ALDEHYDES AND KETONES II. ALDOL

REACTIONS

TIM (Triose Phosphate Isomerase’s)Recycles Carbon via an Enol

1. An enol is a vinyl alcohol, or an alkene-alcohol.

1) An enol intermediate plays a key role in glycolysis, a pathway used by all living

things for production of energy through the breakdown of glucose.

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 -hydroxyl group).

1) This precursor is cleaved to DHAP and GAP by an enzyme called aldolase.

17.1 THE ACIDITY OF THE -HYDROGENS OF CARBONYL COMPOUNDS: ENOLATE IONS

1. One important characteristic of aldehydes and ketone is their ability to undergo

nucleophilic addition at their carbonyl groups:

2. A second important characteristic of carbonyl compounds is the unusual acidity of

hydrogen atoms on carbon atoms adjacent to the carbonyl group.

~ 2 ~

1) These hydrogen atoms are usually called the hydrogens, and the carbon to

which they are attached is called carbon.

3. The -hydrogens are acidic they are unusually acidic for hydrogen atoms

attached to carbon.

1) The pa values for the hydrogens of most simple aldehydes or ketones are of

the order of 19-20 (a = 10–19 ~ 10–20).

2) This means that they are more acidic than hydrogen atoms of ethyne, p = 25 (

= 102s), and are far more acidic than the hydrogens of ethene (pa = 44) or of

ethane (pa = 50).

4. The reasons for the unusual acidity of the -hydrogens of carbonyl compounds are

straightforward: The carbonyl group is strongly electron withdrawing, and when a

carbonyl compound loses an proton, the anion that is produced is stabilized by

resonance.

1) The negative charge of the anion is delocalized.

5. Two resonance structures, A and B, can be written for the anion.

1) In structure A the negative charge is on carbon and in structure B the negative

charge is on oxygen.~ 3 ~

2) Both structures contribute to the hybrid.

3) Although structure A is favored by the strength of its carbon-oxygen bond

relative to the weaker carbon-carbon, 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:

6. When this resonance-stabilized anion accepts a proton, it can do so in either of

two ways:

1) It can accept the proton at carbon to form the original carbonyl compound in

what is called the keto form, or it may accept the proton at oxygen to form an

enol.

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 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.

17.2 KETO AND ENOL TAUTOMERS

1. The keto and enol forms of carbonyl compounds are constitutional isomers.

1) They are easily interconvert in the presence of traces of acids and bases.

2) Interconvertible keto and enol forms are said to be tautomers, and their

introversion is called tautomerization.

2. Under most circumstances, keto-enol tautomers are in a state of equilibrium. (The

surfaces of ordinary laboratory glassware are able to catalyze the interconversion

and establish the equilibrium.)

1) For simple monocarbonyl compounds such as acetone and acetaldehyde, the

amount of the enol form present at equilibrium is very small.

i) In acetone it is much less than 1%; in acetaldehyde the enol concentration is

too small to be detected.

2) The greater stability of the following keto forms of monocarbonyl compounds ~ 5 ~

can be related to the greater strength of the carbon-oxygen bond compared to

the carbon-carbon bond (~364 kJ mol–1 versus ~250 kJ mol–1).

3. In compounds whose molecules have two carbonyl groups separated by one CH2

group (called -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 -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.

3. Base catalyzes the formation of an enol through the intermediate formation of an

enolate anion:

~ 7 ~

A Mechanism for the Base-Catalyzed Enolization

4. Acid can catalyze enolization in the following way:

A Mechanism for the Acid-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 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 carbon:

2) This behavior of ketones can be accounted for in terms of two related properties:

i) the acidity of the 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.

A Mechanism for the Base-Promoted Halogenation of Aldehydes and Ketones

~ 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.

A Mechanism for the Acid-Catalyzed Halogenation of Aldehydes and Ketones

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:

~ 10 ~

i) In both instances the slow step of the mechanism occurs before the intervention

of the halogen.

ii) The initial rates are also independent of the nature of the halogen.

17.3C THE HALOFORM REACTION

1. When methyl ketones react with halogens in the presence of base, multiple

halogenations always occur at the carbon of the methyl group.

1) Multiple halogenations occur because introduction of the first halogen (owing to

its electronegativity) makes the remaining hydrogens on the methyl carbon

more acidic.

