Download Reactions at α-Position In preceding chapters on carbonyl chemistry

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
O
H3C
O
NUC
CH3
H3C
CH3
NUC
Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl
O
H3C
O
E
CH3
H3 C
CH2
E
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
K
5 x 10-9
O
H3C
OH
CH3
keto
H3C
O
Br Br
CH2
H3 C
enol
A carbonyl compound is in equilibrium with an enol
Typically the equilibrium for a ketone though lies heavily in the keto form
The enol form, however, is more reactive than an alkene and can undergo similar reactions as observed with reactions with π bonds CH2
Br
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
O
H3C
CH3
O
O
base
H3C
CH2
H3C
CH2
E
O
H3 C
CH2
E
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
Reactions at α-Position
Since the enolate anion resonates between two atoms, it is important to recognize which atom
will react preferentially with an electrophile
O
H3 C
O
E
CH2
E
H3C
O
CH2
Reaction at carbon
H3C
O
E
CH2
H3C
E
CH2
Reaction at oxygen
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:
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)
Enolate structure
HOMO of enolate
Therefore the enolate reacts
preferentially at the carbon site
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
O
H3C
O
base/nucleophile
CH3
H3C
O
CH2
Formation of enolate
H3C
CH3
NUC
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)
Li
H
N
N
BuLi
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
LDA will therefore quantitatively deprotonate α-carbon without reacting at carbonyl carbon
O
H3C
O
LDA
CH3
H3C
CH2
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
pKa of conjugate
16.7
19.3
24
25
18
O
O
O
O
O
H
CH2
H3 C
CH2
H3CO
Aldehydes are typically
lower pKa than ketones
CH2
(H3C)2N
Esters and amides are
less acidic
CH2
HN
24
CH3
RHC C N
Amidate is more acidic
than α-carbon
Therefore while LDA will quantitatively deprotonate the α-carbon, hydroxide or alkoxide bases (pKa ~ 16) will only deprotonate a small fraction of molecules
O
H3 C
O
NaOH
CH2
H3C
O
LDA
CH3
H3 C
CH2
Reactions at α-Position
The keto/enol equilibrium is also affected by the structure of the carbonyl compound
K
O
10-9
H3C
OH
CH3
H3 C
O
10-7
H
O
3
H3C
Both ketones and aldehydes highly favor
keto form, but aldehyde have relatively
more enol form present
OH
H
CH3
O
O
CH3
O
1013
CH2
H3C
CH2
H
O
β-dicarbonyl compounds have a much
higher concentration of enol form due to
intramolecular hydrogen bond
CH3
OH
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
O
H3C
H+
CH3
O
H3C
O
H3C
H3 C
OH
H2O
CH3
O
NaOH
CH3
H
H3C
OH
H2 O
CH2
CH2
H3C
CH2
Formation of enol allows hydrogens on α-carbon to be exchanged
O
D3C
O
NaOD, D2O
CD3
H3C
O
D+, D2O
CH3
D3C
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
O
H3C
O
OH
H+
H3C
CH3
CH3
α-carbon is chiral
H3 C
CH3
CH3
H+
or
CH3
O
CH3
α-carbon is planar
H3 C
CH3
CH3
racemic
When the keto form is regenerated, the chirality at the α-carbon is lost
The α-position therefore becomes racemic if there is an α-hydrogen present
Halogenation
When enols are generated in the presence of dihalogen compounds, an electrophilic reaction occurs which places a halogen on the α-carbon
O
H3C
O
H+
CH3
H3C
H
CH3
H2 O
OH
H3C
O
Br Br
CH2
H3 C
C
H2
Br
In acidic conditions the halogenation is stopped at one addition because the protonated
carbonyl compound is less stable after a halogen has been added
O
H3C
H
CH3
O
H3C
H
CH3
O
H3C
H
C
H2
O
Br
H3C
H
C
H2
Positive charge is less stable
with adjacent C-Br bond
Br
Halogenation
In basic conditions, however, an enolate is generated instead of an enol
O
H3C
O
NaOH
H3 C
CH3
O
Br Br
CH2
H3 C
C
H2
Br
The enolate is more stable with an attached halogen and therefore under basic conditions the α-position is polyhalogenated
O
H3 C
C
H2
Br
O
NaOH
H3 C
C
H
O
Br Br
Br
H3C
CHBr2
More stable anion
Reaction will continue until all α-hydrogens are replaced with halogen
O
R
O
Br2
CH3
NaOH
R
CBr3
Haloform Reaction
When the α-carbon is a methyl group, the basic halogenation places three halogens on carbon
O
R
O
Br2
NaOH
CH3
R
CBr3
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
O
R
CBr3
O
O
NaOH
R
CBr3
OH
R
CHBr3
O
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
H3C
PBr3
OH
Br2
H H
OH
O
H3 C
H3C
Br
H H
Br2
Br
O
H3 C
H Br
H
The acid halide can easily be converted back into the acid with water work-up
O
H3 C
H2O
Br
H Br
O
H3C
H Br
NH3
OH
!
