Tema 2 QOIII

Tema 2
Compostos amb grups carbonil:

reaccions que impliquen els
carbonis en alfa
Química Orgànica III Llibres de referència:

Universitat de Barcelona Química Orgánica (5ª ed.)- capítol 18
Organic Chemistry (8ª ed.) - chapter 17
Paula Yurkanis Bruice
Editorial Pearson
Química Orgànica III – Universitat de Barcelona
Acidesa dels carbonis en alfa d’un carbonil
Carbonyl group – carbon double

bonded to oxygen - carbonyl
compounds contain this functional
group and are widespread in
biological molecules
Class I carbonyl compounds – nucleophilic acyl substitution reactions - acyl

group attached good leaving group
Class II carbonyl compounds - addition reactions - acyl group attached poor
leaving group
Acidity of -hydrogen atoms:

Class III carbonyl compounds - hydrogen bonded to an -carbon of
aldehydes, ketones, esters, and N,N-disubstituted amides is
sufficiently acidic to be removed by a strong base
Hydrogens attached to sp3 carbons

have very high pKa values
A hydrogen attached to an sp3 carbon adjacent to a carbonyl carbon has a

much lower pKa value
The sp3 carbon adjacent to carbonyl carbon is called an -carbon.

A compound that contains a relatively acidic hydrogen bonded to an sp3
carbon is called a carbon acid.
Hydrogen bonded to an -carbon of aldehydes, ketones, esters, and N,N-
disubstituted amides is sufficiently acidic to be removed by a strong base
4
The pKa values of some carbon acids
Based on pKa value alone, the conjugate base from -hydrogen

deprotonation of an aldehyde or ketone should be slightly more stable than
from an ester, and much more stable than that from an alkane …. why?
Deprotonation of an alkane generates a carbanion with localized electrons

(unstable because electrons reside on an atom that is not very electronegative)
-hydrogen deprotonation of a carbonyl compound generates a carbanion

with delocalized electrons
Delocalization increases stability (The more stable the base, the stronger its
conjugate acid.)
Oxygen is better able to accommodate the electrons than carbon.
A proton on an α-carbon of an aldehyde or a ketone is more acidic (pKa = 16–20)

than a proton on the α-carbon of an ester (pKa = 25) or a N,N-disubstituted amide
(pKa = 30).
Why is an aldehyde or ketone more acidic than an ester ?
Esters and N,N-disubstituted amides are less acidic than aldehydes and
ketones because electrons remaining after deprotonating the -carbon of an
ester or N,N-disubstituted amides are not as readily delocalized - the OR
and NR2 groups also have a lone pair that can be delocalized on the
carbonyl oxygen generating competition between delocalization of these two
pairs of electrons.
Nitrogen-containing compounds
-hydrogen deprotonation of nitroalkanes, nitriles, and N,N-disubstituted amides

delocalize electrons with the electrons on a more electronegative atom than carbon
Only amides without a H on a N have “acidic” α-hydrogens.

-hydrogen deprotonation of -keto esters, and -diketones is even easier.
The acidity of the α-hydrogen increases because the electrons left behind can be
delocalized onto two oxygens
Tautomeria cetoenòlica
Tautomers are isomers that are in rapid equilibrium
Tautomers differ in the location of a double bond and a hydrogen.
For most ketones,

the keto tautomer is more stable than the enol tautomer, and thus
present at a much higher concentration.
The combination of a C=C and O-H bonds is slightly less stable (~ 40 KJ·mol-1)
than the combination of C=O and C-H bonds
-diketones have a
considerably larger fraction of
the enol tautomer because of
(1) intramolecular hydrogen
bonding and (2) conjugation
of the double bond with the
second carbonyl group (but
the keto tautomer is still more
stable.)
The enol tautomer for phenol

