ALDOL REACTIONS
2.In the first stage of glycolysis, a C6 molecule of glucose is divided into two different
C3 molecules [dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-
phosphate (GAP)].
1) This process consumes energy in the form of two ATP molecules.
2) In the second stage of glycolysis, metabolism of one of the C3 intermediates
(GAP) causes the formation of two ATP molecules.
3) To this point the energy yield of glycolysis is zero.
4) Triose phosphate isomerism (TIM, or TPI) recycles the unused C3 intermediate
(DHAP) formed from glucose so that a second passage through Stage II of
glycolysis is possible.
5) Metabolism of the second C3 unit produces two more ATP molecules, resulting
in an overall yield by glycolysis of two ATP from one glucose molecule.
~1~
3.The direct precursor of DHAP and GAP in glycolsis is a type of molecule called an
aldol (an aldehyde or ketene with a β-hydroxyl group).
1) This precursor is cleaved to DHAP and GAP by an enzyme called aldolase.
3.The α-hydrogens are acidic ⇒ they are unusually acidic for hydrogen atoms
attached to carbon.
1) The pΚa values for the α hydrogens of most simple aldehydes or ketones are of
the order of 19-20 (Κa = 10–19 ~ 10–20).
2) This means that they are more acidic than hydrogen atoms of ethyne, pΚ = 25 (Κ
= 102s), and are far more acidic than the hydrogens of ethene (pΚa = 44) or of
ethane (pΚa = 50).
4.The reasons for the unusual acidity of the α-hydrogens of carbonyl compounds are
straightforward: The carbonyl group is strongly electron withdrawing, and when a
carbonyl compound loses an α proton, the anion that is produced is stabilized by
resonance.
1) The negative charge of the anion is delocalized.
~3~
3) Although structure A is favored by the strength of its carbon-oxygen π bond
relative to the weaker carbon-carbon, π bond of B, structure B makes a greater
contribution to the hybrid because oxygen, being highly electronegative is better
able to accommodate the negative charge.
4) We can depict the hybrid in the following way:
7.Both of these reactions are reversible. Because of its relation to the enol, the
resonance-stabilized anion is called an enolate anion.
8.A calculated electrostatic potential map for the enolate anion of acetone is shown:
~4~
1) The map indicates approximately the outermost extent of electron density (the
van der Waals surface) of the acetone enolate anion.
2) Red color near the oxygen is consistent with oxygen being better able to stabilize
the excess negative charge of the anion.
3) Yellow at the carbon where the α hydrogen was removed indicates that some of
the excess negative charge is localized there as well.
4) These implications are parallel with the conclusions above about charge
distribution in the hybrid based on resonance and electronegativity effects.
~5~
3.In compounds whose molecules have two carbonyl groups separated by one −CH2−
group (called β-dicarbonyl compounds), the amount of enol present at equilibrium
is far higher.
1) 2,4-Pentanedione exists in the enol form to an extent of 76%.
4.The greater stability of the enol form of β-dicarbonyl compounds can be attributed
to stability gained through resonance stabilization of the conjugated double bonds
and (in a cyclic form) through hydrogen bonding.
~6~
17.3 REACTIONS VIA ENOLS AND ENOLATE IONS
17.3A RACEMIZATION
1.When a solution of (+)-sec-butyl phenyl ketone in aqueous ethanol is treated with
either acids or bases, the solution gradually loses its optical activity.
2.Racemization takes place m the presence of acids or bases because tale ketone
slowly but reversibly changes to its enol and the enol is achiral.
1) When the enol reverts to the keto form, it produces equal amounts of the two
enantiomers.
~7~
A Mechanism for the Base-Catalyzed Enolization
5.In acyclic ketones, the enol or enolate anion formed can be (E) or (Z).
1) Protonation on one face of the (E) isomer and protonation on the same face of
the (Z) isomer produces enantiomers.
6.Diastereomers that differ in configuration at only one stereo center are sometimes
called epimers.
1) Keto-enol tautomerization can sometimes be used to convert a less stable epimer
to a more stable one.
2) This equilibration process is called an epimerization.
