You are on page 1of 40

SYNTHESIS OF DRUG VI

REACTIONS AT
THE α–CARBON

MUHAMMAD ASWAD
Introduction
• Aldehydes, ketones, esters, and N,N-
disubstituted amides have a second site of
reactivity.
• A hydrogen bonded to a carbon adjacent
to a carbonyl carbon is sufficiently acidic to
be removed by a strong base.
• The carbon adjacent to a carbonyl carbon
is called an α–carbon
• A hydrogen bonded to an is called an α–
hydrogen
#
2
#
Acidity of α–Hydrogen
• Hydrogen and carbon have similar
electronegativities, which means that
the electrons binding them together are
shared almost equally by the two atoms.
• Consequently, a hydrogen bonded to a
carbon is usually not acidic.

#
• This is particularly true for hydrogens
bonded to sp3 hybridized carbons, because
these carbons are the most similar to
hydrogen in electronegativity.
• The high pKa of ethane is evidence of the
low acidity of hydrogens bonded to sp3
hybridized carbons.

#
• A hydrogen bonded to an sp3 hybridized
carbon adjacent to a carbonyl carbon is
much more acidic than hydrogens bonded to
other sp3 hybridized carbons.
• For example, the pKa for dissociation of an
from an aldehyde or a ketone ranges from
16 to 20, and the pKa for dissociation of an
α–hydrogen from an ester is about 25

#
• Notice that, although an is more acidic than
most other carbon-bound hydrogens, it is
less acidic than a hydrogen of water (pKa =
15,7)
• A compound that contains a relatively acidic
hydrogen bonded to an hybridized carbon is
called a carbon acid.

#
#
• Why is a hydrogen bonded to an sp3 hybridized
carbon that is adjacent to a carbonyl carbon so
much more acidic than hydrogens bonded to
other sp3 hybridized carbons?
• An α-hydrogen is more acidic because the base
formed when the proton is removed from the is
more stable than the base formed when a
proton is removed from other sp3 hybridized
carbons, and acid strength is determined by the
stability of the conjugate base that is formed
when the acid gives up a proton
#
• Why is the base more stable? When a
proton is removed from ethane, the
electrons left behind reside solely on a
carbon atom.
• Because carbon is not very electronegative,
a carbanion is relatively unstable and
therefore difficult to form. As a result, the
pKa of its conjugate acid is very high.

#
• When a proton is removed from a carbon
adjacent to a carbonyl carbon, two factors
combine to increase the stability of the base
that is formed.
• First, the electrons left behind when the proton
is removed are delocalized, and electron
delocalization increases the stability of a
compound . More important, the electrons are
delocalized onto an oxygen, an atom that is
better able to accommodate the electrons
because it is more electronegative than carbon.

#
#
• Now we can understand why aldehydes and ketones
(pKa = 16-20) are more acidic than esters (pKa = 25)
• The electrons left behind when an is removed from an
ester are not as readily delocalized onto the carbonyl
oxygen as are the electrons left behind when an α–
hydrogen is removed from an aldehyde or a ketone.
• Because a lone pair on the oxygen of the OR group of
the ester can also be delocalized onto the carbonyl
oxygen, the two pairs of electrons compete for
delocalization onto oxygen.

#
Keto–Enol Tauterism
• A ketone exists in equilibrium with its enol
tautomer.
• Tautomers are isomers that are in rapid
equilibrium.
• Keto–enol tautomers differ in the location of a
double bond and a hydrogen.

#
• For most ketones, the enol tautomer is
much less stable than the keto tautomer.
For example, an aqueous solution of
acetone exists as an equilibrium mixture
of more than 99.9% keto tautomer and
less than 0.1% enol tautomer

#
• The fraction of the enol tautomer in an
aqueous solution is considerably greater for a
β–diketone because the enol tautomer is
stabilized by intramolecular hydrogen bonding
and by conjugation of the carbon–carbon
double bond with the second carbonyl group

#
• Phenol is unusual in that its enol
tautomer is more stable than its keto
tautomer because the enol tautomer is
aromatic, but the keto tautomer is not.

#
• Keto–enol interconversion is also called
keto–enol tautomerization or
enolization.

• The interconversion of the tautomers


can be catalyzed by either acids or
bases.

#
• In a basic solution, hydroxide ion removes a proton from the
α-carbon of the keto tautomer.
• The anion that is formed has two resonance contributors: a
carbanion and an enolate ion.
• The enolate ion contributes more to the resonance hybrid
because the negative charge is better accommodated by
oxygen than by carbon.
• Protonation on oxygen forms the enol tautomer, whereas
protonation on the α-carbon reforms the keto tautomer.