is considerably more stable
than the keto form (unusual)
because generation of the
keto tautomer requires
breaking the aromaticity of
the benzene ring
The mechanism for base-catalyzed keto–enol interconversion
Step 1 - Base (hydroxide) will remove the most acidic proton in solution - proton on the -
carbon of the keto tautomer forming an enolate anion
The enolate ion is stabilized due to two significant resonance contributors
Step 2 - Acid (water - cannot have more acidic compound than this in basic solution!) will
protonate the most basic atom in solution
Protonation of the enolate oxygen atom generates the enol tautomer
Protonation of the enolate -carbon atom regenerates the keto tautomer
The Mechanism for Acid-Catalyzed Keto–Enol Interconversion
Step 1 - Acid (hydronium ion) will protonate the most basic atom in solution - carbonyl
oxygen of the keto tautomer
Step 2 - Base (water - cannot have more basic compound than this in acidic solution!)
will deprotonate the most basic atom in solution - proton on the -carbon of the keto
tautomer forming the enol tautomer
Keto-enol tautomerization: both mechanisms are very similar, and are truly
“catalyzed” - hydroxide or hydronium ions are regenerated in both cases. The
mechanisms only really differ in the order of protonation of the carbonyl oxygen and
deprotonation of the -carbon atom (base-catalyzed has deprotonation first)
Reactivitat d’enols i enolats
An enol is more electron rich (better nucleophile) than an alkene due to

resonance electron donation via the oxygen atom
Enols undergo substitution reactions - -substitution reactions - one

electrophile (E+) is substituted for another (H+) at the -carbon!
Reactivitat d’enols i enolats: Halogenació al carboni  en aldehids i cetones
Acid-Catalyzed Halogenation (Only one α-hydrogen is replaced by a halogen)
Base-catalyzed halogenation (All the α-hydrogens are replaced by a halogen)

Mechanism for Acid-Catalyzed halogenation of aldehydes and ketones
When Br2, Cl2, or I2 is added to a solution of aldehyde or ketone, a halogen replaces
one of the -hydrogens of the carbonyl compound
Step 1 - Acid (hydronium ion) protonates the most basic atom - carbonyl oxygen
Step 2 - Water (cannot have stronger base in acid) deprotonates the most basic atom in
solution - proton on -carbon of the keto tautomer forming the enol tautomer
Step 3 - Enol reacts with an electrophile (halogen - X2) - neutral enols are not as good
nucleophiles as negatively charged enolate ions
This is the same as the mechanism for acid-catalyzed enolization except that Br+ is
the electrophile instead of H+.
Mechanism for Base-Catalyzed halogenation of aldehydes and ketones

When Br2, Cl2, or I2 is added to a solution of aldehyde or ketone, a halogen replaces
all of the -hydrogens of the carbonyl compound:
Step 1 - hydroxide removes the most acidic proton - -carbon, form enolate ion
Step 2 - enolate ion reacts with an electrophile (halogen - X2)
Repeat steps 1 - 2 until all -hydrogens are replaced - each replacement is more rapid than
the previous one because electron-withdrawing halogen increases acidity of any remaining
-hydrogens (for acid catalyzed, electron-withdrawing halogen decreases basicity of
carbonyl oxygen, making additional reactions unfavorable)
This is the same as the mechanism for base-promoted enolization except

that Br+ is the electrophile instead of H+
Reactivitat d’enols i enolats: Halogenació al carboni  en àcids carboxílics
The Hell-Volhard-Zelinski (HVZ) reaction replaces the α-hydrogen of a

carboxylic acid with Br.
Carboxylic acids cannot undergo substitution reactions at the -carbon because a

base will remove a proton from the OH group instead of the -carbon
When carboxylic acids are first treated with PBr3 (generates acyl halide), they can
undergo substitution reactions at the -carbon
Reactivitat d’enols i enolats: Halogenació al carboni  en àcids carboxílics
Step 1 - PBr3 converts a carboxylic acid to acyl bromide, which is in equilibrium with its enol
Step 2 - Enol reacts with an electrophile - (similar to step 2 of acid-catalyzed halogenation)
Step 3 - -brominated acyl bromide (class I carbonyl compound) is readily hydrolyzed to the
-brominated carboxylic acid
Substitució de l’halogen en  en compostos carbonílics
Substituting a proton from an -carbon with a bromine makes the -carbon
electrophilic and allows for reaction with Nu
The bromine on the

α-carbon can be
replaced only by a
weak base
Strong bases cannot be used

for this reaction because they
will form elimination products.
Substitució de l’halogen en  en compostos carbonílics
E2 - generates -unsaturated carbonyl compounds (use a strong,

bulky base to disfavor SN2):
Preparació d’enolats
Generation of an enolate ion depends on the pKa of the carbonyl compound and
the pKa of the base used to remove the -hydrogen
Hydroxide is a weaker base than

the enolate ion, so the equilibrium
disfavors enolate ion formation
Only a small amount of enolate ion is formed.

(The equilibrium lies to the left.)
A stronger base is required (LDA).

