Phys 446 Solid State Physics Lecture 11 Nov 29 (Ch 11)(Ch. 11)
O NUC O H C CH H C CH NUC O - University of Texas at Dallasbiewerm/19H-enolates.pdf · Reactions at...
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Reactions at α-Position In preceding chapters on carbonyl chemistry, a common reaction mechanism observed was a nucleophile reacting at the electrophilic carbonyl carbon site H 3 C O CH 3 NUC H 3 C O NUC CH 3 Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl H 3 C O CH 3 E H 3 C O CH 2 E The electrophile adds to the α-position and allows the synthesis of a variety of substituted carbonyl compounds by reacting different electrophiles
Transcript of O NUC O H C CH H C CH NUC O - University of Texas at Dallasbiewerm/19H-enolates.pdf · Reactions at...
Reactions at α-Position
In preceding chapters on carbonyl chemistry, a common reaction mechanism observed was a nucleophile reacting at the electrophilic carbonyl carbon site
H3C
O
CH3
NUC
H3C
O
NUCCH3
Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl
H3C
O
CH3
E
H3C
O
CH2E
The electrophile adds to the α-position and allows the synthesis of a variety of substituted carbonyl compounds by reacting different electrophiles
Reactions at α-Position
In order to react with electrophiles at the α-position, the carbonyl compound needs to be nucleophilic at the α-position
There are two general methods to become nucleophilic at α-position:
1) React through the enol form
H3C
O
CH3 H3C
OH
CH2
keto enol
A carbonyl compound is in equilibrium with an enol
Br BrH3C
O
CH2Br
The enol form, however, is more reactive than an alkene and can undergo similar reactions as observed with reactions with π bonds
Typically the equilibrium for a ketone though lies heavily in the keto form
K 5 x 10-9
Reactions at α-Position
2) To make a carbonyl compound even more nucleophilic at the α-position, a base can be added to form an enolate
H3C
O
CH3
base
H3C
O
CH2 H3C
O
CH2
The α-position of a ketone is relatively acidic (pKa ~19) because the anion is stabilized by resonance with the carbonyl oxygen
The negatively charged enolate anion can react with an electrophile to form a new bond between the α-carbon and the electrophilic atom
E
H3C
O
CH2E
Reactions at α-Position
H3C
O
CH2
Since the enolate anion resonates between two atoms, it is important to recognize which atom will react preferentially with an electrophile
H3C
O
CH2
EE
H3C
O
CH2E
H3C
O
CH2
E
In order to make this prediction, it is important to recognize which orbital is reacting
As in all nucleophilic reactions, the HOMO of the nucleophile is reacting with the LUMO of the electrophile
Consider the HOMO for the enolate nucleophile:
Enolate structure HOMO of enolate
The charge in the HOMO for the unsymmetrical enolate is far greater on
the carbon than the oxygen (this is offset by a greater electron
density in the lowest occupied orbital)
Therefore the enolate reacts preferentially at the carbon site
Reaction at carbon Reaction at oxygen
Reactions at α-Position
To form an enolate therefore a base can be reacted with a carbonyl compound to deprotonate the hydrogen on the α-carbon
Realize, however, that most strong bases are also strong nucleophiles (remember factors in SN2 versus E2 reactions)
A base/nucleophile used could react either by reaction at carbonyl carbon or by abstracting the hydrogen on the α-carbon
H3C
O
CH3
base/nucleophile
H3C
O
CH2 H3C
O
NUCCH3
Formation of enolate
Reaction at carbonyl
Which pathway is preferred depends on the choice of base/nucleophile used
Reactions at α-Position
To generate enolate need to use a base that will not act as a nucleophile
Common choice is to use lithium diisopropylamide (LDA)
LDA
LDA is a strong base (pKa of conjugate is in high 30’s), while it is very bulky so it will not react as nucleophile on carbonyl