A Mechanism for the Halogenation Step of the Haloform Reaction

~ 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 pa = 13.6).

v) In the last step, a proton transfer takes place between the carboxylic acid and

the trihalomethyl anion.

A Mechanism for the Cleavage Step of the Haloform Reaction

~ 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).

17.4 THE ALDOL REACTION: THE ADDITION OF ENOLATE ANIONS TO ALDEHYDES AND KETONES

1. When acetaldehyde reacts with dilute sodium hydroxide at room temperature (or

below), a dimerization takes place producing 3-hydroxybutanal.

1) 3-Hydroxybutanal is both an aldehyde and an alcohol, it has been given the

common name "aldol," and reactions of this general type have come to be

known as aldol additions (or aldol reactions).

2. The mechanism for the aldol addition illustrates two important characteristics of

carbonyl compounds:

1) the acidity of their hydrogens

2) the tendency of their carbonyl groups to undergo nucleophilic addition

~ 14 ~

A Mechanism for the Aldol Reaction

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 hydrogens

(even though the leaving group is a hydroxide ion) and because the product is

stabilized by having conjugated double bonds.

A Mechanism for the Dehydration of the Aldol Addition Product

~ 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.

17.4B SYNTHETIC APPLICATIONS

1. The aldol reaction is a general reaction of aldehydes that possess an hydrogen.

1) Propanal reacts with aqueous sodium hydroxide to give 3-hydroxy-2-methyl-

pentanal.

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

~ 16 ~

them.

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.

The Chemistry of A Retro-Aldol Reaction in Glycolysis — Dividing Assets to Double the ATP Yield

1. Glycolysis (醣酵解 ) is a fundamental pathway for production of ATP in living

systems.

1) The pathway begins with glucose and ends with two molecules of pyruvate (丙

酮酸鹽[酯]) and a net yield of two ATP molecules.

2) Aldolase, an enzyme in glycolysis, plays a key role by dividing the six-carbon

compound fructose-1,6-diphosphate (derived from glucose) into two compounds

that each have three carbons, glyceraldehyde-3-phosphate (GAP) and 1,3-

dihydroxyacetone phosphate (DHAP).

3) This process is essential because it provides two three-carbon units for the final

stage of glycolysis, wherein the net yield of two ATP molecules per glucose is

realized.

i) Two ATP molecules are consumed to form fructose-l,6-diphosphate, and only

two are generated per pyruvate.

ii) Thus, two passages through the second stage of glycolysis are necessary to

~ 18 ~

obtain a net yield of two ATP molecules per glucose.

2. The cleavage reaction catalyzed by aldolase is a net retro-aldol reaction.

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

~ 19 ~

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

synthesis of two more ATP molecules.

17.4D ACID-CATALYZED ALDOL CONDENSATIONS

1. Aldol condensations can also be brought about with acid catalysis.

1) Treating acetone with hydrogen chloride, for example, leads to the formation of

4-methyl-3-penten-2-one, the aldol condensation product.

2) In general, acid-catalyzed aldol reactions lead to dehydration of the initially

formed aldol addition product.

A Mechanism for the Acid-Catalyzed Aldol Reaction

~ 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 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 ~

17.5A PRACTICAL CROSSED ALDOL REACTIONS

1. Crossed aldol reactions are practical, using bases such as NaOH, when one

reactant does not have an hydrogen and so cannot undergo self-condensation

because it cannot form an enolate anion.

1) We can avoid other side reactions by placing this component in base and then

slowly adding the reactant with an hydrogen to the mixture.

2) Under these conditions the concentration of the reactant with an hydrogen is

always low and much of the reactant is present as an enolate anion.

3) The main reaction that takes place is one between this enolate anion and the

component that has no a hydrogen.

4) The examples listed in Table 17.1 illustrate this technique.

Table 17.1 Crossed Aldol Reactions

This Reactant with No

Hydrogen Is Placed in Base

This Reactant with an Hydrogen Is

Added SlowlyProduct

~ 22 ~

(-methylcinnamaldehyde)

2. The crossed aldol reaction is often accompanied by dehydration.

1) Whether dehydration occurs can, at times, be determined by our choice of

reaction conditions, but dehydration is especially easy when it leads to an

extended conjugated systems.