Preparació d’enolats
Generation of LDA - addition of butyllithium to diisopropylamine in THF at -78 ºC:

Two bulky substituents bonded to nitrogen of LDA make it difficult to get
close to the carbonyl carbon to react as a Nu: - LDA removes a proton
much more quickly than it attacks the carbonyl carbon
Deprotonation of cyclohexanone (pKa = 17) using lithium diisopropylamide

(LDA) (pKa ~ 35):
All the ketone is converted to enolate ion.

(The equilibrium lies to the right.)
Alquilació del carboni en 
Removing a proton from an -carbon makes the -carbon nucleophilic and allows for
reaction with electrophiles
can also be shown as
This method can be used to alkylate the α-carbon of

ketones, esters, and nitriles.
This method can be used to alkylate the α-carbon of

ketones, esters, and nitriles...
… but not aldehydes… we’ll see why later (Aldol addition)

Regioselectivity - for asymmetrical ketones, either -carbon can be alkylated
What determines which product predominates? Reaction conditions…..
kinetic thermodynamic enolate

enolate ion ion
2,6-Dimethylcyclohexanone 2,2-Dimethylcyclohexanone
is the major product is the major product
if the reaction is irreversible if the reaction is reversible
(LDA at −78 °C). (LDA at 0 °C).
Kinetic enolate ion formation - Thermodynamic enolate ion formation -

generated from fastest - generated from the most stable -
hydrogen deprotonation, which hydrogen deprotonation, which generates
is removal of the least sterically the most stable (most substituted) enolate
hindered -hydrogen ion (alkyl substitution increases stability in
enolates as it does in alkenes)
Kinetic conditions (-78°)
irreversibly generate 2,6- Thermodynamic conditions (higher
dimethylcyclohexanone temperature, unhindered base (KH))
reversibly generates the more stable
2,2-dimethylcyclohexanone product
Alquilació i acilació del carboni  via intermedis enamina
Reacting an aldehyde or
ketone with a secondary
amine generates an enamine
Enamines react with electrophiles the same way that enolate ions do (as Nu:).
As a result, aldehydes and ketones can be alkylated at the -carbon by first
forming an enamine of the cabonyl compound.
An E+ can be added to the -carbon of an aldehyde or a ketone by:
1 - converting the compound into an enamine (secondary amine and trace acid)
2 - reaction with electrophile (SN2 reactions work best with methyl halides and
primary alkyl halides)
3 - hydrolysis of imine back to ketone
Using an enamine avoids having to use a strong base (LDA).

Using an enamine intermediate generates only the monoalkylated product
Direct alkylation using a carbonyl compound generates dialkylated and O-alkylated

products as well:
Enamine intermediates can also be used to acylate aldehydes and ketones

Alquilació del carboni en 
,-unsaturated carbonyl compounds - class I and II carbonyl compounds with a

double bond between the - and -carbon atoms
Direct addition (1,2 addition) - Nu: addition at the carbonyl carbon

Conjugate addition (1,4 addition) - Nu: addition at the -carbon
The β-carbon of an α,β-unsaturated aldehyde or ketone can be alkylated via

conjugate addition.
When the nucleophile is a relatively weak base, conjugate addition

predominates.
Alquilació del carboni en  via reacció de Michael
When the nucleophile in conjugate addition is an enolate ion, the reaction is called a
Michael reaction.
The best enolate ions are those flanked by

two EWGs (enolates of -diketones, -
diesters, -keto esters, -keto nitriles)
Michael reactions form 1,5-dicarbonyl compounds.
Michael Reaction - mechanism
Step 1 - Base* (hydroxide) will remove the most acidic proton in solution - proton on the -
carbon of -diketones, -diesters, -keto esters, -keto nitriles forming a resonance-stabilized
enolate anion
Step 2 - Enolate ion reacts with an electrophile - -carbon of -unsaturated carbonyl
compound
Reaction is at the -carbon (conjugated addition product) due to the low reactivity of the
-unsaturated esters and amides used
Step 3 – The -carbon is protonated (rather than oxygen, generates keto)
*Note that if either of the reactants in a Michael reaction has an ester, the base used to
remove the -proton is the same as the leaving group of the ester - this ensures that any
transesterification reactions will not change the nature of the reactant
The best enolate ions are those flanked by two EWGs (enolates
of -diketones, -diesters, -keto esters, -keto nitriles)
Note that if either of the reactants in

a Michael reaction has an ester, the
base used to remove the -proton is
the same as the leaving group of the
ester - this ensures that any
transesterification reactions will not
change the nature of the reactant
Alquilació del carboni en  via una enamina – Reacció de Stork
Stork enamine reaction performs a “Michael reaction,” but uses an enamine in

place of an enolate ion:
(No deprotonation - no base is needed to generate Nu:)