H3C
O
CH3
LDA
H3C
O
CH2
HN BuLi N
Li
LDA will therefore quantitatively deprotonate α-carbon without reacting at carbonyl carbon
Reactions at α-Position
The type of carbonyl compound will also affect the enolate formation
Due to the resonance stabilization of some of the carboxylic acid derivatives, the pKa values vary amongst different carbonyl compounds
H
O
CH2 H3C
O
CH2 H3CO
O
CH2 HN
O
CH3(H3C)2N
O
CH2 C NRHC
pKa of conjugate 16.7 19.3 24 25 18 24
Aldehydes are typically lower pKa than ketones
Esters and amides are less acidic
Amidate is more acidic than α-carbon
H3C
O
CH3
LDAH3C
O
CH2H3C
O
CH2
NaOH
Therefore while LDA will quantitatively deprotonate the α-carbon, hydroxide or alkoxide bases (pKa ~ 16) will only deprotonate a small fraction of molecules
Reactions at α-Position
The keto/enol equilibrium is also affected by the structure of the carbonyl compound
H3C
O
CH3 H3C
OH
CH2
H
O
CH3 H
OH
CH2
H3C
O O
CH3 H3C
O O
CH3
H
O OH
K
10-9
10-7
3
1013
Both ketones and aldehydes highly favor keto form, but aldehyde have relatively
more enol form present
β-dicarbonyl compounds have a much higher concentration of enol form due to
intramolecular hydrogen bond
Enol form is highly favored with phenol due to aromatic stabilization
Reactions at α-Position
The amount of enol present is increased in either acidic or basic conditions
H3C
O
CH3
H+H3C
O
CH3
HH2O
H3C
OH
CH2
H3C
O
CH3NaOH
H3C
O
CH2
H2OH3C
OH
CH2
Formation of enol allows hydrogens on α-carbon to be exchanged
H3C
O
CH3
D+, D2ONaOD, D2O
D3C
O
CD3D3C
O
CD3
Racemization of Enols and Enolates
A consequence of the formation of enols or enolates is the α-carbon goes from sp3 (and potentially chiral) to sp2 (and therefore planar and achiral) hybridization
H3C
O
CH3CH3
H+H3C
OH
CH3CH3
When the keto form is regenerated, the chirality at the α-carbon is lost
H+
H3C
O
CH3CH3
H3C
O
CH3CH3
The α-position therefore becomes racemic if there is an α-hydrogen present
α-carbon is chiral α-carbon is planar
racemic
or
Halogenation
When enols are generated in the presence of dihalogen compounds, an electrophilic reaction occurs which places a halogen on the α-carbon
H3C
O
CH3
H+
H3C
O
CH3
H H2O
H3C
OH
CH2
Br Br
H3C
O
CH2Br
In acidic conditions the halogenation is stopped at one addition because the protonated carbonyl compound is less stable after a halogen has been added
H3C
O
CH3
H
H3C
O
CH3
H
H3C
O
CH2
H
BrH3C
O
CH2
H
Br
Positive charge is less stable with adjacent C-Br bond
Halogenation
In basic conditions, however, an enolate is generated instead of an enol
H3C
O
CH3
NaOHH3C
O
CH2
Br BrH3C
O
CH2Br
The enolate is more stable with an attached halogen and therefore under basic conditions the α-position is polyhalogenated
H3C
O
CH2Br NaOH
H3C
O
CHBr Br Br
H3C
O
CHBr2
Reaction will continue until all α-hydrogens are replaced with halogen
More stable anion
R
O
CH3 NaOHBr2
R
O
CBr3
Haloform Reaction
When the α-carbon is a methyl group, the basic halogenation places three halogens on carbon
Under the basic conditions of the reaction, however, the three halogens convert the methyl group into a good leaving group and thus the hydroxide can react at carbonyl carbon
R
O
CH3 NaOHBr2
R
O
CBr3
R
O
CBr3NaOH
R
O
OHCBr3 R
O
OCHBr3
bromoform
The reaction thus will convert a methyl ketone into a carboxylic acid
Called a “haloform” reaction because the common name for a trihalogen substituted carbon is a haloform (chloroform, bromoform or iodoform)
Halogenation of Carboxylic Acids
Carboxylic acids can also be halogenated in the α-position, but the acid halide needs to be formed first
O
OHH3C
H HBr2
PBr3O
BrH3C
H H
OH
BrH3C
H
Br2O
BrH3C
H Br
The acid halide can easily be converted back into the acid with water work-up
O
BrH3C
H Br
H2OO
OHH3C
H Br
NH3!