#
• In an acidic solution, the carbonyl
oxygen of the keto tautomer is
protonated and water removes a proton
from the α–carbon forming the enol.

#
• Notice that the steps are reversed in the
base- and acid-catalyzed reactions.
• In the base-catalyzed reaction, the base
removes the α-proton in the first step and
the oxygen is protonated in the second step.
• In the acid-catalyzed reaction, the acid
protonates the oxygen in the first step and
the α-proton is removed in the second step.
• Notice also how the catalyst is regenerated
in both the acid- and base-catalyzed
mechanisms. #
How Enols and Enolate Ions React
• The carbon–carbon double bond of an enol
suggests that it is a nucleophile—like an alkene.
• An enol is more electron rich than an alkene
because the oxygen atom donates electrons by
resonance.
• An enol, therefore, is a better nucleophile than an
alkene

#
acid-catalyzed α-substitution reaction

#
Base-catalyzed α-substitution
reaction

#
Halogenation of the α-Carbon of
Aldehydes and Ketones
Acid-Catalyzed Halogenation
• When Br2, Cl2 or I2 is added to an acidic
solution of an aldehyde or a ketone, a
halogen replaces one of the α-hydrogen of
the carbonyl compound

#
• In the first step of this acid-catalyzed reaction, the
carbonyl oxygen is protonated.
• Water is the base that removes a proton from the
forming an enol that reacts with an electrophilic halogen

#
Base-Promoted Halogenation

When excess Br2, Cl2 or I2 is added to a basic


solution of an aldehyde or a ketone, the halogen
replaces all of the α-hydrogen

#
• In the first step of this base-promoted
reaction, hydroxide ion removes a proton
from the α-carbon.
• The enolate ion then reacts with the
electrophilic bromine.
• These two steps are repeated until all the α-
hydrogen are replaced by bromine

#
#
• Each successive halogenation is more rapid than
the previous one because the electronwithdrawing
bromine increases the acidity of the remaining α-
hydrogens.
• This is why all the α-hydrogens are replaced by
bromines.
• Under acidic conditions, on the other hand, each
successive halogenation is slower than the
previous one because the electronwithdrawing
bromine decreases the basicity of the carbonyl
oxygen, thereby making protonation of the carbonyl
oxygen less favorable.
#
The Haloform Reaction
• In the presence of excess base and excess
halogen, a methyl ketone is first converted into a
trihalo-substituted ketone
• Then hydroxide ion attacks the carbonyl carbon of
the trihalo-substituted ketone
• Because the trihalomethyl ion is a weaker base
than hydroxide ion (the of is 14; the of is 15.7), the
trihalomethyl ion is the group more easily expelled
from the tetrahedral intermediate, so the final
product is a carboxylic acid.
• The conversion of a methyl ketone to a carboxylic
acid is called a haloform reaction #
#
α–Halogenated Carbonyl
Compounds in Synthesis

• the α–carbon becomes nucleophilic—it


reacts with electrophiles.

#
• However, when the α-position is
halogenated, the α-carbon becomes
electrophilic—it reacts with nucleophiles.
Therefore, both electrophiles and
nucleophiles can be placed on -carbons.

#
• a-Brominated carbonyl compounds are also
useful to synthetic chemists because once a
bromine has been introduced into the α-position
of a carbonyl compound, an α, β-unsaturated
carbonyl compound can be prepared by means
of an E2 elimination reaction, using a strong
and bulky base to encourage elimination over
substitution

#
Alkylation and Acylation of the α-
Carbon via an Enamine Intermediate

• an enamine is formed when an aldehyde or


a ketone reacts with a secondary amine

#
• Enamines react with electrophiles in the
same way that enolates do

#
• This means that electrophiles can be added to the α–
carbon of an aldehyde or a ketone by first converting
the carbonyl compound to an enamine (by treating
the carbonyl compound with a secondary amine),
adding the electrophile, and then hydrolyzing the
imine back to the ketone.

#
• In addition to being able to be alkylated,
aldehydes and ketones can also be acylated
via an enamine intermediate.

#
Aldol–Addition
• An aldol addition is a reaction in which
both of these activities are observed:
One molecule of a carbonyl
compound— after a proton is removed
from an —reacts as a nucleophile and
attacks the electrophilic carbonyl
carbon of a second molecule of the
carbonyl compound.