~8~
17.3B HALOGENATION OF KETONES
1.Ketones that have an α hydrogen react readily with halogens by substitution.
1) The rates of these halogenation reactions increase when acids or bases are
added, and substitution takes place almost exclusively at the α carbon:
2) This behavior of ketones can be accounted for in terms of two related properties:
i) the acidity of the α hydrogens of ketones
ii) the tendency of ketones to form enols
2.Base-Promoted Halogenations
1) In the presence of bases, halogenation takes place through the slow formation of
an enolate anion or an enol, followed by a rapid reaction of the enolate anion or
enol with halogen.
~9~
3.Acid-Catalyzed Halogenation
1) In the presence of acids, halogenation takes place through the slow formation of
an enol followed by rapid reaction of the enol with the halogen.
4.Part of the evidence that supports these mechanisms comes from studies of reaction
kinetics.
1) Both base-promoted and acid-catalyzed halogenations of ketones show initial
rates that are independent of the halogen concentration.
2) The mechanisms are in accord with this observation:
i) In both instances the slow step of the mechanism occurs before the intervention
~ 10 ~
of the halogen.
ii) The initial rates are also independent of the nature of the halogen.
~ 11 ~
2.When methyl ketones react with halogens in aqueous sodium hydroxide (i.e., in
hypohalite solutions), an addition reaction takes place.
1) Hydroxide ion attacks the carbonyl carbon atom of the trihalo ketone and causes
a cleavage at the carbon-carbon bond between the carbonyl group and the
trihalomethyl group, a moderately good leaving group.
2) This cleavage ultimately produces a carboxylate anion and a haloform (i.e.,
either CHC13, CHBr3 or CHI3).
i) The initial step is a nucleophilic attack by hydroxide ion on the carbonyl
carbon atom.
ii) In the next step carbon-carbon bond cleavage occurs and the trihalomethyl
anion (:CX3–) departs.
iii) This is one of the rare instances in which a carbanion acts as a leaving group.
iv) This step can occur because the trihalomethyl anion is unusually stable; its
negative charge is dispersed by the three electronegative halogen atoms (when
X = Cl, the conjugate acid, CHCl3, has pΚa = 13.6).
v) In the last step, a proton transfer takes place between the carboxylic acid and
the trihalomethyl anion.
~ 12 ~
3.The haloform reaction is of synthetic utility as a means of converting methyl ketones
to carboxylic acids.
1) When the haloform reaction is used in synthesis, chlorine and bromine are most
commonly used as the halogen component.
2) Chloroform (CHCl3) and bromoform (CHBr3) are both liquids which are
immiscible with water and are easily separated from the aqueous solution
containing the carboxyl ate anion.
3) When iodine is the halogen component, the bright yellow solid iodoform (CHI3)
results.
i) This is the basis of a laboratory classification test for methyl ketones and
methyl secondary alcohols (which are oxidized to methyl ketones first under
the reaction conditions).
~ 13 ~
4.When water is chlorinated to purify it for public consumption, chloroform is
produced from organic impurities in the water via the halo form reaction.
1) Many of these organic impurities are naturally occurring, such as humic (腐殖
的) substances.
2) The presence of chloroform in public water is of concern for water treatment
plants and environmental officers, because chloroform is carcinogenic.
3) Thus, the technology that solves one problem creates another.
i) Before chlorination of water was introduced, thousands of people died in
epidemics of diseases such as cholera (霍亂) and dysentery (痢疾).
2.The mechanism for the aldol addition illustrates two important characteristics of
carbonyl compounds:
1) the acidity of their α hydrogens
2) the tendency of their carbonyl groups to undergo nucleophilic addition
~ 14 ~
17.4A DEHYDRATION OF ADDITION PRODUCT
1.If the basic mixture containing the aldol is heated, dehydration takes place and 2-
butenal (crotonaldehyde) is formed.
1) Dehydration occurs readily because of the acidity of the remaining α hydrogens
(even though the leaving group is a hydroxide ion) and because the product is
stabilized by having conjugated double bonds.
~ 15 ~
2.In some aldol reactions, dehydration occurs so readily that we cannot isolate the
product in the aldol form; we obtain the derived enal (alkene aldehyde) instead.