Step 1 - enamine reacts with an electrophile - -carbon of -unsaturated carbonyl
compound
Step 2 - enol tautomerizes to keto form - this always happens with conjugate addition to
regenerate the more stable carbonyl compound
Step 3 - hydrolysis of iminium back to ketone
Addicions aldòliques
The carbonyl carbon of aldehydes and ketones is an electrophile.

Removing a proton from an -carbon makes the -carbon nucleophilic and allows for
reaction with electrophiles
Aldol addition - observation of both of these reactivities using two

molecules of an aldehyde or two molecules of a ketone:
One molecule of the aldehyde or ketone serves as
the electrophile, and the other as a nucleophile.
Note that aldol reactions are reversible

Two aldehydes = -hydroxyaldehyde and good yields of addition product
Two ketones = -hydroxyketone are only obtained if product is
removed from solution as it is formed
Aldol Addition - mechanism for aldehydes
Step 1 - Base (hydroxide) will remove the most acidic proton in solution - proton on the -carbon
forming a resonance-stabilized enolate ion
Step 2 - Enolate ion reacts with an electrophile - carbonyl carbon of a second molecule of the
aldehyde
Step 3 - Negatively charged oxygen obtains a proton from solvent
High reactivity of aldehydes in this competing aldol addition reaction is the reason
for the low yields of -alkylation products - much more likely to find another
molecule of itself as an electrophile than the alkyl halide
Aldol Addition - mechanism for ketones (ketones are less reactive than aldehydes
and react more slowly)
Step 1 - Base (hydroxide) will remove the most acidic proton in solution - proton on the -carbon
forming a resonance-stabilized enolate ion
Step 2 - Enolate ion reacts with an electrophile - carbonyl carbon of a second molecule of the
ketone
Step 3 - Negatively charged oxygen obtains a proton from solvent
An aldol reaction occurs between two molecules of the same carbonyl compound,
thus the product has twice as many carbons as the reacting aldehyde or ketone
A Retro-Aldol Addition
Because an aldol addition is reversible, when the product of an aldol addition (the
-hydroxyaldehyde or -hydroxyketone) is heated with hydroxide ion and water,
the aldehyde or ketone that formed the aldol addition product can be regenerated
Addicions aldòliques: deshidratació dels productes d’addició aldòlica
Alcohols undergo dehydration when they are heated with acid

Aldol Addition - generates a -hydroxyaldehyde or -hydroxyketone - carbonyl with
OH at -carbon
Dehydration of aldol addition products generates -unsaturated aldehydes and
ketones (enones) - rapid reaction because conjugation of the double bond with
the carbonyl carbon increases the stability of the product
The overall reaction is called an aldol condensation.
A condensation reaction combines two molecules

by forming a C—C bond while removing a small molecule
(usually water or an alcohol).
Unlike alcohols that can be dehydrated only under acidic conditions, aldol
condensation can also be accomplished using basic conditions
Sometimes dehydration occurs under the basic conditions used for the aldol
addition without requiring additional heat, especially if the alkene generated
significantly enhances the conjugation (and thus stability) of the product
Aldol condensation can also be accomplished using basic conditions
This elimination reaction is an E1cb reaction (elimination unimolecular conjugate

base). An E1cb reaction occurs only when the carbanion can be stabilized by
electron delocalization.
This base-catalyzed dehydration represents a third kind of elimination reaction

(remember E1 and E2 reactions)
Addició aldòlica creudada
A Crossed Aldol Addition forms 4 products:
1 - A- + B
2 - A- + A
3 - B- + A
4 - B- + B
Without some “control,” mixed aldol addition reactions

are not synthetically useful…
Addició aldòlica creudada: a Claisen-Schmidt condensation
Claisen-Schmidt condensation
Obtaining one product from a crossed aldol addition when one carbonyl compound
does not have -hydrogens
A compound without -hydrogens cannot be made into the enolate -
reduction of possible compounds from 4 to 2… how to get it down to one
(need to eliminate self reaction)?
Experimental delivery - use the compound without -hydrogens in excess in a basic