O
OHH3C
H NH2
These α-bromo acids are very convenient compounds to prepare α-amino acids with reaction with ammonia
alanine
Alkylation of Enolates
Enolates are very useful to form new C-C bonds by reacting the enolate with alkyl halides
H3C
O
CH3
LDA
H3C
O
CH2
CH3Br
H3C
O
CH2CH3
Allows formation of new C-C bond at the α-position, works best with methyl or 1˚ halides as more sterically hindered alkyl halides react through E2 mechanism
When using symmetrical ketones, alkylation at either α-position generates the same product, but when using unsymmetrical ketones two different products can be obtained
H3C
O
CH2CH3
LDA
H2C
O
CH2CH3 H3C
O
CHCH3CH3Br CH3Br
H3CH2C
O
CH2CH3 H3C
O
CHCH3CH3
The conditions used to form the enolate determines which
is favored
or
Alkylation of Enolates
H3C
O
CH2CH3
Differences in enolate formation control preferential pathway
LDA
H2C
O
CH2CH3 H2C
O
CH2CH3 H3C
O
CHCH3 H3C
O
CHCH3
Hydrogen is easier to abstract, therefore this is the
kinetic enolate
Double bond of enolate is more stable, therefore this is the thermodynamic enolate
When trying to control kinetic versus thermodynamic, typically the temperature can be used as the lower temperature favors kinetic and the higher temperature favors thermodynamic
H3C
O
CH2CH3
H3C
O
CH2CH3
1) LDA, -78˚C2) CH3Br
H3CH2C
O
CH2CH3
1) LDA, 40˚C2) CH3Br
H3C
O
CHCH3CH3
Alkylation of Enolates
Alkylation of ketones is therefore relatively straightforward, add one equivalent of LDA at either low temperature for kinetic enolate and high temperature for thermodynamic enolate
and then add the required alkyl halide
Other types of carbonyl compounds can also be alkylated using these conditions
H3CO
O
CH2CH3
1) LDA2) CH3Br
H3CO
O
CHCH3CH3
With esters there is only one α-position and therefore alkylation occurs at this site
With carboxylic acids, first need to deprotonate the acidic hydrogen before deprotonating at α-position, alkylation will then occur at the α-position
HO
O
CH2CH3
NaH
O
O
CH2CH3
LDA
O
O
CHCH3
CH3Br
O
O
CHCH3CH3
Esters:
Acids:
Alkylation of Enolates
Aldehydes:
Alkylation of aldehydes can sometimes be problematic because the aldehyde carbonyl is more reactive than a ketone, therefore the enolate formed can react with the carbonyl
(called an aldol reaction to be seen shortly)
H
O
CH2CH3
LDA
H
O
CHCH3
H
O
CH2CH3
A way to circumvent this potential problem, the aldehyde can be converted to an imine
H
O
CH2CH3
RNH2
H
N
CH2CH3
RLDA
H
N
CHCH3
R 1) CH3Br2) H2O
H
O
CHCH3CH3
The imine anion can react with the alkyl halide and then the α-alkylated imine can be hydrolyzed back to the aldehyde with water
Alkylation of Enolates
β-dicarbonyl:
A distinct advantage with β-dicarbonyl compounds is the α-hydrogen is more acidic and can be quantitatively deprotonated with alkoxide base
H3CO
O O CH3ONa
H3CO
O O CH3Br
H3CO
O O
CH3
When discussing carboxylic acid derivatives, also observed that when a β-keto ester is hydrolyzed to the acid form a decarboxylation readily occurs
H3CO
O O
CH3
NaOHHO
O O
CH3
!