1) An aldol condensation occurs instead of an aldol addition.
2) A condensation reaction is one in which molecules are joined through the
intermolecular elimination of a small molecule such as water or an alcohol.
2.The aldol reaction is important in organic synthesis because it gives us a method for
linking two smaller molecules by introducing a carbon-carbon bond between
them.
~ 16 ~
1) Because aldol products contain two functional groups, −OH and −CHO, we can
use them to carry out a number of subsequent reactions.
3.Ketones also undergo base-catalyzed aldol additions, but for them the equilibrium is
unfavorable.
1) This complication can be overcome, however, by carrying out the reaction in a
special apparatus that allows the product to be removed from contact with the
base as it is formed.
2) This removal of product displaces the equilibrium to the right and permits
successful aldol additions with many ketones.
~ 17 ~
17.4C THE REVERSIBILITY OF ALDOL ADDITIONS
1.The aldol addition is reversible.
1) If the aldol addition product obtained from acetone is heated with a strong base,
it reverts to an equilibrium mixture that consists largely (~95%) of acetone.
2) This type of reaction is called a retro-aldol reaction.
~ 18 ~
1) Details of the mechanism are shown here, beginning at the left with fructose-1,6-
diphosphate:
3.Two key intermediates in the aldolase mechanism involve two functional groups —
an imine (protonated in the form of an iminium cation) and an enamine.
1) In the mechanism of aldolase, an iminium cation acts as a sink for electron
density during C–C bond cleavage (step 2), much like a carbonyl group does in a
typical retro-aldol reaction.
i) In this step the iminium cation is converted to an enamine, corresponding to the
enolate or enol that is formed when a carbonyl group accepts electron density
during C–C bond cleavage in an ordinary retro-aldol reaction.
2) The enamine intermediate is then a source of an electron pair used to bond with a
proton taken from the tyrosine hydroxyl at the aldolase active site (step 3).
3) Lastly, the resulting iminium group undergoes hydrolysis (step 4), freeing
aldolase for another catalytic cycle and releasing DHAP, the second product of
the retro-aldol reaction.
4) Then, DHAP undergoes isomerization to GAP for processing to pyruvate and
~ 19 ~
synthesis of two more ATP molecules.
~ 20 ~
17.5 CROSSED ALDOL REACTIONS
1.An aldol reaction that starts with two different carbonyl compounds is called a
crossed aldol reaction.
1) Crossed aldol reactions using aqueous sodium hydroxide solutions are of little
synthetic importance if both reactants have α hydrogens, because these reactions
give a complex mixture of products.
i) A crossed aldol addition using acetaldehyde and propanal generates at least
four products.
~ 21 ~
Table 17.1 Crossed Aldol Reactions
This Reactant
This Reactant with
with No α
an α Hydrogen Is Product
Hydrogen Is
Added Slowly
Placed in Base
H O
O O C
C6H5 H
HO−
C C
C6H5 H H3CH2C H 10oC, 68% CH3
Benzaldehyde Propanal 2-Methyl-3-phenyl-
2-propanal
(α-methylcinnamaldehyde)
H O
O O
C
C C HO− C6H5 H
C6H5 H C6H5H2C H o
20 C
C6H5
Benzaldehyde Phenylacetaldehyde
2,3-Diphenyl-2-propanal
O
O H3C
O C
C dilute Na2CO3 HO H
C H
H H 40oC, >64% CH3
Formaldehyde 3-Hydroxy-2,3-
2-Methylpropanal
dimethylpropanal
~ 23 ~
2.In the Claisen-Schmidt reactions given above dehydration occurs readily because
the double bond that forms is conjugated both with the carbonyl group and with
the benzene ring. The conjugated system is thereby extended.
~ 24 ~
1) Geranial is a naturally occurring aldehyde that can be obtained from lemongrass
oil.
i) Its α hydrogen is vinylic and, therefore, not appreciably acidic.
ii) Dehydration occurs readily because dehydration extends the conjugated
system.
~ 25 ~
3.This condensation is especially useful because the nitro group of the product can be
easily reduced to an amino group.
