REACTIONS ATTHE α–CARBON

SYNTHESIS OF DRUG VI

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

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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

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Acidity of α–Hydrogen

• Hydrogen and carbon have similar electronegativities, which means that the electrons binding them together are

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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 hydrogensbonded 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

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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.

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• 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

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hydrogen bonded to an hybridized carbon is called a carbon acid.

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• 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

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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

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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

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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.

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• 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

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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 enoltautomer.

• Tautomers are isomers that are in rapid equilibrium.

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• 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

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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

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

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• Keto–enol interconversion is also calledketo–enol tautomerization orenolization.

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• The interconversion of the tautomerscan be catalyzed by either acids orbases.

• 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

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• 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.

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• 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

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• 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 enolsuggests that it is a nucleophile—like an alkene.

• An enol is more electron rich than an alkenebecause the oxygen atom donates electrons by resonance.

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resonance.

• An enol, therefore, is a better nucleophile than an alkene

acid-catalyzed α-substitution reaction

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Base-catalyzed α-substitutionreaction

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Halogenation of the α-Carbon ofAldehydes 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

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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

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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

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• 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.

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electrophilic bromine.

• These two steps are repeated until all the α-hydrogen are replaced by bromine

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• Each successive halogenation is more rapid than the previous one because the electronwithdrawingbromine increases the acidity of the remaining α-hydrogens.

• This is why all the α-hydrogens are replaced by bromines.

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bromines.

• Under acidic conditions, on the other hand, each successive halogenation is slower than the previous one because the electronwithdrawingbromine 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

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• 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

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α–Halogenated CarbonylCompounds in Synthesis

• the α–carbon becomes nucleophilic—it reacts with electrophiles.

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• 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.

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• 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

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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

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

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• 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.

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

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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

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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.