17.5B CLAISEN-SCHMIDT REACTIONS

1. When ketones are used as one component, the crossed aldol reactions are called

Claisen-Schmidt reactions, after the German chemists J. G. Schmidt (who

discovered the reaction in 1880) and Ludwig Claisen (who developed it between

1881 and 1889).

1) These reactions are practical when bases such as sodium hydroxide are used

because under these conditions ketones do not self-condense appreciably.

~ 23 ~

A Mechanism for the Claisen-Schmidt Reaction

~ 24 ~

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.

3. An important step in a commercial synthesis of vitamin A makes use of a Claisen-

Schmidt reaction between geranial and acetone:

~ 25 ~

1) Geranial is a naturally occurring aldehyde that can be obtained from lemongrass

oil.

i) Its hydrogen is vinylic and, therefore, not appreciably acidic.

ii) Dehydration occurs readily because dehydration extends the conjugated

system.

17.5C CONDENSATION WITH NITROALKANES

1. The hydrogens of nitroalkanes are appreciably acidic (pa 10), much more

acidic than those of aldehydes and ketones.

1) The acidity of these hydrogen atoms can be explained by the powerful electron-

withdrawing effect of the nitro group and by resonance stabilization of the anion

that is produced.

2. Nitroalkanes that have hydrogens undergo base-catalyzed condensations with

aldehydes and ketones that resemble aldol condensations.

~ 26 ~

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:

17.5D CONDENSATION WITH NITRILES

1. The hydrogens of nitriles are also appreciably acidic, but less so than those of

aldehydes and ketones.

1) The acidity constant for acetonitrile (CH3CN) is about 10–25 (pa 25).

2) Other nitriles with hydrogens show comparable acidities, and consequently

these nitriles undergo condensations of the aldol type.

17.6 CYCLIZATIONS VIA ALDOL CONDENSATIONS

1. The aldol condensation also offers a convenient way to synthesize molecules with

five- and six-membered rings (and sometimes even larger rings).

1) This can be done by an intra-molecular aldol condensation using a dialdehdye, a

keto aldehyde, or a diketone as the substrate.

2) For example, the following keto aldehyde cyclizes to yield 1-cyclopentenyl

methyl ketone.~ 27 ~

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.

A Mechanism for the Aldol Cyclization

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.

~ 28 ~

2) In reactions of this type, five-membered rings form far more readily than seven-

membered rings

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+.

~ 29 ~

3. Lithium diisopropylamide (abbreviated LDA) can be prepared by dissolving

diisopropylamine in a solvent such as diethyl ether or THF, and treating it with

alkyllithium.

17.7A REGIOSELECTIVE FORMATION OF ENOLATE ANIONS

1. An unsymmetrical ketone such as 2-methylcyclohexanone can form two possible

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).

~ 30 ~

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 carbon of the ketone.

2) When 2-methylcyclohexanone is deprotonated in 1,2-dimethoxyethane

(CH3OCH2CH2OCH3, DME), the LDA removes the hydrogen from the CH2

carbon more rapidly because it is less hindered (and because there are twice as

many hydrogens there to react).

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.

~ 31 ~

Figure 17.1 A directed aldol synthesis using a lithium enolate.

2. Regioselectivity can be achieved when unsymmetrical ketones are used in directed

aldol reactions by generating the kinetic enolate using lithium diisopropylamide.

1) This ensures production of the enolate in which the proton has been removed

from the less substituted a carbon.

3. If the aldol (Claisen-Schmidt) reaction had been carried out in the classic way

~ 32 ~

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 Kineticand Thermodynamic Enoiates (Using a Weaker Base under Protic Conditions)

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

~ 33 ~

benzylated by reacting it with methyl iodide or benzyl bromide, respectively.

2. Alkylation reactions like these have an important limitation.

1) Because the reactions are SN2 reactions and because enolate anions are strong

bases, successful alkylation occur only when 1° alkyl, 1° benzyl, and 1° allylic

halides are used.

2) With 2° and 3° halides, elimination becomes the main course of the reaction.

The Chemistry of Silyl Enol Ethers

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

~ 34 ~

reacts.

1) Chlorotrialkylsilanes tend to react almost exclusively at the oxygen atom of an

enolate.