solution and then slowly add in the compound with -hydrogens
Benzaldehyde cannot be deprotonated, so it will sit in basic solution as a waiting
electrophile
As soon as the ketone hits the basic solution, it will be deprotonated, becoming the
nucleophilic enolate ion
Adding the ketone slowly ensures that the first molecule it encounters to react with is
benzaldehyde, forming the desired mixed aldol addition product
Addició aldòlica creudada
Obtaining one product from a crossed aldol addition when both carbonyl compound
have -hydrogens
If both compounds have -hydrogens, convert one of the compounds into
enolate ions using a very strong base such as LDA and add the other carbonyl
compound slowly.
Experimental delivery - generate the enolate ion of one compound with -hydrogens
using LDA, and then slowly add in the other compound
Cyclohexanone will sit in basic solution as a waiting nucleophile
Butanal, serving as an electrophile, can react with the waiting nucleophile as soon
as it hits the basic solution
Adding butanal slowly ensures that if it does not react with the enolate ion, but
rather becomes an enolate ion itself (deprotonated), can minimize the chance it
will now become a waiting nucleophile
Condensació de Claisen
Claisen condensation - two molecules of an ester undergo a condensation reaction

and generate a -keto ester
Notice what’s different… -ketocarbonyl,

not -hydroxycarbonyl
Experimental note - notice that the base employed is the same as the leaving
group of the ester, so that the reactant will not change if the base were to act as
a Nu: and undergo a transesterification reaction
Condensació de Claisen
The Mechanism for the Claisen Condensation:
Step 1 - Base (methoxide*) will remove the most acidic

proton in solution - proton on the -carbon forming a
resonance-stabilized enolate anion
Step 2 - Enolate ion reacts with an electrophile - carbonyl
carbon of a second molecule of the ester The Claisen condensation,
Step 3 - tetrahedral intermediate can decompose, and unlike an aldol addition, is
eliminates the weaker base (methoxide) a nucleophilic acyl
*base utilized is same as substitution reaction
leaving group from ester
The Claisen Condensation versus Química Orgànica III – Universitat de Barcelona
the Aldol Addition Condensació de Claisen
Aldol addition - a new C-C bond between the -carbon and carbonyl carbon of two
aldehydes/ketones (Class II compounds) generates -hydroxycarbonyl compounds,
which can be dehydrated (aldol condensation) to yield an -unsaturated carbonyl
compounds
Claisen condensation - a new C-C bond between the -carbon and carbonyl carbon
of two esters (Class I compounds) generates a -keto ester
Claisen condensation, utilizing

class I carbonyl compounds
undergoes a nucleophilic acyl
substitution reaction
Aldol addition/condensation,
utilizing class II carbonyl
compounds undergoes a
nucleophilic addition reaction
Claisen
condensation is
reversible…
A successful Claisen Condensation Condensació de Claisen
requires an ester with two α-hydrogens
A second hydrogen is removed to prevent the reaction from reversing to the starting
material.
Despite decomposition of a tetrahedral intermediate by expelling a suitable leaving group,

alkoxide is not a weak base, and can reverse the reaction by serving as a Nu:
Alkoxide ion - conjugate base of an alcohol, most have pKa values ~15
-keto ester - the central -carbon atom is very acidic, being flanked by 2 carbonyl groups,
have pKa values ~10-11
Since the alkoxide ion is a stronger base than the -keto ester anion, a proton is transferred,
driving the reaction to completion by (1) eliminating the alkoxy Nu:, and (2) making the carbonyl
carbons less electrophilic from the electron-donating anion
Experimental considerations - Claisen condensation requires an ester with 2 -hydrogens, an
equivalent amount of base rather than a catalytic amount of base, and an acid workup to
protonate the -ketoester.
Condensació de Claisen mixta
Obtaining one product from a crossed Claisen condensation
The carbonyl compound with α-hydrogens is added slowly to a solution of

the carbonyl compound without α-hydrogens and a base.
Notice base employed is the same as the leaving group of the ester
Obtaining one product from a crossed Claisen condensation
If both carbonyl compounds have α-hydrogens, LDA is used to form the enolate
ion of one of them, and the other carbonyl compound is added slowly.
A Crossed condensation between a ketone and an ester

A Crossed condensation between a ketone and diethyl carbonate

A Crossed Condensation between a Ketone and an Ester
If both the ketone and the ester have α-hydrogens, then LDA is used to form the
needed enolate ion. The other carbonyl compound is then added slowly to the
enolate ion to minimize the chance of it also forming an enolate ion and reacting
with another molecule of its parent ester.
A -diketone is formed when a ketone condenses with an ester.