H3CH2C
O
CH2CH3
Thus this allows a much easier method to alkylate a ketone without needing to use LDA nor controlling kinetic versus thermodynamic (only obtain anion α to both carbonyls)
Alkylation of Enolates
Another option to alkylate a ketone instead of needing to form an enolate is to react the ketone with a secondary amine to form an enamine
H3C
O
CH3
HN
H3C CH2
N
The enamine can then react with an alkyl halide to alkylate the compound
H3C CH2
N CH3Br
H3C CH2CH3
N H2O
H3C
O
CH2CH3
The imminium ion that forms after alkylation is easily hydrolyzed with water to the ketone
The enamine is less reactive than an enolate, but more reactive than an enol
Aldol Reaction
As mentioned when forming enolates with aldehydes a potential problem is an aldol reaction
H
O
CH2CH3
Instead of merely being a potential side product, the aldol reaction can be favored by forming the enolate with alkoxide bases
CH3ONa
H
O
CHCH3
While the enolate is only formed in small concentration due to the differences in pKa, each enolate that is generated is in the presence of an excess of aldehyde
H
O
CH2CH3H
O
CH3
OHCH3
After work-up the product will contain an aldehyde (ald) and a β-hydroxy (ol) functionality, a characteristic of an aldol reaction is the
formation of a β-hydroxy carbonyl
Aldol product
Alexander Borodin (1833-1887)
Borodin is more famous today as a composer, but coinvented the aldol reaction and this could just as easily been called the “Borodin” reaction
Aldol Reaction
The β-hydroxy ketone compounds obtained after an aldol reaction can also be dehydrated
H
O
CH3
OHCH3
H+H
O
CH3
CH3
The dehydration can occur under either acidic or basic conditions, although the dehydration is typically much easier under acidic conditions
The dehydration is favored compared to other alcohols dehydrating to alkenes due to the conjugation of the obtained α,β-unsaturated alkene with the carbonyl
As the conjugation increases, sometimes it is difficult to isolate the β-hydroxy carbonyl and only the α,β-unsaturated carbonyl is obtained
O
CH31) NaOH2) H+
O
CH
CH3Aldol reactions can occur with either
aldehydes or ketones
Aldol Reaction
If a compound contains both an enolizable position and a different carbonyl, then an intramolecular aldol reaction can occur to form a new ring
H3C
O
O
CH3NaOHH2O
O CH3
OHCH3
O CH3
CH3
Once formed the β-hydroxy ketone can also dehydrate to form the α,β-unsaturated ketone
When there are multiple enolizable positions, must consider the different types of possible products
H3C
O
O
CH3 NaOHH2O
H2C
O
O
CH3
H3C
O
O
CH3
O
CH3
O CH3
CH3
5-membered rings are more stable than 7-membered, typically intramolecular aldol reactions are favored in forming either 5- or 6-membered rings
Crossed Aldol Reaction
In addition to considering different enolizable positions in an intramolecular aldol reaction, when two different carbonyls are reacted in an aldol a variety of products are obtained
H3C
O
CH3
H3CH2C
O
CH2CH3
NaOHH2O
H3C
O
CH2
H3CH2C
O
CHCH3
H3C
O OH
CH3CH3 H3C
O OH
CH2CH3CH2CH3
H3CH2C
O
CH3
OH
CH3CH3 H3CH2C
O
CH3
OH
CH2CH3CH2CH3
If the two carbonyls are both present, then the enolate could form on either
Once formed, each enolate could react with either carbonyl that is present to yield 4 different products (assuming the compounds don’t dehydrate to yield potentially more products)
All four products will be obtained in similar amounts as the reactivity difference between different ketones is minimal
This is called a “crossed aldol” or “mixed aldol”
Crossed Aldol Reaction