1) One technique that brings about this transformation uses hydrogen and a nickel
catalyst.
2) This combination not only reduces the nitro group but also reduces the double
bond:
NO2 H2, Ni NH2
C6H5 C6H5
~ 26 ~
2.This reaction almost certainly involves the formation of at least three different
enolates.
1) However, it is the enolate from the ketone side of the molecule that adds to the
aldehyde group leading to the product.
3.The reason the aldehyde group undergoes addition preferentially may arise from the
greater reactivity of aldehydes toward nucleophilic addition generally.
1) The carbonyl carbon atom of a ketone is less positive (and therefore less reactive
toward a nucleophilic) because it bears two electron-releasing alkyl groups; it is
also more sterically hindered.
2) In reactions of this type, five-membered rings form far more readily than seven-
membered rings
~ 27 ~
17.7 LITHIUM ENOLATES
1.The extent to which an enolate anion forms depends on the strength of the base
used.
1) If the base employed is a weaker base than the enolate anion, then the
equilibrium lies to the left.
2) This is the case when a ketone is treated with an aqueous solution containing
sodium hydroxide.
2.On the other hand, if a very strong base is employed, the equilibrium lies far to the
right.
1) One very useful strong base for converting ketones to enolates is lithium
diisopropylamide, (i-C3H7)2N– Li+.
~ 28 ~
enolate.
1) Just which enolate is formed predominantly depends on the base used and on the
conditions employed.
i) The enolate with the more highly substituted double bond is the
thermodynamicically more stable enolate in the same way that an alkene with
the more highly substituted double bond is the more stable alkene.
ii) This enolate, called the thermodynamic enolate, is formed predominantly
under conditions that permit the establishment of an equilibrium.
iii) This will generally be the case if the enolate is produced using a relatively
weak base in a protic solvent.
2.On the other hand, the enolate with the less substituted double bond is usually
formed faster, because removal of the hydrogen necessary to produce this enolate
is less sterically hindered.
1) This enolate, called the kinetic enolate, is formed predominantly when the
reaction is kinetically controlled (or rate controlled).
3.The kinetically favored enolate can be formed cleanly through the use of lithium
diisopropylamide (LDA).
1) This strong, sterically hindered base rapidly removes the proton from the less
substituted α carbon of the ketone.
2) When 2-methylcyclohexanone is deprotonated in 1,2-dimethoxyethane
(CH3OCH2CH2OCH3, DME), the LDA removes the hydrogen from the −CH2− α
carbon more rapidly because it is less hindered (and because there are twice as
many hydrogens there to react).
~ 29 ~
17.7B LITHIUM ENOLATES IN DIRECTED ALDOL REACTIONS
1.One of the most effective and versatile ways to bring about a crossed aldol reaction
is to use a lithium enolate obtained from a ketone as one component and an
aldehyde or ketone as the other.
3.If the aldol (Claisen-Schmidt) reaction had been carried out in the classic way using
hydroxide ion as the base, then at least two products would have been formed in
significant amounts.
1) Both the kinetic and thermodynamic enolate would have been formed from the
ketone, and each of these would have added to the carbonyl carbon of the
aldehyde:
An Aldol Reaction that Produces a Mixture via Both Kinetic
and Thermodynamic Enoiates (Using a Weaker Base under Protic Conditions)
~ 31 ~
17.7C DIRECT ALKYLATION OF KETONES VIA LITHIUM ENOLATES
1.The formation of lithium enolates using lithium diisopropylamide furnishes a useful
way of alkylation ketones in a regioselective way.
1) The lithium enolate formed from 2-methylcyclohexanone can be methylated or
benzylated by reacting it with methyl iodide or benzyl bromide, respectively.
~ 32 ~
O Li+ O− O
H3C H3C H3C CH3
LDA CH3 I
DME (- LiI)
(56%)
O
H3C CH2C6H5
C6H5CH2 Br
(- LiBr)
(42-45%)
1.Because enolate anions have a partial negative charge on an oxygen atom they can
react in nucleophilic substitution reactions as if they were alkoxide anions.