Condensacions intramoleculars: condensació de Dieckman
A Dieckman condensation is an intramolecular Claisen condensation

Condensacions intramoleculars: condensació de Dieckman
The mechanism for a Dieckmann Condensation:
Step 1 - Base (methoxide*) will remove the most acidic proton in solution - proton on the
-carbon forming a resonance-stabilized enolate ion
Note intentional symmetry here, only one -carbon
Step 2 - Enolate ion reacts with E+ - carbonyl carbon within same molecule
Step 3 - tetrahedral intermediate decomposes, eliminating weaker base (CH3O-)
Experimental considerations - any Claisen condensation requires an ester with 2 -
hydrogens, an equivalent (vs. catalytic) amount of base*, and an acid workup.
*base utilized is same as leaving group from ester
Condensacions intramoleculars: addicions aldòliques intramoleculars
Intramolecular aldol additions - different sets of -hydrogens on diketones can

potentially allow two different intramolecular addition products
Two different enolate ions can be formed.

A 5-membered ring is favored over a 3-membered ring.
Intramolecular aldol additions - different sets of -hydrogens on diketones can

potentially allow two different intramolecular addition products
Two different enolate ions can be formed.

A 5-membered ring is favored over a 7-membered ring.
Intramolecular aldol additions - the greater stability of 5- and 6-membered rings

causes them to be formed preferentially
Anel·lació de Robinson
Robinson Annulation - from annulus (Latin for “ring”) - combines a Michael reaction
with an intramolecular aldol condensation (addition followed by dehydration)
A Robinson annulation forms a product with a

2-cyclohexenone ring.
Descarboxilació d’àcids carboxílics amb un grup carbonil en 
(Heterolytic) cleavage of any bond requires there be a good leaving group
Carbanions are not good leaving groups, so hydrocarbons are not

acidic, nor do they readily expel CO2
An alkane does not lose a proton

A carboxylic acid does not lose CO2
Electron delocalization increases stability, obtain “significant” resonance contributors

by placing electrons on the more electronegative oxygen atom
The electrons left behind when H+ is removed are delocalized onto an oxygen.
The electrons left behind when CO2 is removed are delocalized onto an oxygen.
3-oxocarboxylate ions lose CO2 when heated (decarboxylation)
It is easier to remove a proton when the carboxylic acid is in its acidic form
You can have an intramolecular proton transfer if your

molecular orbitals allow (5- or 6-membered rings)
3-Oxocarboxylic acids can be decarboxylated a high temperatures

Decarboxylation - carboxylic acids with a carbonyl group at the 3-position (-

ketocarboxylic acids and -dicarboxylic acids) readily lose CO2 when heated:
Síntesi malònica
A malonic ester synthesis forms a carboxylic acid with two more carbons
than the alkyl halide used in the synthesis.
The starting material for the synthesis is malonic acid.
First two carbons of the desired carboxylic acid come from malonic ester
Rest of the carboxylic acid comes from the alkyl halide used in the second step
Síntesi malònica
Alkylation of the -carbon:

Step 1 - base (ethoxide) removes the most acidic proton - -carbon (pKa = 13)
Step 2 - enolate ion reacts with an electrophile - alkyl halide (SN2)
Hydrolysis of the ester:
Step 3 - acid-catalyzed hydrolysis of the ester
Decarboxylation:
Step 4 - acid treatment and heat decarboxylates the 3-oxocarboxylic acid
Síntesi malònica
Caboxylic acids with two substituents bonded to the -carbon can be prepared by
carrying out two successive alkylations of the -carbon:
Alkylation of the -carbon - times two:

Step 1 - base* (ethoxide) removes the most acidic proton -
-carbon (pKa = 13)
Step 2 - enolate ion reacts with an electrophile - alkyl
halide (SN2)
Hydrolysis of the ester:

Decarboxylation:
Step 4 - acid and heat decarboxylates the 3-oxocarboxylic acid
Síntesi malònica
Planning the Synthesis of a Carboxylic Acid:

Síntesi acetilacètica
An acetoacetic ester synthesis forms a methyl ketone with three more carbons
than the alkyl halide used in the synthesis - -carbon alkylation (acetoacetic ester,
RX) + decarboxylation yields a methyl ketone
The starting material for the synthesis is acetoacetic acid.
Alkylation of the -carbon:

Step 1 - base* (ethoxide) removes most acidic proton - -carbon (pKa = 10.7)
Step 2 - enolate ion reacts with an electrophile - alkyl halide (SN2)
Hydrolysis of the ester - only one ester to hydrolyze:
Decarboxylation - only one acid to decarboxylate:
Step 4 - acid and heat decarboxylates the 3-oxocarboxylic acid
Planning the synthesis of a methyl ketone

Disseny de síntesi: formació d’enllaços C-C
When planning the synthesis of a compound that requires the formation of a new
carbon-carbon bond, first locate the new bond that must be made:
Decide which end will be the nucleophile and which end will be the electrophile.
Carbonyl carbon atoms are always electrophiles


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Compostos amb grups carbonil:

Química Orgànica III Llibres de referència:

Carbonyl group – carbon double

Class I carbonyl compounds – nucleophilic acyl substitution reactions - acyl

Acidity of -hydrogen atoms:

Hydrogens attached to sp3 carbons

A hydrogen attached to an sp3 carbon adjacent to a carbonyl carbon has a

The sp3 carbon adjacent to carbonyl carbon is called an -carbon.

Based on pKa value alone, the conjugate base from -hydrogen

Deprotonation of an alkane generates a carbanion with localized electrons

-hydrogen deprotonation of a carbonyl compound generates a carbanion

A proton on an α-carbon of an aldehyde or a ketone is more acidic (pKa = 16–20)

Why is an aldehyde or ketone more acidic than an ester ?

-hydrogen deprotonation of nitroalkanes, nitriles, and N,N-disubstituted amides

Only amides without a H on a N have “acidic” α-hydrogens.

-hydrogen deprotonation of -keto esters, and -diketones is even easier.

Tautomers differ in the location of a double bond and a hydrogen.

For most ketones,

The enol tautomer for phenol

An enol is more electron rich (better nucleophile) than an alkene due to

Enols undergo substitution reactions - -substitution reactions - one

Acid-Catalyzed Halogenation (Only one α-hydrogen is replaced by a halogen)

Base-catalyzed halogenation (All the α-hydrogens are replaced by a halogen)

Mechanism for Base-Catalyzed halogenation of aldehydes and ketones

This is the same as the mechanism for base-promoted enolization except

The Hell-Volhard-Zelinski (HVZ) reaction replaces the α-hydrogen of a

Carboxylic acids cannot undergo substitution reactions at the -carbon because a

The bromine on the

Strong bases cannot be used

E2 - generates -unsaturated carbonyl compounds (use a strong,

Hydroxide is a weaker base than

Only a small amount of enolate ion is formed.

A stronger base is required (LDA).

Generation of LDA - addition of butyllithium to diisopropylamine in THF at -78 ºC:

Deprotonation of cyclohexanone (pKa = 17) using lithium diisopropylamide

All the ketone is converted to enolate ion.

can also be shown as

This method can be used to alkylate the α-carbon of

This method can be used to alkylate the α-carbon of

… but not aldehydes… we’ll see why later (Aldol addition)

What determines which product predominates? Reaction conditions…..

kinetic thermodynamic enolate

Kinetic enolate ion formation - Thermodynamic enolate ion formation -

An E+ can be added to the -carbon of an aldehyde or a ketone by:

Using an enamine avoids having to use a strong base (LDA).

Using an enamine intermediate generates only the monoalkylated product

Direct alkylation using a carbonyl compound generates dialkylated and O-alkylated

Enamine intermediates can also be used to acylate aldehydes and ketones

,-unsaturated carbonyl compounds - class I and II carbonyl compounds with a

Direct addition (1,2 addition) - Nu: addition at the carbonyl carbon

The β-carbon of an α,β-unsaturated aldehyde or ketone can be alkylated via

When the nucleophile is a relatively weak base, conjugate addition

The best enolate ions are those flanked by

Michael Reaction - mechanism

Note that if either of the reactants in

Stork enamine reaction performs a “Michael reaction,” but uses an enamine in

(No deprotonation - no base is needed to generate Nu:)

The carbonyl carbon of aldehydes and ketones is an electrophile.

Aldol addition - observation of both of these reactivities using two

Note that aldol reactions are reversible

Aldol Addition - mechanism for aldehydes

Alcohols undergo dehydration when they are heated with acid