While reacting two different ketones with alkoxide base is impractical due to the variety of products obtained, the desired product would only be obtained in low yield after a difficult
separation, there are methods to react two different carbonyls in an aldol reaction efficiently
A simple solution is if one of the two carbonyls does not have an enolizable position
H3C
O
CH3
O
HNaOHH2O H3C
O
CH2
O
H
H3C
O
Only enolate possible
The enolate formed could still react with either carbonyl to generate two different products, but since an aldehyde is more reactive than a ketone benzaldehyde will react preferentially
Due to the extra conjugation, more than likely only the dehydrated product will be obtained
Crossed Aldol Reaction
The vast majority of time, however, there will be two carbonyls that either both have enolizable positions or the reactivity of the two carbonyls are similar,
in these cases more than one product will be obtained if using alkoxide bases
A solution for these cases is to quantitatively form the enolate rather than having an equilibrium between the enolate and keto forms with weak base
H3CH2C
O
CH2CH3
LDA
First, quantitatively form the enolate from the desired ketone Then in a second step add the appropriate electrophilic carbonyl to react
and only one product will be obtained
H3CH2C
O
CHCH3
H3C
O
CH3H3CH2C
O
CH3
OH
CH3CH3
By controlling the order of steps, any of the desired aldol products can be obtained
H3C
O
CH3LDA
H3C
O
CH2H3CH2C
O
CH2CH3H3C
O OH
CH2CH3CH2CH3
Crossed Aldol Reaction
The main difference is that the weak base only forms a small amount of enolate and thus once this enolate is generated it is in the presence of the ketone form to react
Therefore both carbonyls would need to be present at the same time and thus a variety of products are obtained
H3C
O
CH3
H3CH2C
O
CH2CH3
NaOHH2O
H3C
O
CH2
H3CH2C
O
CHCH3
H3C
O OH
CH3CH3 H3C
O OH
CH2CH3CH2CH3
H3CH2C
O
CH3
OH
CH3CH3 H3CH2C
O
CH3
OH
CH2CH3CH2CH3
All obtained in ~equal yield
To synthesize only one, which enolate is required can be determined from the structure
H3C
O
CH3
H3CH2C
O
CH2CH3
1) LDA
2)H3C
O OH
CH2CH3CH2CH3
Only product
Claisen Condensation
An aldol reaction refers to any reaction between an enolate nucleophile and a carbonyl electrophile
When using ketone or aldehyde carbonyls, the reaction is equilibrium controlled
When the electrophilic carbonyl is an ester, however, an irreversible last step occurs to drive the reaction to completion
These aldol reactions with an ester are called “Claisen condensations”
H3C
O
CH3 H3C
O
OCH3
NaOCH3
H3C
O
CH2
H3C
O
OCH3
H3C
O O
OCH3CH3
H3C
O O
CH3
NaOCH3
H3C
O O
CH3
Difference in ketone and ester pKa allows ketone
enolate to be formed
β-diketone formed has an acidic methylene (pKa ~10) that is deprotonated in these basic conditions
Claisen Condensation
Claisen condensation can also occur with only an ester present
H3C
O
OCH3
NaOCH3
H2C
O
OCH3
The enolate is harder to form due to the less acidic ester, but if it is the only
carbonyl present it can still form Want to use same alkoxide as ester used, otherwise a transesterification will occur
H3C
O
OCH3
H3CO
O O
OCH3CH3
H3CO
O O
CH3
NaOCH3
H3CO
O O
CH3
Will generate a β-keto ester after acidifying the solution
Rainer Ludwig Claisen (1851-1930)
Dieckmann Condensation
An intramolecular Claisen condensation is called a “Dieckmann” condensation
H3C
O O
OCH3
NaOCH3
H2C
O O
OCH3
O OOCH3
Ketone is more acidic than ester (6-membered ring more stable than 4)
O OIn presence of alkoxide base,
diketone will be deprotonated to drive reaction
Dieckmann condensation can also occur with diester compounds to generate β-keto ester
H3CO
O
O
OCH3 NaOCH3H3CO
O OH+, H2O
!
