23 CH243 Carbonyl Condensation Rxns 140506

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Chapter 23. CarbonylChapter 23. Carbonyl

Condensation ReactionsCondensation Reactions

Why this Chapter?Why this Chapter?

Carbonyl condensation reactions also occuroften in metabolic pathways.

Also one of the general methods used to formC-C bonds.

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Carbonyl compounds are both the electrophile andnucleophile in carbonyl condensation reactions


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23.1 Carbonyl Condensation: The Aldol23.1 Carbonyl Condensation: The Aldol

ReactionReaction

Acetaldehyde reacts in basic solution (NaOt! NaO"# withanother molecule of acetaldhyde

$he β-hydro%y aldehyde product is aldol (aldehyde &alcohol#

$his is a general reaction of aldehydes and 'etones


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Gene

ral CondensationsGeneral Condensations


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Aldehydes & Ketones and Aldol E!ilibri!" Aldehydes & Ketones and Aldol E!ilibri!" $he aldol

reaction isre*ersible!fa*oringthecondensati

on productonly foraldehydeswith no α substituent

+tericfactors areincreasedin the aldol

product


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#echanis" o$ Aldol Reactions#echanis" o$ Aldol Reactions

Aldol reactions! li'eall carbonylcondensations!occur bynucleophilic addition

of the enolate ion ofthe donor moleculeto the carbonylgroup of theacceptor molecule

$he additionintermediate isprotonated to gi*ean alcohol product


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redicting Aldol roductsredicting Aldol roducts

The prod!ct %ill hae an alcohol and a carbonyl in a1'3 relationship (a beta)hydro*y carbonyl+


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/earning Chec'0 now how/earning Chec'0 now how

toto,redict the aldol reaction prod!cts o$:


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23.2 Carbonyl Condensation ers!s Alpha)23.2 Carbonyl Condensation ers!s Alpha)

-!bstit!tion-!bstit!tion

Carbonyl condensations and α substitutions bothin*ol*e formation of enolate ion intermediates

Alpha-substitution reactions are accomplished bycon*erting all of the carbonyl compound toenolate form so it is not an electrophile

5mmediate addition of an al'yl halide tocompletes the al'ylation reaction


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Conditions $or CondensationsConditions $or CondensationsA small amount of base is used to generate a

small amount of enolate in the presence ofunreacted carbonyl compound

After thecondensation! thebasic catalyst is

regenerated


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23.3 ehydration o$ Aldol ,rod!cts:23.3 ehydration o$ Aldol ,rod!cts:

-ynthesis o$ Enones-ynthesis o$ Enones

$he β-hydro%y carbonyl products dehydrate toyield con7ugated enones

$he term 8condensation9 refers to the net lossof water and combination of 2 molecules


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ehydration o$ehydration o$ ββ)/ydro*y Ketones and)/ydro*y Ketones and

Aldehydes Aldehydes

$he α hydrogen is remo*ed by a base! yieldingan enolate ion that e%pels the −O" lea*ing group

:nder acidic conditions the O" group is

protonated and water is e%pelled 12


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/earning Chec'0/earning Chec'0

What is the str!ct!re o$ the enone obtained $ro" aldolcondensation o$ acetaldehyde?

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23. sin0 Aldol Reactions in -ynthesis23. sin0 Aldol Reactions in -ynthesis

5f a desired molecule contains either a β-hydro%y carbonyl or a con7ugated enone! itmight come from an aldol reaction


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23. #i*ed Aldol Reactions23. #i*ed Aldol Reactions

A mi%ed aldol reaction between two similar aldehyde or'etone partners leads to a mi%ture of four possible products $his is not useful


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,ractical #i*ed Aldols,ractical #i*ed Aldols

5f one of the carbonyl partners contains no α hydrogens and the carbonyl is unhindered (suchas ben=aldehyde and formaldehyde# it is a goodelectrophile and can react with enolates! then ami%ed aldol reaction is li'ely to be successful

2-methylcyclohe%anone gi*es the mi%ed aldolproduct on reaction with ben=aldehyde


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#i*ed Aldols With Acidic Carbonyl#i*ed Aldols With Acidic Carbonyl

Co"po!ndsCo"po!nds Knoeena0el ariationKnoeena0el ariation

thyl acetoacetate is completely con*ertedinto its enolate ion under less basic conditionsthan monocarbonyl partners

