AdiChemistry

ALDOLREACTION
ADDITION&CONDENSATION

The Aldol addition reaction involves the addition of carbon of an enolizable aldehyde or ketone to the
carbonylgroupofanotheraldehydeorketoneandthusbygivingahydroxycarbonylcompoundalsoknownasan
aldol(indicatingbothaldehydeandalcoholgroups).Thereactioniscatalyzedmorecommonlybyabaseorsome
timesbyanacid.
Ifthehydroxycarbonylcompoundcontaininganhydrogenundergoessubsequentdehydrationtoyieldan
,unsaturated carbonyl compound, the entire process is also called as Aldol condensation. The dehydration
step is possible under the aldol reaction conditions or mostly carried out by heating in presence of an acid or
sometimesduringacidicworkup.

Thisreactionisapowerfulmeansofmakingcarboncarbonbonds.ThenewCCbondformedisshown in red
colorinabovereactionsequence.

Mechanismofaldolreaction
Reactionconditionsandcontrolofproductmixture
Crossedaldolreactions
Directedaldolreactions
Examples

MECHANISMOFALDOLREACTION

Inbasicmedium:

*Thefirststepinbasecatalyzedaldolreactionistheabstractionofanhydrogenfromtheenolizablecarbonyl
compoundtogivearesonancestabilizedenolateanion.Usuallythisstepisslowandratedetermining.
 Note: Usually hydroxide ion is used as a base, since it is less basic than the enolate ion. This ensures the
formation of only small amount of enolate ion and is a necessary condition for further reaction of this ion with
unionized carbonyl compound. Otherwise, if strong bases like amide are used, all the reactant molecules are
convertedtoenolateionsandnofurtheradditionispossible.
*Thenextstepisthenucleophilicadditionofenolateaniontothecarbonylgroupofsecondaldehydeorketone
molecule.Thefinalproductformedafterproticworkupisahydroxycarbonylcompound(analdol).

Note:Inaldolreaction,theenolizablealdehydeorketoneactsasnucleophile,whereasthecarbonylgroupof
othermoleculeactsaselectrophiliccentre.

Inacidicmedium:

*Initiallyanenolisgeneratedfromtheenolizablecarbonylcompoundduringtheacidcatalyzedaldolreaction.

*Thusformedenolreactswiththeprotonatedcarbonylgroupofanothermolecule.

Dehydration:

The spontaneous dehydration of hydroxy carbonyl compound containing an hydrogen may be possible
underthealdolreactionconditionsorbyheatinginacidmedium.Theformationofstable,unsaturatedcarbonyl
compoundisthedrivingforceforthisstep.Hencetheinitialaldoladditionproductisoftennotisolated.
Dehydrationinbasicmedium:

It proceeds via E1cB (Elimination Unimolecular conjugate Base) mechanism. Initially, the hydroxide ion
removes acidic hydrogen to yield an enolate ion, which is a conjugate base of aldol. In the second step, the
hydroxideionislostfromtheenolateiontofurnishthe,unsaturatedcarbonylcompound.

Dehydrationinacidicmedium:


ALDOLREACTIONCONDITIONS&CONTROLOFTHEPRODUCTMIXTURE

Aldolreactionwithtwosamealdehydemolecules

Boththealdolreactionandcondensationarereversible.Inaldolreactionsbetweentwomoleculesofthesame
aldehydearegenerallyquitesuccessful,sincetheequilibriumliesfartotheright,andtheyieldsareveryhigh.

E.g. The formation of aldol (hydroxy butyraldehyde) from two molecules of acetaldehyde and subsequent
dehydrationtocrotonaldehydeoccursreadilyinpresenceofabaselikeNaOHorNa2CO3oranacidlikeHCl.

Note:Therearetwogeometricisomers(i.e.,EandZ)possibleforcrotonaldehyde.

Aldolreactionwithtwosameketonemolecules

However the equilibrium lies to the left in case of ketones. The equilibrium is to be shifted to the right to
achievesatisfactoryyieldsbyadjustingthereactionconditions.ASoxhletextractorisgenerallyemployedtoserve
thispurpose.

A mixture of products is formed in case of unsymmetrical ketones if both the groups have hydrogens.
Howeversuchketonesreactpreferentiallyatlesshinderedside.

E.g.Themajoradditionproductformedwhen2butanoneistreatedwithabaseisshownbelow.

Note: However, each of above addition products undergoes dehydration easily by giving E & Z isomers of
corresponding ,unsaturated carbonyl compound. Thus four isomeric ,unsaturated carbonyl compounds are
formedinthereactionuponcompletionofreaction.

Crossedaldolreactions(ClaisenSchmidtreactions)

Withtwodifferentenolizablecarbonylcompounds

Amixtureofadditionproductsareformedwhentwodifferentenolizablecarbonylcompoundsaresubjectedto
aldolreactionconditions.

For example, four different addition products are formed (without considering the stereoisomers), when two
differentenolizablealdehydesarereactedi.e.,twoaldolsfromreactionbetweenmoleculesofthesamealdehyde
andtwocrossedaldolproductsfromdifferentaldehydemolecules.
E.g.Whenamixtureofacetaldehydeandpropionaldehydearetreatedwithabase,amixtureoffouraddition
productsareformedasshownbelow.