O
The β-keto ester can then be hydrolyzed to acid and decarboxylated
Walter Dieckmann (1869-1925)
Knoevenagel Reaction
Emil Knoevenagel(1865-1921)
Another variant of the aldol condensation involves the formation of an enolate from an acidic position, usually a β-dicarbonyl, using an amine base
H3CO
O O
OCH3
HN
H3CO
O O
OCH3
Due to the more acidic β-dicarbonyl compound, the enolate can be formed with amine base
O
H
H
O
OCH3
O
H3CO
If generated in presence of ketone or aldehyde, an aldol reaction occurs which typically readily dehydrates
A key factor in a Knoevenagel reaction is the extra stability of the formed enolate, allows formation exlusively at more
acidic position even in presence of the less acidic ketone or aldehyde and thus can be formed even with weaker bases
(typically amines)
Michael Reaction
Arthur Michael (1853-1942)
O
CH3
Michael reactions, or sometimes called Michael additions, can occur when the electrophile has an α,β unsaturation
When reacting with a nucleophile, the nucleophile can react in two different ways: 1) React directly on the carbonyl carbon (called a 1,2 addition)
2) React instead at the β-position (called a 1,4 addition)
In a 1,4 addition, initially an enolate is formed which can be neutralized in work-up to reobtain the carbonyl
Or the enolate can be reacted with a different electrophile in a second step to create a product that
has substitution at both the α and β positions
NUC O
NUCCH3
O
NUC
1,2 addition 1,4 addition (Michael)
H
O
NUC
E O
NUCE
Michael Reaction
Whether a reaction proceeds with 1,2 addition or 1,4 addition (Michael) is often dependent upon the type of nucleophile being used
Strong nucleophiles often favor 1,2 addition
O
CH3
CH3MgBr OH
CH3CH3
Grignard reagents and hydride delivery agents (LAH)
favor 1,2 addition
Stabilized nucleophiles, however, favor 1,4 addition
O
CH3
(CH3)2CuLi O
H3CCuprates favor 1,4 addition
Other stabilized nucleophiles favoring Michael addition are β-dicarbonyl enolates and enamines
Michael Reaction
Michael addition using β-dicarbonyl enolates
H3CO
O O
OCH3
NaOCH3
H3CO
O O
OCH3
O
CH3 OO
H3CO
OH3CO
If a β-diester is used, then the ester can be hydrolyzed and decarboxylated
1) H+, H2O2) !
OO
HOMichael addition using an enamine
H3C
N
O
CH3 O
CH3
N
H3C
H+, H2O O
CH3
O
H3C
The imminium salts generated initially can be hydrolyzed to the ketone
Michael Reaction
When an enamine is used as the Michael donor with an α,β unsaturated carbonyl as the Michael acceptor, the reaction is called a “Stork” reaction after its inventor
Gilbert Stork (b 1921)
The Stork reaction allows the formation of a 1,5 dicarbonyl compound
N
O
CH32) H+, H2O
1)
O O
CH3
An advantage for the Stork reaction is that an enolate of a ketone generally reacts in a 1,2 addition
H3C
OO
CH3 OCH3
H3CO
By forming the enamine first, a Michael addition can occur instead
Michael Reaction
We observed an example of a Michael reaction when discussing radical reactions in an earlier chapter
Calicheamicin γ1
O
O
NHCO2CH3S
HO
binding groupO
O
NHCO2CH3
HO
binding group
S
HO
S
Obinding group •
•
O
NHCO2CH3
Bergman cyclization
HO
S
Obinding group
O
NHCO2CH3
DNA
DNA diradical
DNA cleavage
O2
Michael addition
Robinson Annulation
Robert Robinson (1886-1975)
Many of these reactions can be used in combination to create interesting structures, one combination is to do a Michael reaction followed by an intramolecular aldol reaction
(called a Robinson annulation)
ONaOCH3
O
A small amount of enolate is formed by reacting a ketone
with an alkoxide base
O
CH3O O
CH3
Eventually the Michael addition will occur
CH3OH
O O
CH3
NaOCH3
O O
CH2
O
O
The Michael product under these conditions can equilibrate to place
enolate at other α-carbon
By placing enolate at this position, an intramolecular
aldol reaction can occur that generates a 6-membered ring
Upon work-up this aldol dehydrates to form π bond
O
O
OCH3
Robinson Annulation
Robinson annulation is a convenient method to synthesize polycyclic ring junctions
NaOCH3CH3OH
O
The two α-carbons have different acidities and thus
reaction occurs selectively at more acidic position
O
OCH3
Allows synthesis of fused polycyclic structures in high yield
For example, this fused ring system is similar to steroid
ring structures
