Carbonyl)Condensaon) Reac-ons)...• Carbonyl)condensaon)reac-ons)also)occur) o6en)in)metabolic)pathways.) • Also)one)of)the)general)methods)used)to)form) CCbonds. Why)this)Chapter?)

Carbonyl Condensa-on Reac-ons

• Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensa-on reac-ons

Condensa-on Reac-ons

• Carbonyl condensa-on reac-ons also occur o6en in metabolic pathways.

• Also one of the general methods used to form C-‐C bonds.

Why this Chapter?

• Acetaldehyde reacts in basic solu-on (NaOEt, NaOH) with another molecule of acetaldehyde

• The β-‐hydroxy aldehyde product is aldol (aldehyde + alcohol) • This is a general reac-on of aldehydes and ketones

Carbonyl Condensa-on: The Aldol Reac-on

• The aldol reac-on is reversible, favoring the condensa-on product only for aldehydes with no α subs-tuent

• Steric factors are increased in the aldol product

The Equilibrium of the Aldol

Aldehydes and Ketones and the Aldol Equilibrium

• Aldol reac-ons, like all carbonyl condensa-ons, occur by nucleophilic addi-on of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule

• The addi-on intermediate is protonated to give an alcohol product

Mechanism of Aldol Reac-ons

• Carbonyl condensa-ons and α subs-tu-ons both involve forma-on of the enolate ion intermediates

• Alpha-‐subs-tu-on reac-ons are accomplished by conver-ng all of the carbonyl compound to enolate form so it is not an electrophile

• Immediate addi-on of an alkyl halide completes the alkyla-on reac-on

Carbonyl Condensa-on versus Alpha-‐Subs-tu-on

• A small amount of base is used to generate a small amount of enolate in the presence of unreacted carbonyl compound

• A6er the condensa-on, the basic catalyst is regenerated

Condi-ons for Condensa-ons

• The β-‐hydroxy carbonyl products dehydrate to yield conjugated enones

• The term “condensa-on” refers to the net loss of water and combina-on of 2 molecules

Dehydra-on of Aldol Products: Synthesis of Enones

• The α hydrogen is removed by a base, yielding an enolate ion that expels the –OH leaving group

• Under acidic condi-ons the –OH group is protonated and water is expelled

Dehydra-on of β-‐Hydroxy Ketones and Aldehydes

• Removal of water from the aldol reac-on mixture can be used to drive the reac-on toward products

• Even if the ini-al aldol favors reactants, the subsequent dehydra-on step pushes the reac-on to comple-on

Driving the Equilibrium

• If a desired molecule contains either a β-‐hydroxy carbonyl or a conjugated enone, it might come from an aldol reac-on

Using Aldol Reac-ons in Synthesis

• Subsequent transforma-ons can be carried out on the aldol products • A saturated ketone might be prepared by cataly-c hydrogena-on of

the enone product

Extending the Synthesis

• A mixed aldol reac-on between two similar aldehyde or ketone partners leads to a mixture of four possible products

• This is not useful

Mixed Aldol Reac-ons

• If one of the carbonyl partners contains no α hydrogens and the carbonyl is unhindered (such as benzaldehyde and formaldehyde) it is a good electrophile and can react with enolates, then a mixed aldol reac-on is likely to be successful

• 2-‐methylcyclohexanone gives the mixed aldol product on reac-on with benzaldehyde

Prac-cal Mixed Aldols

• Ethyl acetoacetate is completely converted into its enolate ion under less basic condi-ons than monocarbonyl partners

• Aldol condensa-ons with ethyl acetoacetate occur preferen-ally to give the mixed product

Mixed Aldols With Acidic Carbonyl Compounds

A Crossed Aldol Addi-on

the crossed aldol addi-on forms four products

• Treatment of certain dicarbonyl compounds with base produces cyclic products by intramolecular reac-on

Intramolecular Aldol Reac-ons

• Both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule.