O
H3C
OH
H NH2
alanine
These α-bromo acids are very convenient compounds to prepare α-amino acids with reaction with ammonia
Br
Alkylation of Enolates
Enolates are very useful to form new C-C bonds by reacting the enolate with alkyl halides
LDA
O
H3C
CH3Br
O
H3C
CH3
O
CH2
H3C
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
O
H3C
CH2CH3
O
O
LDA
or
H2C
CH2CH3
H3C
CHCH3
CH3Br
The conditions used to form
the enolate determines which
is favored
CH3Br
O
O
H3CH2C
CH2CH3
H3C
CHCH3
CH3
Alkylation of Enolates
Differences in enolate formation control preferential pathway
O
H3C
O
LDA
CH2CH3
H2C
CH2CH3
H2 C
O
O
O
CH2CH3
Hydrogen is easier to abstract,
therefore this is the kinetic enolate
H3C
CHCH3
H3C
CHCH3
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
1) LDA, -78˚C
2) CH3Br
O
H3C
CH2CH3
H3CH2C
1) LDA, 40˚C
2) CH3Br
O
H3C
O
CH2CH3
CH2CH3
O
H3C
CHCH3
CH3
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
Esters:
1) LDA
2) CH3Br
O
H3CO
O
CH2CH3
H3CO
CHCH3
CH3
With esters there is only one α-position and therefore alkylation occurs at this site
Acids:
O
HO
O
NaH
CH2CH3
O
O
LDA
CH2CH3
O
O
CH3Br
CHCH3
O
CHCH3
CH3
With carboxylic acids, first need to deprotonate the acidic hydrogen before deprotonating at α-position, alkylation will then occur at the α-position
Alkylation of Enolates
Aldehydes:
O
O
H
O
LDA
H
CH2CH3
H
CH2CH3
CHCH3
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)
A way to circumvent this potential problem, the aldehyde can be converted to an imine H
N
RNH2
O
CH2CH3
H
R
CH2CH3
N
LDA
H
R
CHCH3
1) CH3Br
2) H2O
O
H
CHCH3
CH3
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:
O
O
CH3ONa
O
O
CH3Br
H3CO
H3CO
O
O
H3CO
CH3
A distinct advantage with β-dicarbonyl compounds is the α-hydrogen is more acidic and can
be quantitatively deprotonated with alkoxide base
When discussing carboxylic acid derivatives, also observed that when a β-keto ester is
hydrolyzed to the acid form a decarboxylation readily occurs
O
O
O
NaOH
O
H3CH2C
HO
H3CO
CH3
O
!
CH2CH3
CH3
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
H
N
N
O
H3C
H3 C
CH3
CH2
The enamine can then react with an alkyl halide to alkylate the compound
CH3Br
N
H3 C
CH2
H2O
N
H3 C
CH2CH3
O
H3 C
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
O
O
H
O
CH3ONa
CH2CH3
H
H
CHCH3
O
CH2CH3
OH
CH3
H
CH3
Aldol product
Instead of merely being a potential side product, the aldol reaction can be favored by forming the enolate with alkoxide bases
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
After work-up the product will contain an aldehyde (ald) and a βhydroxy (ol) functionality, a characteristic of an aldol reaction is the
formation of a β-hydroxy carbonyl
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
O
OH
CH3
H
O
H+
CH3
H
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
Aldol reactions can
occur with either
aldehydes or ketones
O
CH3
1) NaOH
2) H+
O
CH3
C
H
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
O
O
CH3
H3 C
NaOH
CH3
O
CH3
OH
CH3
H2 O
O
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
O
O
CH3
H2C
O
CH3
H3 C
O
CH3
O
NaOH
H2 O
O
O
CH3
H3C
CH3
CH3
O
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
O
H3 C
O
O
CH3
H3 C
CH2
OH
CH3
CH3
H3 C
NaOH
H2 O
O
H3CH2C
CH2CH3
O
O
H3CH2C
CHCH3
O
CH3
CH2CH3
CH2CH3
H3 C
OH
H3CH2C
OH
CH3
CH3 H3CH2C
O
OH
CH3
CH2CH3
CH2CH3
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
O
O
H3 C
H
O
CH3
H
H2 O
O
O
NaOH
H3 C
CH2
H3C
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
O
O
H3CH2C
O
LDA
H3CH2C
CH2CH3
H3C
CHCH3
O
CH3
OH
H3CH2C
CH3
CH3
CH3
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
By controlling the order of steps, any of the desired aldol products can be obtained
O
O
H3C
O
LDA
CH3
H3 C
H3CH2C
CH2
O
CH2CH3
H3 C
OH
CH2CH3
CH2CH3
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
O
H3 C
O
O
CH3
H3 C
OH
CH3
CH3
H3 C
CH2
NaOH
H2 O
O
H3CH2C
CH2CH3
O
O
H3CH2C
CHCH3
O
CH3
CH2CH3
CH2CH3
H3 C
OH
H3CH2C
OH
O
CH3
CH3 H3CH2C
OH
CH3
CH2CH3
CH2CH3
All obtained in ~equal yield