Again, each of these addition products gives two geometrical isomers upon dehydration, leading to eight
differentcondensedproducts.Thatiswhythealdolreactionbetweentwodifferentenolizablecarbonylcompounds
isseldomemployedinorganicsynthesis.

However,thecrossedaldolreactionshavesyntheticutilityintwocases:

i)CrossedAldolreactionswithtwodifferentcarbonylcompoundsoneisenolizable
andanotherisnonenolizable

Onlyonecrossedaldolproductisformedwhenoneofthecarbonylcompoundlackshydrogen.
E.g. Cinnamaldehyde is formed as the only crossed aldol product when acetaldehyde (enolizable) reacts with
benzaldehyde(nonenolizable)inbasicmedium.

Note:Inabovereaction,theselfaldolcondensationofacetaldehydeisacompetingreaction.Tosuppressthis,
along with the possible cannizzaroreaction, slow addition of acetaldehyde to benzaldehyde maintained in a mild
alkalinemediumissuggested.

ii)CrossedAldolreactionsbetweenanaldehydeandaketone.

Since the carbonyl carbon of aldehyde is more electrophilic than that of ketone, the reaction between an
aldehyde an a ketone is synthetically viable. The carbon of ketone usually adds to the carbonyl carbon of
aldehyde,leadingtoonlyonemajorproduct.
E.g. The aldol reaction of acetaldehyde with acetophenone leads to the formation of 1phenylbut2en1one
predominantly.
 DIRECTEDALDOLREACTIONS

The directed aldol reactions involve preformed enolate of the carbonyl compound using strong base like LDA.
Thelithiumenolateistreatedwithanothercarbonylcompoundtoachievedesiredcrossedaldoladdition.

Thelithiumenolatecanbeeithercis(Z)ortrans(E).Cisenolateusuallygivessynadditionproductandtrans
enolategivesantiadditionproduct.

Inmostofthecases,thecisformiskineticallyfavoredandhencesynketolisformedselectivelyasthemajor
productofaddition.

Thisdiastereoselectivityisduetotheformationofcyclicsixmemberedtransitionstate(ZimmermanTraxler
transition state) in which the bulky group of carbonyl compound favorably takes pseudoequatorial position,
whereasthebulkygroupontheenolatehastotakepseudoaxialposition.Thisleadstosynproduct.

E.g.

Howeverwithcyclicsystems,thetransenolatesareformedduetoringconstraints.Henceantiadditionproduct
isformedasmajorproduct.Theringcarbonmustbeatpseudoaxialpositioninthecyclictransitionstate.Hence
theantiadditionproductisformedasmajorproduct.
 EXAMPLESOFALDOLREACTION

1)AcetoneyieldsdiacetonealcoholwhentreatedwithBa(OH)2asanadditionproduct.

However, mesityl oxide is formed when acetone is treated with dry HCl due to subsequent dehydration of
initiallyformeddiacetonealcohol.

Themesityloxidemayfurthercondensewithanothermoleculeofacetonetogivephorone.

2)Anintramolecularversionofaldolcondensationisillustratedbelowwith6oxoheptanal.

Sincethecarbonylcarbonofaldehydeismoreelectrophilicthanthatofketoneandfivememberedringismore
entropyfavoredthansevenmemberedring,theaboveproductisformedpredominantly.
 ALDOLREACTIONMULTIPLECHOICEQUESTIONS

1)Whichoneofthefollowingisnotlikelytobeformedduringaldolreaction?

a)hydroxycarbonylcompound
b),unsaturatedcarbonylcompound

c)hydroxycarbonylcompound
d)Alloftheabovearepossible
2)Enolateformedduringaldolreactionactsasa/an:

a)electrophile
b)nucleophile

c)Lewisbase
d)protondonor

3)Thenumberofaldolcondensationproductspossiblewhenamixtureofbenzaldehydeand
acetaldehydeistreatedwithastrongbase?
a)2

b)1
c)3
d)4

4)Whichofthefollowingcannotundergoaldolreaction?
a)Methanal

b)Ethanal
c)Propanone

d)Propanal
5)Inwhichofthefollowingcase(s),thedehydrationofhydroxycarbonylcompoundformedinthe
aldolreactionisNOTpossible?

a)Extendedconjugationinthefinalproducti.e.,unsaturatedcarbonylcompound.
b)Heatingthereactionmixture.
c)Nonaqueousreactionconditions.

d)Absenceofhydrogenbetweencarbonylandhydroxylgroupsinthealdol.
6)Thecorrectstatement(s)regardingaldolreactionis/are:

a)Thecarbonylgroupofmoleculeactingaselectrophiliccenterisconvertedtohydroxylgroupinthealdol.
b)Benzaldyhydedoesnotundergoaldolreaction.

c)Onlyoneproductisformedwhenamixtureofacetoneandacetaldehydeistreatedwithanalkali.
d)ACCbondisformedduringeliminationstep.

Author:AdityavardhanVutturi