1) Because they have a partial negative charge on a carbon atom they can also react
as carbanions.
2) Nucleophilies that are capable of reacting at two sites, are called ambient
nucleophile.
2.Just how an enolate anion reacts depends, in part, on the substrate with which it
reacts.
1) Chlorotrialkylsilanes tend to react almost exclusively at the oxygen atom of an
~ 33 ~
enolate.
2) Reagents used include chlorotrimethylsilane, tert-butylchlorodimethylsilane
(TBDMSCl), and tert-butylchlorodiphenylsilane (TBDPSCl).
4.The enolate anion can be "trapped" by converting it to the trimethylsilyl enol ether.
1) This procedure is especially useful because the trimethylsilyl enol ether can be
purified, if necessary, and then converted back to an enolate.
2) One way of achieving this conversion is by treating the trimethylsilyl enol ether
with an aprotic solution containing fluoride ions.
~ 34 ~
5.This reaction is a nucleophilic substitution at the silicon atom brought about by a
fluoride ion.
1) Fluoride ions have an extremely high affinity for silicon atoms because Si–F
bonds are very strong.
~ 35 ~
2.Treating the α-benzeneselenenyl ketone with hydrogen peroxide at room
temperature converts it to an α,β-unsaturated ketone.
1) These are very mild conditions for the introduction of a double bond (room
temperature and a neutral solution), and this is one reason why this method is a
valuable one.
~ 36 ~
17.9 ADDITION OF α,β-UNSATURATED ALDEHYDES
AND KETONES
2.In many instances both modes of addition occur in the same mixture.
~ 37 ~
1) In this example, simple addition is favored and this is generally the case with
strong nucleophiles.
2) Conjugate addition is favored when weaker nucleophiles are employed.
3.If we examine the resonance structures that contribute to the overall hybrid for an
α,β-unsaturated aldehyde or ketone (see structures A-C), we shall be in a better
position to understand these reactions.
~ 38 ~
i) A nucleophilic reagent is expected to attack either the carbonyl carbon or the β
carbon.
4.Almost every nucleophilic reagent that adds at the carbonyl carbon of a simple
aldehyde or ketone is capable of adding at the β carbon of an α,β-unsaturated
carbonyl compound.
1) In many instances when weaker nucleophiles are used, conjugate addition is the
major reaction path.
~ 39 ~
A Mechanism for the Conjugate Addition an Amine
~ 40 ~
2.With an alkyl-substituted cyclic α,β-unsaturated ketone, as the example just cited
shows, lithium dialkylcuprates add predominantly in the less hindered way to give
the product with the alkyl groups trans to each other.
~ 41 ~
2.The sequence that follows illustrates how a conjugate aldol addition (Michael
addition) followed by a simple aldol condensation may be used to build one ring
onto another.
1) This procedure is known as the Robinson annulations (ring forming) reaction
(after the English chemist, Sir Robert Robinson, who won the Nobel Prize in
Chemistry in 1947 for his research on naturally occurring compounds).
2) Now that the bridgehead carbon is tetrahedral, the geometry of the bicyclic
structure favors conversion of the enediyne to a 1,4-benzenoid diradical by a
~ 42 ~
reaction called the Bergman cycloaromatization (after R. G. Bergman of the
University of California, Berkeley).
3) Once the calicheamicin diradical is formed it can pluck two hydrogen atoms
from the DNA backbone, converting the DNA to a reactive diradical and
ultimately resulting in DNA cleavage and the death of the cell.
HO O CO2Me
Me O NH
Me MeS S
I O H S H
S O N O
O
HO
O OMe OH O
Me O OMe H O
HO Me N
MeO MeO
OH calicheamicin γ1I
~ 43 ~
HO O CO2Me 1. nucleophilic
NH attack O O Sugar
HO
2. conjugate H CO2Me
Sugar addition
S H O N
S H
SMe S
calicheamicin γ1I
Bergman
cycloaromatization O O Sugar
HO
H CO2Me
N
H
S
DNA
DNA O2 DNA double
diradical strand cleavage
HO O O Sugar
H CO2Me
N
H
S
~ 44 ~
~ 45 ~
~ 46 ~