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5/26/2018 Reaksi Kondensasi Karbonil

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Chapter 23. Carbonyl

Condensation Reactions

Why this Chapter?

Carbonyl condensation reactions also occur often in

metabolic pathways.

Also one of the general methods used to form C-Cbonds.

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Carbonyl compounds are boththe electrophile and

nucleophile in carbonyl condensation reactions


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23.1 Carbonyl Condensation: The Aldol

Reaction

Acetaldehyde reacts in basic solution (NaOEt, NaOH)with another molecule of acetaldhyde

The b-hydroxy aldehyde product is aldol(aldehyde +alcohol)

This is a general reaction of aldehydesand ketones


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General Condensations


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Aldehydes & Ketones and Aldol Equilibrium

The aldol

reaction isreversible,

favoring the

condensatio

n product

only foraldehydes

with no

substituent

Steric factorsare

increased in

the aldol

product


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Mechanism of Aldol Reactions

Aldol reactions, likeall carbonyl

condensations,

occur by nucleophilic

addition of the

enolate ion of the

donor molecule to

the carbonyl group of

the acceptor

molecule The addition

intermediate is

protonated to give an

alcohol product


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Predicting Aldol Products

The product will have an alcohol and a carbonyl in a1,3 relationship (a beta-hydroxy carbonyl)

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Learning Check: Know how toPredict the aldol reaction products of:

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23.2 Carbonyl Condensation versus Alpha-

Substitution

Carbonyl condensations and substitutions bothinvolve formation of enolate ion intermediates

Alpha-substitution reactions are accomplished byconverting all of the carbonyl compound to enolateform so it is not an electrophile

Immediate addition of an alkyl halide to completesthe alkylation reaction


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Conditions for Condensations A small amount of base is used to generate a small

amount of enolate in the presence of unreactedcarbonyl compound

After the condensation,the basic catalyst isregenerated


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23.3 Dehydration of Aldol Products:

Synthesis of Enones

The b-hydroxy carbonyl products dehydrate to yield

conjugated enones

The term condensation refers to the net loss of

water and combination of 2 molecules


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Dehydration of b-Hydroxy Ketones and

Aldehydes

The hydrogen is removed by a base, yielding anenolate ion that expels the OH leaving group

Under acidicconditions the OH group is protonated

and water is expelled 12


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Driving the Equilibrium

Removal of water from the aldol reaction mixture canbe used to drive the reaction toward products

Even if the initial aldol favors reactants, the subsequentdehydration step pushes the reaction to completion


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Learning Check:

What is the structure of the enone obtained from aldolcondensation of acetaldehyde?

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23.4 Using Aldol Reactions in Synthesis

If a desired molecule contains either a b-hydroxycarbonyl or a conjugated enone, it might come froman aldol reaction


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23.5 Mixed Aldol Reactions

A mixed aldol reaction between two similar aldehyde orketone partners leads to a mixture of four possibleproducts

This is not useful


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Practical Mixed Aldols

If one of the carbonyl partners contains no hydrogens and the carbonyl is unhindered (such asbenzaldehyde and formaldehyde) it is a goodelectrophile and can react with enolates, then a mixedaldol reaction is likely to be successful

2-methylcyclohexanone gives the mixed aldol producton reaction with benzaldehyde


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Mixed Aldols With Acidic Carbonyl

CompoundsKnoevenagel variation

Ethyl acetoacetate is completely converted into its

enolate ion under less basic conditions than

monocarbonyl partners

Aldol condensations with ethyl acetoacetate occur

preferentially to give the mixed product


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23.6 Intramolecular Aldol Reactions Treatment of certain dicarbonyl compounds with

base produces cyclic products by intramolecular

reaction


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23.7 The Claisen Condensation Reaction

Reaction of an ester having an hydrogen with 1equivalent of a base to yield a b-keto ester


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Similar to aldolcondensation:nucleophilic acylsubstitution of an esterenolate ion on thecarbonyl group of a

second ester molecule

Mechanism of the Claisen

Condensation

If the starting ester has morethan one acidic a hydrogen, the

product b-keto ester has a doubly

activated proton that can be

abstracted by base

Requires a full equivalent of base

rather than a catalytic amount

The deprotonation drives the

reaction to the product


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Learning Check:

Predict the product of Claisen condensation of ethyl propanoate


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23.8 Mixed Claisen Condensations

Successful when one of the two esters acts as the

electrophilic acceptor in reactions with other ester

anions to give mixed b-keto esters


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Esters and Ketones

Reactions between esters and ketones, resulting inb-diketones

Best when the ester component has no hydrogensand can't act as the nucleophilic donor


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23.9 Intramolecular Claisen Condensations: The

DieckmannCyclization

Intramolecular Claisen condensation

Best with 1,6-diesters (product: 5-memberedb-ketoester) and 1,7-diesters (product: 6-membered b-ketoester)


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Alkylation of Dieckmann Product

The cyclic b-keto ester can be further alkylated and

decarboxylated as in the acetoacetic ester synthesis


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23.10 Conjugate Carbonyl Additions: The

Michael Reaction

Enolates can add as nucleophiles to ,b-unsaturated

aldehydes and ketones to give the conjugate addition

product


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Best Conditions for the Michael Reaction

When a particularly stable enolate ion

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


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Mechanism of the Michael Nucleophilic

addition of a

enolate iondonor to the bcarbon of an,b-unsaturatedcarbonylacceptor


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Generality of the Michael Reaction

Occurs with a variety of ,b-unsaturated carbonyl compounds

(aldehydes, esters, nitriles, amides, and nitro compounds)

Donors

include b-

diketones,

b-keto

esters,

malonic

esters, b-

keto

nitriles,and nitro

compound

s


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Learning Check:

Make the following using a MichaelReaction:

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23.11 Carbonyl Condensations with

Enamines: The Stork Reaction

Enamines are equivalent to enolates in theirreactions and can be used to accomplish thetransformations under milder conditions

Enamines are prepared from a ketone and a

secondary amine


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Enamines Are Nucleophilic Overlap of the nitrogen lone-pair orbital with the double-

bond orbitals increases electron density on the carbon atom


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Enamine Addition and Hydrolysis

Enamine adds to an ,b-unsaturated carbonylacceptor

The product is hydrolyzed to a 1,5-dicarbonyl

compound


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Learning Check: Prepare Using a Stork Enamine

Reaction

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23.12 The Robinson Annulation Reaction

A two-step process: combines a Michael reaction with an

intramolecular aldol reaction

The product is a substituted 2-cyclohexenone


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Robinson Annulation Example Synthesis of estrone

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23.13 The Cannizaro Reaction

The adduct of an aldehyde and OH cantransfer hydrideionto another aldehyde C=O resulting in a simultaneousoxidation and reduction (disproportionation)


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23.14 Some Biological Carbonyl


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

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