To synthesize only one, which enolate is required can be determined from the structure
O
H3C
O
1) LDA
CH3
H3 C
O
2)
H3CH2C
CH2CH3
OH
CH2CH3
CH2CH3
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”
O
O
H3C
O
CH3
H3C
NaOCH3
OCH3
H3C
Difference in ketone and
ester pKa allows ketone
enolate to be formed
O
H3 C
H3C
O
CH2
OCH3
O
CH3
CH3
OCH3
H3C
NaOCH3
O
O
H3 C
O
O
CH3
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
O
NaOCH3
O
H3C
OCH3
O
H2C
H3C
OCH3
OCH3
O
O
CH3
OCH3
H3CO
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
O
O
H3CO
CH3
NaOCH3
O
Rainer Ludwig Claisen
(1851-1930)
H3CO
O
CH3
Will generate a β-keto ester after
acidifying the solution
Dieckmann Condensation
An intramolecular Claisen condensation is called a “Dieckmann” condensation
O
H3 C
NaOCH3
O
O
H2C
OCH3
O
O
O
OCH3
OCH3
Ketone is more acidic than ester (6-membered ring more stable than 4)
Walter Dieckmann
(1869-1925)
O
O
In presence of alkoxide base, diketone will be deprotonated to drive reaction
Dieckmann condensation can also occur with diester compounds to generate β-keto ester
O
OCH3
H3CO
O
O
NaOCH3
H3CO
O
H+, H2O
O
!
The β-keto ester can then be hydrolyzed to acid and decarboxylated
Knoevenagel Reaction
Another variant of the aldol condensation involves the formation of an enolate from an acidic
position, usually a β-dicarbonyl, using an amine base
O
H
N
O
H3CO
O
O
O
OCH3
H3CO
O
H
O
H3CO
OCH3
Due to the more acidic β-dicarbonyl compound,
the enolate can be formed with amine base
OCH3
H
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)
Emil Knoevenagel
(1865-1921) Michael Reaction
Michael reactions, or sometimes called Michael additions, can occur when the electrophile has an α,β unsaturation
O
NUC
H
O
NUC
O
O
CH3
NUC
CH3
1,2 addition
NUC
1,4 addition
(Michael)
E
O
NUC
E
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
Arthur Michael
(1853-1942)
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
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
CH3MgBr
O
OH
CH3
CH3
CH3
Grignard reagents and hydride delivery agents (LAH)
favor 1,2 addition
Stabilized nucleophiles, however, favor 1,4 addition
O
O
(CH3)2CuLi
CH3
Cuprates favor 1,4 addition
H3C
Other stabilized nucleophiles favoring Michael addition are β-dicarbonyl enolates and enamines
Michael Reaction
Michael addition using β-dicarbonyl enolates
O
O
H3CO
NaOCH3
O
OCH3
O
H3CO
O
O
CH3
O
H3CO
OCH3
H3CO
If a β-diester is used, then the ester can be hydrolyzed and decarboxylated
O
1) H+, H2O
2) !
O
O
HO
Michael addition using an enamine
O
N
H3 C
CH3
N
H3 C
H+, H2O
O
CH3
O
H3C
The imminium salts generated initially can be hydrolyzed to the ketone
O
CH3
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
The Stork reaction allows the formation of a 1,5 dicarbonyl compound
O
1)
CH3
2) H+, H2O
N
O
O
CH3
An advantage for the Stork reaction is that an enolate of a ketone
generally reacts in a 1,2 addition
O
O
O
CH3
CH3
H3 C
H3C
O
Gilbert Stork
(b 1921)
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
HO
O
S
NHCO2CH3
HO
Michael
addition
O
NHCO2CH3
S
binding group
O
binding group
O
Bergman cyclization
DNA
HO
O
CO2CH3
NH
DNA
diradical
O2
S
binding group
HO
O
DNA
cleavage
O
CO2CH3
NH
•
S
binding group
O
•
Robinson Annulation
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)
O
O
O
NaOCH3
A small amount of enolate is
formed by reacting a ketone
with an alkoxide base
O
CH3
CH3
Eventually the Michael addition
will occur
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
Robert Robinson
(1886-1975)
O
Upon work-up this aldol
dehydrates to form π bond
CH3OH
O
CH3
NaOCH3
O
O
O
O
O
CH2
Robinson Annulation
Robinson annulation is a convenient method to synthesize polycyclic ring junctions
OCH3
O
The two α-carbons have
different acidities and thus
reaction occurs selectively at
more acidic position
OCH3
O
NaOCH3
CH3OH
O
Allows synthesis of fused polycyclic structures in high yield
For example, this fused ring
system is similar to steroid
ring structures