2) Reagents used include chlorotrimethylsilane, tert-butylchlorodimethylsilane

(TBDMSCl), and tert-butylchlorodiphenylsilane (TBDPSCl).

3. Silylation is a nucleophilic substitution at the silicon atom by the oxygen atom of

the enolate because the oxygen-silicon bond that forms in the trimethylsilyl enol

ether is very strong (much stronger than a carbon-silicon bond).

1) This factor makes formation of the trimethylsilyl enol ether highly exothermic,

and, consequently, the free energy of activation for reaction at the oxygen atom

is lower than that for reaction at the carbon.

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 ~ 35 ~

with an aprotic solution containing fluoride ions.

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.

6. Another way to convert a trimethylsilyl enol ether back to an enolate is to treat it

with methyllithium.

17.8 -SELENATION: A SYNTHESIS OF -UNSATURATED CARBONYL COMPOUNDS

1. Lithium enolate react with benzeneselenenyl bromide (C6H5SeBr) (or with

C6H5SeCl) to yield products containing a C6H5Se– group at the position.

~ 36 ~

2. Treating the -benzeneselenenyl ketone with hydrogen peroxide at room

temperature converts it to an ,-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.

3. Mechanistically, two steps are involved in the conversion of the -

benzeneselenenyl ketone to the ,-unsaturated ketone.

1) The first step is an oxidation brought about by the H2O2.

2) The second step is a spontaneous intramolecular elimination in which the

negatively charged oxygen atom attached to the selenium atom acts as a base.

~ 37 ~

17.9 ADDITION OF -UNSATURATED ALDEHYDES AND KETONES

1. ,-Unsaturated aldehydes and ketones react with nucleophilic reagents in two

ways.

1) They may react by a simple addition, that is, one in which the nucleophile adds

across the double bond of the carbonyl group; or they may react by a conjugate

addition.

2) These two processes resemble the 1,2- and the 1,4-addition reactions of

conjugated dienes.

2. In many instances both modes of addition occur in the same mixture.

~ 38 ~

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

,-unsaturated aldehyde or ketone (see structures A-C), we shall be in a better

position to understand these reactions.

1) Although structures B and C involve separated charges, they make a significant

contribution to the hybrid because, in each, the negative charge is carried by

electronegative oxygen.

2) Structures B and C also indicate that both the carbonyl carbon and the

carbon should bear a partial positive charge.

3) The hybrid should be represented in the following way:

~ 39 ~

i) A nucleophilic reagent is expected to attack either the carbonyl carbon or the

carbon.

4. Almost every nucleophilic reagent that adds at the carbonyl carbon of a simple

aldehyde or ketone is capable of adding at the carbon of an ,-unsaturated

carbonyl compound.

1) In many instances when weaker nucleophiles are used, conjugate addition is the

major reaction path.

A Mechanism for the Conjugate Addition of HCN

2) Another example of this type of addition is the following:

~ 40 ~

A Mechanism for the Conjugate Addition an Amine

17.9A CONJUGATE ADDITION OF ORGANOCOPPER REAGENTS

1. Organocopper reagents, either RCu or R2CuLi, add to ,-unsaturated carbonyl

compounds, and they add almost exclusively in the conjugate manner.

~ 41 ~

2. With an alkyl-substituted cyclic ,-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.

17.9B MICHAEL ADDITIONS

1. Conjugate additions of enolate anions to ,-unsaturated carbonyl compounds are

known generally as Michael additions (after their discovery, in 1887, by Arthur

Michael, of Tufts University and later of Harvard University).

1) An example is the addition of cyclohexanone to C6H5CH=CHCOC6H5:

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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).

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The Chemistry of Calicheamicin 1I Activation Cleavage of DNA

1. The molecular machinery of calicheamicin 1I for destroying DNA is unleashed

by attack of a nucleophile on the trisulfide linkage shown in the accompanying

scheme.

1) The sulfur anion that initially was a leaving group from the trisulfide

immediately becomes a nucleophile that attacks the bridgehead alkene carbon.

i) This alkene carbon is electrophilic because it is conjugated with the adjoining

carbonyl group.

ii) Attack by the sulfur nucleophile on the alkene carbon is a conjugate addition.

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

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.

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