds in the minor groove of DNA a sulfide is generated
O
O
NHCO2CH3S
HO
binding groupO
O
NHCO2CH3
HO
binding group
S
HO
S
Obinding group
O
NHCO2CH3 HO
S
Obinding group
O
NHCO2CH3
Bergmancycloaromatization
DNA
DNA diradical
DNA double strand cleavageO2
Michael
After the Michael addition occurs, the conformational change causes the Bergman
cyclization to occur eventually leading to cell death after DNA cleavage
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Robinson Annulation
This is a very convenient method to form 6-membered rings
Perform a Michael addition followed by an aldol condensation
CH3ONa
O ONa O O ONa
O OO ONa
O
CH3OH
CH3ONa
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Convenient Method to Synthetically Produce Multi-Ring Systems
steroid ring system
HO
H
H H
H
cholesterol
nature has more efficient ways to synthesize steroids but you can see how Robinson
Annulation can be used to prepare 6-6 and 6-5 ring junctions in a one pot reaction