• The least strained product is formed because the reac-on is reversible

Mechanism of Intramolecular Aldol Reac-ons

• Reac-on of an ester having an α hydrogen with 1 equivalent of a base to yield a β-‐keto ester

The Claisen Condensa-on Reac-on

Mechanism of the Claisen Condensa-on

• Similar to aldol condensa-on: nucleophilic acyl subs-tu-on of an ester enolate ion on the carbonyl group of a second ester molecule

• If the star-ng ester has more than one acidic α hydrogen, the product β-‐keto ester has a doubly ac-vated proton that can be abstracted by base

• Requires a full equivalent of base rather than a cataly-c amount

• The deprotona-on drives the reac-on to the product

Features of the Claisen Condensa-on

• Successful when one of the two esters acts as the electrophilic acceptor in reac-ons with other ester anions to give mixed β-‐keto esters

Mixed Claisen Condensa-ons

A Crossed Claisen Condensa-on

the carbonyl compound with α-‐hydrogens is added slowly to a solu-on of the carbonyl compound without α-‐hydrogens and

a base

• Reac-ons between esters and ketones, resul-ng in β-‐diketones

• Best when the ester component has no α hydrogens and can't act as the nucleophilic donor

Esters and Ketones

A Crossed Condensa-on Between a Ketone and an Ester

LDA is used to form the enolate ion and the other carbonyl compound is added slowly

Summary of Crossed Condensa-ons

if both carbonyl compounds have α-‐hydrogens

LDA is used to form the desired enolate ion and the other carbonyl compound is added slowly

if only one carbonyl compound has α-‐hydrogens

the carbonyl compound with α-‐hydrogens is added slowly to a solu-on of the carbonyl compound without α-‐hydrogens and

a base

• Intramolecular Claisen condensa-on • Best with 1,6-‐diesters (product: 5-‐membered β-‐ketoester) and 1,7-‐diesters (product: 6-‐membered β-‐ketoester)

Intramolecular Claisen Condensa-ons: The Dieckmann Cycliza-on

Mechanism of the Dieckmann Cycliza-on

• The cyclic β-‐keto ester can be further alkylated and decarboxylated as in the acetoace-c ester synthesis

Alkyla-on of Dieckmann Product

• Enolates can add as nucleophiles to α,β-‐unsaturated aldehydes and ketones to give the conjugate addi-on product

Conjugate Carbonyl Addi-ons: The Michael Reac-on

• Example: Enolate from a β-‐keto ester or other 1,3-‐dicarbonyl compound adding to an unhindered α,β-‐unsaturated ketone

Best Condi-ons for the Michael Reac-on

• Nucleophilic addi-on of a enolate ion donor to the β carbon of an α,β-‐unsaturated carbonyl acceptor

Mechanism of the Michael Reac-on

• Occurs with a variety of α,β-‐unsaturated carbonyl compounds (aldehydes, esters, nitriles, amides, and nitro compounds)

• Donors include β-‐diketones, β-‐keto esters, malonic esters, β-‐keto nitriles, and nitro compounds

Generality of the Michael Reac-on

• Enamines are equivalent to enolates in that their reac-ons and can be used to accomplish the transforma-ons under milder condi-ons

• Enamines are prepared from a ketone and a secondary amine

Carbonyl Condensa-ons with Enamines: The Stork Reac-on

• Overlap of the nitrogen lone-‐pair orbital with the double-‐bond π orbitals increases electron density on the α carbon atom

Enamines Are Nucleophilic

• Enamine adds to an α,β-‐unsaturated carbonyl acceptor • The product is hydrolyzed to a 1,5-‐dicarbonyl compound

Enamine Addi-on and Hydrolysis

• A two-‐step process: combines a Michael reac-on with an intramolecular aldol reac-on

• The product is a subs-tuted 2-‐cyclohexenone

The Robinson Annula-on Reac-on

• Malonyl ACP is decarboxylated and enolate is formed • Enolate is added to the carbonyl group of another acyl group

through a thioester linkage to a synthase • Tetrahedral intermediate gives acetoacetyl ACP

Some Biological Carbonyl Condensa-on Reac-ons

Retrosynthe-c Analysis

Designing a Synthesis to Make New Carbon–Carbon Bonds

locate the new carbon−carbon bond that must be formed

Solu-on



solu-on

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Carbonyl)Condensaon) Reac-ons)...• Carbonyl)condensaon)reac-ons)also)occur) o6en)in)metabolic)pathways.) • Also)one)of)the)general)methods)used)to)form) CCbonds. Why)this)Chapter?)