Aldol condensations with ethyl acetoacetateoccur preferentially to gi*e the mi%ed product


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23.4 5ntra"olec!lar Aldol Reactions23.4 5ntra"olec!lar Aldol Reactions $reatment of certain dicarbonyl compounds with base

produces cyclic products by intramolecular reaction


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+imilar to aldolcondensation0nucleophilic acylsubstitution of anester enolate ion onthe carbonyl group of

a second estermolecule

#echanis" o$ the Claisen#echanis" o$ the Claisen

CondensationCondensation

5f the starting ester has morethan one acidic a hydrogen!the product β-'eto ester hasa doubly acti*ated protonthat can be abstracted bybase

;e


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7earnin0 Chec8:7earnin0 Chec8:

,redict the prod!ct o$ Claisen condensation o$ ethyl propanoate


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23.9 #i*ed Claisen Condensations23.9 #i*ed Claisen Condensations

+uccessful when one of the two esters acts asthe electrophilic acceptor in reactions withother ester anions to gi*e mi%ed β-'eto esters


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Esters and KetonesEsters and Ketones

;eactions between esters and 'etones! resultingin β-di'etones

>est when the ester component has no α hydrogens and can?t act as the nucleophilic donor


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23. 5ntra"olec!lar Claisen Condensations: The23. 5ntra"olec!lar Claisen Condensations: The

iec8"anniec8"ann Cycli;ationCycli;ation

5ntramolecular Claisen condensation >est with 1!,-diesters (product0 )-memberedβ-'etoester# and 1!-diesters (product0 ,-membered β-'etoester#


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Al8ylation o$ iec8"ann ,rod!ct Al8ylation o$ iec8"ann ,rod!ct

$he cyclic β-'eto ester can be further al'ylatedand decarbo%ylated as in the acetoacetic estersynthesis


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23.1< Con=!0ate Carbonyl Additions: The23.1< Con=!0ate Carbonyl Additions: The

#ichael#ichael ReactionReaction

nolates can add as nucleophiles to α!β-unsaturated aldehydes and 'etones to gi*ethe con7ugate addition product


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#echanis" o$ the #ichael#echanis" o$ the #ichael Nucleophilic

addition of a

enolate iondonor to the β carbon of anα!β-unsaturatedcarbonylacceptor


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Generality o$ the #ichael ReactionGenerality o$ the #ichael Reaction Occurs with a *ariety of α!β-unsaturated carbonyl compounds

(aldehydes! esters! nitriles! amides! and nitro compounds#

onorsinclude β-di'etones! β-'etoesters!malonicesters! β-'eto

nitriles!and nitrocompounds


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/earning Chec'0/earning Chec'0

Ba'e the following using a Bichael ;eaction0

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23.11 Carbonyl Condensations %ith23.11 Carbonyl Condensations %ith

Ena"ines: The -tor8 ReactionEna"ines: The -tor8 Reaction

namines are e


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Ena"ines Are !cleophilicEna"ines Are !cleophilic

O*erlap of the nitrogen lone-pair orbital with thedouble-bond π orbitals increases electron densityon the α carbon atom


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Ena"ine Addition and /ydrolysisEna"ine Addition and /ydrolysis

namine adds to an α!β-unsaturated carbonyl acceptor $he product is hydroly=ed to a 1!)-dicarbonyl compound


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/earning Chec'0/earning Chec'0repare :sing a +tor' namine ;eaction

3)


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23.12 The Robinson Ann!lation Reaction23.12 The Robinson Ann!lation Reaction

A two-step process0 combines a◦ Bichael reaction with an

◦ intramolecular aldol reaction

$he product is a substituted 2-cyclohe%enone


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;obinson Annulation;obinson Annulation

%ample%ample+ynthesis of estrone

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23.13 The Canni;aro Reaction23.13 The Canni;aro Reaction

$he adduct of an aldehyde and O" can transfer hydrideion to another aldehyde CO resulting in a simultaneouso%idation and reduction (disproportionation)


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23.1 -o"e >iolo0ical Carbonyl23.1 -o"e >iolo0ical Carbonyl


Balonyl AC is decarbo%ylated and enolate is formednolate is added to the carbonyl group of another

acyl group through a thioester lin'age to a synthase

$etrahedral intermediate gi*es acetoacetyl AC

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23 CH243 Carbonyl Condensation Rxns 140506